Pharmacy Exam

Guide
Step I
PHARMACEUTICS-I
(Physical
Pharmacy-I)
1st Edition
(p1c1)

-----------------------------------------------------------------------------------------------------------------------------

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 DISCLAIMER
Care has been taken to confirm the accuracy of the information present and to describe
generally accepted practices. However, the authors, editors, and publisher are not responsible
for errors or omissions or for any consequences from application of the information in this
book and make no warranty, expressed or implied, with respect to the currency,
completeness, or accuracy of the contents of the publication. Application of this information
in a particular situation remains the professional responsibility of the practitioner; the clinical
treatments described and recommended may not be considered absolute and universal
recommendations.

We DO NOT own the rights of the pictures and some context. All rights reserved to their
copyright owner, those context and pictures are just used as a reference in this book.

The authors, editors, and publisher have exerted every effort to ensure that drug selection
and dosage set forth in this text are in accordance with the current recommendations and
practice at the time of publication.
 Compiled By:
Abdul Sattar Rashid

Ali Ahsan

Ammara Khalique

Anmol Tahreem

Fareed Ahmed Rang Ali

Hamza Rohail

Laiq Ur Rehman Khan

Mehrab Fatima

Memoon Babar

Muhammad Qasim Yousaf

Ramsha Tahir

Sadia

Salbia Shereen

Sharmeen BaiG

Umair Javaid

Zafeer Naeem
Dedicated to Our Parents

And TeacherS
 Acknowledgement

The future belongs to those who believe in the beauty of their

dreams.
The preparation of this book “Pharmacy Exam Guide” was
just a dream of some students of Doctor of Pharmacy,
University of Central Punjab, which could not be fulfill
without the help and support of our teachers and parents.
We appreciate the tireless efforts of Our Teachers who
encouraged us always to achieve our endeavor, no matter,
how hard they can be.
We are much indebted to Our Parents for inspiring and
motivating us to achieve the great goals in life.
 Pharmacy Orientation 1

Chapter 1 Pharmacy Orientation ............................................................................................ 2

Chapter 2 History of Pharmacy .............................................................................................. 8
Chapter 3 Official Books of Pharmacy ................................................................................ 11
Chapter 4 Precipitation .......................................................................................................... 13
Chapter 5 Crystallization ....................................................................................................... 15
Chapter 6 Distillation ............................................................................................................. 19
Chapter 7 Miscellaneous Pharmaceutical Processes ........................................................ 31
Chapter 8 Solution ................................................................................................................. 35
Chapter 9 Solubility ............................................................................................................... 40
Chapter 10 Solubilization ........................................................................................................ 44
Chapter 11 Surfactants ............................................................................................................ 45
Chapter 12 Micellization .......................................................................................................... 48
Chapter 13 Ionization ............................................................................................................... 51
Chapter 14 Hydrolysis ............................................................................................................. 56
Chapter 15 Micrometrics ......................................................................................................... 57
Chapter 16 Dispersed System ................................................................................................ 64
Chapter 17 Emulsion ............................................................................................................... 74
Chapter 18 Suspensions ......................................................................................................... 79
Chapter 19 Adsorption ............................................................................................................ 86
Chapter 20 Rheology ............................................................................................................... 90
Chapter 21 Rate and Order of Reaction ................................................................................. 97
Chapter 22 Stability Studies ................................................................................................. 101

Pharmacy Exam Guide

 Pharmacy Orientation 2

Chapter 1 PHARMACY ORIENTATION

1.1 PHARMACY
The art and science of preparing and dispensing drugs
and medicines is called Pharmacy

1.2 PHYSICAL PHARMACY 1.6 QUALITY CONTROL

Physical Pharmacy is associated with an area of
 Qualitative/quantitative
pharmacy that deals with the quantitative and
checks of RM, intermediate
theoretic principles of science as they apply to the
and finished products
practice of pharmacy.
 Tests are performed on
products
1.3 INDUSTRIAL PHARMACY  Assay – determine the %
 The pharmaceutical industry is responsible purity of active ingredient
for the production of drugs, ensuring that
they are safe, effective and of high quality. 1.7 DRUG SALES AND MARKETING
 Pharmacist applies all the scientific
 Marketing
knowledge & skill during production, storage
1. Product managers
and distribution operations.
2. Set policies/
 Services provided by the pharmacist in
targets for the
different departments of the industry are
sales team
research, medical information & monitoring
 Sales
products safety, regularity affairs, medical
1. Contact
script writing, manufacturing & quality
prescribers
control, supplies, management and many
regarding
other departments.
company’s
products
1.4 RESEARCH & DEVELOPMENT ( R & D) 2. Explain products
 Formulation in detail
 Reformulation
 Drug-excipient Compatibility 1.8 DRUG ESTABLISHMENT
Testing
 Manufactures, imports,
 Determine proper route of
repacks, distributes
administration of drug
pharmaceuticals
 Product’s stability including
the proper packaging
material 1.9 DRUG MANUFACTURERS
 Innovations  With manufacturing
facilities, engaged in
1.5 PRODUCTION production operations
 Conversion of raw
materials to finished
products.
 Supervises the operation,
GMP must be observed,
involved in planning
production.

1.10 DRUG TRADER

 Registered owner of drug product

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 Pharmacy Orientation 3

 Procures the RM and packaging  Research activities both medical and

components pharmaceutical
 Provides production monograph, QC  Teaching Techniques ( inservice training
standard, procedures programs)
 Subcontracts a manufacturing lab  Pharmacy administration in hospital

1.11 DRUG DISTRIBUTOR/ IMPORTER 1.17 CLINICAL PHARMACY

 Imports RM, active ingredients,  Recent innovation in Pharmacy Practice
finished product for its own use or (1970)
for wholesale distribution  Patient –oriented profession

1.12 DRUG DISTRIBUTOR/ EXPORTER 1.18 ACTIVITIES

 Exports RM, active ingredients,  Makes rounds with doctor,
finished product to other countries maintains patient histories,
monitors drug therapy, advises
1.13 DRUG DISTRIBUTOR/ WHOLESALE patient on drug use, side effects,
and drug interactions, ADR’s
 Procures RM, active ingredients,  Direct pt involvement ( conducting
finished product from local admissions, discharge, interviews)
establishment for local distribution  Drug Utilization Reviews, education
on whole sale basis to improve drug’s use
 US : Doctors write Rx; pharmacists
prescribe the medicine
1.14 HOSPITAL PHARMACY  Important that clinical Pharmacist is
familiar with different lab tests and
 A department or service in hospital under
interpretation of results
the direction of competent pharmacist
 Associated with decreased hospital
 Pharmacists work with physiscians, nurses,
mortality rates, decreased drug
patient and other hospital personnel
cost, decreased length of stay of
 From which all medications are supplied to
patient
nursing units
 Pharmaceutical care – optimal use
 Part of the health care team.
of medications to achieve specific
outcomes that improve a patient’s
1.15 ACTIVITIES quality of life
 Compounding, provides stock medication,
performs moderate scale manufacturing
(dermatologicals, TPN) 1.19 PATIENT-ORIENTED PHARMACIST
 Responsible for Drug control system in
hospital
CONSIDERS:
 Responsible for the professional care of the
pt regarding drug use
 Manager of hospital pharmacy
 Part of PTC, managing Drug Information
Service

1.16 HOSPITAL PHARRMACIST MUST BE

KNOWLEDGEABLE ON
 Drugs and their action
 Pharmaceutical Manufacturing Program
 Control procedure regarding
o QC (prep of TPN/ admixtures)
o Drug distribution through out the
hospital

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 Pharmacy Orientation 4

1.23 RESEARCH & DEVELOPMENT

 Discovery/ isolation of new drugs
for treating diseases
 The development of better drugs
through chemical modification
Examples:
Amoxicillin  Co-amoxiclav
Diuretics  K sparing diuretics

1.24 PHARMACEUTICAL JOURNALISM

 Gifted with writing and editing
talents
 Magazines, brochures, newsletter
about different drugs for marketing
1.20 BARRIERS TO CLINICAL PHARMACY purposes
PRACTICE
 Lack of interest of top mgnagement 1.25 MANAGEMENT
 Higher costs
 Other professionals are unhappy 1.26 ORAGANIZATION MANAGEMENT
 Lack of incentive for pharmacist
 Lack of training/ specializing areas  Pharmacist can work as manager in
to develop expertise differnent departments of Industry,
Hospital, Pharmacy and many other
Govt. or Private institutions.
1.21 DRUG WHOLESALE  Pharmacists are working as officers
of diffrent recognized associations
[Link] D RUG W HOLESALING  Pharmacist can organize different
 Important part of distributive workshops and seminars to keep
scheme, provides mechanism to pharmacists abreast with latest
obtain various products information in drug treatment and
manufactured by different labs from technology
single agency
 Less hazards in stock handling,
record keeping and bill paying for
1.27 GOVERNMENT SERVICES
the retailer
1.28 PHARMACIST IN GOVERNMENT
SERVICE
 Officer in Army, Navy, Air force
 Hospital pharmacist
 Ministry of Health (licensing ,
inspection, registration)
 Drug Regulatory Authority and drug
1.22 PHARMACY EDUCATION
registration
 Most important segment of  Drug testing laboratory (analyst,
pharmacy microbiologist)
 Represented by colleges of  Consultant ( mental health, family
pharmacy planning, pollution, poisons, self-
 Responsible for the nature and medication, immunization)
quality of pharmaceutical education
 Knowledge of diffrent physical,
biological sciences qualifies a
1.29 FORENSIC PHARMACY
pharmacist to teach  It is related to the pharmacist’s skills used to
 Masteral/ Doctoral degree help the medico legal problems such as DNA
test, Semen test or legal emergencies.

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 Pharmacy Orientation 5

1.30 NUCLEAR PHARMACY important role in decreasing the mortality

and morbidity in the public.
 Nuclear pharmacy focuses on preparing
radioactive isotopes for diagnostic tests & for
treating certain diseases.
1.37 TYPE OF PHARMACY
 Nuclear pharmacists undergo additional
training specifically to handle the radioactive [Link] C HAIN
isotopes, unlike in community & hospital E.g. GUARDIAN, WATSON, CLINIX, FAZAL
pharmacies. DIN & SONS

[Link] I NDEPENDENT
1.31 E.g. Green Pharmacy, Decent Pharmacy
etc.
1.32 MEDICAL COMMUNICATION
1.38 NATURE OF BUSINESS
1.33 MEDICAL COMMUNICATIONS
 Newest/ rapidly developing [Link] R ETAIL
field  sell direct to end user/customer
 Computer handling of  Pharmacy license from Ministry of Health
medical data
1.39 WHOLESALE
1.34 COMMUNITY/ RETAIL PHARMACY  supply to other retailers, General
Practitioners (Clinics), Hospitals etc
HISTORY  Wholesale License from Ministry of Health
Community pharmacy was also named as:
 Apothecary
 Druggist
 Chemist 1.40 LAYOUT OF THE COMMUNITY
 Pharmaceutical Chemist PHARMACY
 Retail Pharmacist
 Prescription Counter & Consulting Area
 Community Pharmacist (1993)
 Front Area – e.g. OTC Area
 Controlled Substances
1.35 COMMUNITY PHARMACY  Store
 Community pharmacy symbolizes the  Refrigeration
adoption of a new degree of professionalism  Computer systems – Point-Of-Sale,
by street pharmacist. Inventory, Accounting etc
 This will arouse community expectations  Equipment-display
which demand care, commitment and  Purchasing & Inventory Control
excellence.
 It is not just a title acquired by passing the 1.41 PRESCRIPTION COUNTER &
exam; it demands dedication and highest
degree of professionalism.
CONSULTING AREA
 The prescription processing area 
1.36 INTRODUCTION Pharmacist use to prepare prescriptions
 Consultation area  Strictly for the
 Community pharmacist is the professional pharmacist’s use
who would be in direct access to the public
and whose duties are widely sought after by
the public and patients.
1.42 FRONT AREA
 A community/retail pharmacist works  OTC drugs like Panadol, Zentel.
according to legal and ethical guidelines to  Cosmetics, toiletries, rehabilitation products
ensure the correct and safe supply of & other merchandises
medical products to the general public  Vitamins and supplements
 As we are the person who will be in direct
contact with the public we have to play an 1.43 CONTROLLED SUBSTANCES

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 Pharmacy Orientation 6

 Kept in a locked storage cabinet o Be able to explain complex and

o Under supervision of pharmacist sometimes sensitive information to
 Psychotropic Drugs the general public & other
o Require prescriptions and must healthcare professionals
record  Concern for the welfare of the general public
o Repeated checking of the products,  An understanding of business principles;
labeling, packaging  A professional and confident manner;
 Cough Mixture  The ability to inspire the trust of others;
o Contain Dextromethorphan  A willingness to take on a high level of
responsibility.
1.44 STORE/ STORAGE
 To keep the excess stocks
1.49 ROLES OF COMMUNITY PHARMACIST
 General store or Drug store (must lock) Community Pharmacist assumes 3 roles:
 Dry, cool place
[Link] R ETAILER
1.45 REFRIGERATION Makes goods and services available
A refrigerator to store drugs:
[Link] M ANAGER
 Required to be kept at temp between 2 &
o Uses limited resources efficiently and
8C
effectively
 Exclusively for medications
 No food or beverages
[Link] P ROFESSIONAL
Provide valued services through trust,
1.46 COMPUTER SYSTEMS commitment and competence
 Familiar with computer hardware & software
 Hardware  Pharmacies are required to have a
o Monitor, CPU, keyboard, mouse, pharmacist on duty all the time.
scanner, modem, printer  Most pharmacies have experienced support
 Software staff who work under the personal
o Point of Sales, Accounting, supervision of the pharmacist.
Inventory e.g. UNIX  Therefore, community pharmacists, by far
 Most chain pharmacies are linked together the largest segment of the profession,
o Facilitate the sharing of information require scientific, administrative, supervisory,
between pharmacies counseling and pharmaceutical skills of a
very high standard
1.47 PURCHASING & INVENTORY CONTROL  Dispensing prescription medicines to the
 Must complete a purchase order (PO) public on a prescription or without
o Product name prescription– check dosage, ensure the
o Amount & price medicine are correct and safe and label it
 Order transmitted directly to the  Liaising with doctors about prescriptions;
manufacturer  supervising the preparation of any medicines
 During receiving  carefully check the (not all are supplied as ready made-up by the
product against the PO manufacturer);
 Damaged products must be reported  keeping a register of controlled drugs for
without delay & returned to the legal and stock control purposes;
manufacturers
 Must check all products for expiration dates

1.48 COMMUNITY PHARMACIST MUST

SHOW:
 Good communication skills
o Be able to listen carefully to what
patients says

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 Pharmacy Orientation 7

 Sexually transmitted diseases

 Health promotion
 Environmental hazards

 selling over-the-counter medicines

 Counseling and advising the public on the

treatment of minor ailments and any adverse
side-effects of medicines or potential
interactions with other medicines/
treatments;
 Providing specialist health check
services, such as monitoring blood
pressure and cholesterol levels, diabetes
screening and pregnancy testing.
 Preparing dosette and cassette boxes,
usually or the elderly but also for those
with memory/ learning difficulties,
where tablets are placed in
compartments for specified days of the
week;
 Overseeing the ordering and safe
storage of medical products and, in
some cases, arranging the delivery of
prescription medicines to patients;
 Keeping up-to-date with current
pharmacy practice, new drugs and their
uses.
 maintaining computerized records;
 Managing, supervising and training
pharmacy support staff;
 Budgeting and financial management;
 Promoting sales and developing the
business.
 Selling healthcare and other products,
such as toiletries, cosmetics and
rehabilitations product e.g. wheel chair.

1.50 OTHER IMPORTANT ROLES

 Rationale use of drugs
 Nutritional counseling
 Alcohol, drug abuse and smoking cessation
 Individualization of drug therapy
 Family planning
 Poisoning prevention
 Control of communicable diseases
 Pregnancy and infant care

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 History of Pharmacy 8

o The asipu ( magical healer )

Chapter 2 HISTORY OF PHARMACY o The asu ( empirical healer )
 The asipu relied more heavily on spells and
2.1 BEFORE THE DAWN OF HISTORY magical stones far more than plant materials.
 From beginnings as remote and simple as  The asu drew upon a large collection of drugs
these came the proud profession of and manipulated them into several dosage
pharmacy. It’s development parallels that of forms that are still basic today such as
man. suppositories, pills and ointments.
 Among the several characteristics unique to  The asipu and asu were not in direct
Homo Sapiens is our propensity to treat competition and sometimes cooperated on
ailments, physical and mental with difficult cases.
medicines.
 Ancient man learned from instinct, from 2.6 DAYS OF PAPYRUS EBERS
observation of birds and beasts. Cool water,  Though Egyptian medicine dates from about
a leaf, dirt or mud was his first soothing 2900 B.C, best known and most important
application. Pharmaceutical record is the “Papyrus Ebers”
 By trial, he learned which served him best. (1600 B.C), a collection of 800 prescriptions
Eventually he applied his knowledge for the mentioning 700 drugs. The drugs are chiefly
benefit of others. botanical although mineral and animal drugs
are also noted.
2.2 PRE-HISTORIC PHARMACY  Such botanical substances as acacia, castor
 Since humanities earliest past, Pharmacy has bean and fennel are mentioned along with
been a part of everyday life. Some of apparent references to such minerals as iron
mankind’s oldest settlements such as oxide, sodium carbonate, sodium chloride
Shanidar support the contention that pre and sulfur.
historic people gathered plants for medicinal
purposes. By trial and error, the knowledge 2.7 GREEK CIVILIZATION
of the healing properties of certain natural During the millennium that followed the roots of
substances grew. modern medical profession in the west arouse from
 When healers at shanidar or other Greek civilization.
prehistoric settlements approached disease,
they placed it within the context of their
general understanding of the world around 2.8 ASKLEPIOUS (GOD OF HEALING)
th
them, which was alive with good and evil  Beginning in the 7 century BC, the wise and
spirits. The magical portions for curing were kind Asklepios gradually superseded Apollo
part of the duty of the Shaman (usually in- as the greatest of the healing gods.
charge of all or most things supernatural in  At the touch of his hands or of the tongue of
tribe) his sacred serpent, miraculous things
 The Shaman diagnosed and treated most happened.
serious illnesses. He compounded the  The staff of Asklepios entwined by a Sacred
remedies needed to keep away the serpent gradually emerged as the official
influences of evil spells or spirits. symbol of medicine around the world.
 On the right hand of Asklepious stood
2.3 ANTIQUITY (ANCIENT TIMES) Hygeia, one of his daughter.
 Her arm entwined by a serpent and holding a
bowl thought to have contained a healing
2.4 EGYPTIAN TIMES poison.
When organized settlements aroused in the great  And in the earliest records one finds a similar
fertile valley of Nile and the Indus River, changes mixed concept of drug or Pharmakon , a
occurred that gradually influenced the concepts of Greek word that meant “magic spells’’ or
disease and healing. “poison”.

2.5 BABYLONIANS 2.9 HIPPOCRATES

 For the Babylonians, medical care was  From another period in Greek history the
provided by two classes of practioners: greatest name

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 History of Pharmacy 9

 That is still with us today is that of Physician 2.12 MIDDLE AGES

Hippocrates known as the “father of
medicine”.
 He is one of the most important name in the 2.13 SAINTS COSMAS AND DAMIAN
development of Pharmacy as a profession  Twinship of health professions, Pharmacy
based on scientific knowledge rather than a and medicine is nowhere more strikingly
mixture of medicine and spiritual acts. portrayed than by
 During this period the word Pharmakon o Damian, the apothecary and
came to mean “a purifying remedy”. o Cosmas, the Physician
 He mentioned around 200-400 drugs as well  They were the twin brothers of Arabian
as methods of carrying out various descent .Their twin careers were cut short in
Pharmaceutical processes. the year 303 by martyrdom.
 They were the pattern saints of Pharmacy
2.10 and medicine and many miracles are
attributed to them
DIOSCORIDES
 He was a Greek Physician and botanist (first
century A.D). He was the first scientist to 2.14 MUSLIM ERA (GOLDEN ERA OF
deal botany as an applied science of
Pharmacy . PHARMACEUTICAL PROGRESS)
 His work “De Materia Medica”, is considered As Western Europe struggled, a new civilization
a milestone in the development of arouse among those who followed the teachings of
Pharmaceutical botany and in the study of Muhammad (P.B.U.H).The formerly nomadic people
naturally occurring medicinal materials. This who united into the nations of Islam conquered huge
area of study is today known as areas of middle east and Africa and eventually
“Pharmacognosy” expanding into Spain and eastern Europe.

 He explained methods of preparing crude [Link] A BBASID C ALIPHATE

drugs from opium and many other botanical In Baghdad, the first Pharmacy was established in 754
drugs. He developed the art of identification, under the Abbasid caliphate during the Islamic golden
collection, purification and proper storage of age.
botanical drugs. The clear-cut separation of the two professions,
physicians and Pharmacist was done in 800 A.D in
2.11 CLAUDIUS GALEN Abbasid caliphate.
 He was a renowned Greek Pharmacist and
[Link] Y AHANNA B IN M ASAWAYH
Physician. He practiced and taught both
He was one of the contributors to Arabic Pharmacy.
medicine and pharmacy in Rome, his
He Wrote a book “Ibn-e-Masawayh” which includes
Principles of Preparing and compounding
30 aromatics, their Physical properties, method of
medicines ruled in the western world for
detecting adulteration (spoil) and Pharmacological
1500 years.
effects.
 He aimed to create a perfect system of
Ibn-e-Masawayh recommended saffron for liver and
Physiology, Pathology and treatment of
stomach ailments.
illness.
 He wrote 500 books on medicine including
numerous drugs of natural origin, formulae [Link] A BU - H ASSAN A LI B IN S AHL R ABBAN AT
and methods of compounding. T ABARI
 It was his tremendous work in the field of He wrote a famous book “ paradise of wisdom”. It
crude natural origin drugs that still today his contains discussions on the nature of man, cosmology
name is associated with that class of (study of stars), embryology, diet and diseases.
pharmaceuticals compounded by mechanical
means –“Galenical Preparations”. [Link] S ABUR B IN S AHL
 The most famous of his formulas is one for a The first medical formulary to be written in Arabic is
cold cream called Galen’s cerate, essentially “al-Aqrabadin”. In it, he gave medical recipes stating
similar to that known today. the methods and techniques of compounding these
remedies, their Pharmacological actions, the dosages
and the means of administration.

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 History of Pharmacy 10

[Link] A BU BAKR M UHAMMAD A R R AZI That, in southern Italy, Pharmacy was separated from
He was one of the greatest Physician in Islam But at Medicine.
the same time he was supporter of the art of Al- Frederick II, was Emperor of Germany. At his palace,
Chemy. he presented subject Pharmacists with the first
To a great extent, he influenced the development of European edict completely separating their
Pharmacy and medical therapy throughout the responsibilities from those of Medicine, and
middle ages. He wrote two books named Ar-Asrar and prescribing regulations for their professional practice
Sirr Al Asrar.
2.17 PARACELSUS - BORNBASTUS VON
[Link] A L G HAFIQI
He was the highly respected Physician in cordova (
HOHENHEIM (1493-1541)
muslim spain) an that he was also interested in Perhaps no person in history exercised such a
Pharmacy as well revolutionary influence on Pharmacy and
Medicine as did Aureolus Theophrastus. Bornbastus
[Link] A BU A L Q ASIM A L Z AHRAWI Von Hohenheim (1493-1541),
He was Pioneer in the preparation of medicines by A Swiss Physician and chemist who called himself
sublimation and distillation. Also he worked on the Paracelsus. He influenced the transformation of
extraction or urinary bladder stones. Pharmacy from a profession based primarily on
botanical science to one based on chemical science.
[Link] I BN - E -S INA
Among the brilliant contributors to the sciences of 2.18 SWEDE KARL WILHELM SCHEELE
Pharmacy and Medicine during the Arabian era was
He was a Swedish Pharmacist and extracted several
one genius who seems to stand for his time - the
plant acids like lactic acid , citric acid ,tartaric acid,
Persian, Ibn-e-Sina (about 980-1037 A.D.), called
benzoic acid etc
Avicenna by the Western world. Pharmacist, poet,
physician, philosopher and diplomat. Avicenna was an
intellectual giant, a favorite of Persian princes and 2.19 EDWARD JENNER
rulers. Remarkable advance in medicine and Pharmacy took
He wrote in Arabic. He wrote the famous book “ Kitab place in the year 1796 when edward jenner
Al Shifa ( the book of healing ). He also described 700 performed the first vaccination on a human patient
preparations, their properties, mode of action and
their indications.
2.20 FRIEDRICK SERTURNER
[Link] A L –B ERUNI He was a german Pharmacist and isolated Morphine
He wrote one of the most valuable Islamic works from opium
entitled “Kitab-ul-Saydalah” ( the book of drugs )
where he gave detailed knowledge of the properties 2.21 JOSEPH PELLETIER & JOSEPH
of drugs and outlined the role of Pharmacy and the
functions and duties of the Pharmacist.
CAVENTOU
He was known as father of Arabic Pharmacy. They were French and isolated several alkaloids like
strychnine and brucine from nux vomica and quinine
and cinchonine from cinchona. Pelletier together with
2.15 MODERN AGE & EARLY RESEARCH Pierre Robiquet isolated caffeine and Robiquet
independently separated codeine from opium.
Upon this time, Pharmacy remained a function of
medicine. But with increasing variety and complexity
of compounding, forced physicians to quit pharmacy
and focus more on healing.

2.16 FREDERICK-II - SEPARATION OF

PHARMACY AND MEDICINE
In European countries exposed to Arabian Influence,
public pharmacies began to
Appear in the 17th century.
However, it was not until about 1240 A.D.

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 Official Books of Pharmacy 11

Chapter 3 OFFICIAL BOOKS OF 3.5 DEVELOPMENT OF PHARMACOPOEIA

PHARMACY  The development of Pharmacopoeia must be
credited to the discovery of printing
th
techniques in the15 century. It was felt that
3.1 ORIGIN AND DEVELOPMENT OF there should be some authoritative
PHARMACOPOEIAS formulary, at least for some particular
community.
The word Pharmacopoeia is derived from Greek, st
 1 book published by College of Florence
Pharmakon and poieo. It indicates a book issued by a
in1498. It contains the important work of
recognized body or authority containing a list of drugs
Nicholas.
and formulas for medicinal preparations, together st
 The city of Nuremberg was 1 community to
with description of these substances and standards to
process a Pharmacopoeia who was legally
which they must conform.
binding on the apothecaries of that city in
1529. They adopted 100 year old book
3.2 ORIGIN “Luminare Majus” published in 1406.
Prior to Pharmacopoeias apothecary have to look for  In 1546 it was replaced by Dispensatorium of
guidance and knowledge to books written by Valerius Cordus.
individuals who have achieved fame in medicines.  This action of Nuremberg stimulated others
These books may be divided into 2 classes: to publish their own pharmacopoeias.
th
 The Herbal  In 16 century, pharmacopoeias of London,
 The Formularies Augsburg, Antwerp, Lyons, Basle, Valencia,
Cologne, Paris and Amsterdam emerged.

3.3 THE HERBAL

3.6 LONDON PHARMACOPOEIA
 These books contain information about
medicinal plants, their properties and recipes  It was published in 1618 by College of
for preparing remedies. The most important Physicians and contains more than 2000
book was “The Meteria Medica” by drugs and preparations. Mostly old work was
Dioscorides. It contains more than 600 plants gathered. It remained English
and herbs having medicinal value and also pharmacopoeia for 3 centuries.
animal and mineral substances.  Numerous editions were published.
 This book remained authority for more than
1500 years. Its complete edition was printed 3.7 FUSION OF NATIONAL
in 1529. PHARMACOPOEIAS
 Another important name is “Pliny the Elder”
23-79 A.D. reported 1000 plants of medicinal  Medical Act of 1858 ordered the fusion of
value. London, Edinburgh and Dublin
pharmacopoeias to form British
Pharmacopoeia.
3.4 THE FORMULARIES  The General Council of Medical Education
 These were the more authoritative books for and Registration of UK was given exclusive
physicians and consists chiefly of recipes and rights of publishing, printing and selling the
list of medicinal substances and were book.
st
variously styled as “Compendium,  1 edition with the collaboration of
Dispensatorium or Antidotarium” Pharmaceutical Society appeared in 1864.
 These books based on ancient Greek, Roman Subsequent editions in 1867, 1885, 1898,
and Arabian writers. 1914 and sixth in 1932.
 The most widely known book was  A pharmacopoeia commission was
Antidotarium of Nicholas describing the established in 1914 to revive and make
preparation of confectioneries, lozenges, amendments in official books.
ointments, pills, syrups and many other
classes of preparations and also prescribed 3.8 FORMULARIES
apothecaries weight and measure system
i.e., the grain and drachms still employed in  These are supplementary to
present day pharmacy. Pharmacopoeias.

Pharmacy Exam Guide

 Official Books of Pharmacy 12

 The scope of Pharmacopoeia is mainly Public receives pharmaceutical products of

restricted to drugs and preparations which at uniform and consistent quality and strength.
the time of publication are of sufficient
importance. 3.10 INTERNATIONAL PHARMACOPOEIA
 Information regarding drugs and
preparations which are widely used but are  In 1951, WHO published the Pharmacopoeia
not official and also the recently introduced Internationalis, a compilation in two volumes
substances which have not yet proved (volume 2 in 1955).
sufficiently important for inclusion in  It designed a collection of standards which
pharmacopoeia must be sought elsewhere. could serve as reference for the
 Various books of this kind appeared from establishment of international standards.
nd rd
time to time, but the most important were.  Its 2 edition was published in 1963 and 3
a) British Pharmaceutical Codex edition comprising 5 volumes in 1979.
(B.P.C.)
b) Extra Pharmacopoeia (E.P.) 3.11 EUROPEAN PHARMACOPOEIA
 B.P.C. is published by Pharmaceutical
st nd  In 1964 a council of Europe was established
Society. 1 edition was published in 1907, 2
and included 7 countries, whose council of
in 1911 than in 1915, 1922 and 1923.
ministers adopted a resolution to establish
 E.P. was published in 1883 by W.. Martindale
an European Pharmacopoeia.
and W. W. Westcott. In 1933 after the death
 The 7 countries were Belgium, France,
of W. H. Martindale (son of W. Martindale)
Germany, Italy, Luxemburg, the Netherlands
the rights of this book were purchased by
and UK. Latter on Switzerland was accepted
society. th
as 8 member.
 These countries signed a document by which
this Pharmacopoeia was made legal and
3.9 USP & NF binding for all.
st
 Pharmacopoeia and Formulary are published 1 volume published in 1969
nd
by some recognized authority and this is in 2 volume in 1971 and
rd
most cases is Government. 3 volume in 1975
 But in US both the National Pharmacopoeia
and NF have been published by private
organizations.
 In US legal recognition of drug standard
occurred in 1906, when First Food and Drug
Act was enacted.
 Under this act both the USP (originally
published in 1820 by the United States
Pharmacopoeial Convention) and NF
(established in 1888 by American
Pharmaceutical Association) received full
recognition by US Govt.
 Both USP and NF were published by private
initiatives but have had the impact of Law.
 In 1974 United States Pharmacopoeial
Convention purchased the NF from American
Pharmaceutical Association.
 USP was originally published and revived by
Physicians, the NF always remained a project
of Pharmacists.
 USP published revisions while NF publishes
th
editions every 5 year.
 Both USP AND NF cooperated to fulfill the
common objective i.e., to provide standards
which serve as the basic measures of
strength, quality, purity, packaging and
labeling of drugs to ensure that the American

Pharmacy Exam Guide

 Precipitation 13

Chapter 4 PRECIPITATION 4.5 CLARIFICATION OF LIQUIDS THROUGH

PRECIPITATION
4.1 PRECIPITATION In many cases, part of the matter to be removed in
 It is a process of separating solid particles order to ensure a clear product is formed by
from a previously clear liquid i.e., a solution, precipitation as a result of physical or chemical
by physical or chemical changes. change. The important methods are:
 Precipitates can form when two soluble salts i) Precipitate due to change of solvent
react in solution to form one or more ii) Precipitate of proteins
insoluble products. iii) Precipitate by proteins (Adsorption)
 Precipitates can also form when the
temperature of a solution is lowered. The
lower temperature reduces the solubility of a [Link] P RECIPITATION DUE TO CHANGE OF
salt, resulting in its precipitation as a solid. SOLVENTS
 The separated solid is called “Precipitate”, Whenever precipitate by change of solvent is done,
the cause of precipitation is called the sufficient time of 12-24 hours is given for solid
“precipitant” and liquid which remains in the particles to settle down and then separated by
vessel above the precipitate is called the filtration. Tinctures are usually clarified in this way,
“Supernatant liquid”. alternate solvent be water and alcohol.

[Link] P RECIPITATION OF P ROTEINS

The conversion of proteins into an insoluble form and
then removal by filtration may be considered as a
preliminary to clarification. For example, Liquid
extract of Liquorices, Pituitary Extract, Purified Ox
bile.

[Link] P RECIPITATION BY P ROTEINS

( ADSORPTION )
It has a limited application in Pharmacy. It is used to
remove tannins from wine and the proteins being
used are gelatin or isinglass. These substances swell in
cold water but are insoluble, and form with tannins,
4.2 APPLICATIONS an adsorption compound which is also insoluble.
It has many applications:

4.3 OBTAINING SOLID SUBSTANCES 4.6 PURIFICATION OF ORGANIC

It provides a convenient method of obtaining solid COMPOUNDS
substances in the form of fine particles e.g., The organic compounds derived from natural sources
precipitate of CaCO3 (precipitated chalk). are seldom pure. They are often mixed with other
substances which also occur with them. Similarly the
compounds prepared in the laboratory are generally
4.4 PURIFICATION OF SOLIDS mixed with the products which may also have been
formed during the course of reaction, in order to
One of the most important uses of precipitation is in
study its properties and to determine its formula. A
the purification of solids. Process as applied to
given substance must be free of all impurities and
purification is termed recrystallization. The impure
obtained in a state of purity. The methods employed
solid is dissolved in a suitable solvent at elevated
for purification depend on the nature of the organic
temperature. On cooling the bulk of the impurities
compound and the impurities present in it.
remain solubilized while the purified solid product
precipitates.
The process commonly used for purification of
organic substances is;
i) Precipitation/ Crystallization

Pharmacy Exam Guide

 Precipitation 14

ii) Sublimation 4.12 WASHING PRECIPITATE

iii) Distillation
iv) Fractional distillation  Most precipitates are produced in the
v) Steam distillation presence of one or more soluble compounds.
vi) Distillation under reduced pressure Since the soluble compounds are frequently
not volatile at the drying temperature of the
precipitate, so it is necessary to wash the
precipitate to remove impurities as
4.7 PRECIPITATION REACTIONS CAN BE completely as possible.
USED FOR MAKING PIGMENTS  Washing is done with minimum portion of
liquid. It is better to wash with a number of
small portions of the washing liquid, which
are well drained between each washing.
4.8 REMOVING SALTS FROM WATER IN  Following factors must be kept in mind
WATER TREATMENT before washing;
i) It should have no solvent action
on precipitate.
ii) It should not disperse the
4.9 IN CLASSICAL QUALITATIVE INORGANIC precipitate.
ANALYSIS iii) It should not form volatile or
insoluble product with precipitate.
iv) It should be easily volatile at the
drying temperature of precipitate.
4.10 METHOD OF PRECIPITATION  In general pure water should not be used
 Precipitation is usually carried out in unless it is certain that it will not dissolve
resistant-glass beakers, and the solution of precipitate. To overcome this problem ion is
the precipitant is added slowly and with usually added. For this Ammonium Salts are
efficient stirring of the suitably diluted usually selected.
solution. The addition must always be made
without splashing; this is best achieved by
allowing the solution of the reagent to flow 4.13 DRYING AND IGNITING PRECIPITATE
down the side of the beaker. Only a  After a precipitate has been filtered and
moderate excess of reagents are added to washed, it must be brought to a constant
complete the precipitation. composition before it can be weighed. The
 As a general rule, precipitations are not further drying and igniting the precipitate
filtered off immediately after they have been will depend on the nature of the precipitate,
formed. In most cases it is allowed to stand and the nature of the filtering medium. The
for 12-24 hours so that particles achieve the choice of drying or igniting depends on the
size which can be easily filtered. temperature to which the precipitate is
heated.
 In general drying is applied when
4.11 FILTRATION o
temperature is below 250 C.
 Filtration is the process of separating the (For maximum temperature ovens and
precipitate from the mother liquor, the ignition is applied up to a temperature of
o
object is to get the precipitate and the 1200 C.)
filtering medium quantitatively free from the
solution. The system employed for filtration
are;
i) Filter paper
ii) Porous filtered plates made of
resistant glass, silica or porcelain.
 The choice of filtering media depends upon
the nature of precipitate and cost.

Pharmacy Exam Guide

 Crystallization 15

of covalent crystals include diamond and zinc sulfide

Chapter 5 CRYSTALLIZATION crystals.

5.1 CRYSTALLIZATION 5.5 METALLIC CRYSTALS

 The process of crystallization is reversal of Individual metal atoms of metallic crystals sit on
dissolution changes, in which solid melts. lattice sites. This leaves the outer electrons of these
 A typical crystal has regular geometric form atoms free to float around the lattice. Metallic
with sharp straight edges and plane surfaces. crystals tend to be very dense and have high melting
When fractured it breaks into pieces with points.
plane faces meeting in sharp edges.
 This crystalline nature of powders and
metals is revealed only by microscopic 5.6 IONIC CRYSTALS
examination. The atoms of ionic crystals are held together by
 The regular external form of crystal is formed electrostatic forces (ionic bonds). Ionic crystals are
by a regular assembly of atoms or ions hard and have relatively high melting points. Table
arranged in a space lattice having a uniform salt (NaCl) is an example of this type of crystal.
geometrical form.
 The arrangement of these units is the most 5.7 MOLECULAR CRYSTALS
important characteristic of a crystal, even if
external form is destroyed by powdering, the These crystals contain recognizable molecules within
internal structure remains. their structures. A molecular crystal is held together
 Crystals may vary in size and shapes owing to by non-covalent interactions, like Vander-Waals-
the conditions under which they are formed. Forces or hydrogen bonding. Molecular crystals tend
to be soft with relatively low melting points. Rock
candy, the crystalline form of table sugar or sucrose,
5.2 CLASSIFICATION is an example of a molecular crystal.
For classification all crystals are referred to 7 groups.
i) Cubic ii) Tetragonal 5.8 POLYMORPHISM
iii) Orthorhombic iv) Hexagonal
v) Monoclinic vi) Triclinic  Many substances exist in two or more
vii) Rhombohedral crystalline forms called “Polymorphs”.
 The differences are due to difference in
crystalline structure which give rise to
difference in physical properties e.g.
solubility.

 This variety of polymorphism exhibited by

elements is termed “Allotropy”.
 Reversible is called enantiotropic and
irreversible monotropic.
 Polymorphism is known to occur in many
steroids, sulphonamides and barbiturates.
 Detection of different polymorphic forms has
been achieved by X-ray Diffraction and
infrared adsorption of crystalline solid.
5.3 CRYSTALS GROUPED BY PROPERTIES  When crystalline solid is dissolved in solvent,
There are four main categories of crystals, as grouped the crystalline structure is lost so that
by their chemical and physical properties: different polymorphs of the same substance
will show same absorption spectra in
solution.
5.4 COVALENT CRYSTALS
A covalent crystals has true covalent bonds between 5.9 EXAMPLES
all of the atoms in the crystal. You can think of a
covalent crystal as one big molecule. Many covalent  Sulphathiazole exits in two polymorphic
crystals have extremely high melting points. Examples forms. Form-I undergoes a change in crystal
o
structure at 174 C to Form-II.

Pharmacy Exam Guide

 Crystallization 16

 Cortisone acetate exists in several forms but 5.12 THEORY OF MIERS

only one is stable in aq. suspension.
 Biological activity of Chloromphenicol  This theory postulates that a definite
palmitate has been correlated with relationship exists between the
polymorphic behavior. concentration and the temperature at which
 Four different polymorphic forms of crystals will spontaneously form in an initially
theobroma oil have different melting points. unseeded solution.
It is used in making suppositories which  The form of that relationship is “super
melts at room temperature. By melting the solubility curve” roughly parallel to and
oil of theobroma at the lowest possible above the normal solubility curve.
o
temperature (about 33 C) the stable beta
form is not lost and suppository stable at
room temperature is produced.
 In the formulation of drugs known to exist as
polymorphs, it is essential that the form
present in the final preparation should be
stable.

5.10 ISOMORPHISM
 Many chemical substances of similar
chemical constitution form crystals of similar
shape and are said to be isomorphous (the
same shape).
 e.g. MgSO4.7H2O and ZnSO4.7H2O
 Na2HPO4.12H2O and Na2HSO4.12H2O
 Another property of isomorphous substances  The Theory states that between the two
is the formation of mixed crystals e.g., curves (meta stable zone) there will be no
solutions of Potash alum and Chrome alum spontaneous nucleation, but above the super
are mixed and allowed to crystallize, a solubility curve there is spontaneous
homogenous mixture of two double salts is nucleation.
obtained (pale violet crystals)
 In crystallization process the nuclei
formation should be under control since the
5.11 MECHANISM OF CRYSTALLIZATION number of nuclei will control the size of
 The solution must be saturated before any crystals. Slow cooling yields large crystals
solid matter can be crystallized. due to reduction in number of nuclei formed
 If the temperature of saturated solution is and rapid cooling results in small crystals due
lowered or solvent is allowed to evaporate, to increased number of nuclei formed.
then the excess of solid material separates
out. 5.13 FORMATION OF NUCLEI
 Super saturation can be achieved by Nuclei may originate in the following ways:
lowering the temperature carefully without  Spontaneously due to cooling of a super
separation of crystals. saturated solution in labile zone.
 Formation of crystals from solution involves  Deliberate seeding with minute crystals.
two steps;  Crystals left from previous batch.
o Creation of crystalline nuclei.
 Attrition of existing crystals giving rise to
o Growth of these nuclei into crystals.
fragments that act as seeds. The degree of
 Nuclei may arise spontaneously (rare) or by stirring will affect.
seeding (seeding is introduction of a minute
crystal of solute).
 The driving force for this nucleation and
subsequent growth of crystal is the super
saturation of solution.

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 Crystallization 17

5.14 SIZE OF CRYSTALS the solvent level in the test tube, but should not
exceed the height of the test tube. Stopper the Dewar
The size of crystals usually depends upon the flask with a cork stopper and let the vessel sit for a
conditions of crystallization. week. A more elaborate version of this involves a
Very small crystals are obtained by rapid cooling with thermostatic oven rather than a Dewar flask.
frequent stirring. It is generally avoided because of
difficulty in washing and less purity.
Medium size crystals are obtained when hot solution
5.19 VAPOR DIFFUSION
is allowed to cool slowly without mechanical This method is good for milligram amounts of
disturbance in a warm room. material. A solution of the substance is prepared
On large scale from refrigerating plant tubes lines are using solvent S1 and placed in test tube-T. A second
circulated around the tank in outer jacket or in coiled solvent-S2 is placed in a closed beaker-B. S2 is chosen
tubes within the solution. such that when mixed with S1 the solute will become
Very large crystals are obtained by setting aside a less soluble. The test tube containing S1 is then
large volume of solution and allowing it to evaporate placed in the beaker and the beaker is sealed. Slow
spontaneously. The liquid should be rendered diffusion of S2 into T and S1 out of T will cause
perfectly clear by filtration and guarded against dust. crystals to form. If S2 is more volatile than S1 the
Seeding is done. solvent level will increase and prevent
microcrystalline crusts from forming on the sides of T.
5.15 MOTHER LIQUOR
Mother liquor is the liquid remaining after
5.20 SOLVENT DIFFUSION (LAYERING
crystallization. It is usually not discarded, but is TECHNIQUE)
subjected to further concentration and again set This method also is good for milligram amounts of
aside to crystallize. This process is repeated until materials which are sensitive to ambient laboratory
whole dissolved solute is crystallized. conditions (air, moisture). Dissolve the solute in S1
and place in a test tube. Slowly dribble S2 into the
5.16 CRYSTALLIZATION TECHNIQUES tube so that S1 and S2 form discreet layers. This will
only be successful if, (1) The density of S2 < S1 and,
5.17 SLOW EVAPORATION (2) Care is exercised in creating the solvent layer.
Using a syringe is the best way to add the second
This is the simplest way to grow crystals and works solvent. The narrower the tube , the easier it is to
best for compounds which are not sensitive to build up the layer. Five millimeter NMR tubes are
ambient conditions in the laboratory. Prepare a excellent vessels to use for this crystal growing
solution of the compound in a suitable solvent. The technique. CH2Cl2/C2H5OH is a good solvent
solution should be saturated or nearly saturated. combination to try this method (if your compound is
Transfer the solution to a CLEAN crystal growing dish insoluble in ether).
and cover. The covering for the container should not
be air tight. Aluminium foil with some holes poked in
it works well, or a flat piece of glass with microscope
5.21 REACTANT DIFFUSION
slides used as a spacer also will do the trick. Place the This is similar to the other diffusion methods except
container in a quiet out of the way place and let it that solutions of the reactants are allowed to diffuse
evaporate. This method works best where there is into one another. If the product of the reaction is
enough material to saturate at least a few milliliters insoluble, crystals of the product will form where the
of solvent. reactants mix. It is mentioned in literature of this
technique being used with diffusion in silica gels.
5.18 SLOW COOLING
This is good for solute-solvent systems which are less
5.22 SUBLIMATION
than moderately soluble and the solvent's boiling Simply seal a sample under vacuum in a glass tube
o
point is less than 100 C. Prepare a saturated solution and place the tube in an oven for a few days or
of the compound where the solvent is heated to just weeks. Larger crystals tend to grow at the expense of
it's boiling point or just below it. Transfer the solution smaller ones. If it doesn't work raise the temperature
to a CLEAN large test tube and stopper. Transfer the of the oven or move to another hotter one. In some
test tube to a Dewar flask in which hot water (heated cases a tube furnace can be used. Vacuum
to a temperature of a couple of degrees below the sublimation is ideal for very air sensitive compounds
solvent boiling point). The water level should exceed as the tubes can be loaded in dry boxes.

Pharmacy Exam Guide

 Crystallization 18

5.23 CONVECTION heated, and then gradually cooled so that, as each of

its constituent components crystallizes, it can be
One may attempt to grow crystals by convection by removed in its pure form from the solution.
creating a thermal gradient in the crystal growing This technique is often used in chemical engineering
vessel. The idea behind this method is that the to obtain very pure substances, or to recover saleable
solution becomes more saturated in the warm part of products from waste solutions, e.g., Benzoic acid,
the vessel and is transferred to the cooler region Paraffin, Naphthalene, Nitrochlorobenzene, Xylene
where nucleation and crystal growth occur. To create etc.
the convection one may use either local heating or
local cooling. The velocity of the convection current is
proportional to the thermal gradient across the
vessel. Care must be taken to not make the gradient
too large, or the convection will be too rapid and
inhibit crystal growth.

5.24 CRYSTAL GROWTH IN SUSPENSIONS

Crystal growth in suspensions is undesirable because
crystals have a tendency to bind together forming a
hard cake which is difficult to redisperse.
Crystal growth may lead to other undesirable changes
e.g., large crystals tend to produce gritty texture for
topical or ophthalmic use.
The causes of crystal growth in suspensions are:
1. Temperature fluctuations
Rise in temperature causes increased
solubility and a fall causes super saturation
and hence crystallization.
2. Solid present in the meta stable zone where,
they have greater solubility than stable state,
so that solution is supersaturated with
respect to latter.
3. Small crystals have a greater solubility than
large crystals so that solution is
supersaturated with respect to latter.
4. Change of crystal structure due to presence
of dispersing solvent.

5.25 METHODS OF PREVENTING

It includes;
1. Use of narrow size range.
2. Grinding the solid in the presence of
dispersing fluid.
3. Use of surface active agents which are
adsorbed on the surface of crystals.

e.g., a simple suspensions of cortisone acetate

powder for use as eye drop is liable to crystal growth.
It can be avoided by grinding with hydrated
Aluminium hydroxide and inclusion of methyl
cellulose.

5.26 FRACTIONAL CRYSTALLIZATION

A process by which a chemical compound is separated
into components by crystallization. In fractional
crystallization the compound is mixed with a solvent,

Pharmacy Exam Guide

 Distillation 19

o Enables to be cleaned readily so as

Chapter 6 DISTILLATION to remove all the traces of previous
product.
6.1 DISTILLATION o Enables a broken part to be
 Distillation is a method of separating replaced without the expense of an
mixtures based on differences in volatility of entirely new condenser.
components in a boiling liquid mixture.  Condensers are used in an upright or oblique
 Distillation differs from evaporation in two position in order to:
important respects: o The film of condensed liquid which
o The liquid from which the vapour act as a bad conductor of heat
arises is usually heated to boiling drains away as rapidly as possible
point and maintained there during o The cooling water flows in a
the process. While in evaporation direction which is reverse of that of
the temperature is kept usually the condensed liquid
below the boiling point of the liquid  There are three principal classes of
to be removed. condensers:
o The vapour which arises is made to o Single surface condenser
pass through an apparatus called a o Double surface condenser
condenser which cools the vapour, o Multi tubular condensers
thereby reforming the liquid.
6.6 SINGLE SURFACE CONDENSER
6.2 DISTILLATE The commonest form is the Liebig condenser of which
 A liquid product condensed from vapor the spiral or worm condenser and the ball condenser
during distillation may be regarded as modification.

6.3 RECEIVER
 Receiver adapters are used to allow
collection of distillates emerging from a
condenser.

6.4 STILL
 A still is the apparatus used for distillation.

6.5 CONDENSER
 The selection of the condenser is essential to
success in many distillation processes.
 The quantity of water need for the
condensation of a vapour to the liquid state
is partly dependent upon the boiling point of
the liquid and partly upon the latent heat of
the vapour.
 The efficiency of a condenser dependent
upon
o The area of the cooling surface –
cooling capacity is directly
proportional to area
o The heat conducting qualities of the
cooling surface.
o Metal is better conductor of heat 6.7 DOUBLE SURFACE CONDENSER
than glass. In these, the vapour passes through an annular space
 The usefulness of a condenser is enhanced cooled on its inner and outer surface by cold water.
by its construction:

Pharmacy Exam Guide

 Distillation 20

6.9 REFLUX CONDENSER

It is not a particular form of condenser; it describes
any condenser use for preventing the volatilization of
6.8 MULTI TUBULAR CONDENSER liquid or liquids undergoing heating. Condensers are
often used in reflux, where the hot solvent vapors of
These resemble the Liebig’s condenser but have
a liquid being heated are cooled and allowed to drip
several tubules instead of one. They are usually made
back.
up of metal and are used in large scale work.
6.10 WATER COOLED CONDENSER
In systems involving heat transfer, a condenser is a
device or unit used to condense a substance from its
gaseous to its liquid state, typically by cooling it.

6.11 AIR CONDENSER

An air condenser is the simplest sort of condenser.
There is only one tube, and the heat of the fluid is
conducted to the glass, which is cooled by air.

6.12 APPLICATION OF SIMPLE DISTILLATION

 The process of simple distillation is widely
used in the preparation of many official
compounds, e.g. Ethers, Amyl Nitrite, and
Spirit of Nitrous Ether
 Distillation is also used to concentrate liquids
and to separate solids from liquids when
liquids to be separated is valuable e.g.
alcohol, ether.

Pharmacy Exam Guide

 Distillation 21

 Steam under pressure is the usual source of Continuous process has more advantage over
heat for large stills discontinuous economically as it saves heat, labour
 Distilled water is an important product of and time.
distillation.
A few broken pieces of clean unglazed porcelain may
6.13 DISTILLED WATER be placed in the distillation flask to prevent
“bumping”.
Distilled water is used in all official preparations in
which water is required. Ordinary drinking water
usually contains traces of calcium and magnesium
6.16
salts derived from the soil through which it has AUTOMATIC STILL FOR WATER
passed. Distilled water is prepared by the distillation DISTILLATION
of drinking water.
The solid impurities are not volatile and therefore can
be removed by distillation while the gaseous
impurities are volatile so they pass over with the
steam and contaminate the distillate. The gaseous
impurities (Importantly ammonia) are removed in two
ways.

6.14 REMOVAL OF GASES IMPURITIES

[Link] B Y F RACTIONAL C OLLECTION OF THE
D ISTILLATE
In this method, advantage is taken of the fact that
gases are more volatile than water and therefore pass
over in the first portion of the distillate which may be
rejected.

[Link] B Y P RE - HEATING THE W ATER TO BE

D ISTILLATE
The same fact is used but applied differently. The
water to be distillated is heated to 90°C, or higher,
before admission to the still and thus the most of the
gaseous impurities are volatilized before distillation
commences.

6.15 REMOVAL OF SOLID IMPURITIES

[Link] B Y F RACTIONAL C OLLECTION – A
D ISCONTINUOUS P ROCESS
About 80% of the distillation is collected, this being
the product.
About 10% of the water undergoing distillation still
remains in the still when distillation is stopped.
Distillation to dryness or nearly so, may
decomposition of solids with formation of volatile
substances which would contaminate the distillate.

[Link] B Y P RE -H EATING – A C ONTINUOUS

P ROCESS
Distillate is collected continuously because the water
in the still is maintained at a constant level; hence
decomposition of solid impurities cannot occur.

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 Distillation 22

 If after reducing pressure of a liquid equals

to external pressure on its surface, the
process becomes distillation under reduced
pressure, but if the maximum vapour-
pressure of the liquid is lower than the
pressure on its surface evaporation is lower
than the pressure on its surface, evaporation
only occurs and the process is correctly
described as evaporation under reduced
pressure. In practice, both processes are
referred to as evaporation under reduced
pressure.

6.17 WATER FOR INJECTION

 Water for injection is prepared by distillation
from a glass or metal still fitted with an
entrainment separator to prevent pyrogens
being carried out over to the distillate in the
spray. It must comply with the limit test
prescribed officially for distilled water an in
addition test for sterility ant the absence of
pyrogens must be satisfied.
 Sterile Water for Injection USP is a clear,
colorless, odorless liquid. It is sterile,
hypotonic, non-pyrogenic, and contains no
bacteriostatic or antimicrobial agents. Sterile
Water for Injection USP is a diluent or
solvent suitable for intravascular injection
after first having been made approximately
isotonic by the addition of suitable solute.

6.18 DISTILLATION UNDER REDUCED

PRESSURE
 Liquid boils when its vapour pressure is equal
to the hydro-statistic pressure (Surface
Pressure).
 Mass of vapour formed is proportional to
vapour- pressure of evaporating liquid and
inversely proportional to external pressure.

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 Distillation 23

 To Prevent Destruction of Enzymes

 To Prevent Racemization
 To Prevent Hydrolysis of Glycosides and
Alkaloids
 A light friable product is desired i.e. to
influence physical form

6.20 DISTILLATION OF IMMISCIBLE LIQUID –

DISTILLATION IN STEAM
 Distillation of two immiscible liquids is called
distillation in steam when one of the
immiscible liquids is water.
 Theory
 Mixture boils when VP1+VP2=
External pressure
 Mixture boiling point < either of
the constituent
 Boiling point of mixture remains
stationary until one of the
constituent is completely removed.
 Composition of vapours distilling
over remains constant unless one of
the constituent is completely
removed.
 The composition of vapours
distilling over, by volume, is directly
proportional to the vapour pressure
pressures of the liqud.

6.21 APPLICATION IN PHARMACEUTICS

6.22 PREPARATION OF VOLATILE OILS

 The Boiling Point of many volatile oils is
above 200 °C and at these high temperature
chemical changes e.g. oxidation would in
some instances take place.
 Distillation of volatile oil with water follows
the law governing the distillation immiscible
6.19 APPLICATION liquids namely that distillation of immiscible
 Distillation under reduced pressure is used liquids, namely that distillation takes place
for purposes of concentration when when the sum of the vapour pressure equal
 The constituents of the extraction liquids are to atmospheric pressure. Hence the boiling
thermo-labile i.e. to minimize chemical point of such a mixture would be lower than
change

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 Distillation 24

that of the constituent with lower boiling the upper bend. Because the spout leads
point of water (100 °C). from the bottom of the receiver only water
 It helps in: can overflow and in this manner the bulk of
o Separation of volatile oil at lower the water is automatically separated from
temperature the oil.
o Preventing carbonization of the
drug
o Direct heating of a mixture of a drug
and water by a naked flame would
similarly cause partial carbonization
of the layer of drug resting on the
bottom of the still and again volatile
decomposition product would give
an empyreumatic odour to the
volatile oil, impair its value.
o Perforated heat is applied, upon
heating steam rises through the
perforations, passes through the
drug ad on to the condenser
carrying with it the volatile oil.
o A layer of water is run into the still
and the drug suitably comminuted,
is placed in the wire basket. Steam
is admitted to jacket of the still and
the water therein raised to boiling.
At this point, steam is admitted into
the still itself by the free-stream
pipe, thus heating the drug and
reducing the condensation of steam
therein. The oil vapour and steam
are condensed in the worm
condenser, and drip into the 6.23 2. DISTILLATED AROMATIC WATERS
Florentine receiver. In this most of
the oil is mechanically separated
from the water. 6.24 DISTILLATION OF MISCIBLE LIQUIDS -
FRACTIONAL DISTILLATION
 Fractional distillation is the separation of
a mixture into its component parts,
or fractions, such as in separating chemical
compounds by their boiling point by heating
them to a temperature at which one or more
fractions of the compound will vaporize. It is
a special type of distillation.
 The total pressure is the sum of the partial
pressures; thus if A and B are two miscible
liquids, and P1 and P2 represents their
respective partial pressure, the mixture boils
when
P1 + P2 =External Pressure (normally 1
[Link] S EPARATION OF O IL AND W ATER
atmosphere)
 The distillate is usually collected in a vessel
 With certain expectations noted later, the
called Florentine receiver. It is separated into
vapour arising from two miscible liquids at
upper oily layer and lower water layer. As
boiling point
the receiver fills the liquid also passes into
the spout whence it overflows upon reaching

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 Distillation 25

 Is richer in the component exerting the No. 1 (70°C up to 73°C), No. 2 (73°C up to
greater partial pressure – as would be
expected from the facts noted for immiscible
liquids and
 Is therefore different in composition from
the liquid yielding it.
 A boiling-point curve for mixture of A and B
may be obtained by preparing a graded
series of mixtures, determining the boiling
point of each and plotting against
composition. Similarly, the vapour yielded by
each member of the series at its boiling point
may be yielded by each member of the series
at its boiling point may be analyzed and its
composition plotted against the boiling point
of the liquid giving rise to it. Provided with
such curves, the composition of the vapour
which any mixture of A and B yields at its
boiling point may be found by drawing a line 76°C) etc.
from this point, parallel with the abscissa-  The mixture will properly commence to boil
axis, to cut the other curve (thus connecting at about 70 – 77 °C, and the distillate would
liquid and vapour at the same temperature), therefore be collected in receiver No.3 (76°
and drawing lines from these points to the up to 79°C), receiver No. 4 taking its place at
abscissa-axis. 79°C, and so on until the temperature
 Assume a mixture of the two miscible liquids reached 100°C, indicating that only water
A and B containing 20 % of A and 80 % of B, remained in the distillation flask, at which
A having lower boiling point than B. When point distillation would be stopped.
the boiling point of the mixture is reached,  The contents of receiver No.3 (i.e. the first
the liquid gives rise to a vapour richer in A collected) would then be placed in a clean
than the liquid which gave rise to it, the distillation flask and heated to boiling.
vapour containing 60 % of A. If this vapour is Distillation would probably commence at 70°
condensed the resulting liquid when heated to 71°C, and the distillate would therefore be
to boiling point give rise to a vapour collected in receiver No.1, receiver No.2
containing more than 60 % of A, the taking its plave at 73°C, and at 76°C.
proportion of A present, as shown in the Distillation would be stopped. The flask
diagram, being now 90 %. If this vapour is allowed to cool and te contents of receiver
condensed and the resulting liquid is heated No.4 added. Upon resumption of distillation
to boiling, the vapour formed now contains the liquid would probably commence to boil
98 % of A. If this vapour is condensed and re- between 73°C and 76°C, and the distillate
heated, it produces a vapour containing 100 would therefore be collected in receiver
% of A. No.2, receiver No. 3 taking its place at 76°C,
and at 79°C. Distillation would again be
6.25 DISCONTINUOUS FRACTIONAL stopped the flask allowed to cool, and the
DISTILLATION contents of receiver No.5 added. The first
distillate from this would go into the
 The above forms the basis of the appropriate receiver probably No.3 and the
discontinuous method of fractional fractions up to 84°C, (receiver No.5),
distillation, which may be carried out as collected at which point the contents of
shown in the following example, in which A is receiver No. 6 would be placed in the
a liquid with a boiling point 70°C, B is water, distillation flask and so on.
the mixture consisting of equal parts of A  The whole process would then be repeated,
and B, As the difference in the boiling point starting with the contents of receiver No.2
is 30°C, it would be convenient to collect the and collecting from it this distillate passing
distillate in 10 fractions, changing the over from 70°C to 73°C (i.e. collecting in
receiver for each rise of 3°C, in the receiver No.1) stopping distillation , adding
temperature, the receivers being labeled, the contents of receiver No.3 and proceeding

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 Distillation 26

as before. Ultimately the “middle fraction”

(i.e. those from 73°C up to 100°C) would be
reduced almost to zero. The contents of
receiver No.1 would be then be redistilled
and the fraction boiling at 70°C collected this
being pure A.

6.26 CONTINUOUS FRACTIONAL

DISTILLATION
 The tedium of the discontinuous method led
to the introduction of simpler methods of
effecting fractionation, the principle of which
is shown in the figure below. Assume again a
mixture of A 20 % with B 80 %, heated to
boiling in a distillation flask and as shown in
the lowest pair of curves, giving rise to a
vapour containing 60 %A. The latter impinges
on a cool surface ( at the second pair of
curves), condenses there and is partially re-
vaporized (i.e. heated to its boiling point) by
more hot vapour arising from the distillation
flask. As shown (first condensation and
partial re-vaporization in figure), the vapoir
which arises will contain 90 % A. the latter
impinges on a higher cool surface (at the
third pair of curves), condenses there and is
again re-vaporized by the succeeding upward
flow of hot vapour. Again a vapour richer in
A rises, now containing 98 % A; a repetition
of the process at a still higher cooling surface
(third condensation and partial re-
vaporization in figure), yield pure A.
 The above forms the basis of the continuous
method of fractional distillation and
necessarily involves the use of special still-
head in which condensation and re-
vaporization is effected continuously. These
special still-heads are called fractionating
column.

6.27 CONSTANT BOILING TEMPERATURES

(AZEOTROPIC MIXTURE)

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 Distillation 28

6.28 COMPARISON

the apparatus described above. The principal

structure as shown in the diagram is two
towers, one called the analyzer, the other
the rectifier. The weak alcoholic liquid,
6.29 APPLICATION OF FRACTIONAL previously heated, passes down the analyzer
DISTILLATION through a series of perforated copper plates
and in its downward passage meets an
ascending current of superheated steam. At
6.30 PREPARATION OF ALCOHOL each plate the weak alcoholic liquid is
Alcohol is one of the important pharmaceutical heated, some of the alcohol vaporized and
substances in the preparation of which fractional carried along in the steam so that upon
distillation is employed. The important stages in the reaching the bottom of the tower. The weak
preparation of alcohol are: alcoholic liquid has been completely
 The preparation of a sugar solution from deprived of alcohol.
suitable material  The steam and alcoholic vapour then pass up
 Malt is usually employed in conjunction with the rectifier, which acts in much the same
cheap materials, e.g. maize and rice, which way as a fractionating column, allowing the
contain starch, which is converted to sugars alcohol vapour to pass on to a condenser,
by the action of diastase contained in the but condensing the steam and a small
malt. proportion of the alcohol vapour. This
 Fermentation of this sugar solution by the condensed liquid is returned to the analyser.
action of yeast The rectifier is cooled by the weak alcoholic
 This converts the bulk of the sugar into liquid which passes downward through a
alcohol and carbon dioxide, but numerous coiled pipe in the rectifier. In this way, the
other substances are formed in small weak alcoholic liquid is heated is ready for
amount of which the more important are entry into the analyzer.
glycerin, succinic acid and higher  The distillate obtained from the Coffey still
homologues of ethyl alcohol which are may contain as much as 95 % of alcohol. This
known as fuel oil. The fermentation liquid, alcohol is not pure. It is purified by the
called the wort, usually contains only 10 to distillation with water which precipitates the
14 % of alcohol. fused oil, filtration through animal charcoal
 Fractional Distillation of this fermented liquid followed by redistillation in a still called a
in a special form of still called Coffey’s still, rectifying still.
which is quite different in construction from

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 Distillation 29

 Dehydrated Alcohol may be prepared from

95 % alcohol by taking advantage of the fact
that alcohol, water and benzene from a
ternary constant of boiling point mixture. If
therefore, sufficient benzene is added to
form this mixture with all the water present
and some of the alcohol, distillation will
result this ternary mixture volatilizing first
when it can be rejected. Subsequently the
remaining anhydrous alcohol is distilled.

6.31 DESTRUCTIVE DISTILLATION

Destructive or dry distillation is the process of
effecting decomposition of organic substances by
heating them strongly without access of air.
 Destructive distillation of Wood
 Destructive distillation of Coal
 Destructive distillation of Shale.

6.32 DESTRUCTIVE DISTILLATION OF WOOD

The wood of Pinus sylvestris and other species of
Pinus are used for distillation;
This distillation yields the following products;
 Gases (methane, ethane, ethylene,
CO and hydrogen.
 A liquid distillate called
pyroligneous acid.
 Charcoal or impure carbon left in
the klin.
The wood yields 40-50% of its own weight of crude
pyroligneous acid, the principal constituents of which
are;
 Methyl of Wood Alcohol
3 - 4%
 Acetic Acid
6 - 8%
 Acetone 0.1-
0.5%

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 Distillation 30

 Water
80%
 Tar (in solution and suspension)
7%

6.33 CREOSOLE (OIL OF TAR)

From the destructive distillation of beech-wood which
is richer in guaiacol. The Tar is distilled and the
o
fraction of distillate obtained between 200 and
o
220 C is collected and separated and it consists
principally of
 Guaiacol
 Creosole

6.34 WOOD CHARCOAL

Material left in the retorts or kilns and consists of
carbon with inorganic substances (ash) about 7%.

6.35 DESTRUCTIVE DISTILLATION OF COAL

Destructive distillation of Coal yields two layers:
 Aqueous layer (ammonium
hydrogen carbonate, ammonium
hydrosulphide and other
compounds
 Tarry layer (crude coal tar)
Prepared coal tar contains phenols, basic compounds
(e.g. aniline, pyridine, acridine), sulphur compounds
(notably thiophene) and hydrocarbons (e.g. benzene,
zylene, anthracene and naphthalene)

6.36 DESTRUCTIVE DISTILLATION OF SHALE.

Principle compound is Ichthammol obtained from the
tar obtained by destructive distillation of Shale.
Each ton of Shale yields 12-15 gallons of tarry oily
distillate. This is redistilled and the fraction obtained
o o
between 100 -300 C is used in the manufacture of
ichthammol.
This is subjected to following three processes:
 Sulphonation
 Washing
 Neutralization
Ichthammol contains:
 Ammonium Ichthosulphonate (
>10.5%)
 Ammonium Sulphate (<1/4 )
th

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 Miscellaneous Pharmaceutical Processes 31

cannot be completely exsiccated without

Chapter 7 MISCELLANEOUS decomposition e.g. FeSO4.7H2O, contains 7
PHARMACEUTICAL PROCESSES molecules of water, loses 6 molecules on water
bath but decomposes before losing the last one.
7.1 EFFLORESCENCE
7.4 DESICCATION
A large number of crystals exist in hydrated form
i.e. molecules of water combine with their own Desiccation or drying is a process of removing
molecules. This attached water is called water of mechanically admixed water from substances
crystallization. It should be noted that the (different from exsiccation).
presence of water of crystallization is not Strictly speaking the term desiccation refers to
essential to the crystal structure e.g.; NaCl, KNO3, the complete removal of water and term
tartaric acid and many other inorganic or organic desiccated substance is used for those
substances have definite crystalline structure substances from which water has been
without water of crystallization. They are called completely removed. The term “dry” is
anhydrous substances. frequently used to explain substances which still
Hydrated substances under normal condition contain mechanically admixed water, provided
generate a small but definite aqueous vapor this water is not noticeable to the touch e.g.
pressure due to their water of crystallization. The majority of dry vegetable drugs such as senna
vapor pressure due to water in atmosphere is leaves contains about 12% moisture. In pharmacy
o many processes are used for separation of liquid.
approximately 10 mm of Hg at 15 C. If the vapor
pressure of hydrated substance exceeds The process used in drying may be classified to
atmospheric pressure, then the substance tends the degree of dryness needed.
to give up its water to form substances with less
water molecules or anhydrous substances. This 7.5 GRAVITATIONAL DRYING
phenomenon is known as “Efflorescence”.
It includes:
 Decantation
7.2 DELIQUESCENCE  Filtration
If a substance has lower aqueous vapor pressure  Drainage
than the surrounding atmosphere, then it may  Absorption
take up water forming a definite hydrate
containing a higher proportion of combined First two are methods of separation rather than
water and a solution of substance in water is drying. These methods constitute the processes
formed. This property is known as deliquescence. by which the desired solid is separated from the
It may take place in case of anhydrous greater portion of the liquid i.e. they are
substances. Substances liable to this change are processes of drying preliminary to drying by
called deliquescent or hygroscopic. evaporation.

7.3 EXSICCATION 7.6 TRITURATION

Process of removing water of crystallization i.e. Trituration is the name of the process for
combined water from a substance is called reducing the particle size of a substance by
exsiccation i.e. a process of efflorescence grinding, as by grinding of powders in a mortar
controlled and accelerated. The temperature with a pestle. Trituration additionally refers to
needed to remove water of crystallization varies the production of a homogeneous material
widely, e.g. CuSO4.5H2O loses 2 molecules of through mixing.
o o
water at 30 C, 2 more at 100 C and last one at
o
200 C. It is important to note that prolong 7.7 LEVIGATION
heating at low temperature will not be effective,
It is the process of wet grinding. The material to
only desired temperature will remove water of
be grounded is made into a paste with water. On
crystallization. Heating is carried out on a water
the small scale grinding of paste may be effected
bath or in an oven. If definite hydrated substance
in a mortar using a flat headed pestle. On the
is required, temperature is carefully controlled.
large scale, a mill like edge runner mill is used.
Salts containing large proportion of water of
The materials subjected to wet grinding include
crystallization (e.g. Na2CO3.10H2O) usually liquefy
Kaolin B.P., prepared chalk, and calamine. The
in its own water when heated. Certain salts
process of levigation on small scale has almost

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 Miscellaneous Pharmaceutical Processes 32

ceased because now manufacturers supply 7.11 LATENT HEAT OF VAPORIZATION:

levigated powders. At the end of levigation
process, the paste contains fine particles with a To maintain a liquid at the same temperature
small proportion of coarse particles which have during evaporation, it is necessary to supply heat.
escaped grinding. The fine particles are separated This heat which doesn’t make itself evident by a
from the coarse particles by the process of rise in temperature is called latent heat of
elutriation. vaporization. It is important to remember that
more heat is required to evaporate water that to
rise its temperature
7.8 ELUTRIATION
It is the process of separation depending upon 7.12 EVAPORATION
the low density of fine particles and high density
of coarse particles. The paste prepared by Vaporization in which molecules or vapors
levigation is mixed with a large volume of water escaping from a liquid aren’t collected but
and the mixture is allowed to stand for some allowed to diffuse into atmosphere is called
time, during which the heavy coarse particles evaporation.
settled to the bottom of the vessel. The upper It is one of the most important process in the
layer of liquid still contains the fine particles in manufacture of pharmaceutical preparation e.g.
suspension. The upper liquid is poured of or preparation of liquids, soft and dry extracts,
decanted and the fine particles are allowed to extraction of enzymes, hormones, antibiotics and
settle to the bottom. The wet paste consisting of many other substances. There are many factors
fine particles, is then dried. On small scale, which influence evaporation e.g. physical factors,
process can be carried out in a conical measure Pharmaceutical and technical factors.
(flask) by simply pouring out the upper liquid
containing fine particles. On large scale, 7.13 PHYSICAL FACTORS INCLUDE:
elutriation tanks are used. They have stirring gear
a. Surface area of liquid exposed to
and a number of taps at regular intervals from
atmosphere.
top to bottom. This saves time.
b. Difference between maximum and
actual vapor pressure of atmosphere.
7.9 VAPORIZATION c. Ratio between pressure on the liquid
Matter exists in three states: and its vapor pressure.
 Liquid
 Solid 7.14 PHARMACEUTICAL AND TECHNICAL
 Gas
FACTORS:
The Kinetic energy postulates that molecules of
matter are in a state of constant motion. The a. Temperature.
molecules at the surface of substance may leave b. Temperature and time of evaporation.
if they have a free path and their velocity is c. Temperature and moisture content .
sufficiently great. In other words some of the d. Type of product require.
molecules pass into and become intermingled e. Films and deposits.
with the atmosphere. This is called vaporization. f. Cost and convenience.
Rise in temperature increases the velocity of the
molecules, hence more molecules escape from a 7.15 SUBLIMATION
hot substance. The vapors form in this way exerts
Solids with higher vapor pressure can pass
a pressure called vapor pressure which varies
directly from the solid to the gaseous state
with temperature.
without melting. This process is known as
sublimation. The reserve process is i.e.
7.10 COOLING EFFECT OF EVAPORATION: recondensation to solid phase may be referred as
The molecules escapes from the surface are deposition.
those possessing sufficiently high velocity, such
molecules have the greatest kinetic energy. This 7.16 PROCESS OF SUBLIMATION CAN BE
explains why a liquid which is evaporating
CLASSIFIED INTO DIFFERENT TYPES :
becomes cool because the molecules with the
greatest heat content escape. Type 1: Solid vapor
solid

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 Miscellaneous Pharmaceutical Processes 33

Vaporization the surface of charcoal and is said to be adsorbed

Condensation by charcoal.
The essential feature of adsorption is therefore
Type 2: Solid liquid vapor
the occurrence of a difference between volume
liquid solid
concentration and surface concentration and
adsorption is said to be positive when volume
Type 1 is true sublimation which occurs in very
concentration diminishes while surface
few compounds.
concentration increased and negative when
Type 2 is really distillation process because volume concentration increases and surface
vapors arise from liquid but in pharmacy the concentration diminishes.
process is common though erroneously described
as sublimation. 7.18 ACTIVATION OF ADSORPTIVE AGENT:
The difference between the types is chiefly due
to pressure. If a solid can, at some special It’s a treatment whereby the surface of particles
temperature exert a vapor pressure equal to the is freed from impurities, thereby ensuring
external pressure, it will on heating to this point, maximum adsorption, or treatment leading to
pass directly to vapors and the reverse changes the formation of very small colloidal size
will occur on cooling vapors i.e. the sublimation particles, thus increasing the surface area.
will occur. For example, activated charcoal prepared from
If a solid cannot, at any temperature, exert a coconut shells is subjected to the action of steam
vapor pressure equal to its external vapor and air at high temperature whereby impurities
pressure, on heating, it will first liquefy and when are removed. Activated charcoal is used in
vapor pressure of the liquid equals to the removing coloring materials from solvent used in
external pressure, the liquid will boil and dry cleaning, from sugar juices in the preparation
vaporizes and reverse will occur on cooling the of sucrose. It is also used in gas masks to adsorb
vapors i.e. sublimation of type 2 will occur. poisonous gases.
G
r Lloyds’s agent is a special hydrated aluminum
a silicate which is superior to Fuller’s earth which
p chiefly consists of aluminum silicate, used as
h adsorptive in the preparation for Vitamin B1 B.P.
E XAMPLES OF TYPE 1: arsenic trioxide
E XAMPLES OF TYPE 2: iodine and camphor.
Triple point pressure of iodine is 91 mm of Hg
o
and it melts at 114 C. Whereas the triple point
pressure of camphor is 380 mm of Hg and it
o
melts at 180 C.

[Link] T YPE 3 SUBLIMATION :

Solidliquidvapors solid

7.17 ADSORPTION 7.19 FUSION

It may be defined as concentration of a substance Fusion or liquefaction is the process of heating a
at the interphase or boundary between two solid until it melts. Melting occurs sharply at a fix
heterogeneous phases e.g. solid or gas, two point or solid may pass gradually through a soft
insoluble liquids, a solid and a liquid, a solid and a stage to form a liquid. The process is widely used
solution. in pharmaceutical works specially for melting
When charcoal is shaken with Strychnine fats, waxes and resins for the preparation of
Hydrochloride solution, the strychnine-HCl ointments, suppositories and plasters.
concentrates in a very thin layer which wets the
charcoal. If the free liquid is filtered off, the thin 7.20 CALCINATION
layer of concentrated strychnine-HCl remains at

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 Miscellaneous Pharmaceutical Processes 34

It is the process whereby an inorganic substance advantage is absence of filtering media. They are
is strongly heated so that any volatile component used for varnishes, lacquers (sealing coat after
is driven off. It is used in gravimetric analysis and polishing), oils of all kinds, animal fats and also
in the preparation of Calcii hydroxidum (Calcium used in the preparation of Insulin and Penicillin.
Hydroxide), magneneii oxidum leve (light
calcinated magnesia), zinc oxidum (zinc white). 7.24 FREEZE DRYING (LYOPHILLIZATION)
This term is used to describe drying by
7.21 IGNITION
sublimation from the frozen condition and has
Organic matter when strongly heated in air, first become well known process in recent years
carbonizes and then upon further heating, the because of its use for the drying of blood plasma,
carbon oxidizes to form carbon dioxide and an blood serum and different antibiotics.
ash remains. This process is called as ignition or
incineration or ashing. The process is applied in The process involves freezing the solution of the
the official estimation of several organic salts of materials in a suitable container connected to a
the alkali metals. high vacuum system. A partial pressure of water
vapors less than that of material being dried is
attained. Under these conditions, the water
7.22 CENTRIFUGATION sublimes from the frozen mass until the material
It is the process whereby a substance or a liquid is desiccated. There are mainly three stages:
is rotated at a very high speed either to remove  Freezing
the liquid from the substance (for drying) or to  Removal of vapors
separate suspended particles in a liquid.  Aseptic transfer to the final container.
Drying by centrifugal force is used in some According to the USP and BP, less than 2%
industries and the machines used are called moisture in penicillin injection is required.
“hydro extractors”. The process consist in placing
the materials to be dried in a drum containing 7.25 FREEZING:
numerous holes and rotating at a very high
speed. The water is thrown off from the material. This is done by external cooling with mechanical
refrigeration. The freezing temperature varies
The process is also used in laboratory work for with different materials; important thing is that
draining and drying crystals. the material should remain frozen throughout
drying process.
7.23 CENTRIFUGAL SEPARATION
The speed of sedimentation of a solid suspended
7.26 WATER REMOVAL:
in a liquid suspension depends upon the size of This is affected by ejector pumps or by rotary
the particles, the viscosity of liquid and difference pumps. Sometimes, desiccants have been used
in densities between the solid and liquid. The additionally to remove the last traces of
speed of sedimentation is also governed by force moisture.
of gravity.
By means of centrifugal apparatus, the 7.27 DRYING IN BULK OF FINAL CONTAINER:
suspended particles maybe subjected to a force The biological materials dried by sublimation are
many times greater than the force of gravity and usually intended to be in sterile condition
sedimentation is speeded up to a remarkable especially for injections. Drying in an ampule or
extent. bottle is satisfactory and reduces contamination
The suspension is contained in a rotating risks.
container called bowl. The heavy solid particles Aseptic transfer of liquid is simpler than of a dry
are forced to the periphery of the bowl, the powder. Similarly a sterility test on a sample of
lighter liquid remains in the center. Large scale concentrated liquid is satisfactory than one on
centrifugal separators work continuously, the dry powder.
suspension being fed upwards into the rotating
bowl where the solid is collected on the walls and
the clear liquid passes out at the top center.
Centrifugal separators play a considerable role in
pharmaceutical clarification processes. One great

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 Solution 35

A solution consists of two or more substances; the

Chapter 8 SOLUTION substance which is greater in amount is called the
A solution is a homogeneous mixture of two or more solvent while the substance which is lesser in amount
substances. A solution may exist in any phase. is referred as solute.
Generally in liquid and solid solution the liquid is
8.1 SYSTEM taken as solvent while the solid substance is the
solute irrespective of material quantity. Similarly in
System is the bounded space which is under
case of a solution consisting of water and any other
consideration.
solid or liquid substance, the water is taken as solvent
while the other substance is the solute irrespective of
8.2 PHASE the material quantity.
Phase is a distinct homogeneous part of a system
separated by definite boundaries from other parts of 8.10 TYPES OF SOLUTIONS ACCORDING TO
the system.
STATES
8.3 DISPERSION
Dispersion consists of at least two phases with one or
more dispersed (internal) phase contained in a single
continuous (external) phase.

8.4 TYPE OF DISPERSION

 True solution
 Colloidal dispersion
 Coarse dispersion

8.5 TRUE SOLUTION 8.11 TYPES OF SOLUTE

A true solution is defined as a mixture of two or more
components that form a homogeneous molecular 8.12 NON-ELECTROLYTE
dispersion, Or a one phase system. The particle size in
true solution is less than 1nm. A true solution cannot The substances that do not ionize when dissolved in
scatter light and cannot be visualized by microscopy. water and do not conduct electric current is called
non-electrolyte, e.g. solution of sucrose, urea and
glycerin.
8.6 COLLOIDAL DISPERSION
The colloidal dispersion can be heterogeneous or 8.13 ELECTROLYTE
homogeneous (one-phase system). The particle size in
colloidal dispersion is greater than true solution but The substances that ionize when dissolved in water
less than coarse dispersion i.e. 1 to 500 nm. and conduct electric current is called electrolyte.
There are further divided into
1. Strong Electrolyte: Substance that
8.7 COARSE DISPERSION completely ionized in water, e.g. HCl and
The particle size in coarse dispersion is greater than Sodim Sulphate.
500nm (0.5µm). There are two common type of 2. Weak Electrolyte: Substances that partly
coarse dispersion in pharmaceutics ionized in water, e.g. Ephedrine and
1. Emulsions (liquid-liquid dispersion) Phenobarbital.
2. Suspension (solid-liquid dispersion)
8.14 PHYSICAL PROPERTIES OF SUBSTANCES
8.8 BINARY SOLUTION
 EXTENSIVE PROPERTIES : Properties
A solution consisting of only two substances is known
which depend on the quantity of the matter
as binary solution.
in the system, e.g. mass and volume.

8.9 SOLUTE & SOLVENT  INTENSIVE PROPERTIES : Properties

which are independent of the amount of the
substances in the system, e.g. temperature,

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 Solution 36

pressure, density, surface tension, and  P ERCENT BY V OLUME (%V/V): milliliters of

viscosity of pure liquid. solute in 100mL of solution.
The physical properties of the substance can be  P ERCENT W EIGHT - IN -V OLUME (% W / V ):
classified into following: grams of solute in 100mL of solution.
1. ADDITIVE PROPERTIES: depend on the  M ILLIGRAM P ERCENT : milligram of solute in
total contribution of the atoms in the 100mL of solution.
molecule or the sum of properties of the Molarity is the general unit that used in the most of
constituents in a solution, e.g. molecular chemistry calculation; we usually use this unit to
weight. define the concentration of the solution in
stoichiometry calculation. Molality usually uses to
2. CONSTITUTIVE PROPERTIES: depend on
define the physical properties of the solution like
the arrangement and number or kind of
vapor pressure, boiling point elevation, and freezing
atoms within a molecule, e.g. refraction of
point depression of solution. We use normality in the
light, electric properties and solubility (also
volumetric calculation especially in the titration
are additive properties)
calculation.
3. COLLIGATIVE PROPERTIES: depend
IDEAL SOLUTION: A solution in which there is no
mainly on the number of particles in a
change in the properties of the components, other
solution, e.g. osmotic pressure, vapor
than dilution, when they are mixed to form a solution;
pressure lowering, freezing point depression
no heat is evolved or absorbed during the process,
and boiling point elevation.
and the final volume represent the additive
properties of the individual constituent. It means
8.15 CONCENTRATION EXPRESSION complete uniformity of attractive forces.
MOLES: Moles is the gram molecular weight of a ESCAPING TENDENCY: The tendency to escape or
substance. expand is called escaping tendency. The escaping
tendency of hotter body is greater than the escaping
GRAM EQUIVALENT WEIGHT: It is the mass of a tendency of colder one.
given substance which will:
 Supply or react with one mole of hydrogen
cations H+ in an acid–base reaction; or 8.16 RAOULT’S LAW
 Supply or react with one mole of electrons− Raoult’s law states that, any particular temperature,
in a redox reaction. the partial pressure of one component of a binary
mixture is equal to the mole fraction of that
The Concentration of solution can be expressed in component multiplied by its vapor pressure in the
following terms: pure state at this temperature.
 M OLARITY (M): Moles of solute in 1 liter of According to Raoult’s law, in an ideal solution the
solvent. partial pressure (P) of each volatile constituent is
 N ORMALITY (N): Gram equivalent weight of equal to the vapour pressure of the pure constituent
o
solute in 1 liter solvent. (P ) multiplied by its mole fraction (X).
o
 M OLALITY ( M ): moles of solutes in 1000g of P=P ×X
solvent.
 M OLE F RACTION (X): ratio of moles of one REAL SOLUTION: Solution which does not follow
constituent of a solution to the total moles the Raoult’s Law is called non-ideal solution or real
of all constituent. solution.
The real solution show deviation from Raoult’s Law,
which are

Where X1 is the mole fraction of constituent

8.17 NEGATIVE DEVIATION
1 while the X2 is the mole fraction of constituent 2 When the adhesive attraction between
and n1 and n2 are the numbers of moles of respective molecules of different species exceed the
constituent in the solution. cohesive attraction between like molecules, the
 M OLE P ERCENT : moles of constituent of vapour pressure of the solution is less than
100 moles of the solution. expected from Raoult’s Law and d negative
 P ERCENT BY W EIGHT (% W / W ): Gram of deviation occur.
solute in 100g of solution.

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 Solution 37

8.18 POSITIVE DEVIATION Where and

When the adhesive attraction between If the weight of the solvent (w1) is 1000g then
molecules of different species is less than the
cohesive attraction between like molecules, the
vapour pressure of the solution is greater than
expected from Raoult’s Law and d positive We know that W2/M2= m
deviation occur.
So

8.19 COLLIGATIVE PROPERTIES

8.20 LOWERING OF VAPOUR PRESSURE

When a non-volatile solute is combined with a volatile
solvent, the solute decreases the escaping tendency
of solvent, which on the basis of Raoult’s Law lower
the vapour pressure of the solution. Manometric 8.21 ELEVATION OF BOILING POINT
method is used to determine vapour pressure. A solution will boil at higher temperature than a pure
If the vapour pressure of solvent with dilute solute is solvent boil because of the lowering of vapour
o
P1, and pure solvent is P1 . X1 and X2 are the mole pressure; this colligative property is called boiling
fraction of solvent and solute then according to point elevation. Cottrell apparatus is used for finding
Raoult’s law, elevation of boiling point.
Elevation of boiling point
We know that,
Lowering of vapour pressure

Putting the value of X1 in first equation we get, The ratio of elevation of boiling point is proportional
to the lowering of vapour pressure

0
As P is boiling point constant it can be considered
o
proportional to ∆P/P
The relative lowering of vapour pressure depend only
on the mole fraction of solute.
As, According to Raoult’s Law

So,
So

As n2 is negligible in a very dilute solution so n 1 + n2 ≈

n1
As

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 Solution 38

n
1 + n2 ≈ n1
So
So

Where and
If the weight of the solvent (w1) is 1000g then
As
n
1 + n2 ≈ n1
So
We know that W2/M2= m

Where and
If the weight of the solvent (w1) is 1000g then

OR

Where Kb is the ebullioscopic constant, which can be

defined boiling point elevation for an ideal 1m We know that W2/M2= m
solution.

OR

Where Kf is the cryoscopic constant, which can be

defined freezing point depression for an ideal 1m
solution.
As we know

So the above equation can be written as

8.22 DEPRESSION OF FREEZING POINT
A solution will freeze at low temperature than a pure
solvent freeze because of the lowering of vapour
pressure; this colligative property is called depression
of freezing point. Beckmann’s Apparatus or
Equilibrium Apparatus is used to determine
depression of freezing point.
Depression of freezing point

Lowering of vapour pressure

The ratio of depression of freezing point is

proportional to the lowering of vapour pressure

8.23 OSMOTIC PRESSURE

Osmosis is defined as the passage of solvent into a
0
As P is freezing point constant it can be considered solution through semi-permeable membrane (is
o
proportional to ∆P/P barrier which allow only the molecules of one
component to pass through). This process tends to
equalize the escaping tendency of solvent on both
According to Raoult’s Law sides of semi-permeable membrane. The escaping
tendency can be measured in term of vapour

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 Solution 39

pressure or the closely related colligative property The four colligative properties discuss above can be
osmotic pressure. used to determine the molecular weight of solvent in
Osmotic pressure is defined as the pressure greater the following way:
than that above the pure solvent, that must be
applied to the solution to prevent the passage of the
solvent through a perfect semipermeable membrane. As n2 is negligible in a very dilute solution so n 1 + n2 ≈
The phenomena of osmosis depends upon the fact n1
that the chemical potential of a solvent molecule is
less than that exsist in the pure [Link]
therefore passes spontaneously into the solution until Where and
the chemical potentials of solvent and solution are
equal.

By rearranging we get,

The molecular weight of a non-volatile solute can

similarly determine from depression of freezing point
as shown:

As we know 1000W2/W1 is the weight of solute per

kilogram of solvent , molality can be expressed as,

So the above equation can be written as

By rearranging we get,

Similarly by boiling point elevation the equation will

become,

8.25 APPLICATION:
D ISADVANTAGES OF DETERMINATION OF
MOLECULAR WEIGHT BY BOILING POINT METHOD are
that the solute must be nonvolatile and the substance
is not decomposed at boiling temperatures.
Osmotic pressure osmometers are shown in the
A DVANTAGE OF DETERMINATION OF MOLECULAR
figure above. It works on the same phenomena. Once
WEIGHT BY FREEZING POINT METHOD is that the
equilibrium has been attained, the height of the
solute can be volatile as the freezing point only
solution in the capillary tube on the solution side of
depends on the vapour pressure of solvent. Freezing
the membrane is greater by the amount h than the
point method can be easily carried out and yields high
height in the capillary tube on the solvent side, the
accuracy of result.
osmotic pressure can be measured by following
formula D ISADVANTAGE OF USING FREEZING POINT OR
BOILING POINT METHOD is that they must be carried
out at definite temperature.
A DVANTAGE OF USING O SMOTIC P RESSURE IS that
there is no need of definite temperature in osmotic
8.24 MOLECULAR WEIGHT DETERMINATION pressure, so for high polymers osmotic pressure is
use, such as for proteins molecular weight.

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 Solubility 40

Chapter 9 SOLUBILITY
9.1 SOLUBILITY
Solubility in quantitative terms is defined as the
concentration of solute in a saturated solution at a
certain temperature, and in a qualitative way, it may
be defined as the spontaneous interaction of two or
more substances to form a homogeneous molecular
dispersion.
Solubility is rate and extent of solute to go into
solvent to get homogenize until equilibria.
9.5 THE BIOPHARMACEUTICS
9.2 SATURATED, UNSATURATED, OR CLASSIFICATION SYSTEM
SUPERSATURATED
 Saturated solutions are holding as much
solute as possible at a given temperature
 Unsaturated solutions will be able to dissolve
more
 Supersaturated solutions are holding more
than they should be able to at a given
temperature

9.6 PROCESS OF SOLUBILIZATION

The process of solubilization involves the breaking of
inter-ionic or intermolecular bonds in the solute, the
separation of the molecules of the solvent to provide
space in the solvent for the solute, interaction
between the solvent and the solute molecule or ion.
Process is explained in three steps as follow:
9.6.1 STEP 1
Holes Open in the Solvent

9.3 CONCEPTS OF SOLUBILITY

9.6.2 STEP 2
 Like dissolves like.
Molecules of the solid breaks away from the bulk
 Polar dissolves polar.
 Nonpolar dissolves Nonpolar.

9.6.3 STEP 3
The freed sold molecule is integrated into the hole in
the solvent.

9.4 EXPRESSION FOR APPROXIMATE

SOLUBILITY
9.7 PROCESS OF SOLUBILZATION

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 Solubility 41

A mechanistic perspective of solubilization process for

organic solute in water involves the following steps:
1. break up of solute-solute intermolecular
bonds
2. break up of solvent-solvent intermolecular
bonds
3. formation of cavity in solvent phase large
enough to accommodate solute molecule
4. vaporization of solute into cavity of solvent
phase
5. formation of solute-solvent intermolecular
bonds
6. reformation of solvent-solvent bonds with
solvent restructuring

9.8 FACTOR INFLUENCING SOLUBILITY 9.8.4 HYDROPHOBICITY OF S OLUTE

1. Temperature  Hydrophobicity (from the Greek hydro,
2. Surface area of solute meaning water, and phobos, meaning fear) is
3. Hydrophobicity of solute the physical property of a molecules (known
4. Pressure as a hydrophobe) that is repelled from a
5. Nature of solute and solvent mass of water.
 Hydrophobic molecules tend to be nonpolar
9.8.1 EFFECT OF TEMPERATURE and, thus, prefer other neutral molecules
 Generally in many cases solubility increases
and non-polar solvents. Hydrophobic
with the rise in temperatue and decreases
molecules in water often cluster together,
with the fall of temperature but it is not
forming micelles.
necessary in all cases. However, we must
follow tow behaviors:
9.8.5 EFFECT OF PRESSURE
 In endothermic process solubility increases  The effect of pressure is observed only in the
with the increase in temperature and vice case of gases.
versa.  An increase in pressure increases solubility of
gas in liquid.
 F OR EXAMPLE : solubility of potassium
 For example carbon di oxide is filled in cold
nitrate increases with the increase in
drink bottles under pressure.
temperature.
 In exothermic process solubility decreases 9.8.6 NATURE OF SOLUTE AND SOLVENT
with the increase in temperature.  Solubility of a solute in a solvent purely
 For example: solubility of calcium oxide depends on the nature of both solute and
decreases with the increase in temperature. solvent.
 Gases are more soluble in cold solvent than  A polar solute dissolved in polar solvent.
in hot solvent.  And a non-polar solute is freely soluble in a
non-polar solvent.
9.8.2 SURFACE AREA OF SOLUTE
 A polar solute has low solubility or insoluble
 The size and shape of small particles (those
in a non-polar solvent.
in the micrometer range) also affect
solubility. Solubility increases with the TECHNIQUES OF SOLUBILITY ENHANCEMENT
decreasing particle size and hence increasing I .Physical Modifications
the surface area of solute. A. Particle size reduction
9.8.3 EFFECT OF PARTICLE SIZE a. Micronization
b. Nanosuspension

B. Modification of the crystal habit

a. Polymorphs
b. Pseudopolymorphs

C. Drug dispersion in carriers

a. Eutectic mixtures
b. Solid dispersions
c. Solid solutions

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 Solubility 42

[Link] MODIFICATION P OLYMORPHISM

A. Change of the pH Amorphous >Metastable polymorph >Stable
B. Use of buffer polymorph
9.8.11 C: SOLUBILIZATION BY SURFACTANTS:
PHYSICAL METHOD : M ICROEMULSION
9.8.7 A) PARTICLE SIZE REDUCTION - A microemulsion is a four-component system
9.8.8 A) MICRONIZATION composed of external phase, internal phase,
MICRONISATION INCREASES THE surfactant and cosurfactant.
- Surfactant having HLB value greater than 18
DISSOLUTION RATE OF DRUGS THROUGH
acts as solubilising agent.
INCREASED SURFACE AREA.
CONVENTIONAL METHODS OF PARTICLE SIZE II. CHEMICAL MODIFICATIONS
REDUCTION COMMINATION AND SPRAY 1) BY CHANGE OF PH
DRYING , MILLING TECHNIQUES USING JET  For organic solutes that are ionizable,
MILL, COLLOID MILLS ETC . changing the pH of the system may be
simplest and most effective means of
increasing aqueous solubility.
 Change of pH by 1 fold increase solubility by
10 fold
9.8.12 2) USE OF BUFFER
 Buffer maintains the pH of the solution
overtime and it reduces or eliminate the
potential for precipitation upon dilution. On
dilution pH alteration occurs that decrease
b)Nanosuspensions
solubility .
Nanosuspensions are sub-micron colloidal dispersion
 If it changes by one pH unit ,that decrease
of pure particles of drug, which are stabilised by
ionization of the drug and solubility
surfactants.
decreases by 10 fold.
- increase in dissolution rate due to larger surface
area. MARKET PRODUCT BUFFER
- absence of ostwald ripening due to narrow size Mithohexital sodium pH 9-11
range of particle. Phenytoin sodium pH 10-12.3
9.8.13 OTHER TECHNIQUES
[Link] T ECHNIQUES FOR PRODUCTION OF 9.8.14 COSOLVENCY :
N ANOSUSPENSION  Cosolvents are prepared by mixing miscible
A ) H OMOGENIZATION : or partially miscible solvents.
 Cosolvents have some degree of hydrogen
[Link] CONVENTIONAL HOMOGENIZERS bond donating and hydrogen bond accepting
ability as well as small hydrocarbon regions.
[Link] SONICATORS  The resulting solution has intermediate to
that of organic solvent and water that reduce
water interaction.
[Link] HIGH SHEAR FLUID PROCESSORS
Aqueous solvent -
[Link].1 B ) W ET MILLING : Etahnol,sorbitol, glycerin,

propylyne glycol,polyethylene
[Link] A CTIVE DRUG IN THE PRESENCE OF
glycol
SURFACTANT IS DEFRAGMENTED BY
Non aqueous solvent - glycerol
MILLING .
dimethyl ketal,glycerol
9.8.9 OTHER TECHNIQUES FOR REDUCTION OF formal,
THE PARTICLE SIZE glycofurol, dimethyl
 Recrystallization
 Supercritical fluid process acetamide , ethyl carbonate
 Spray drying COMPLEXATION
9.8.10 B. MODIFICATION OF THE CRYSTAL HABIT Inclusion complexes are formed by the insertion of
the nonpolar molecule or the nonpolar region of one

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 Solubility 43

molecule (known as guest) into the cavity of another

molecule or group of molecules.

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 Solubilization 44

 Steroids for ophthalmic Preparation

Chapter 10 SOLUBILIZATION Optical Clarity Requirement limits the use of
Micellar core is Praffin like and so capable of oily solution so non-ionic surfactants
dissolving oil soluble molecules. (polysorbate or polyethylene sorbitian,
esters of fatty acids are used to prepare
10.1 DEFINITION solution of steroids in water.
 Essential/Volatile Oils are solubilized using
The process whereby water insoluble substances are
the principle of solubilization
brought into solution by incorporation into micelles is
 Water insoluble vitamins (A, D, E and K)
termed as solubilization.
Fat soluble vitamins are made water soluble
e.g. multivitamin syrups/ drops
10.2 FACTOR AFFECTING SOLUBILIZATION
 Problem of ‘Cloud Point’ is always there
10.3 NATURE OF SURFACTANT because it is decrease with added
substances. Sucrose esters are used though
 In homologous series of Ionic surfactant
increase hemolytic properties.
solubilizing power increases with increase of
hydrocarbon chain length
 Many other drugs like
 In non-ionic surfactants an increase in
 Analgesics
oxyethylene chain length decreases the
 Sedatives
solubilizing power.
 Sulfonamide
 Antibiotics etc.
10.4 NATURE OF THE SOLUBILIZATE These drugs are also solubilized using the
 No relation between the amount of solubilizing technique.
solubilized and the physical properties of
solubilized molecule exists.
 An increase in alkylation Length of
homologous series of solubilizate results into
decrease in solubility
 Unsaturated compounds are relatively more
soluble than their saturated counter parts
 Branching of solubilizate has no effect but
cyclization generally increase the
solubilization

10.5 EFFECT OF TEMPERATURE

In most system the amount of solubilized increases
with increase in temperature this is particularly true
in non-ionic surfactant as an increase in temperature
gives/ causes an increase in micellar size.

10.6 PHARMACEUTICAL APPLICATION OF

SOLUBILIZATION
A wide range of insoluble drugs have been formulated
using the principle of solubilization
 Phenobic Compounds (Cersol, Chlorocersol,
Chlorokylenol, Thymol etc.) are solubilizing in
water exploiting the principle of
solubilization. e.g. Dettol
 Solubilization of Iodine in Non-Ionic
Surfactant
Such preparation is known as iodophores
Iodophores are less corrosive when used for
surgical sterilization than Iodide-Iodine
System.

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 Surfactants 45

Chapter 11 SURFACTANTS 11.5 IONIC SURFACTANT

11.1 SURFACTANTS 11.6 ANIONIC

 Surfactants are wetting agents that lower the In aqueous solution these
surface tension of a liquid, allowing easier ionizes into a large anion,
spreading, and lower the interfacial tension responsible for
between two liquids. emulsifying ability, and a
 A surfactant or surface active agent is a small cation.
substance that, when dissolved in water, In solution, the head is
gives a product, the ability to remove dirt negatively charged. This is
from surfaces such as the human skin, the most widely used type
textiles, and other solids. of surfactant for
 Each surfactant molecule has a hydrophilic laundering, dishwashing
(water-loving) head that is attracted to water liquids and shampoos
molecules and a hydrophobic (water-hating) because of its excellent
tail that repels water and simultaneously cleaning properties and high (based on sulfate,
attaches itself to oil and grease in dirt sulfonate or carboxylate anions)
An example : Sodium dodecyl sulfate (SDS)
 Surfactants are also referred to as
wetting agents and foamers. Surfactants
lower the surface tension of the medium
in which it is dissolved. By lowering this
interfacial tension between two media
or interfaces (e.g. air/water, water/stain,
stain/fabric) *The most commonly used anionic surfactants are
alkyl sulphates, alkyl ethoxylate sulphates and soaps.

11.7 ANIONIC SURFACTANTS HAVE 5

SUBGROUPS

[Link] A LKALI METALS AND A MMONIUM S OAPS

These are Na, K or NH4 slats of long chain fatty acids,
such as olive, stearic and recinoleic. They usually
produce O/W which are stable at pH above 10. They
11.2 NATURAL AND SYNTHETIC ORIGIN are sensitive to even weak acids. These are
+3 +2 +2
SURFACTANTS incompatible with polyvalent such as Al , Ca , Mg ,
+2
Zn which causes phase inversion. They are not
They can be either. Surfactants from natural origin suitable for internal consumption or for broken skin
(vegetable or animal) are known as oleo-chemicals due to high pH.
and are derived from sources such as palm oil or
tallow. Surfactants from synthetic origin are known as [Link] S OAPS OF D IVALENT AND T RIVALENT
petro-chemicals and are derived from petroleum.
M ETALS
+2 +2 +2
Ca , Mg , Zn salts of fatty acids of these elements
11.3 produce W/O emulsions. They are also not used
internally but are less sensitive to acids.
11.4 CLASSIFICATION OF SURFACTANTS
[Link] A MINE S OAPS
1) Ionic surfactant
A number of amines form salts with fatty acids. Most
a) Anionic 2 2
important is triethanolamine (N(CH .CH OH)3).
b) Cationic
c) Zwitterionic (amphoteric)
2) Non-ionic surfactants
[Link] A LKYL S ULPHATES

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 Surfactants 46

These are esters of fatty alcohols and H2SO4. The These surfactants do not have an electrical charge,
most important are Na-Lauryl sulphate and Na- which makes them resistant to water hardness
cetostearyl sulphate. They alone produce O/W deactivation.
emulsions of low stability. But produce stable They are excellent grease removers that are used in
emulsion in conjunction with fatty alcohols. laundry products, household cleaners and hand
dishwashing liquids.
[Link] A LKYL P HOSPHATES All soluble surface active agents have;
These are similar to alkyl sulphates but the alcohols  A hydrophobic group i.e. a long chain of
are phosphated instead of sulphated. They are also hydrocarbon
used in combination with fatty alcohols.  A hydorphilic group i.e. carboxy,
hydroxy, amino group.

11.8 CATIONIC 11.11 TYPES OF NON-IONIC SURFACTANTS

The quaternary ammonium compounds comprises 1) Glyco and Glycerol Esters
the most important group of cationic surfactants. 2) Sorbitan Esters
They have disinfectant and preservative qualities as 3) Macrogol Esters (Polyethylene or
well as emulsifying properties. Polyoxyethylene glycol esters)
In solution, the head is positively charged. (based on 4) Macrogol Ethers
quaternary ammonium cations) 5) Poly-sorbates
An example : Benzethonium chloride (BZT) 6) Poloxalkols
7) Polyvinyl alcohols
8) Higher fatty alcohols
 The most commonly used non-ionic
surfactants are ethers of fatty alcohols

An example : Cocamide MEA

11.9 ZWITTERIONIC (AMPHOTERIC)

These surfactants are very mild, making them
particularly suited for use in personal care and
11.12 MICELLE
household cleaning products. A micelle (rarely micella, plural micellae) is an
They can be: aggregate of surfactant
1) anionic (negatively charged), molecules dispersed in a liquid
2) cationic (positively charged) or colloid.
3) non-ionic (no charge) in solution, A typical micelle in aqueous
 depending on the acidity or pH of the solution forms a roughly
water. spherical or globular aggregate
with the hydrophilic "head"
An example of an amphoteric/zwitterionic surfactant regions in contact with
is alkyl betaine surrounding solvent,
sequestering the hydrophobic tail regions in the
micelle center.

11.13 MECHANISM OF SURFACTANT

e.g. :Cocamidopropyl betaine Surfactants can work in three different ways:
1) Roll-up,
2) Emulsification, and
3) Solubilization

11.10 NON-IONIC SURFACTANTS 11.14 ROLL-UP MECHANISM

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 Surfactants 47

The surfactant lowers the oil/solution and 11.21 ADHESIVE

fabric/solution interfacial tensions and in this way lifts
the stain of the fabric. Adhesive is a compound that adheres or bonds two
items together.

11.22 INK
Ink is a liquid containing various pigments and/or
dyes used for colouring a surface to render an image
or text. Ink is used for drawing or writing with a pen
or brush.

11.23 LAXATIVE
11.15 EMULSIFICATION
Laxative is a preparation used for encouraging
The surfactant lowers the oil-solution interfacial defecation, or the expulsion of feces. Laxatives are
tension and makes easy emulsification of the oily soils most often taken to treat constipation.
possible.
11.24 OTHER APPLICATION OF
SURFACTANTS
 Wetting
 Ski Wax
 Snowboard Wax
 Foaming
 Defoaming
11.16 SOLUBILIZATION  Quantum dot coating
Through interaction with the micelles of a surfactant  Biocides (Sanitizers)
in a solvent (water), a substance spontaneously  Hair Conditioners (after shampoo)
dissolves to form a stable and clear solution.  Spermicide (Nonoxynol 9)

11.17 APPLICATIONS OF SURFACTANT

Surfactants play an important role in many practical
applications and products, including:

11.18 DETERGENT
Detergent is a compound, or a mixture of compounds,
intended to assist cleaning. The term is often used to
differentiate between soap and other chemical
surfactants used for cleaning purposes.

11.19 FABRIC SOFTENER

Fabric softenr (also called Fabric Conditioner) is used
to prevent static cling and makes the fabric softer.

11.20 EMULSIFIER
Emulsifier (also known as an emulgent or surfactant)
is a substance which stabilizes an emulsion.

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 Micellization 48

Surfactant Type Aggregate

Chapter 12 MICELLIZATION Structure
 With the increasing concentration of Simple Spherical or
amphiphiles i.e. after CMC certain physical surfactants with ellipsoidal
properties show profound deviation from single chains micelles
their general trends and relatively
 Some of these properties show increasing large head groups
trend while other show decreasing trend
 This is due to the self-association of Simple Relatively large
monomers to form micelles surfactants with cylindrical or
 The process of forming micelles is known as relatively small rod-shaped
micellization. head groups, or micelles
 Micelles are always of dynamic equilibrium ionic surfactants
that means, number of monomers associate in the presence
to form micelle remain same however some of large amounts
monomers leave micelle while other of electrolyte
monomers from the bulk join micelles to Double-chain Vesicles and
keep the number constant. surfactants with flexible bilayer
 M ICELLES : As the concentration of monomer large structures
is increased, aggregation occurs over a head groups and
narrow concentration range. These flexible chains
aggregates which may contain 50 or more Double-chain Planar
monomers are called micelles. A micelles lie surfactants with extended
within the size range of colloidal system. small bilayer
 CMC : the concentration of monomer at head groups or structures
which micelles form is termed as the critical rigid, immobile
micelle concentration. chains
 M ICELLIZATION : the process of micelle Double-chain Reversed or
formation is known as micellization surfactants with inverted
 Compounds forming micelles are called: small micelles
Surfactant, surface active agent or head groups, very
amphiphiles large, bulky
 There are drugs which also from micelles and hydrophobic
are known as micellar drugs e.g. cholorquine, groups
diphenhydramine, orphenadrine,
chlorphenoramine etc. 12.3 INCREASING AND DECREASING TREND
OF MICELLES
12.1 TYPES OF MICELLES

12.2 MICELLE SHAPE AS PER TYPE OF

SURFACTANT

General Expected

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 Micellization 49

These properties can be used to determine the CMC.

12.4 DETERMINATION OF CMC

Below the CMC the concentration of amphiphiles
undergoing adsorption at the air-water interface
increases as the total concentration of amphiphiles is
raised. Eventually a point is reached at which both the
interface and the bulk phase become saturate with
monomers. This is called CMC. Any further
amphiphiles added in excess of this concentration
aggregates to form micelles in the bulk phase and in
this manner the free energy of the system is reduced.
It affects some physical properties of the system.
Some properties shows increasing trend while some
other shows decreasing trend.

 Antiparkinoism Drugs are used to

reduce muscular rigidity
neurological disorder marked by
hypokinesia (abnormally diminished
motor activity tremor and muscular
rigidity).
E.g. the surface tension decreases up to the CMC and
above the CMC, the surface tension remains constant, [Link] O THER E XAMPLES
this shows that the interface is saturated and micelle
formation has taken place in the bulk phase. [Link].1 P HENOTHIAZINE T RANQULIZER
 Priomazine
12.5 FACTORS AFFECTING THE CMC AND  Chlorpromazine
MICELLE SIZE  Promethazine

[Link].2 A NTIDEPRESSANTS
12.6 NATURE OF THE HYDROPHOBIC GROUP  Imipramine
Hydrophobic group plays important role in  Amitriptyline
determining type of association of group.  Nor-triptyline
Micellar amphiphiles have hydrocarbon They have tricyclic hydrophilic moieties
groups’ constracted from hydrocarbon  Many aromatic and hetero aromatic
chains. Increase in length of this chain will ring structure (dyes, purines,
decrease CMC and increase aggregation pyrimidine) associate in non-
number. micellar process.
Many drugs are surface active agents and
form micelles. For example, diphenyl
methane drugs. (diphenhydramine, 12.7 NATURE OF HYDROPHILIC GROUP
orpheradrine, chlorphennoxamine etc.)
Hydrophilicity/ Hydrophobicity and  Ionic hydrophilic groups of
substitute on such drugs play very important amphiphiles show different
role in the determination of CMC and properties then Non- ionic
Aggregation number hydrophilic groups may be due to
Some representative examples: difference in charge.
 In general non-ionic surfactants
have “low CMC” and high

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 Micellization 50

aggregation numbers although they  Temperature has no profound

have same length of hydrocarbon effect on CMC and aggregation No.
chain. This is because in non-ionic of Ionic Surfactant.
surfactant no electrical work during
the process of micellization.

12.8 EFFECT OF THE COUNTER-ION

 In case of cationic surfactant as the counter
- - -
ion is charged in series, Cl , Br , I , micelle
- - -
size is an increase in order for Cl < Br < I .
 In case of anionic surfactant as the counter
+ + +
ion is charged in series ,Na , K , Cs , micelle
+ + +
size is an increase in order for Na < K <Cs .
 More weakly hydrated a counter ion larger
the micelle formed. 12.12 APPLICATION
 Micelle increases bioavailability of
12.9 EFFECT OF HYDROPHOBIC GROUP poorly soluble drugs.
 If hydrophobic group is aromatic, micelle  Polymeric micelle is used to target the
does not form. tumor site by passive as well as active
 Length of hydrocarbon chain is directly mechanism.
proportional to micelle size & inversely  Micelle is used in ophthalmic drug
proportional to CMC. We express this in delivery system that effectively delivers
mathematical term, the drug to posterior tissue of eyeball.
Log [CMC] = A – Bm  Micelle is used to encapsulate the
Where, antibiotic & anticancer drugs.
 A & B are homologous series constant.
 m is the no. of carbon atom in chain.

12.10 ADDITION OF ELECTROLYTES

Electrolytes reduce the charges (force) on
ionic surfactants so there is reduction in the
magnitude of the force of repulsion between
the charges had groups on the micelles.
Hence, there is reduction in CMC and
increase in aggregation number.

12.11 EFFECT OF TEMPERATURE

 This effect in particularly seen in
non-ionic surfactants.
 Solution of non-ionic surfactants
when heated they turn turbid at a
characteristic temperature known
as “cloud temperature”
 Turbidity at “cloud point” is due to
separation of the solution into
“two” phases. i.e. dispersed phase
of dispersion medium.
 At temperature up to cloud point
there is increase in Aggregation No.
and decrease in CMC.

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 Ionization 51

Chapter 13 IONIZATION
13.1 THEORY OF IONIZATION 13.2 LAW OF MASS ACTION
Ionization theory was presented by Arrhenius in 1887
which consist of following postulates:  Law of mass action is stated by Guldberg and
 The substances called electrolytes are Waage. It states about the influence of the
believed to contain electrically charged concentration of the reactants on the rate of
particles called ions. These charges are reaction.
positive for H+ ion or ions derived from  Law of mass action states that the rate at
metals and negative for the ions derived which substance reacts is proportional to its
from non-metals. Number of electrical active mass and the rate of chemical reaction
charges carried by an ion is equal to the is proportional to the product of the active
valency of corresponding atom. masses of the reactants.
 Molecules of electrolytes (acids, bases and  Active mass is the number of moles per liter.
salts) dissociate into oppositely charged ions It is represented by placing the chemical
on dissolution in water, e.g. formula of the substance in square brackets.
+ -
NaCl Na +Cl For example HCl is represented as [HCl].
+
HCl H +Cl-
+ -
13.3 EXPLANATION OF LAW OF MASS
NaOH Na + OH
 The number of positive and negative charges ACTION
on the ions must be equal so that the Consider a sample reaction of
solution as a whole remains neutral.
 In solution, the ions are in a state of A + B ↔ X +Y
disorderly or random motion. Upon colliding
they may combine to give unionized As per the law of mass action the rate of forward
molecules. Thus ionization is a reversible reaction = α *A+ *B+
process in which the solution contains ions of
electrolyte together with unionized
molecules. = Kf [A] [B]
+ -2
H2SO4(aq) 2H (aq) + SO4 (aq)
Where Kf is proportionality constant and is termed as
 The extent of ionization or the degree of
rate constant for forward reaction.
ionization depends upon the nature of
[Link] electrolytes such as HCl
Similarly, rate of backward reaction= α *X+ *Y+
etc. ionize completely in water. Weak
electrolytes such as acetic acid (CH3COOH)
=Kb [X] [Y]
ionize only slightly
 Ionization is not affected by electric current.
Were Kb is the proportionality constant and is
 When electric current is passed through an
termed as rate constant for backward reaction.
electrolytic solution, charges move towards
their respective electrodes, i.e. cations
towards anode and anions towards cathode. 13.4 LAW OF CHEMICAL EQUILIBRIUM
When these ions reached their respective When the above stated law of mass action is applied
electrodes, they change into neutral species to a reaction in equilibrium, the result is termed as
by the gain or loss of electron. the law of chemical equilibrium.
For example the reaction,
 The dissociation of electrolyte depend upon: aA + bB ↔ xX + yY
o Nature of electrolyte
o Degree of dilution According to law of mass action:
o Temperature The rate of forward reaction= α *A+a *B+b
 The electrical conductivity depends upon :
o The number of ions present in the = Kf [A]a [B]b
solution
o Speed of ions Similarly, the rate of backward reaction= α *X+x *Y+y

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 Ionization 52

ionized, and a very high degree of ionization as fully

=Kb [X]x [Y]y ionized.

13.7 MEASUREMENT OF DEGREE OF

Similarly, the rates of both the reactions are same at
the state of equilibrium. IONIZATION
Kf [A]a [B]b =Kb [X]x [Y]y

kf [X]x [Y]y
---- = -----------
Kb [A]a [B]b

Kf and Kb are constant at constant temperature and

the ratio of Kf / Kb is also constant at constant 13.8 IONIZATION OF WATER
temperature. It is represented by K and is termed as
equilibrium constant. The above reaction is given as The ions are produced by the self-ionization reaction
+ −
H2O H3O + OH
[X]x [Y]y
K = -------------- This equilibrium applies to pure water and any
[A]a [B]b aqueous solution.
Approximating activities by concentrations, the
and the expression is termed as law of chemical chemical equilibrium constant, Keq, for this reaction
equilibrium. is given by:

The law of chemical equilibrium states the product of

molar concentration of the products raised to the
power equal to its co-efficient, divided by the product
of the molar concentration of the reactants raised to
its co-efficient, is constant at constant temperature
and is termed as equilibrium constant. If the concentration of dissolved solutes is low, the
concentration [H2O] can be taken as being constant
13.5 CHARACTERISTICS OF EQUILIBRIUM at c.
Expressed with activities a, instead of concentrations,
CONSTANT the thermodynamic equilibrium constant for the
 Its value remains constant at a given water ionization reaction is:
temperature irrespective of the direction of
approach.
 The value of the equilibrium constant
remains constant at given temperature and
pressure irrespective of the concentration of
the reactants and products. Which is numerically equal to the more traditional
 The value of equilibrium constant depends thermodynamic equilibrium constant written as:
on the nature and temperature of the
reaction but it remains unaffected in the
presence or absence of catalyst.
 It gives information about the reaction under the assumption that the sum of the chemical
proceeding in a particular direction at a given potentials of H+ and H3O+ is formally equal to twice
temperature. the chemical potential of H2O at the same
temperature and pressure.
13.6 DEGREE OF IONIZATION In infinitely dilute aqueous solution, the activity of
water solvent is unity.
The degree of ionization refers to the proportion of
The ionization constant, dissociation constant, self-
neutral particles, such as those in a gas or aqueous
ionization constant, or ionic product of water,
solution that are ionized into charged particles. A low
symbolized by Kw may be given by:
degree of ionization is sometimes called partially

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 Ionization 53

13.11 COMMON ION EFFECT AND BUFFER

EQUATION FOR A WEAK ACID AND ITS
SALT
+]
where [H3O is the concentration of hydrogen or
hydronium ion, and *OH−+ is the concentration of 13.12 TYPE A
hydroxide ion.
This expression is developed by considering the effect
The ionic product of water can be also expressed on
of a salt on the ionization of a weak acid when the salt
activity basis as:
and acid has a common ion
e.g. when sodium acetate is added to acetic acid, the
At 25 °C Kw is equal to 1.0×10−14. dissociation constant for a weak acid is
[ ][ ] -5
= 1.75 x 10
13.9 PH [ ]

pH is a measure of the acidity or basicity of an distributed due to the acetate ion supplied by the
aqueous solution. Solutions with a pH less than 7 are salt. Hence in order to maintain the constant 1.75 x
-5
said to be acidic and solutions with a pH greater than 10 , the hydrogen ion in nominator will decrease and
7 are basic or alkaline. Pure water has a pH very close the HAc in demoniatior increases. So that the
to 7. constant Ka remains unaltered and the equilibrium is
subjected towards the reactants. The ionization of
13.10 BUFFER acetic acid is represented
 Buffers are compounds or mixture of
- +
compounds that by their presence in their HAc + H2O Ac + H3O
solution resists change in pH upon the
addition of small quantities of acid or alkali. by the addition of common ion Ac-. This is an example
The resistance to a change in pH is known as of common ion effect.
buffer action. The pH of the final solution is obtained by arranging
 The substances used to produce buffer the equilibrium equation of dissociation constant.
action are called buffers and usually consists
of mixture of: [ ]
[ ]
Type “A”: A weak acid and its conjugate base [ ]
that is a salt If the acid is weak and ionized only slightly then the
Type “B”: A weak base and a conjugate acid expression HAc may be considered to represent the
total concentration and it may be simply written as
-
acid in a slightly ionize acetic solution. The Ac ion
only comes from the salt that is sodium acetate since
one mole of sodium acetate yields one mole of
-
acetate ion. The total concentration of Ac ion may be
replaced by the term salt.

[ ]
[ ]
[ ]

Equation may be expressed in term of log

-log [H3O] = - logKa – log [Acid] + log [Salt]

From this buffer equation is obtained for weak acid

and its salt
[ ]
[ ]

This equation can give you calculation in range of 4 –

10 pH.

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 Ionization 54

13.13 TYPE B  HIn is unionized form and In- is the ionize

form, unionize form gives acid color and
Buffer solution of weak bases and their salts are ionize form gives basic colour. When an acid
ordinarily not prepared because of volatility and is added to the solution of indicator, the H
+

instability of the base and secondly because of the ion concentration increases and HIn
dependence of pH on pKw which is often affected by predomination and give acid colour. When a
temperature change e.g. ephedrine and ephedrine +
base is added [H3O ] is reduced and more
HCl is often used in pharmaceutical solution as buffer. ionized form is produce so the color changes.
Their buffer equation can also derive analogous to [ ]
deserve weak acid buffer. [ ]
[ ]
[ ]
[ ]
13.16 BUFFER CAPACITY
The magnitude of a resistance of a buffer to pH
[ ]
[ ] change is reffered as buffer capacity β.
Comparing both equations we get, It is also called buffer efficiency, buffer index and
[ ] buffer value.
[ ] [ ] It is the ratio of the increment of strong base (or acid)
to the small change in pH brought by this addition.
[ ]
pH = pKw – pKb + log
[ ]

∆ β is the small increment in gram equivalent per liter

of strong base added to a buffer solution to produce a
13.14 FACTORS EFFECTING P H OF A BUFFER pH change of ∆pH.
SOLUTION According to equation, the buffer capacity has a value
of one when one gram equivalent of base produce a
 Addition of neutral salts to buffers, change pH change of 1 in one liter buffer solution.
the pH of the solution by altering the ionic
strength.
 Dilution of buffer solution i.e. the addition of
13.17 BUFFERS IN PHARMACEUTICAL AND
H2O in moderate quantities may not change IN BIOLOGICAL SYSTEM
pH but can cause small positive or negative Blood is maintained at a pH of about 7.4 by 8.0 called
deviation because it can act as weak acid or primary buffers in erythrocytes. The plasma contains
base. carbonic acid/ bicarbonates and acid/alkali Na salts of
 Temperature H3PO4 as buffers. Plasma proteins which behave as
The pH of acetate buffers increases with acid in blood can combine with bases and so act as
temperature whereas pH of boric acid and buffers. In erythrocytes two buffer systems consist of
sodium borate buffer decreases with hemoglobin / oxhemoglobin and acid/alkali K salts of
increase in temperature and basic buffers H3PO4. When the pH of blood goes 7 or above 7.8 Life
are more effected by change in temperature. is in serious danger. The pH of blood in diabetic coma
is alleged to drop as low as 6.8. Lacrimal fluids or
13.15 PH INDICATORS tears have pH of 7.4. They have a high dilution value
 Indicators may be considered as weak acid or of 1:15 with neutral distilled water before an
weak basis that act like buffers and also alternation in pH is noticed.
exhibit color changes as heir degree of
dissociation varies with pH. E.g. methyl red 13.18 PREPARATION OF PHARMACEUTICAL
shows its fuel alkaline color yellow at pH BUFFERS
about 6 and full acid color red at pH 4.
 So indicator offers a convenient way of Following steps should be followed:
calorimetric method of determining the pH  Select a weak acid having pKa value
of solution. approximately equal to the pH at which the
 The dissociation of an acid indicator can be buffer is to use.
expressed as  By the help of the buffer equation, calculate
[ ][ ] the ratio of salt and weak acid required to
[ ] obtain the desired (pH).
 Consider the original concentration of buffer
salt and acid needed to obtain a suitable

Pharmacy Exam Guide

 Ionization 55

buffer capacity. Concentration of 0.05 – 0.5

M is sufficient and a buffer capacity of 0.01 –
0.1 is sufficient.
 Other factors like availability, stability,
toxicity, sterility etc. are also considered.
 Finally determine the actual pH and buffer
capacity with the help of the pH paper of pH
meter.

13.19 BUFFERED ISOTONIC SOLUTION

 In addition to pH adjustment pharmaceutical
solution should also have same osmotic
pressure so that of the body fluids. Isotonic
solutions cause no swelling or contraction of
tissue with which they come in contact. It
can be demonstrated by mixing as small
quantity of blood with aqueous sodium
chloride solution with different toxicity
(NaCl 0.9g/100 ml ) is considered to be
isotonic and other solution containing higher
is considered hypertonic and less than 0.9g is
considered hypertonic 2.0% boric acid
solution is iso-osmotic with blood but can
also pass through cell membrane easily.
Therefore a solution containing a drug
calculated to be isosmotic with blood is
isotonic only when the blood is isotonic only
when the blood cells are impermeable to
solvent only.
 Mucous lining of eye act as true semi-
permeable membrane which does not allow
toxic acid to cross.

13.20 MEASUREMENT OF TOXICITY

 The toxicity of solutions may be determined
by one of two methods.
 First is the hemolytic method in which the
effect of various solution of drug is observed
on the appearance of red blood cells
suspended in the solution.
 Second approach used to measure toxicity is
based on any of the methods that determine
colligative properties. The most important
are:
o White Vincent Method
o The Sprowls Method

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 Hydrolysis 56

Chapter 14 HYDROLYSIS 14.4 ADJUSTING PH

The reaction of water with esters and salts of weak Drugs may be stabilized by adjusting the pH of the
acids or weak bases is called hydrolysis. It is a solution to a value at which the compound is found to
chemical process in which a molecule is cleaved into exhibit lowest rate constant. If the reaction is subject
two parts by the addition of a water molecule. One to general acid- base catalysis, the buffer used for pH
+
fragment of the molecule gains a H ion from water adjustment must be chosen carefully. The buffer
and other group gains –OH negative ion. should provide an optimum pH for both maximum
There are two types of hydrolysis: stability and greatest therapeutic activity of the drug.
 Molecular hydrolysis In most cases the therapeutic activity depends upon
 Ionic hydrolysis. the presence of free base rather than ionized salt in
solution. e.g. pylocarpine exist as 99% base a pH 9
and only 0.1% at pH 4.
14.1 IONIC HYDROLYSIS
It occurs when salts of weak acids or bases interacts
with water to give an alkaline of basic solution e.g.
14.5 COMPLEXATION
Sodium Acetate hydrolyzes in water into acetic acid Some dugs form complexes with others which exhibit
and NaOH. The solution is alkaline (because of NaOH). their hydrolysis e.g. benzocaine in aqueous solution
We are more concerned with molecular hydrolysis of forms a complex with caffeine to form benzo-caffeine
aspirin, procaine, and atropine. In daily life hydrolysis complexes. Only the benzocaine which is free in the
process is involved in different reactions e.g. in solution will be hydrolyzed.
saponification, triglyceride (fats) are hydrolyzed with
an aqueous base like NaOH. Fatty acids react with 14.6 SUPPRESSING THE SOLUBILITY OF DRUG
base to form soaps. Hydrolysis is also used in
By suppressing the solubility, decreases the
liberation of energy from ATP, phosphate linkage is
concentration of drug in solution e.g. the rate of
broken down by hydrolysis to release energy which is
degradation of penicillin in procaine penicillin solution
used in the biosynthesis of molecules and active
was shown to be due to that portion which is in
transport of ions or molecules through cell
solution form. It is found that solubility may be
membrane.
reduces by the use of various additives such as
Aspirin is particularly susceptible to hydrolysis above
gluconate, sorbitol, dextrose and citrates.
pH 10.

14.7 REMOVAL OF H2O

Hydrolytic decomposition may further be prevented
by the removal of water. The drug may be stored in
dry form and used as such or suspended as an
According to Higuchi et al, procaine decomposes insoluble powder in a suitable vehicle. Even in the
mainly by hydrolysis, the degradation being due, solid state, drug may decompose e.g. decomposition
primarily to the breakdown of the uncharged and of solid aspirin due to temperature and humidity.
singly charged forms. The reaction is catalyzed by
hydroxyl ions.
It was found that atropine undergoes alkaline and
acidic hydrolyses at different pH levels. Above pH 4.5,
the catalytic reaction involves hydroxyl ions and
below pH 3, hydrogen ions are involved. pH for
o
maximum stability is between 4.1-3.2 at 100 C.

14.2 FACTORS AFFECTING HYDROLYSIS:

 Moisture
 pH
 Temperature
 Solvent

14.3 PROTECTION AGAINST HYDROLYSIS:

Pharmacy Exam Guide
 Micrometrics 57

Griseofulvin can be greatly

Chapter 15 MICROMETRICS increased by particle size reduction.
 Reduction of particles size also
15.1 MICROMETRICS increase the rate of absorption of
The Science and Technology of small particles is tetracycline, Aspirin and
known as Micrometrics. Sulphonamides.
9. Reduction of particle size of nitrofurantoin
increased the rate of absorption. Therefore
15.2 MICROMETRICS DEALS WITH the toxic effect due to rapid absorption.
 Particle size and Size Distribution 10. Before being used in the preparation of
 Methods of Determining particles size pharmaceuticals, solid materials are first
 Particle shape and surface area characterized to determine their chemical
 Pore size and physical features, including;
 Angle of repose  Morphology
 Purity
15.3 IMPORTANCE OF STUDY OF  Solubility
 Flow ability
MICROMETRIC  Stability
1. Knowledge and control of the size and the  Particle size/ Size distribution
size range of particle is of profound  Compatibility with any other formulation
importance in pharmacy. components
2. Size and surface area can be related to the
physical, chemical and pharmacological 15.4 DIFFERENT MEANS OF EXPRESSING
properties of a drug.
3. Particle size affect its release from dosage PARTICLE SIZE
forms that are administered orally,
parenterally, rectally and topically
4. Physical stability and pharmacologic
response of suspensions, emulsion and
tablets depends on particle size.
5. It is also important in flow properties and
proper mixing of granules and powders in
tableting.
6. Both Tablets and capsules are produced
using equipments which controls the mass of
drug and other particles by volumetric filling.
Therefore any interference with the
uniformity of fill, volumes may alter the mass
of drug incorporated into the tablet or
capsules. Thus reduce the uniformity of the
medicine.
7. Powders with different particle sizes have
different flow and packing properties which
15.5 METHODS OF DETERMINING PARTICLE
alter the volumes of powder during each SIZE
encapsulation or tablet compression.  Optical Microscopy
8. The rate of solution depends on the several
 Sieving Methods
factors. One factor is the particle size. Thus
 Sedimentation Methods
particles having small dimensions will tend to
increase the rate of solution.
15.6 PARTICLE VOLUME MEASUREMENT
For example:  Coulter Counter Method (Electrical stream
 Griseofulvin has a low solubility sensing method)
after oral administration but is  Laser light scattering methods
rapidly distributed following
absorption. The solubility of

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 Micrometrics 58

15.7 METHODS OF DETERMINING SURFACE passes a given sieve aperture in any 5

minutes interval
AREA
 Adsorption method 15.11 ADVANTAGES
 Air permeability method
1. This method is very simple.
2. Not expensive
15.8 SIEVING METHOD 3. Easy to operate
Sieving method is an ordinary and simple method. It is
widely used as a method for the particle size analysis. 15.12 DISADVANTAGES
1. Not too much precise method.
15.9 RANGE OF ANALYSIS 2. Not applicable for all disperse systems.
The International Standards organization (ISO) sets a
lowest sieve diameter of 45 µm and since powders 15.13 SEDIMENTATION METHODS
are usually defined as having a maximum diameter of
Sedimentation Method is also an ordinary and simple
1000 µm, this could be considered to be the upper
method. It is widely used as a method for the particle
limit.
size analysis.
In practice sieves can be obtained for size analysis
over a range from 5 to 125,000 µm.
15.14 RANGE OF ANALYSIS

Sieve analysis is usually carried out using dry powders

Although, for powders in liquid suspension or which
agglomerate during dry sieving, a process of wet
sieving can be used.

15.10 PRINCIPLE OF MEASUREMENT

 Sieve analysis utilizes a woven, punched or
electroformed mesh often in brass, bronze 15.15 SAMPLE PREPARATION AND ANALYSIS
or stainless steel with known aperture (hole) CONDITIONS
diameters which form a physical barrier to
particles.  In this method
particle size can
 Most sieve analysis utilize a series, stack (
be determined
Load /Mountain or nest (layer) of sieves
by examining
which have the smallest mesh above a
the powder as
collector tray followed by meshes which get
it sediments
progressively coarser towards the top of the
out.
series.
 In cases where
 A sieve stack usually comprises 6-8 sieves
the powder is
with a progression based on a √2 or 2√2
not uniformly
change in diameter between adjacent
dispersed in a
aperture.
fluid it can be
 Powder is loaded on to the coarsest sieve of
introduced as a
the assembled stack and the nest is
thin layer on
subjected to mechanical vibration for, say 20
the surface of
minutes.
the liquid.
 After this time, the particles are considered
 If the powder is
to be retained on the sieve mesh with an
lyophobic, e.g.
aperture corresponding to the minimum or
hydrophobic in
sieve diameter.
water, it may be necessary to add dispersing
 A sieving time of 20 minutes is arbitrary and
agent to aid wetting of the powder.
BS 1796 recommends sieving to be
continued until less than 0.2% material

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 Micrometrics 59

 In case where the powder is soluble in water

it will be necessary to use non- aqueous
liquids or carry out the analysis in a gas.

15.16 PRINCIPLE OF MEASUREMENT

 Particle size analysis by sedimentation
method can be divided into two main
categories according to the method of Where, ANDREASEN PIPETTE
measurement used. v = rate
 One of the type is based on measurement of of settling
particle in a retention zone. h = Distance of the fall in time, t
 Another type uses a non-retention dst = the mean diameter of the particles
measurement zone. based on the velocity of sedimentation
 An example of a non-retention zone ρs = density of the particles
measurement is known as the pipette ρo = density of the dispersion medium
method. g = Acceleration due to gravity
 In this method , known volumes of ηo = Viscosity of the medium
suspension are drawn off and the
concentration differences are measured with  Note: The question holds spheres falling
respect to time. freely without hindrance and at a constant
 One of the most popular of the pipette rate.
methods was that developed by Andreasen
and Lundberg and commonly called the 15.17 COULTER COUNTER METHOD
Andreasen pipette. (ELECTRICAL STREAM SENSING ZONE
 The Andreasen fixed-position pipette
consists of a 200 mm graduate cylinder METHOD)
which can hold about 500 ml of suspension Coulter Counter Method (Electrical stream sensing
fluid. zone method) is a sophisticated method. It is a
 A pipette is located centrally in the cylinder precise and accurate method.
and is held in position by a ground glass
stopper so that its tip coincides with the zero
level.
15.18 RANGE OF ANALYSIS
 A three way tap allows fluid to be drawn into
a 10 ml reservoir which can then be emptied
into a beaker or centrifuge tube.
 The amount of powder can be determined
by weight following drying or centrifuging.
 The weight of each sample residue is
therefore called the weight of undersize and 15.19 SAMPLE PREPARATION AND ANALYSIS
the sum of the successive weight is known as CONDITIONS
the cumulative weight of undersize. It can be
expressed directly in weight units or percent
of the total weight of the final sediment.
 The data of cumulative weight of undersize is
used for the determination of particle weight
distribution, number distribution.
 The largest particle diameter in each sample
is then calculated from Strokes’ Law.
 The particle size may be obtained by gravity
sedimentation as expressed in Strokes’ law.

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 Micrometrics 60

 Powder samples are dispersed in an 15.25 BULK DENSITY

electrolyte to form a very dilute suspension.
 The suspension is usually subjected to Bulk density = Mass of Powder/Bulk volume
ultrasonic agitation for a period to break up Bulk density depends primarily on particle size
any particle agglomerates. distribution, particle shape and tendency of particles
 A dispersant may also be added to aid to adhere together.
particle deagglomeration. Based on bulk density powders are classified as:
 A typical Coulter counter has one or more  Heavy – high bulk density (low bulk volume)
micro channels that separate two chambers  Light - Low bulk density (high bulk volume)
containing electrolyte solutions. As fluid
containing particles or cells is drawn through
each micro channel, each particle causes a
brief change to the electrical resistance of
the liquid. The counter detects these
changes in electrical resistance that is
proportional to the volume of the particle
passing the orifice.

15.20 ADVANTAGES 15.26 APPLICATIONS

1. It is one of the precise and accurate methods.  To check the uniformity of bulk chemicals
2. Analysis range is wide. (Quality control measures)
 Determination of size of capsule for a given
15.21 DISADVANTAGES dose of material.(higher the bulk volume,
1. It is a sophisticated method lower will
2. It is an expensive method be bulk
density
and bigger
15.22 LASER LIGHT SCATTERING METHODS the size of
Light scattering is measured by two different capsule)
instruments  It helps in
selecting
15.23 CLASSICAL LIGHT SCATTERING / the
proper
STATIC LIGHT SCATTERING size of a container, packing material, mixing
Here, the intensity of the scattered light is measured apparatus in the production of tablets and
as a function of angle capsules.

15.24 DYNAMIC LIGHT SCATTERING (DLS)

Dynamic light scattering (DLS), sometimes referred to
15.27 TRUE DENSITY
as Quasi-Elastic Light Scattering (QELS), is a non- It is the density of the material itself.
invasive, well-established technique for measuring True density= Weight of Powder/True Volume of
the size and size distribution of molecules and Powder
particles typically in the submicron region, and with True volume is the volume obtained excluding the
the latest technology lower than 1nm. void volume and intra particle pores
Typical applications of dynamic light scattering are
the characterization of particles, emulsions or
molecules, which have been dispersed or dissolved in 15.28 METHOD TO DETERMINE TRUE
a liquid. The Brownian motion of particles or
molecules in suspension causes laser light to be
DENSITY
scattered at different intensities. Analysis of these 15.28.1 Gas Displacement Method
intensity fluctuations yields the velocity of the (Porous ):
Brownian motion and hence the particle size using In this method helium pycnometer is used to
the Stokes-Einstein relationship. determine the true volume from the equation:
COULTER COUNTER

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 Micrometrics 61

In general the porosities will be between 30 to

50%.However they vary based on packing
arrangement.

 Vc is the volume of the empty sample

chamber (known from a prior calibration
step)
 Vr is the volume of the reference volume
(again known from a prior calibration step)
 P1 is the first pressure (i.e. in the sample
chamber only)
 P2 is the second (lower) pressure after
expansion of the gas into the combined
volumes of sample chamber and reference
chamber.

By substituting this Vt and true weight of the sample

in the equation we can determine the true density.
15.32 APPLICATIONS OF POROSITY:
[Link] L IQUID D ISPLACEMENT M ETHOD  Porosity
(N ON -P OROUS ): influences
Pycnometer or specific gravity bottle may be used. the rate of
True density = W 2 -W 1 /W 4 – W 2 disintegratio
Where, n and
dissolution.
W1 = weight of pycnometer Higher the
W2 = weight of pycnometer + sample porosity
W3 = weight of sample(W 2 –W 1 ) faster the
W4 = weight of pycnometer with powder and filled rate of
with the solvent dissolution.
 Based on
porosity solids can
15.29 GRANULE DENSITY be classified as
Granule density is determined for the granules that porous and non-
are employed in the manufacture of tablets. porous.
Granule density = Granule wt / Granule volume  Porosity is applied
in the studies of
15.30 METHOD adsorption and
diffusion of drug
Mercury displacement method: Granule volume is materials.
related to the weight of mercury that is displaced by
the granules in the pycnometer.
15.33 ANGLE OF REPOSE:
15.31 POROSITY It is the maximum angle possible between the surface
of pile of powder and horizontal plane.
Porosity is defined as the ratio of void volume to the Angle of repose helps in quantifying the frictional
bulk volume.
forces.
Porosity(€) = void volume/bulk volume
The frictional forces mainly contribute to improper
€ = (V b – flow of powder.
V p )/ V b Tan ∂ = h/r
%€ = (1-
Where,
V p /V b )100 h = height of pile
r = radius of the base of pile

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 Micrometrics 62

15.38 PARTICLE SHAPE

Particle shape Powder particles are very complicated
objects with no definite form. It is generally very
difficult to describe their shapes.
They have therefore been conventionally described
and classified by the use of various terms:

15.34 CARR’S CONSOLIDATION INDEX

It is also known as compressibility.
It is indirectly related to flow rate, cohesiveness and
particle size.
Carr’s index= Tapped density-Fluff density/ Tapped
density

15.35 METHOD
Fluff density = w/vo g/cc
Tapped density =w/v50 g/cc

15.39 IMPORTANCE OF PARTICLE SHAPE

Particle shape is important because it can influence
many critical powder properties such as:
15.36 HAUSER’S RATIO  The powder flow ability
 Compatibility
 Content uniformity
 Dissolution
 Drug release
 Bioavailability
 Stability

 These factors ultimately affect the safety and

efficacy of a dosage form,.

 Spherical particles tend to have greater flow

ability than irregularly shaped particles as
the irregularly shaped particles can interlock
with each other resulting in poor flow and
bridging in hoppers, etc.
 On the other hand, materials with larger
15.37 APPLICATIONS OF MICROMETRICS irregularly shaped particles which fragment
 Release and dissolution to a limited degree during compression have
 Absorption and drug action higher compatibility. This is due to a higher
 Physical stability number of interparticulate contact points
 Dose uniformity that allow more interparticulate bonding.
 Also the edges and corners of the irregularly
shaped particles can undergo higher degree

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 Micrometrics 63

of deformation due to the existence of

lattice defects thus allowing higher bonding
strength between compact particles.
 As the surface roughness of the particle
increases, the possibility for a particle to find
a position at an adjacent surface which
promotes bond formation will increase thus
more force is needed to break these
bondings which yield a higher crushing
strength.
 Particle shape can also influence particle size
analysis. The particle size distribution
measured by sieve analysis can be influenced
by particle shape, because irregularly shaped
particles take longer to reach their final
sieve.

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 Dispersed System 64

Molecul Colloidal Coarse

Chapter 16 DISPERSED SYSTEM ar Dispersi Dispersion
Dispersi on
Dispersed systems consist of one phase, known as the
dispersed phase, distributed throughout a continuous
on
phase or dispersion medium. Size 0.1 to 1.0 to Greater than
There are two types of dispersed system 1.0 nm 500 nm 500 nm
Seen No Yes Yes (Seen
[Link] H OMOGENEOUS D ISPERSE S YSTEM under through
A homogeneous mixture is a mixture where the electron ordinary
components that make up the mixture are uniformly microsco microscope
distributed throughout the mixture. pe as well)
E.g. Air, saturated sugar water
Pass Yes Yes No
Homogeneous Disperse System is further divided
into:
through
[Link] I ONIC D ISPERSION ordinary
Dispersion which consists of ions as a dispersed phase filter
is known as Ionic Dispersion. paper
E.g. NaCl + H2O  Na+ + Cl- (ions) Pass Yes No No
[Link] M OLECULAR D ISPERSION through
Dispersion which consists of molecules as a dispersed semi-
phase is known as Molecular Dispersion permiabl
S IZE OF D ISPERSED P HASE : 0.1 nm to 1.0nm e
membran
[Link] H ETEROGENEOUS D ISPERSE S YSTEM e
A heterogeneous mixture is one which has a non- Diffusion Rapidly Very No Diffusion
uniform composition. Rate Slowly
E.g. Colloidal Kaolin Solution
Example Ions, Colloidal Pharmaceuti
Heterogeneous Dispersed System is further divided
into:
Glucose, Silver cal Emulsion,
[Link] C OLLOIDAL S OLUTION O2 Solution, Suspension,
A heterogenous system in which the size of the molecule Natural RBC
dispersed phase is from 1.0 nm to 500 nm. s and
(500nm = 0.5 um) Synthetic
Disperse phase may be: Polymers
 Single large molecule (proteins)
 Group of small molecule (Colloidal solution 16.3 DISPERSED SYSTEM EXAMPLES FROM
of Gold)
 Group of Ions (Aqueous soap solution) DAILY LIFE
Dispersed Dispersed Colloidal Coarse
[Link] 2. C OARSE D ISPERSION Phase Medium dispersion Dispersion
A heterogeneous system in which the size of the Example Example
dispersed phase is above 500nm (or 200nm)
Liquid Gas Fog Spray
Disperse phase may be group of large molecules
Solid Gas Smoke Dust
[Link] Carbonate in H2O.
Liquid Liquid Oil Emulsion
There are two major dosage forms in coarse
Granules
dispersion which includes Emulsion and Suspension
Solid Liquid Colloidal Kaolin in
Gold Water
16.2 TYPES OF DISPERSE SYSTEM ON THE Solution in
BASIS OF SIZE Water
On the basis of particle size of dispersed phase in
dispersed system, dispersed system is divided into
three types: 16.4 COLLOIDAL DISPERSED SYSTEM
[Link] C LASSIFICATION OF C OLLOIDAL S YSTEM

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 Dispersed System 65

On the basis of the interaction between dispersed S UB - COLLOIDAL : When present in liquid medium at
phase and dispersion medium, colloidal solution may low concentration, the amphiphiles exist separately
be classified into three types:- are of such a size as to be sub colloidal.
1. Lyophilic Colloids M ICELLES : As the concentration of monomer is
2. Lyophobic Colloids increased, aggregation occurs over a narrow
3. Association/Amphiphilic Colloids concentration range. These aggregates which may
contain 50 or more monomers are called micelles. A
16.5 LYOPHILIC COLLOIDS micelles lie within the size range of colloidal system.
Systems containing colloidal particles that interact to
CMC : the concentration of monomer at which
micelles form is termed as the critical micelle
an appreciable extent with the dispersion medium are
concentration.
referred as lyophilic (solvent-loving) colloids.
Lyophilic Colloids are furthersub-classed into two M ICELLIZATION : the process of micelle formation is
groups: known as micellization
[Link] H YDROPHILIC
In which the dispersion medium is water (aqueous). [Link] T YPES OF M ICELLES ON THE B ASES OF
E.g. Colloidal solution of gelatin, acacia, insulin or T HEIR S HAPE
albumin in H2O.
[Link] 2. L IPOPHILIC
In which the dispersion medium is organic solvent
(non-aqueous) or we may say lipid loving.
E.g. Colloidal solution of rubber or polystyrene in
benzene.

[Link].1 S OLVATION
Solvation, also sometimes called dissolution, is the
process of attraction and association of molecules of
a solvent with molecules or ions of a solute.

[Link].2 H YDRATION
Hydration is the process of attraction and association [Link] D ETERMINATION OF CMC
of molecules of water with molecules or ions of a Below the CMC the concentration of amphiphiles
solute. It is similar to solvation but is specific to water undergoing adsorption at the air-water interface
only. increases as the total concentration of amphiphiles is
raised. Eventually a point is reached at which both the
16.6 LYOPHOBIC COLLOIDS interface and the bulk phase become saturate with
monomers. This is called CMC. Any further
Systems containing colloidal particles that have little amphiphiles added in excess of this concentration
or no interaction with the dispersion medium are aggregates to form micelles in the bulk phase and in
referred as lyophilic (solvent-hating) colloids. this manner the free energy of the system is reduced.
E.g. colloidal solution of inorganic particles (silver, It affects some physical properties of the system.
sulfuretc.) in H2O. Some properties shows increasing trend while some
Special treatment is needed for the preparation of other shows decreasing trend.
lyophobic colloids which include high degree of super-
saturation followed by formation and growth of
nuclei.

16.7 ASSOCIATION COLLOIDS

Association or Amphiphilic colloids consists of
amphiphiles (surface-active agents, or monomers) are
characterized by having two distinct regions of
opposing solution affinities within the same molecule
or ions.
Monomers: It consists of polar (hydrophilic) and non-
polar (hydrophobic) part within same molecule.

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 Dispersed System 66

These properties can be used to determine the CMC. 16.9 OPTICAL PROPERTIES
[Link] T HE F ARADAY -T YNDALL E FFECT
When strong beam of light is passed through a
colloidal solution, a visible cone, resulting from the
scattering of light by the colloidal particles is formed.
This is Faraday-Tyndall Effect.
An intense light beam is passed through the solution
against a dark background at right angles to the plane
of observation, and, although the particles cannot be
seen directly the bright spots corresponding to
particles can be observed and counted.

[Link] E LECTRON M ICROSCOPE

The electron microscope is capable of yielding
pictures of the actual particle even those approaching
E.g. the surface tension decreases up to the CMC and the molecular dimension is now widely used to
above the CMC, the surface tension remains constant, observe the size, shape and structure of colloidal
this shows that the interface is saturated and micelle particles.
formation has taken place in the bulk phase.
[Link] L IGHT S CATTERING
[Link] This property depends on the Faraday-Tyndall effect
and is widely used for the determination of molecular
[Link] C LASSIFICATION OF A SSOCIATION weight of colloids. It can also be used to obtain
C OLLOIDS information on the shape and size of particle.
Type Compoun Amphiphile Gege
d nion [Link] P ARTICLE S IZE
(ion Above describe properties can be used to determine
the particle size of the colloidal system.
of
oppo
site 16.10 KINETIC PROPERTIES OF COLLOIDS
charg Grouped under this heading are several properties of
e) colloidal systems that relate to motion of particles
with respect to the dispersion medium the motion
Ionic Sodium CH3(CH2)11OSO3- Na+
may be thermally (Brownian movement, diffusion
Lauryl
osmosis) gravitationally induced (sedimentation) or
SO4 applied externally (viscosity)
Cationi Cetyltrime CH3(CH2)15N+(CH3 Br -
c thyl- )3 [Link] B ROWNIAN MOTION
ammoniu The particles are observed to be in continual and
m erratic motion due to the bombardment of the
bromide particle by molecules of the suspension medium. The
Amphol Dimethyl CH3(CH2)11N+(CH3 - amount of the displacement is inversely proportional
ytic dodecyla )2(CH3)3OSO2- to the mass of the particle and the viscosity of the
(Zwitte mmonio- suspension medium. Brownian movement is seen in
microscopic particles. It was studied by Zsigmondy
rionic) popanesul
then Robert Brown in 1827 first recorded the
fonate
Brownian movement with pollen grains.

[Link] D IFFUSION
16.8 PROPERTIES OF COLLOIDS Particles diffuse spontaneously from a region of
1. Optical Properties higher concentration to one of lower concentration
2. Kinetic Properties until the concentration of the system is uniform
3. Electro-Kinetic Properties throughout. Diffusion is a direct result of Brownian
movement.

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 Dispersed System 67

[Link] O SMOTIC P RESSURE Cathode Cation (positively charged) contains the

The osmotic pressure π of a dilute colloidal solution is dispersion
described by Van’t Hoff equation When a potential is applied across the electrodes the
particles migrate to oppositely charged electrode. The
Where c is the concentration of solute. This equation rate of particle migration is observed by means of
can be used to calculate the molecular weight of ultra-microscopeand is a function of the charge on
colloid in dilute solution. the particle. Because the shear plane of the particle is
Sedimentation located at the periphery of the tightly bound layer the
The velocity, v, of sedimentation of spherical particles rate determining potential is the zeta potential.
having density ρ in a medium of density ρ 0 and
viscosity h0 is given by Stoke’s law: [Link].1 I NFLUENCE OF P H
pH plays very important role in electrophoresis for
example, “protein”. The carboxylic acid and amino
Where g is the acceleration due to gravity. If the groups of protein behave differently in different pH.
 In Alkaline pH (OH )
-
particles are subjected only to force of gravity then
the lower size limit of particles obeying Stoke’s Protein behaves as anion (negatively
equation is about 0.5 μm. This because Brownian charged) because of carboxylic acid portion.
movement becomes significant and tends to offset  In Acid solution
sedimentation due to gravity and promotes mixing Protein behaves as cation (positively
instead. charged) due to protonation of amino group.
 At intermediate pH or balance pH
[Link] V ISCOSITY Protein appears as neutral i.e. no charge on
Viscosity is an expression of the resistance to flow of protein
a system under an applied stress. The more viscous a  Such ions are known as Zwitter ions leading
liquid is the greater is the applied force required to to participation of protein.
make it flow at a particular rate.  This point at which precipitation occurs is
The shape of particles of the disperse phase effect the called isoelectric point.
viscosity of colloidal dispersion. Sphero-colloids form  Each protein has its specific isoelectric point
dispersion of relatively low viscosity whereas linear  Only a particular protein precipitates a
particles system is more viscous. particular isoelectric point so this property is
The relationship of shape and viscosity reflect the utilized to purify proteins/ protein like
degree of solvation of particles. compounds.
In lyophilic colloids viscosity increases while lyophobic
colloids do not have much effect on viscosity. [Link] E LECTROOSMOSIS
Electroosmosis is essentially opposite in principle to
electrophoresis. In it the application of potential
16.11 ELECTRICAL PROPERTIES OF COLLOIDS causes a charged particle to move relative to the
The properties of colloid that depends on or are liquid which is stationary. If the solid is rendered
affected by the presence of ca charge on the surface immobile the liquid now moves relative to the
of particle are discussed under this heading. charged surface. This is electroosmosis, so called
because liquid moves through a plug or membrane
[Link] E LECTRO -K INETIC P HENOMENA across which a potential is applied. It also provide
The movement of a charged surface with respect to another method for obtain the zeta potential by
an adjacent liquid phase is the basic principle determining the rate of flow of liquid through the
underlying four electro-kinetic phenomenal: plug under the standard conditions
1. Electrophoresis [Link] S EDIMENTATION P OTENTIAL
2. Electroosmosis The potential difference between top and bottom due
3. Sedimentation Potential to sedimentation under the influence of gravity.E.g. In
4. Streaming potential suspension.
Sedimentation Potential occurs when dispersed
[Link] E LECTROPHORESIS particles move under the influence of
Electrophoresis involves the movement of charged either gravity or centrifugation in a medium. This
particle through a liquid under the influence of motion disrupts the equilibrium symmetry of the
applied potential difference (electric field). particle's double layer. Within the double layer,
An electrophoresis cell is fitted with two electrodes: the viscous flow around the layer because the particle
Anode  Anion (negativelycharged) and, drags ions away from the particles, which causes a
slight displacement between the surface charge and

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 Dispersed System 68

the electric charge of the diffuse layer. As a result, the

moving particle gains dipole moment. These dipole
moments generate an electric field which is
called sedimentation potential.
[Link] S TREAMING POTENTIAL
It is the potential difference set up when a liquid is
forced through a fixed plug of porous nature.

16.12 ELECTRICAL DOUBLE LAYER

When a solid is immersed in a liquid it acquires an
electric charge on its surface and there is a non-
uniform distribution of ions of opposite charge in the
liquid adjacent to the sold. The liquid in the region of
the solid surface is considered to be in two parts, the
diffuse double layer. One part consists of a layer of
ions fixed in relation to the surface; the second part
extends some way into the liquid until there is a
uniform distribution of positive and negative ions in
the bulk of the liquid (diffuse layer).
There is rapid fall in potential between the solid
surface through the fixed layer and then a gradual fall
in potential through the diffuse layer to the bulk of
the liquid.
The difference in potential between the outer surface
of the fixed layer and the bulk of the liquid phase is
termed as the zeta potential (ζ), or electro-kinetic
potential. 16.13 EFFECT OF MIXING DIFFERENT
Since the fixed layer remains attached to the solid it is
the zeta potential that is responsible for COLLOIDS
electrophoresis and for the streaming potential since
the diffuse layer is in the movable liquid. [Link] M UTUAL P RECIPITATION
The addition of the electrolytes to a solid-liquid When twosolutions of oppositely charged colloids are
system reduces the zeta potential or even reverses mixed, the particles of opposite sign are attracted to
the sign. Thee electrolyte supplies addition anions each other and the charges neutralized. Coagulation
and cations so that the density of ions of opposite can then take place and precipitation occurs.
charge to the charge on the wall is increases. Thus the However, if a large excess of one of the solution is
ionic atmosphere is compressed near the surface and used the neutralized particles adsorb the excess
the potential gradient in the fixed layer is greatly charged particle and the system remain stable.
increased so that the potential in the diffuse mobile
layer is decreased. [Link] C OACERVATE F ORMATION
The addition of an electrolyte to a hydrophilic colloid
brings about precipitation by neutralizing the charge
and by removing the water layers enveloping the
colloid. If this is carried out gradually an intermediate
stage is reached where liquid droplets separate which
coalesce to form a separate phase; this is
coacervation.
A layer of hydrophilic colloid formed around the
dispersed phase, and the process is known as
coacervation.
It may also be referred as hydration when water is the
continuous medium.

[Link] S ENSITIZATION
At low concentration of hydrophilic colloids various
hydrophobic particles come together due to

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 Dispersed System 69

adsorption of hydrophilic colloids on different particle [Link].2 S YNERESIS

at the same time. Syneresis is the extraction or expulsion of a liquid
from a gel or jelly.
[Link] P ROTECTION
A high concentration of hydrophilic colloids each of 16.14 COMPARISON OF PROPERTIES OF
hydrophobic colloidal particle will have separate layer
of hydrophilic colloid leading to the protective effect. DIFFERENT COLLOIDS
Hence increasing the stability of phobic particles or Properties/Ch Lyophilic LyophoAssoci
phobic colloids.
aracteristics Colloids bic ation
[Link].1 P ROTECTION E FFECT Colloids
Colloid
Quantity of hydrophilic colloids required to stabilize/ s
protect phobic particle is based on the following Dispersibility Protein(sin Inorgani Aggreg
Gold Number and Disperse gle c ate of
It is the number of mg of protective colloids that must Phase molecule) Particle mono
be added to 10 cm3 of standard colloidal suspension Group of s (silver, mers
of gold to prevent flocculation on the addition of
smaller Fe (OH) Micelle
1cm3 of 10% NaCl solution.
Congo red Number
molecules 3, s of
Depends on the flocculatin of a standard dispersion of (colloidal Sulphur Organi
congro red by a given amount of KCl. gold etc.) c
solution) Not Compo
[Link] P RECIPITATION OF H YDROPHILIC Group of easily und
C OLLOIDS ions (aq. dispers Colloid
High concentration of salts (NaCl, KCl etc.) results into Soap ed al
neutralization of charge and dehydration leading to solution) Range
precipitation of hydrophilic colloids. Easily Easily
Dispersed Dispers
[Link] G EL AND J ELLIES (S OLID ed
C OLLOIDS ) Interaction Interact  Very Hydrop
Gel and jellies are colloids with a liquid as dispersion and dispersion Solvation/ little hilic,
medium and solid as dispersed phase.
medium hydration interact lipophil
According to x-ray examination gel is crystalline
structure while jellies are not crystalline in structure.
and so ion ic part
Low concentration is required to form [Link] it stable unstabl interac
Individual particles forming a frame work of ramifying e tion
aggregates in which the liquid dispersion medium is Stable
enmeshed. Viscosity High No such High
[Link] H EAT REVERSIBLE JELLIES (acacia in effect with
Jelly is only a dissolved into the water. It will change H2O; high
state to a solid when cooled, but, when heated, it will rubber in conc.
melt. If heated (slowly) the water will evaporate and benzene) Micelle
leave the jelly crystals behind. Sort of like salty water. s
They might not look the same, but the water will
becaus
return to its original state. Thus, jelly is a reversible
change.
e
E.g. gelatin, pectin, agar etc. asymm
etrical
[Link].1 H YSTERESIS Stability Stable with Unstabl In
 Time interval between cooling and settling towards high conc. e at aqueo
i.e. melting of jellies, called hysteresis. electrolytes Of salts, very us
 Settling of jellies promoted by heating, by salting out low solutio
addition of hydroxyl compound (like effect due concent n CMC
glycerin).
to ration is
 Setting is delayed by NO and Cl.
 It is totally prevented by KI.
neutralizat of salt is reduce

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 Dispersed System 70

ion and require d by Kr is the rapid flocculation while Ks stand for slow
dehydratio d the flocculation in the presence and absence of energy
barrier.
n (neutral additio
ization n of
[Link] E NERGY
and electro Particles are under constant Brownian motion, so
dehydra lyte stability is determined by the interaction between the
tion) particles.
Reversibility Reversible Not Not Two types of the forces are involved
of reversib Seen  Repulsive forces
precipitation le  Attractive forces
Stability after Stable Unstabl Not
prolong e Seen Theoretically if repulsive forces are dominating, the
system will be stable and if attractive forces are
dialysis
increasing the dispersion will coalesce/fuse.
Protective Has at high Has not Not Practically repulsive forces are necessary to
Effect concentrat seen counteract the attractive forces (mainly Van der Waal
ion attractive forces) and are generated by two ways as
Tyndall Cone Weak Strong Scatter under
Effect light  By electrical Double Layer or surface charge
but not of particles and is called electrical
formati stabilization or electrostatic stabilization.
on of  By the repulsion due to interaction between
cone the adsorbed polymer layers, including the
adsorbed molecules of dispersion medium
and is called steric stabilization or polymeric
stabilization or steric hindrance.
16.15 NATURE OF THE DISPERSED
PARTICLES [Link] E LECTRICAL OR E LECTROSTATIC
S TABILIZATION
A GGREGATE : primary particles are joined together at DLVO Theory by Derjaguin and Landan (from Soviet
crystal faces like clusters Union) and Verwey and Overbeek (from Netherland)
A GGLOMERATE : Particles are joined only at edges or is related to surface charge to stability. It also known
corners forming loose or more open structure then as classical theory for colloidal stabilization.
aggregate.  It works through balance between attractive
C OALESCENCE OR F USION : Particles fuse with and repulsive forces. Total potential i.e.
concomitant loss in surface area
F LOCCULATION (F): Surface sites of particles may be  Where VA = Van der Waal attractive forces
blocked which mean no fusion to a new particle. and VR = electrical repulsive forces.
Flocculation can be Reversible flocculation or  VA increases rapidly as particle approach
irreversible flocculation each other and this effect is less in VR
 The sharp increase in VR at very close
approach of particles is due to repulsion
16.16 STABILITY OF COLLOIDS/ DISPERSE
between the electron clouds of atoms of the
SYSTEM particles and is known as VR
Born
(i.e. Born
A stable dispersion is the one that resists any change Repulsive Energy)
in the state of the system which consists of free
particles undergoing Brownian motion.
Two stand point regarding stability are
 Kinetic
 Energy

K INETIC
It is determined by the stability ration “W” as a
degree of stability i.e.

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 Dispersed System 71

 Potential Energy curve passes through

maximum called Vmax which constitute an
energy barrier against the adherence of the
particles.
 Primary minimum is formed due to very
close approach of particles.
Born
 VR is also due to close approach of  By the adsorption of polymer a layer will be
particles formed in whichPhobic portion of polymer
 Lower the value of Vmax greater the chance adsorbs onto phobic surface and philic will
of particles to adhere and vice versa. dangle around and will develop interaction
 Height of Electric barrier/ activation energy with the dispersion medium due to philicity.
prevents particles to adhere. To overcome (I.e. phobic surface is covered by a layer with
this Vmax , some energy is required. Thermal its outer philic portion).
energy (KT) is present in the system, if Vmax
is >> KT dispersion will be stable and if KT The stabilization of dispersion due to adsorbed layers
>>Vmax then instability will result. of polymer is generally known as steric stabilization
 According to DLVO theory the magnitude of and is considered of two types:
Vmax depends on dimension of particles and
their surface charge or surface potential [Link].1 E NTROPIC S TABILIZATION
 If particles are sufficiently large then VT may Interpenetration of adsorbed layers leads to
develop secondary minimum at a quite concentration of polymer chains and loss of
distance from primary minimum. configuration entropy
 If secondary minimum is greater than KT Energetically Unfavorable
then flocculation of the system will result but
will be reversible
 Flocculation at primary minimum is
irreversible
 Stability of the system can be increased by
preventing the particles form approaching
each other i.e. by a balance between [Link].2 E NTHALPIC STABILIZATION
repulsive and attractive forces. Adsorbed polymer chains solvated and
interpenetration would require some desolvation
[Link] S TERIC OR P OLYMERIC
Unfavorable enthalpic change
S TABILIZATION
From the shape of total Potential (VT) curve the
height of Vmax can be increased by constructing a
physical barrier around the particle by non-ionic
surfactants. It will increase the distance of particles
from their centers.

[Link] C ONCLUSION
 Five possible forces can be identified

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 Dispersed System 72

 Electrostatic force of repulsion including ψs,  Sharedelectrons are closer to

ψς,ζ (zeta potential) and d. electronegative atom
 Van der Waal attractive forces or  Positive and negative centers do not coincide
electromagnetic forces of attraction  This separation of charge gives rise to
 Born repulsive forces permanent dipole movement.
 Steric stabilization as steric forces depends  In a compound various bond giver overall
upon the geometry and conformation of permanent dipole movement
molecules at the interface.  If it is finite i.e.>0 then molecules is P.D.M. if
 Solvation forces its value is zero then molecule is non-polar.
 Non polar molecule may still contain polar
16.17 bonds since zero value for dipole moment
may be due to opposing bond moment i.e.
bond moment with equal value but in
16.18 FORCES BETWEEN MOLECULES IONS opposite direction.
AND ATOMS
Two Types:
[Link] I NDUCED D IPOLE MOMENT
 Completely Covalent bonds are formed by
 Repulsive forces
complete equal sharing of electron of two
 Attractive forces
atoms so no dipole moment.
 If ions or molecule with permanent dipole
[Link] R EPULSIVE F ORCES
moment is brought near on end of this bond
Repulsive forces are of two types:
the shared electron may be displaced
[Link] G ENERAL R EPULSION towards one or other involved atoms.
General reluctance of electron clouds when atoms are  This will give induced dipole movement
too close. Reluctancy is proportion to the distance of
(I.D.M).
atoms.
12
Repulsions 1/r Three components i.e. Ions, P.D.M and I.D.M are
[Link] C OLUMBIC R EPULSION present so six types of attraction can be formed i.e.
Columbic repulsion between two similarly charged 1. Ion-ion
ions 2. Ion – PDM
3. Ion- IDM
4. PDM- PDM
5. PDM- IDM
6. IDM – IDM

r = distance Ion involvement leads to electrostatic charges other

If other than E0 then E0 = Er so than ions i.e.
 PDM –PDM
 PDM – IDM
E0 = Erwhich is relative  IDM- IDM
Those are the Van der Waal’s attractive
[Link] A TTRACTIVE FORCES forces.
Attraction is based on nature of components.
[Link] L ONDON OR D ISPERSION
[Link].1 C OMPONENTS A TTRACTIVE F ORCES
Components are of three types Force between non-polar molecules due to vibration
1. Ions of electrons or mutual induction of dipole s within the
2. Permanent dipole molecule.
3. Induced dipole
[Link] H YDROGEN B ONDING
[Link] F ORMATION OF I ONS (S OLVATION )
Formation of ions takes place by transferring of Attraction between hydrogen atom and
electrons from one atom to other. electronegative atoms e.g. O2, N2, F2 etc.

[Link] P ERMANENT D IPOLE M OMENT

 In covalent bond when their complete
16.19 PREPARATION OF COLLOIDS
sharing of electron does not occur

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 Dispersed System 73

[Link].1 L YOPHILIC C OLLOIDS 2H2S + SO2 3S + 2H2O

Because of the affinity of the lyophilic colloids for the [Link] R EDUCTION
dispersion medium these colloids are relatively easy Colloidal solution of silver form AgNO3 with the help
to form. As there is a considerable interaction of various reducing agents like hydrogen tannic acid,
between the disperse phase and the dispersion formaldehyde etc.
medium, they form spontaneously by placing the [Link] H YDROLYSIS
colloidal material in contact with proper solvent. For Colloidal solution Fe(OH)3 by adding solution of ferric
example acacia and gelatin disperse easily to form salts into boiling water
colloidal dispersion when kept in contact with water. [Link] P RECIPITATION
Colloidal solution of arsenic sulfide, H2S passes
[Link].2 H YDROPHOBIC C OLLOIDS through arsenic trioxide, Resin form Tincture.
Since there is a lack of affinity between the molecules
of disperse phase and dispersion medium, lyophobic [Link] P EPTIZATION
colloids are more difficult to prepare. For neutral particles charge creating agents are used
There are three methods to prepare colloids e.g. Glycerin, Sucrose, Lactose, Dextrose etc. Due to
1. Dispersion charge particles repel each other and so colloids are
2. Condensation formed.
3. Peptization

[Link] D ISPERSION 16.20 PHARMACEUTICAL APPLICATION OF

Dispersion can be done in three ways: COLLOIDS
1. Physical Colloids have found a number of pharmaceutical
2. Electrical applications including the following:
3. Mechanical  Because of their large surface areacolloids
show greater efficiency for absorption or
[Link] P HYSICAL D ISPERSION
adsorption. Kaolin because of its small
Lyophilic colloids showing affinity for dispersion
particle size show good adsorption
medium.
properties for toxins. Similarly Colloidal
Hydrophilic  e.g. gum acacia and gelatin in hot
Aluminum hydroxide shows better rate of
water
neutralization of stomach acid.
Lipophilic e.g. polysterene in benzene and pyroxylin
 Particle Size Reduction also alters some of
in alcohol.
the therapeutic properties of drugs. For
[Link] E LECTRICAL DISPERSION example colloidal iron is less severewhile
Electrical current passes through/ between poles of colloidal iodine is less toxic than their ionic
metal submerged in water or other dispersion salts. Similarly colloidal silver is more
medium which make the particles disrupted and form effective germicidal while colloidal mercury
colloids.e.g. colloids of Au Ag etc. is effective for the treatment of syphilis
[Link] M ECHANICAL D ISPERSION  Hydrophilic colloids are used as suspending
Colloids are prepared by reducing into smaller agents and as protective for hydrophobic
particles. colloids
By Colloidal Mill (which consist of two parts, one is  Dextran Injection is a colloidal dispersion
fixed and other is mobile). and is used as plasma substitute.
E.g. Colloidal Kaolin, Zinc Oxide, Sulfur etc.  Colloidal preparations have also been used
By irradiation cavities are formed which collapse as diagnostic agents. For example, Lange’s
into smaller particles Gold Solution is used to detect syphilis
inpatient. Normal spinal fluid protects the
[Link] C ONDENSATION OR M OLECULAR gold solution from the precipitating effect of
A GGREGATION sodium chloride whereas in syphilitic case, it
Simple reaction are involved like fails to prevent it.
 Oxidation
 Reduction
 Hydrolysis
 Precipitation

[Link] O XIDATION
E.g. Colloidal solution of sulfur

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 Emulsion 74

The Hydrophilic-lipophilic balance of a surfactant is a

Chapter 17 EMULSION measure of the degree to which it is hydrophilic or
lipophilic, determined by calculating values for the
17.1 COARSE DISPERSION different regions of the molecule.
Coarse Dispersion consists of dispersed phase of size The HLB value can be used to predict the surfactant
above 500 nm. Two dosage forms in coarse dispersion properties of a molecule.
are
 Emulsion
 Suspension

17.2 EMULSION
A heterogeneous system in which two immiscible
liquids are used one is distributed into the other and
the system is stabilized by stabilizing agent
(emulsifier).

17.3 TYPES
One liquid phase in emulsion is essentially polar (e.g.
Aqueous) and the other is relatively non polar (e.g oil)
Followings are the types:

[Link] O IL IN WATER (O/W)

In this type of emulsion oil globules are
dispersed in continuous aqueous medium.

[Link] W ATER IN O IL (W/O)

In this type of emulsion water particles are in
dispersed phase while oil is as a continuous 17.6 MECHANISM OF EMULSION
medium. STABILIZER/ EMULSIFIER FOR
[Link] M ULTIPLE E MULSION (O/W/O, EMULSION STABILITY
W/O/W)
Multiple emulsions are complex [Link] M ONOMOLECULAR A DSORPTION
polydispersed systems where both oil in Stability of Emulsion may be due to:
water and water in oil emulsion exists  Reduction in interfacial tension by the
simultaneously which are stabilized by formation of monolayer of emulsifiers
lipophilic and hydrophilic surfactants  Combination of emulsifier are used rather
respectively. than single emulsifier

[Link] M ICRO - EMULSION

Emulsion in which the dispersed phase is in
the form of very small droplets usually
produced and maintained with the aid of
surfactants and having diameters of from 50
to 500 angstroms for drug delivery.

17.4 EMULSIFYING AGENT

An agent used for stabilizing Emulsion is known as
emulsifying agent, stabilizing agent for emulsion,
emulsifier, emulgent.

17.5 HYDROPHILIC-LIPOPHILIC BALANCE

(HLB)

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 Emulsion 75

Creaming, in the laboratory sense, is the migration of

the dispersed phase of an emulsion, under the
influence of buoyancy. The particles float upwards or
sink, depending on how large they are and how much
less dense or denser they may be than the continuous
phase

[Link] M AINTENANCE OF E LEGANCE

Appearance, color, odor and other physical parameter
should remain same in case of stable emulsion.

17.8 INSTABILITY OF PHARMACEUTICAL

EMULSION
Instability is indicated by
 Flocculation and creaming
 Coalescence and breaking
 Other physical and chemical changes
 Phase inversion

[Link] C REAMING
Creaming, in the laboratory sense, is the migration of
Some combination gives complex film, closely packed the dispersed phase of an emulsion, under the
film, so excellent combination of emulsifiers (a) while influence of buoyancy. The particles float upwards or
other don’t give closely packed film and not a good sink, depending on how large they are and how much
complex so it will be poor combination of emulsifiers less dense or denser they may be than the continuous
(b). There are some combinations which give closely phase. It may be upward or downward creaming.
packed but poor complexation so are not favorable Creaming is mostly reversible and shaking of emulsion
combination (c). gives original shape.

[Link] M ULTI -M OLECULAR A DSORPTION [Link] F LOCCULATION

Stability of emulsion is due to following two reasons It is a process in which is a process wherein colloids
 Hydrated lyophilic colloids come out of suspension in the form of floc or flake. It
could be reversible or irreversible.
 Protective effect of colloids

[Link] S OLID P ARTICLE A DSORPTION [Link] C OALESCENCE AND B REAKING

Solid particles welted by oil and water and Coalescence is the process by which two or more
concentrated at the interface. Example droplets, bubbles or particles merge during contact to
form a single daughter droplet, bubble or particle. If
 Bentonite (hydrated Alumunium silicate)
there is no coalescence of internal phase emulsion
 Veegum (magnesium alumiunum silicate)
will remain stable. Dispersed phase totally serpearted
 Carbon black etc
from the dispersion medium

17.7 STABILITY OF EMULSION [Link] O THER P HYSICAL AND C HEMICAL

Stability of pharmaceutical emulsion is characterized C HANGES
by Following parameter should be kept in optimum:
[Link] V ISCOSITY
[Link] A BSENCE OF COALESCENCE OF INTERNAL Phase volume ratio (relative volume of water and oil
PHASE in emulsion).
Coalescence is the process by which two or more  Critical Point is the concentration of internal
droplets, bubbles or particles merge during contact to phase which emulsion break down.
form a single daughter droplet, bubble or particle. If  50/50 ratio is the best ratio between water
there is no coalescence of internal phase emulsion and oil concentration.
will remain stable.
17.9 PHASE INVERSION
[Link] N OT BEING CREAMED

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 Emulsion 76

It means internal phase is inverted to external phase  Polyoxyethylene sorbitan mono oleate for
i.e O/W emulsion is changed to W/O emulsion or vice O/W emulsion.
versa.
Phase Inversion is usually due to: [Link] I ONIZING
 Finer particles  Cationic (quaternary ammonium Compound)
 Addition of some chemicals  e.g. Cetyl trimethyl ammonium bromide,
For example O/W emulsion stabilized with cetyl trimethyl ammonium iodide.
sodium seterate and can be inverted to W/O
by adding calcium chloride which causes
inversion.
 Temperature
 Microbial Growth
 Altering Phase Volume Ratio

17.10 EXPLANATION FOR PHASE INVERSION

 In O/W emulsion, non-ionic surfactants are
used. This O/W emulsion contains oil swollen
micelles and emulsified oil/globules
 With increase of temperature
 Oil swollen micelles start breaking, size of
emulsified globules start increasing.
 With further increase of temperature oil
phase, surfactant and water phase
completely separate
[Link].1 A NIONIC ( E . G . A LKALI SOAPS OR
 Near this temperature water insoluble
surfactant starts forming w/o emulsion SOAPS OF INORGANIC ELEMETS )
contain water swollen micelles and [Link].1.1 MONOVALENT ALKALI SOAPS
- + +
emulsified droplets. RCOO + Na  RCOONa  O/W emulsion

17.11 CONTINENTAL METHOD OF DIVALENT ALKALI SOAPS

2+
(RCOO)2 Ca  (RCOO)2 + Ca  W/O emulsion
EMULSION PREPARATION SODIUM OLEATE
+ -
In O/W emulsion, emulsifier is mixed with oil, it is C17H33COONa  C17H33COO + Na
shaken well and then gradually water is added to [Link].1.2 SULPHATE (SODIUM LAURYL SO4)
prepare emulsion. This procedure is sometime known Sulphonate (Sodium Cetyl Suphonate)
as continental method. [Link].1.3 ACCORDING TO HLB (HYDROPHILIC -
LIPOPHILIC BALANCE ).
17.12 EMULSIFYING AGENTS
There are two types of emulsifying agent 17.13 THEORIES OF EMULSIFICATION
1. Theory of Viscosity
[Link] N ATURAL E MULSIFYING A GENTS : 2. Fischer’s Theory of Hydrate
 Gums (Acacia, Tragacanth etc.) 3. The Interfacial Tension Theory
 Mucilages 4. The Adsorption Theory (Film Formation)
 Waxes 5. Oriented Adsorption Theory
 Proteins (Gelatin, Casein etc) 6. Molecular Complex Formation Theory
 Phospholipids (Eggs phospatidyl choline EPC)
 Carbohydrates (Dextran) [Link] T HEORY OF V ISCOSITY
 Cellulose Derivatives (Sodium Alginate) It states that more viscous emulsion the greater is the
 Cholesterol stability. But it is not always true.
E.g. Milk has low viscosity but most stable, O/W
[Link] S YNTHESIS emulsion.
[Link] N ON -I ONIZING : Cold Cream is an example of more viscous emulsion,
 Ester of higher fatty acids and alcohol e.g O/W emulsion.
sorbitan monooleate for W/O emulsion
[Link] F ISCHER ’ S T HEORY OF H YDRATE

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 Emulsion 77

It states that disperse phase form colloidal hydrate or [Link] M OLECULAR C OMPLEX
colloidal complex. E.g. O/W emulsion, oil form F ORMATION
colloidal complex and in W/O emulsion water form When two substances form complex at the interface
colloidal complex and known as solvate. then immediate emulsification will result due to
However, the theory fails to answer and explain the “Complex Formation” for example solution of Sodium
stability of emulsion. Cetyl Sulphate when mixed with Cholesterol.

[Link] I NTERFACIAL T ENSION T HEORY

APPLICATIONS OF EMULSION
Greater is the interfacial tension, less table will be the
C OSMETIC AND P HARMACEUTICAL A PPLICATION
emulsion as more attraction of the dispersed globules  Pharmaceutical applications according to
experiences. rate of administration like topical, oral and
parenteral.
[Link] T HE A DSORPTION T HEORY  Cosmetic and tropical applications are the
Upon the addition of solute, surface tension is same.
reduced due to solute – solvent attraction and due to
adsorption of solute molecules at the surface. [Link] P ATIENT
Formation of surface film is film of emulsifier at the COMPLIANCE / ACCEPTANCE
interface and is hydrated from both the sides of Medicinal agents having objectionable taste and
phases. Tension on both sides reduced. Greater texture are best formulated in emulsion. Examples:
tension will pull the film and form concave shape. mineral oil bared laxatives, oil soluble vitamins (A, D,
The phase on the concave side readily form globules E and K) and high fat nutritive preparation.
and enveloped by the other phase.
[Link] B IOAVAILABILITY
[Link] O RIENTED A DSORPTION T HEORY  Some therapeutic agents shows high
The types of substances are bioavailability in emulsion form. Example
 Non-Polar like ethane, where electrical Griseofulvin.
charge is balanced.  High Nutrition Value with minimum volume
 Polar like ethyl Alcohol and water where of triglyceride fat emulsion.
charge is not balance.  Example I/V fat emulsion, Intralipids,
lipofundin and lipofundin –S.
Polar substances are dissolved/arranged in polar  Particle Size of these emulsions is controlled.
solvent and non-polar towards non-polar solvent (e.g.  These are isotonic and must not be diluted
Paraffin). during administration.
[Link] H ARKIN ’ S O RIENTED W EDGE
T HEORY [Link] M ODERN D RUG D ELIVERY
A LKALI S OAP LIKE : Na and K salts (Monovalent) more C ONCEPT
loving to water  Unabsorbable macromolecules are absorbed
to some extent when given orally.
 Example: insulin and heparin are absorbed
when given orally in emulsion.

[Link] T ROPICAL AND C OSMETICS

P REPARATION
Patient acceptance can be improved for example by
improving:
D IVALENT AND T RIVALENT SALTS
++ +++  Viscosity
e.g. Ca and Mg
 Appearance
 Degree of greasiness
 O/W emulsion used for washable drug bases
and W/O emulsion are useful for dry skin and
used as an emollient
o Emollient is an agent which softens
or soothes the skin or soothes
irritated internal surface.

[Link] R ADIOPAQUE E MULSION IN X-R AY

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 Emulsion 78

 Radiopacity is quality or property of

obstructing the passage of radiant energy as
in X-ray, the represented areas appearing
light or white on exposure.

[Link] P REVENTION OF CRYSTALLIZATION

IN I NJECTABLE
 Emulsifiers presence in parenteral dosage
form reduce tendency of crystallization
responsible for thrombophlebitis
(inflammation of vein associated with
thrombus formation).
o Thrombus is a solid mass formed in
living heart/vein from blood
constituents.

[Link] E MULSION USED AS OXYGEN

CARRIERS IN BLOODS REPLACEMENT .
Emulsification of perflourinated hydrocarbons is
required for using them as oxygen carriers in blood
replacement.

17.14 BIOPHARMACEUTICAL ASPECTS OF

EMULSIONS
 Improving drug bioavailability by the use of
lipid O/W emulsions as vehicle for lipophilic
drugs (Diazepham, Propofol) for IV use.
 It increases of bioavailability of Griseuflavin
given an emulsion form: [Fats are emulsified
by bile salts and administration of already
emulsified form.
 Increase the opportunity for solublilization
and hence transport across the microvilli by
fat absorption pathways.
 Emulsion of Indoxole has greater
bioavailability than other dosage form.
 Medium chain triglycerides and mono and di
glycerides promotes the adsorption of
cefrioxone and cefoxitin as well as that of
cyclosoprin A.
 Emulsifier also enhances he membrane
permeability.
 Absorption of particles from the gut by the
lymphoid tissue suggests revision regarding
absorption of many drugs from GIT.

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 Suspensions 79

 Pharmaceutical suspensions may be

Chapter 18 SUSPENSIONS formulated to provide controlled drug
delivery, e.g. as intramuscular injections
18.1 DEFINITION
 Suspensions may be defined as coarse 18.4 DISADVANTAGES
dispersion containing finely divided drug
 Pharmaceutical suspensions are
particles (the suspensoid) distributed
fundamentally unstable and therefore
somewhat uniformly throughout a vehicle in
require formulation skill to ensure that the
which the drug exhibits a minimum degree
physical stability of the formulation is
of solubility.
retained over the period of the shelf-life.
 The diameter of the disperse phase may
 The formulation of aesthetic suspension
range from 0.5 to 100 µm.
formulations is difficult.
 A pharmaceutical suspension is a coarse
 Suspension formulations may be bulky and
dispersion in which insoluble particles,
therefore difficult for a patient to carry.
generally greater than 1 µm in diameter

18.5 TYPES OF SUSPENSIONS

 A flocculate or floc is a loose open structure
or cluster of particles.
 A suspension consisting of particles in this
state is termed flocculated
 And a suspension without floc is termed
deflocculated.

18.2 CHARACTERISTICS
The characteristics of an acceptable pharmaceutical
suspension include the following:
 A low rate of sedimentation
 The disperse phase must be easily 18.6 NATURE OF SOLIDS
redispersed with gentle shaking
 The flow properties of the suspension should  Diffusible
enable the formulation to be easily removed  Poorly wettable
from the container (e.g. bottle, injection vial)  Indiffusible
 Aesthetically pleasing.
[Link] D IFFUSIBLE S OLIDS
18.3 ADVANTAGES  Insoluble but wettable
 Readily mixed
 Pharmaceutical suspensions are a useful  Remain suspended for long period of time
drug delivery system for therapeutic agents  e.g. Mg trisilicate, kaolin
that have a low solubility.
 Pharmaceutical suspensions may be
formulated to mask the taste of therapeutic [Link] P OORLY W ETTABLE S OLIDS
agents.  Insoluble and poor wettable
 Pharmaceutical suspensions may be  Difficult to disperse
employed to administer drugs to patients  Form clumps
who have difficulty swallowing solid-dosage  Wetting agent is required
forms.  E.g. sulphur

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 Suspensions 80

[Link] I NDIFFUSIBLE S OLIDS  Low, medium and high viscosity grades are
 Insoluble commercially available.
 Not remain dispersed  In case of HV-CMC, the viscosity significantly
 Viscosity enhancer is required decreases when temperature rises to 40 ºC
 e.g. Zinc oxide, chalk from 25 ºC.
 Therefore, to improve viscosity and stability
18.7 SUSPENDING AGENTS of suspension MV-CMC is widely accepted.

 Natural (acacia, tragacanth, starch) [Link] C ARBOMERS

 Semisynthetic (MC, HEC, Sod CMC)  Carbomer is any of a series of polymers of
 Synthetic (carbomers) acrylic acid
 Inorganic agent (Clay, bentonite)  Used as thickening agents and emulsion
 Miscellaneous (gelatin) stabilizers.
 readily absorb water to form gels or thick
Or they may be classified as: solutions that are non-toxic, stable, and
 Polysaccharides resist spoilage
 Natural (acacia, tragacanth, starch)  The various types indicated by a numerical
 Semisynthetic (MC, HEC, Sod CMC) suffix such as Carbomer 940 or Carbomer
 Synthetic (carbomers) 973, which indicates the average molecular
 Inorganic agent (Clay, bentonite) weight of the polymer chains.

18.8 PREPARATION OF SUSPENSIONS

[Link] A CACIA
Suspensions for oral administration are usually
 Acacia senegal
manufactured in one of two methods:
 Gum arabic
(1) Dispersion method (direct incorporation)
 Acacia gum is a brittle, odorless and
(2) Condensation method (precipitation
generally tasteless material that contains a
method)
number of neutral sugars, acids, calcium and
other electrolytes
 It is very soluble in water, but does not
[Link] D ISPERSION METHOD
dissolve in alcohol.
 In this method the soluble components are
normally dissolved in the appropriate
[Link] M ETHYLCELLULOSE
volume of diluent (vehicle).
 Methylcellulose is available in several
 The solid therapeutic agent is then dispersed
viscosity grades.
into the vehicle with the aid of mixing, prior
 The difference in viscosity is due to
to correction for volume.
difference in methylation and polymer chain
 The mixing rate employed during the
length.
addition is an important determinant in the
 Methylcellulose is more soluble in cold
manufacture of the formulation.
water than hot water.
 The particle size of the suspended drug
 Methylcellulose is stable at pH range of 3-11.
within the formulation may then be reduced
using a ball mill. Alternatively, the particle
size of the active ingredient may be
[Link] H YDROXY E THYLCELLULOSE optimized (by particle size reduction
 Hydroxyethylcellulose (HEC) is another good techniques) prior to incorporation into the
suspending agent having somewhat similar vehicle.
characteristics to methylcellulose.
 In HEC hydroxyethyl group is attached to
[Link] C ONDENSATION (P RECIPITATION
cellulose chain.
METHOD )
 Unlike methylcellulose, HEC is soluble in both
 In this method the drug is dissolved in the
hot and cold water and do not form gel on
vehicle (or a portion of the available
heating.
volume), prior to precipitation (the salt
formed is insoluble).
[Link] C ARBOXY M ETHYLCELLULOSE (CMC)
 Such systems are frequently deflocculated
 Carboxy methylcellulose is available at
and are therefore mixed at low shear rates.
different viscosity grades.

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 Suspensions 81

 The excipients are then dissolved in the

vehicle, or dissolved in a portion of the
vehicle, which is then added to the
suspension of drug.
 At this stage the formulation may be
exposed to high shearing rates to ensure
homogeneity.
 The volume of the formulation is then
corrected by adding the required mass of 18.11 FREE SETTLING & HINDERED
diluent. SETTLING
 One potential problem with this technique is
 Stokes’ equation was derived for an ideal
the production of ionic byproducts from the
situation in which uniform, perfectly
precipitation interaction. If the concentration
spherical particles in a very dilute suspension
of these is too high, then the precipitated
settle without producing turbulence, without
therapeutic agent requires to be washed
colliding with other particles of the
with an aqueous solvent.
suspensoid, and without chemical or physical
attraction or affinity for the dispersion
18.9 PROBLEM IN STABILITY OF SUSPENSION medium, which is called free settling.
 Caking  But suspensions are
 Flocculation o Concentrated
 Particle growth o Particles are not spherical
 Adhesion of particles to container wall This is called Hindered Settling.
 Sedimentation
18.12 SEDIMENTATION PARAMETERS
18.10 SEDIMENTATION RATE OF THE Two parameters to assessment of the sedimentation
PARTICLES OF A SUSPENSION of drug:
(1) Sedimentation volume
The various factors involved in the rate of settling of (2) Degree of flocculation
the particles of a suspension are embodied in the
equation of Stokes law.
[Link] S EDIMENTATION VOLUME (F)
 This is the ratio of the volume of the
sediment (Vs) to the initial volume of the
suspension (Vi):

 The sedimentation volume may range from

less than 1 to values that are greater than 1.
 The sedimentation volume of deflocculated
suspensions is usually small, whereas the F
value for flocculated systems is high (i.e.
close to or greater than 1) due to the large
volume occupied by the flocculated
structure.

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 Suspensions 82

[Link] D EGREE OF FLOCCULATION ( Β )

 The degree of flocculation is defined as the
ratio of the ultimate sedimentation volume
of the flocculated suspension to the ultimate
sedimentation volume of the deflocculated 18.13 FLOCCULATION AND
suspension.
DEFLOCCULATION IN SUSPENSIONS
[Link] F LOCCULATE
D
 Rapid settle down
 Not elegant

[Link] D EFLOCCULA
TED
 Slow settle down
 Cake

Therefore, partially deflocculated

 This is usually the preferred measurement as suspensions are ideal preparation
it provides a point of reference, i.e. the
suspension before and after flocculation.
 The minimum value of β is 1, when
flocculated suspension sedimentation
volume is equal to the sedimentation volume
of deflocculated suspension.
[Link] E XAMPLE
Suppose:
 Initial volume of the suspension (Vi) = 100 ml
 Volume of the sediment (Vs) = 44 ml
 Sedimentation volume F = ?
 Degree of flocculation (β) = 1.5
 Sedimentation volume of deflocculated
suspension= ?

[Link] S OLUTION
18.14 ZETA POTENTIAL

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 Suspensions 83

 The zeta potential is defined as the Controlled flocculation of particles is obtained by

difference in potential between the surface adding flocculating agents, which are:
of the tightly bound layer (shear plane) and  Electrolytes
electro-neutral region of the solution  Surfactants
 Polymers
 Since this potential governs the degree of
repulsion between the adjacent, similarly
charged, dispersed particles. [Link] E LECTROLYTES
 Zeta potential has practical application in  Electrolytes decrease electrical barrier
stability of systems containing dispersed between the particles and bring them
particles. together to form floccules.
 If the zeta potential is reduced below a
certain value, the attractive forces exceed
the repulsive forces, and the particles come
together.
 This phenomenon is known as flocculation.

 Thus the phenomenon of flocculation and

deflocculation depends on zeta potential
carried by particles.
 The flocculated suspension is one in which
zeta potential of particle is -20 to +20 mV.
 Deflocculation of particles is obtained when
the zeta potential is higher than the critical
value and the repulsive forces supersede the
attractive forces.
 These deflocculated particles when sediment
form a close packed arrangement with the
smaller particles filling the voids between the
larger ones. -SOLID HARD CAKE
 When this zeta potential goes below the
critical value, the attractive forces supersede
the repulsive forces and flocculation occurs. 
They reduce zeta potential near to zero value
 These loosely packed particles or floccs settle
that results in formation of bridge between
faster than the defflocculated particles
adjacent particles, which lines them together
because of their larger sizes.
in a loosely arranged structure.
 But unlike deffloculated particles this
 If we disperse particles of bismuth subnitrate
sediment of floccs does not form solid cake.
in water
 This sediment of floccs is easy to redisperse
 the system is deflocculated.
by minute agitation.
 By increasing concentration of monobasic
potassium phosphate co-relation between
apparent zeta potential and sedimentation
18.15 CONTROLLED FLOCCULATION volume, caking, and flocculation can be
demonstrated.

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 Suspensions 84

 Optimum concentration is necessary because

 The addition of monobasic potassium these compounds also act as wetting agents
phosphate to the suspended bismuth to achieve dispersion.
subnitrate particles causes the positive zeta  At optimum concentrations they reduce the
potential to decrease owing to the surface tension between liquid medium and
adsorption of negatively charged phosphate solid particles.
anion.  The particles are attracted towards to each
 With continued addition of the electrolyte, other by van der-waals forces and forms
the zeta potential eventually falls to zero and loose agglomerates.
then increases in negative directions.
 Only when zeta potential becomes [Link] P OLYMERS
sufficiently negative to affect potential does  Polymers possess long chain in their
the sedimentation volume start to fall. structures.
 Starch, alginates, cellulose derivatives,
[Link] S URFACTANTS carbomers, tragacanth
 Both ionic and non-ionic surfactants can be  The part of the long chain is adsorbed on the
used to bring about flocculation of surface of the particles and remaining part
suspended particles. projecting out into the dispersed medium.
 Bridging between these later portions, also
leads to the formation of flocs.

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 Suspensions 85

 To prevent degradation of drug or to

improve stability of drug. E.g.
Oxytetracycline suspension
 To mask the taste of bitter of unpleasant
drug. E.g. Chloramphenicol palmitate
18.16 FLOCCULATION IN STRUCTURED suspension
VEHICLES  Suspension of drug can be formulated for
Structured vehicles are those containing thickening or topical application e.g. Calamine lotion.
suspending agents.  Suspension can be formulated for parentral
These are used to increase the viscosity of the application in order to control rate of drug
suspension. absorption, E.g. penicillin procaine
These structured vehicles entrapped the particle and  Vaccines as a immunizing agent are often
reduces the sedimentation of flocculated suspension. formulated as suspension. E.g. Cholera
vaccine
Too high viscosity is not desirable as:  X-ray contrast agent are also formulated as
 It causes difficulty in pouring and suspension. E.g. Barium sulphate for
administration. examination of alimentary tract
 It may affect drug absorption since they
adsorb on the surface of particle and 18.18 ROUTE OF ADMINISTRATION
suppress the dissolution rate.
 Orally
 As injectable form -- I/M, S/C
Structured vehicle is not useful for Parenteral
suspension because they may create problem in  Drug reservoir as transdermal patches
syringeability due to high viscosity.  Aerosol

18.17 APPLICATIONS
 Suspension is usually applicable for drug
which is insoluble or poorly soluble. E.g.
Prednisolone suspension

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 Adsorption 86

 Stychinine HCl onto Activated Charcoal (Solid

Chapter 19 ADSORPTION – Liquid)
 Activated Charcoal used in Respirators for
Adsorption consists of two components: civilian and forces (Solid- Gas)
A DSORBENT  Decrease in surface tension is due to surface
Kaolin, pectin, altpulgite, talc, Magnisum trisilicate, active agent for example liquid-gas bonding.
Al(OH)3, Simithicone, CaCO3 (Activated Charcoal),  Emulsifying agent as emulsion stabilizers in
Mg(OH)3 etc. case of liquid- liquid bonding.
[Link].1 A DSORBATE  Langmuir regarded adsorption phenomenon
Toxins, Strychnine HCl, Digoxin and many as function of unsaturated valencies and
other drugs sharing of electrons. Sometimes bonds are
strong and sometimes weak.
19.2 ADSORPTION
It is an accumulation of substance at the interface or 19.7 POSITIVE ADSORPTION
boundary between two and heterogeneous phases. Solution of Strychnine HCl shaken with activated
For example, Solid-Gas, Oil- H2O, Gas- Liquid, or Solid charcoal resulted into different concentration of
– Liquid. strychnine HCl at surface of charcoal than in the bulk.
“It is essentially a surface phenomenon”. (Volume Concentration)
If surface concentration is greater than volume
19.3 ABSORPTION concentration adsorption is called positive adsorption
It implies the penetration one component throughout
the body of a second. The distinction between 19.8 NEGATIVE ADSORPTION
adsorption and absorption is not always clear. If surface concentration is less than the bulk (volume
concentration) the adsorption is called negative
19.4 SORPTION adsorption.
When there is not any distinction between adsorption
and Absorption, then a non-committal word 19.9 FACTOR AFFECTING ADSORPTION
“Sorption” is used.
[Link] S OLUBILITY OF THE A DSORBATE
19.5 TYPES OF ADSORPTION
Two Types:
Highly soluble substance has poor/less adsorption on
adsorbent surface due to more firm solute – solvent
[Link].1 P HYSICAL A DSORPTION
bonds. This empirical rule is known as Lundeliu’s
It is an adsorption at the surface through
Rule.
weak “van der waal” forces.
Example, I2 adsorption on carbon from its solution
[Link].2 C HEMICAL A DSORPTION into CCl4, CHCL3 and CS2 was [Link].5 respectively. It is
It involves stronger valence forces; it is more close to inverse ration for solubility of I2 into these
potent and usually involves “Ion Exchange solvents.
Process”  Phobic substances adsorb more than philic.
 Keeping philic moiety constant D
 Frequently both physical and chemical hydrocarbons chains vary, adsorption
adsorption may be involved. increases as the series ascended.
 For example, in adsorption of “Toxins” in the
stomach by “Attapulgite” and “Kaolin” [Link] P H
Chemisorption involves cation exchange with  Ionization is effected by pH which actually
the basic group of Toxins and physical affects the solubility of drugs.
adsorption of the remainder of the molecule.  In drugs with single molecules, adsorption
increases when ionization is suppressed. It is
maximum when drug is completely
unionized.
19.6 OTHER EXAMPLE OF ADSORPTION  Amphoteric Compound (D +ve and –ve
Charge)

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 Adsorption 87

 Adsorption is maximum at isoelectric point. [Link] T YPES OF C HROMATOGRAPHY

 pH and solubility act in concert [Link] A DSORPTION C HROMATOGRAPHY
 Unionized form of drugs in aqueous soln. has Adsorbents like Kreselgur, charcoal, cellulose, MgO,
low solubility. CaO, PO4, CO3, etc are packed in column (Stationary
 Of the two i.e. pH and Solubility, Solubility or Fixed Phase)
has more pronounced effect Water, alcohol, chloroform etc as mobile phase.
Example: [Link] P ARTITION CHROMATOGRAPHY
 Adsorption of hyoscine and Atropine on Two immiscible liquids are used
Magnesium Trisilicate. H2O and CH3Cl (liquids) with silica gel which acts
 Hyoscine is completely unionized but has less support for liquid as fixed phase and CH3Cl or other
adsorbed than atropine which is 50% liquids as mobile phase.
ionized. Because Hyoscine is highly soluble [Link] P APER C HROMATOGRAPHY
(1:9.5 parts of H2O) than atropine (1:400 Normally filter paper is used. Two types:
parts of H2O). So solubilization is inversely  Ascending
proportion to adsorption.  Descending
When mobile phase is at bottom or at the top
[Link] N ATURE OF A DSORBENT respectively
 Physio-chemical nature of adsorbent plays
significant role on the rate and capacity of [Link] W ORKING OF C HROMATOGRAPHY
adsorption. 1. Preparation of sample and its injection
 Finely divided particles have more 2. Sample goes to column (Fixed phase)
adsorption capacity because of more surface 3. It comes across and mobile phase and
area. separation of components solutes complete
 Adsorbents can be converted into activated 4. Separated components is taken to detector
form to increase the capacity of adsorption. and recorded.
Example: Activated Charcoal
i. Special treatment to remove surface 19.11 APPLICATION OF ADSORPTION
impurities
ii. To convert into small particles Adsorption has the application in:
Activated charcoal is prepared from coco-nut shells. 1. Preparative and Analytical Chromatography
 Dust particles removed by steam and air. 2. Heterogeneous catalysis
 Then converting into small particles. 3. Water purification
4. Solvent recovery
[Link] T EMPERATURE
Adsorption is an exothermic process and an increase 19.12 MEDICAL AND PHARMACEUTICAL
in temperature will decrease adsorption. APPLICATIONS
Small variation may not have much influence.
[Link] A DSORPTION OF NOXIOUS
[Link] P RESSURE
SUBSTANCE FROM ALIMENTARY CANAL
At solid-gas interface amount adsorbed is
Universal and antidote (activated charcoal, MgO and
n Tannic acid) when used orally, reduces toxic levels of
= KP
poisoning.
Where P = Pressure and K and n were constant.
[Link] R EMOVAL OF T OXIC E LEMENTS
[Link] C ONCENTRATION FROM B LOOD
At solution solid particle it can be given as Some adsorbents are used to remove toxic elements
n
= KC by subjecting its dialysis through “hemodialysis”
Where C = concentration, K & n = constants. membrane over charcoal and adsorbents
(chlorpheniramine, colchicine, Phenytoin, aspirin etc.)

19.10 CHROMATOGRAPHY [Link] T REATMENT OF SEVERE DRUG

OVERDOSES
Separation of components solutes in a solution
 Extracorporeal method has been developed
exploits the principle of adsorption. Smallest
named “Haemoperfusion”
difference in their absorbability or differences in their
distribution/ partition between two phases.

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 Adsorption 88

 Microencapsulation of activated charcoal by [Link] B.P.C MIXTURE OF

Arcylic Hydrogel, a biocompatible material M AG . TRISILCATE AND BELLADONNA .
preventing Embolism and removal of Complete adsorption hyoscine onto magnisum
platelets. trisilicate which is an adsorbent.
 In vivo – In vitro relationship regarding [Link] C ARDIOACTIVE G LYCOSIDES
adsorptive capacity of adsorbents. (D IGOXIN , D IGITOXIN , D IGITONIN ETC )
 No relationship exists. ADSORB ONTO ANTACIDS .
Reason:
 GIT and biological system have many other
things which alter the adsorption ratio.
Example:
 In vitro – 5g activated charcoal bin 8g of
Aspirin
 In vivo – 30g of activated charcoal inhibits
the GIT adsorption of 3g of Aspirin by 50%.

[Link] A DSORPTION PROBLEMS IN D RUG

F ORMULATION
Drugs containing antacids and other drugs, when
given, the above problem results. Adsorbents are
non-specific nutrients, drugs and enzymes when given
orally.
Example:
[Link] P ROMAZINE GIVEN ABOVE OR D
ADSORBENTS
19.13 OTHER USES OF ADSORPTION
PHENOMENON
[Link] D ECOLOURIZATION
During purification (by partitioning, crystallization and
precipitation) chemical is tinted so colour is removed
by adding activated charcoal or other appropriate
adsorbents
Precaution: Adsorption active principle like alkaloid
drugs on kieselguhr, adsorption is decreased.
[Link] L INCOMYCIN
Kaopectate is a combination of Kaolin and Pectinic
[Link] A DSORPTION OF WATER V APORS :
acid.
Alumina and silica gel remain in solid forms even after
40% adsorption of H2O. CaCl2 and P2O5 also adsorb
H2O but liquefy after water adsorption.
Alumina and silica gel are preferred.

[Link] A DSORPTION OF P YROGENS

Pryrogen are low molecular weight drugs (glucose,
sodium citrate, calcium gluconate etc.) can be
pyrogen free but high molecular weight drugs get
adsorbs highly on adsorbents so cannot be pyrogen
free.

[Link] S URFACE A REA D ETERMINATION

[Link] PAS ( PARA - AMINOSALICULIC Properties of powders are highly influenced
ACID ) AND R IFAMPICIN E.g. rate of soln. rate of oxidation, hygroscopic,
Availability of rifampicin is reduced due to bentonite sedimentation behavior, resistance to gas flow, bulk
used as an excipient. Bentonite is naturally occurring density and associated packing problems.
mineral (montmorillonite) and hydrated aluminum
silicate.

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 Adsorption 89

[Link] M ONITORING OF P ORE S IZE OF

F ILTER P APERS
Membrane filtration for sterility pore size decreases
to 450 nm.

[Link] S TABILITY OF C OLLOIDS

Protective colloids (lyophilic colloids for lyophobic
colloid’s stability)

[Link] S TABILITY OF E MULSIONS

By using emulsifying agents of appropriate HLB no.
(Hydrophilic – lipophlic balance)
Pharmacological Activity due to Adsorption at
Receptor Sites.

[Link] R HEOLOGICAL P ROPERTIES OF

S USPENSIONS
Heterogenous system behave differently than
homogenous system behave differently than
homogenous systems.
Adsorption at walls of container also adsorption into
the container’s wall.

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 Rheology 90

2
η= N sec / m
Chapter 20 RHEOLOGY 2
η= dyne cm / cm cm/sec
2
η= dyne sec / cm
20.1 RHEOLOGY
 Rheology is derived from two Greek work [Link] B ASIC UNIT IS P OISE - J EAN L OUIS M ARIE
“Rheo” means to flow and “Logos” means P OISEUILLE
science so Rheology is the study of flow Poise (force of 1 dyne per square centimeter
properties of liquids and deformation of maintains a difference in velocity of 1 centimetre per
solids. second between two parallel planes 1 centimetre
 Science concerned with the deformation of apart)
 1 Pa.s = 1 N s/m
2
matter under the influence of stress.
 The flow of simple liquids can be described  1 Poise = 100
by viscosity, an expression of the resistance centipoises
to flow; however, other complex dispersions  Poise = 1
cannot be simply expressed by viscosity. centipoises

20.2 SHEAR STRESS [Link] I NTERCONV

ERSION
 The force per unit area F/A required to bring
 P = 0.1 Pa·s
about flow is called SHEAR STRESS.
 cP = 0.001 Pa·s.= 1 mPa·s
 Since the units of force are Newtons and the
2
units of area are m it follows that the units
of Shear Stress are N/m
2
20.5 KINEMATIC VISCOSITY
2
 This is referred to as the PASCAL (i.e. 1 N/m Kinematic viscosity is the ratio of absolute or dynamic
= 1 Pascal) and is denoted by the symbol ς viscosity to density - a quantity in which no force is
(in older textbooks you may see it denoted involved
as τ). Kinematic viscosity = η/ρ

20.3 SHEAR RATE Units are Stock / centistokes (cS) – George Gabriel
Stokes
 The difference of velocity (dv) between two
planes of liquid separated by an infinitesimal
distance (dr) is called velocity gradient rate 20.6 NEWTON
of shear. The SI unit of force, equal to the force that produces
 G=dv/ dr an acceleration of one meter per second per second
 Directly proportion to F on a mass of one kilogram.
 Directly proportion distance b/w layers
20.7 DYNE
20.4 ABSOLUTE VISCOSITY (DYNAMIC
The standard centimeter-gram-second unit of force,
VISCOSITY ) equal to the force that produces an acceleration of
 The resistance to flow encountered when one centimeter per second per second on a mass of
one layer or plane of fluid attempts to move one gram.
over another identical layer or plane of fluid
at a given speed. Absolute viscosity is also 20.8 PASCAL
called dynamic viscosity
The SI unit of pressure or stress, equal to one newton
 The Shear Rate obtained from an applied
per square meter.
Shear Stress will be dependent upon the
material’s resistance to flow i.e. its
VISCOSITY. 20.9 RELATIVE VELOCITY
 Since the flow resistance =force / Relative velocity is a measurement of velocity
displacement it follows that: between two objects moving in different frames of
reference
VISCOSITY = SHEAR STRESS / SHEAR RATE η = σ/G
η= (F/A) / (dv/dr)
η= (F dr / A dv)
20.10 FLUIDITY
2
η= N m / m m/sec Reciprocal of viscosity is called fluidity.

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 Rheology 91

Ф =1/η  Plastic flow is associated with the presence

of flocculated particles in concentrated
suspensions.
20.11 NEWTON’S LAW OF FLOW  Plastic flow does not begin until a shearing
stress, corresponding to a yield value, is
 The rate of flow (D) is directly proportional to the exceeded.
applied stress (τ).  The curve intersects the shearing stress axis
 Fluids that obey Newton’s law of flow are but does not cross through the origin.
referred to as Newtonian fluids and fluids which  The materials are said to be “elastic” at shear
deviate are known as non-Newtonian fluids. stresses below the yield value.
 Flocculated solids are light, fluffy
conglomerates of adjacent particles held
together by weak van der Waals forces.
 The yield value exists because a certain
shearing stress must be exceeded in order to
break up van der Waals forces.
 A plastic system resembles a Newtonian
system at shear stresses above the yield
value.
 Yield value, is an indicator of flocculation
(higher yield value, greater degree of
 Newtonian fluids e.g Water, benzene flocculation).

20.12 NON-NEWTONIAN FLUIDS 20.13 PSEUDOPLASTIC FLOW

 Most pharmaceutical fluids (including colloidal
dispersions, emulsions, and liquid suspensions)
do not follow Newton’s law of flow, and the
viscosity of the fluid varies with the rate of shear.
 There are three types of non-Newtonian flow:
 plastic,
 pseudoplastic
 dilatant.

[Link] P LASTIC FLOW

 Pseudoplastic flow is exhibited by polymers in

solution.
 A large of number of pharmaceutical
products, including natural and synthetic
gums (eg, liquid dispersions of tragacanth,
sodium alginate, methyl cellulose, and
sodium carboxymethylcellulose) exhibit
pseudoplastic flow properties.
 Pseudoplastic substances begin flow when a
shearing stress is applied, ie, there is no yield
value (it does cross the origin).
 Viscosity of a pseudoplastic substance
 decreases with increasing shear rate.
Substances that undergo plastic flow are
 With increasing shearing stress, the rate of
called Bingham bodies.
shear increases; these materials are called
 Require force to bring about flow
shear-thinning systems.
 Do not flow till shear stress exceed Yield
value

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 Rheology 92

 Shear thinning occurs when molecules

(polymers) align themselves along their long
axes and slip and slide past each other.

20.14 DILATANT FLOW

 Certain suspensions with a high percentage
of dispersed solids exhibit an increase in
resistance to flow with increasing rates of
shear.
 This type of behavior may be exhibited by
dispersions containing a high percentage
(≥50%) of small, deflocculated particles.
 Dilatant materials increase in volume when
sheared.
 They are also known as shear-thickening
systems (opposite of pseudoplastic systems).
 When the stress is removed, the dilatant
system returns to its original state of fluidity.
 Viscosity increases with increasing shear
rate.
 Dilatant materials may solidify under 20.15 THIXOTROPY
conditions of high shear.
 An isothermal and comparatively slow
recovery, on standing the material, of a
consistency lost through shearing.
 Change by touch
o Thixis ---- touch
o Tropos ---- change
 As shear stress increases viscosity decreases
 On removing stress viscosity is regained after
lag time.

stress application stress
removal
Gel --------------------------> Sol -------
-----------------> Gel

 Thixotropy is a nonchemical isothermal gel-

sol-gel transformation.
 If a thixotropic gel is sheared (by simple
shaking), the weak bonds are broken and a
lyophobic solution is formed.
 On standing the particles collide, flocculation
occurs, and the gel is reformed.
 Bentonite gel

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 Rheology 93

20.17 DILATANT SYSTEM

stress application stress removal
Sol --------------------------> Gel --------------
-------------> Sol

20.16
RHEOGRAMS/FLOW CURVES
/CONSISTENCY CURVE The advantage that thixotropic preparations have is
 Rheograms is plot of shear stress as a that the particles remain in suspension during
function of shear rate. storage, but when required for use, the pastes are
 for thixotropic materials, rheograms are readily made fluid by tapping or shaking.
highly dependent on the rate at which shear  The shearing force on the injection as it is
is increased or decreased and the length of pushed through the needle ensures that it is
time a sample is subjected to any one rate of fluid when injected; however, the rapid
shear. resumption of the gel structure prevents
 A hysteresis loop is obtained. excessive spreading in the tissues, and
 A up-curve consequently a more compact depot is
 A down-curve produced than with nonthixotropic
 Both not superimposable suspensions.

20.18 IRREVERSIBLE THIXOTROPY

 Structure does not reform
 Lag time is so long (LAG TIME is the period of
time between two closely related events or
phenomena e.g., time between stimulus &
response or between cause & effect)
 Gel of higher mol wt polysccharides

20.19 RHEOPEXY

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 Rheology 94

 Rheo ---- flow

 Pexia --- solid
 A property of certain sols which set to gel
form more quickly when mechanical means
are used to hasten the orientation of the
particles.
 time-dependent change
 Non-newtonian fluids – gypsum pastes and
printers ink.

20.20 NEGATIVE THIXOTROPY

 Negative thixotropy is also known as
antithixotropy, which represents an increase
rather than a decrease in consistency on the
down-curve (an increase in thickness or
resistance to flow with an increased time of
shear).
 It may result from an increased collision [Link] E
frequency of dispersed particles (or polymer XAMPLE
molecules) in suspension, which causes Viscosity of water = 0.89 cP
increased interparticle bonding with time. Density of water = 1 g/ml
 At rest the large floccules break up and Flow time of water = 48 sec
gradually return to the original state of small Density of liquid = 0.85 g/ml
floccules and individual particles. Flow time of liquid = 20 sec
 Observed in magnesia magma Viscosity of liquid = ?
[Link] S OLUTION
20.21 ANTITHIXOTROPY
 flocculated
 1-10%

20.22 DILATANCY
0.89/η2 = 1 x 48 / 0.85 x 20
 Deflocculated η2 = 0.89 x 0.85 x 20 / 48
 >50% η2 = 0.315 cP or mPa s

20.23 INSTRUMENTS – VISCOMETERS

A viscometer (also called viscosimeter) is an [Link] F ALLING S PHERE V ISCOMETER
instrument used to measure the viscosity and flow
parameters of a fluid.
 Capillary viscometer
 Falling or rising body viscometer
 Rotational viscometer

[Link] C APILLARY V ISCOMETER

 Involve measuring the time for a fluid to flow
through a capillary
tube.
 Oswald viscometer is common used
 Refined by Cannon, Ubbelohde
 The viscosity of water is 0.890 mPa·s at 25
degrees Celsius, and 1.002 mPa·s at 20
degrees Celsius.
Stockes’ law: the force that retards a sphere
moving through a viscous fluid is directly

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 Rheology 95

proportional to the velocity of the sphere,  Torque is proportional to viscosity

the radius of the sphere, and the viscosity of
the fluid.
 Stockes’ law is the basis of the falling sphere 20.24 APPLICATIONS OF RHEOLOGY
viscometer
 Fluid is stationary in a vertical glass tube.
 A sphere of known size and density is
allowed to descend through the liquid. [Link] E MULSION
 Measure the time it takes to pass two marks  Emulsion (lotion and creams) exhibit non-
on the tube. newtonian behavior
 Electronic sensing can be used for opaque  Lotions – pseudo-plastic
fluids.  Cream (semi solid) – plastic
 Knowing the terminal velocity, the size and  Different rheological behaviors can be
density of the sphere, and the density of the conferred by varying the conc. of dispersed
liquid, Stokes' law can be used to calculate phase and conc/nature of emulsifying
the viscosity of the fluid agents.
 Shear-thinning emulsion are preferred as
 Formula cream
2
η = d g (ρs - ρl) / 18 v  Thixotropic lotion exhibit considerable
η = viscosity consistency when allowed to stand at rest in
d= diameter bottle. Once the bottle is shaken they lose
g= acceleration due to gravity their consistency and easily pour from bottle.
ρs = density of sphere  Stability and release of drug may also
ρl= density of liquid depend on rheological characteristics
V = terminal velocity
[Link] S USPENSIONS
 Most of suspensions exhibit plastic or
[Link] R OTATIONAL V ISCOMETERS pseudo-plastic characteristics along with
 Rotational viscometers use the force thixotropy
required to turn  Rheological
an object in a fluid which can indicate the properties
viscosity of that fluid. depend on
 The viscometer determines the required the degree of
force for rotating a disk or bob in a fluid at flocculation
known speed. of dispersed
o “Cup and Bob" viscometers phase,
o “Cone and Plate” viscometers type/quantity
[Link] “C UP AND B OB " V ISCOMETERS of suspending
 Couette type viscometer (cup is rotated) agent/thicken
 Searle type viscometer (bob is rotated) ing agents
 Sample is placed in the space between added.
 outer wall of bob and inner wall of cup  Pseudoplastic
 Cup/bob is driven by motor ity along with thixotropy is preferred.
 Sample is sheared  Proper selection of rheological
 Torque is measured characteristics also improve the physical
 Torque is proportional to viscosity stability of suspensions

[Link] “C ONE AND P LATE ” VISCOMETERS [Link] O INTME

 Consists of stationary “plate” and revolving NT AND G EL
“cone”  Rheological
 Sample is placed at the centre of plate characteristics
 Plate is raised into position under cone directly affect
 Cone is driven by motor stability, elegance
 Sample is sheared in the narrow gap b/w and extrudability
cone and plate from tube
 Torque is measured  Capacity to take
up solid/liquids,

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 Rheology 96

adherence/spreadability on the skin and

release of drug from base, are also affected
 Most of topical semisolid show plastic flow
(hydrocarbon bases). Dilatancy and
pseudoplastic behaviors with thixotropy is
also observed.
 Flow behaviors ranges from plug flow to
stream line flow
 Powder and granules
 Good Rheological characteristics of
granules/powder are required to ensure
uninterrupted flow from hopper to die
cavities
 Also important during encapsulation.
 Stickiness and roughness of surface should
be reduced for adequate flow.

[Link] P ROCESSES
[Link] M IXING
Large impeller at low shear rate is required
for shear thinning system. To ensure
effective mixing.
Semisolid exhibiting dilatant properties
should be processed with a low shear mixer
to prevent a consistency build up.
[Link] T RANSFER
Rheology is also important during fluid
transfer from one site to another.

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 Rate and Order of Reaction 97

o C is the concentration of reactants, and

Chapter 21 RATE AND ORDER o n is the order of the reaction.
OF REACTION  Usually, pharmaceutical degradation can be
treated as a Zero-order or first-order.
 The first step of the example reaction,
21.1 STABILITY
“The ability of a Pharmaceutical product to retain its
chemical, physical, microbiological and
biopharmaceutical properties within specified limits  The rate of reaction = k1 [N2O5], i.e. there is
throughout its shelf life” ). only one concentration term and the
“The capacity of a drug product to remain within reaction is known as first order.
specifications established to ensure its identity,  In the second step,
strength, quality and purity”
The extensive chemical degradation of the active  where k1 and k2 are the reaction rate
ingredient can cause: constants. Thus there are two concentration
 Substantial loss of active ingredient from the terms and the reaction is known as second
dosage form order.
 Can produce a toxic product that has
undesirable effects [Link] Z ERO O RDER
 Instability of the product can cause  In a zero-order reaction, the rate is
decreased bioavailability. independent of the concentration of the
reactants (rate is constant)
21.2 KINETICS  Other factors, such as absorption of light in
certain photochemical reactions, determine
Kinetics is the study of the rate at which processes
the rate.
occur.
 Zero-order reaction can be expressed as
The kinetic studies are useful in providing information
that:
 Gives an insight into the mechanism of the
changes involved, and
 Allows prediction of the degree of change
that will occur after a given time 
 Apply where reaction sites are saturated
(enzyme kinetics, drug receptor interaction)
21.3 RATE OF REACTION/ PROCESS  A constant rate of drug release from a
 The velocity with which a reaction or process dosage form is highly desirable
occurs is called RATE of Reaction.  A plot of the amount decomposed (as
 It is expressed as dC/dt (the change in ordinate) against time (as abscissa) is linear
concentration, or C; within a given time with a slope of k0
interval, or dt).  The units of k0 are concentration time-1.
 Reaction rates depend on certain conditions  Many decomposition reactions in the solid
(e.g. reactant conc., temperature, pH, phase or in suspensions apparently follow
presence of solvents or additives). Radiation zero-order kinetics.
and catalytic agents (e.g. polyvalent cations)
also have an effect.

21.4 ORDER OF A REACTION / PROCESS

 The way in which the concentration of the
drug or reactant in a chemical reaction
affects the rate is called order of a reaction
or process.
 The rate of a reaction is proportional to the
concentration to the nth power, where n is
the order of the reaction. That is,
n
dC/dt α C
o dC/dt is the rate of a reaction,

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 Rate and Order of Reaction 98

 If there are two reactants and one is in large and hardly alters during the course of the
excess, the reaction may still follow first- reaction.
order kinetics because the change in  [H2O] can be taken as a constant and
concentration of the excess reactant is incorporated into the second-order rate
negligible. This type of reaction is a PSEUDO constant, k':
FIRST - ORDER REACTION . Rate = k'
 Consider the hydrolysis of ethyl acetate: [CH3COOEt]
 CH3COOEt + H2O ---> CH3COOH + EtOH  Thus the reaction is, in effect, first order with
 Strictly the reaction is second order and the a rate constant k'. This applies to many drug
rate of decompositions by hydrolysis in aqueous
 reaction is expressed as: solution.
 Rate = k2 [CH3COOEt] [H2O]
[Link] S ECOND - ORDER R EACTION
[Link] F IRST O RDER  The rate depends on the concentration of
 In a first order reaction, the rate depends on two reacting species, A and B.
the concentration of a single reactant  For the usual case where the initial
 In first order reaction, drug concentration concentrations of A and B are different, the
decreases exponentially with time rate equation is:


 A plot of time (as ordinate) against the 1/c
 A plot of time (as ordinate) against the
(as abscissa) is linear.
logarithm of the amount remaining (as  The units of k2 are concentration–1 time–1.
abscissa) is linear.
 The units of k1 are time–1.

21.5 DETERMINATION OF ORDER AND RATE

CONSTANT FROM EXPERIMENTAL DATA
Substituting the data into the integrated equations
 If there are two reactants and one is in large
and observing which plot is a straight line.
excess, the reaction may still follow first-
order kinetics because the change in
concentration of the excess reactant is
negligible. This type of reaction is a pseudo
first-order reaction.
 Consider the hydrolysis of ethyl acetate:
CH3COOEt + H2O ---> CH3COOH + EtOH
 Strictly the reaction is second order and the
rate of reaction is expressed as:
Rate = k2
[CH3COOEt] [H2O]
 In a dilute aqueous solution of ethyl acetate,
[H2O] is very large compared to [CH3COOEt]

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 Rate and Order of Reaction 99

(e.g. low molecular weight alcohols, such as

the polyethylene glycol (PEGs) to stabilize
the drug.
 Rate is altered because:
1. Alters the transition state
2. The activity coefficients
3. pka
4. Surface tension
5. Viscosity
 In some cases, additional reaction pathways
are generated. For example, with an
increasing concentration of ethanol in an
aqueous solution, aspirin degrades by an
extra route and forms the ethyl ester of
acetylsalicylic acid.

[Link] C HANGE IN P H
+
 H catalysis predominates at lower pH,
-
whereas OH catalysis operates at higher pH.
 At intermediate pH, the rate may be pH
+
independent or may be catalyzed by both H
-
and OH .
 Effect of pH on degradation kinetics is
determined

21.6 FACTORS THAT AFFECT REACTION

RATES
[Link] T EMPERATURE
 An increase in temperature causes an
increase in reaction rate, as expressed in the
equation first suggested by Arrhenius.
-Ea/Rt
k= A e or
log k = log A – (Ea/2.303 1/RT)
o k is the specific reaction rate
constant.
[Link]
o A is a constant known as the
frequency factor. P RESENCE OF A DDITIVES
o Ea is the energy of activation,  Buffer affects the rate of degradation,
o R is the molar gas constant, and primarily as a result of salt increasing the
o T is the absolute temperature. ionic strength.
 Increasing salt concentrations (e.g.,. citrate,
phosphate), can substantially affect the
[Link] P RESENCE OF S OLVENT .
magnitude of pka. In this way, they change
 Many dosage forms require the
the rate constant.
incorporation of a water miscible solvent

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 Rate and Order of Reaction 100

 Buffer salts can also promote drug

degradation through general acid or base
catalysis.
 Surfactants may acceralate or decelerate
drug degradation.
 Acceleration of degradation is common and
is caused by miceller catalysis.
 Stabilization of a drug through the addition
of a surfactant is less common.

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 Stability Studies 101

Chapter 22 STABILITY STUDIES 22.6 TYPE/NATURE

 Long term (real time)
22.1 STABILITY To claim shelf life
 Accelerated
 “The ability of a Pharmaceutical product to
Product development
retain its chemical, physical, microbiological
and biopharmaceutical properties within
specified limits throughout its shelf life” 22.7 STORAGE CONDITIONS
General case
(WHO GUIDANCE, 1996) 
o o
Accelerated 40 C + 2 C / 75%RH + 5% RH
 “The capacity of a drug product to remain 
o o
Long term 25 C+ 2 C / 60 %RH + 5% RH
within specifications established to ensure its
identity, strength, quality and purity” [Link] D RUG PRODUCTS INTENDED TO BE
STORED IN A REFRIGERATOR
(FDA GUIDANCE, 2006)

o o
Accelerated 25 C+ 2 C / 60%RH + 5% RH
 The extent to which a product retains, within

o o
specified limits, throughout its period of Long term 5 C + 3 C
storage and use, the same properties and
characteristics possessed at the time of its 22.8 CLIMATIC ZONES
packaging. Four climatic zones have been defined based on
characteristic prevalent annual climatic conditions:
22.2 STABILITY STUDIES  Climatic Zone I
 Stability studies provide the evidences on  Climatic Zone II
how the quality of a drug substance/ product  Climatic Zone III
varies with time under the influence of a  Climatic Zone IV
variety of environmental factor such as
temperature humidity and light. [Link] C LIMATIC Z ONE I
 Stability data is used to determine:  Temperate Climate
o
o shelf life o 20 C and 42RH
o storage conditions  Canada, Germany
o packaging  Long term (real time)
o
o 25 C / 60%RH
 Accelerated
22.3 SHELF LIFE o
o 40 C / 75%RH
 The time period during which a
pharmaceutical product is expected to [Link] C LIMATIC Z ONE II
remain within the approved shelf life  Subtropical & Mediterranean climate
specifications, provided that it is stored o
o 21.6 C and 52RH
under the labeled storage conditions.  Iraq, Jordan
 Long term (real time)
o
22.4 SPECIFICATIONS o 25 C / 60%RH
 Accelerated
 The combination of physical, chemical, o
o 40 C / 75%RH
biological, and microbiological tests and
acceptance criteria for these tests.
[Link] C LIMATIC Z ONE III
 Hot & Dry
22.5 PURPOSE o
o 26.4 C and 37RH
 Evaluation of influence of product related  France, Korea
factors on stability of Dosage Form  Long term (real time)
o
 physical and chemical properties of o 30 C / 65%RH
excipients,  Accelerated
o
 dosage form and its composition, o 40 C / 75%RH
 the nature of container-closure system
 packaging material [Link] C LIMATIC Z ONE IV
 Manufacturing conditions  Very hot/Humid
o
o 26.7 C and 76RH

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 Stability Studies 102

 Pakistan, India 22.10 STABILITY PROTOCOLS

 Long term (real time)
o
o 30 C / 65%RH 1. Type, size and number of batches
 Accelerated 2. Type, size and source of container and
o
o 40 C / 75%RH closure
3. Container storage orientation test time point
4. Sampling time points
22.9 TESTING PARAMETERS 5. Sampling plan
6. Test storage conditions
[Link] T ABLETS 7. Test parameters
 Dissolution 8. Test methods
 Friability / hardness 9. Acceptance criteria
 Water content
[Link] T YPE , S IZE AND N UMBER OF
[Link] H ARD G ELATIN C APSULES B ATCHES
 Dissolution  1-3
 Water content o research
 Brittleness o production batch
 First three batches
[Link] E MULSIONS
 Phase separation [Link] L ABORATORY S CALE B ATCH
 Mean size and distribution of dispersed  early stage of development
globules  100-1000 time less
 pH  helps in suitable manufacturing process
 Viscosity
[Link] P ILOT S CALE B ATCH
 Level of microbial contamination
 A batch of an active substance or
pharmaceutical product manufactured by a
[Link] O RAL S USPENSIONS procedure that is fully representative of and
 pH simulating that to be applied to a full
 Viscosity production scale batch.
 Formation of precipitates  Not < 10 time
 Redispersibility
[Link] P RIMARY B ATCH
 Mean size and distribution of particles
 A batch of an active substance or
 Level of microbial contamination
pharmaceutical product used in a formal
stability study, from which stability data is
[Link] O RAL S OLUTIONS submitted in a registration application for
 Clarity for solution the purpose of establishing a re-test period
 pH or shelf life respectively.
 Level of microbial contamination
[Link] P RODUCTION B ATCH
 Specific gravity
 A batch of an active substance or
 Color change
pharmaceutical product manufactured at
production scale by using production
[Link] P OWDERS FOR O RAL S USPENSIONS equipment in a production facility as
 Water content
specified in the application.
 Reconstitution time
[Link] T YPE , S IZE AND S OURCE OF
[Link] T OPICAL P RODUCTS
C ONTAINER AND C LOSURE
 Homogeneity
 Same as proposed for marketing
 pH
 May include secondary pack but not shipper
 Redispersibility (for lotions)
 Separate testing f available in different
 Viscosity
containers
 Particle / globule size distribution
 Container storage orientation test time point
o Upright
[Link] O PHTHALMIC P RODUCTS
o Inverted or on-the-side position
 Sterility
 Particle size distribution (for suspensions)

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 Stability Studies 103

[Link] S AMPLING T IME P OINTS [Link] T EST M ETHODOLOGY

(F REQUENCY )  Test and its method follow Official
 At the accelerated storage conditions, a compendia
minimum of three time points for sampling,  If not given in compendia the validate it
including the initial and final time points  Validate for specificity, precision, linearity,
from a 6 month study period are reproducibility and range
recommended.
 Accelerated 0, 15, 30, 60 [Link] A CCEPTANCE C RITERIA
and 90 days  Fixed numerical limits when result is in
 Long term 0, 3, 6, 9 12, 18, quantitative terms (Moisture, viscosity,
24 and 36 months particle size, assay etc)
 If available in different strength then  For qualitative tests (color, ordour, phase
reduced testing plan are adopted separation etc) it may be PASS or FAIL
 Bracketing design
 Matrixing design 22.11 STABILITY CHAMBERS /ROOMS
[Link] B RACKETING DESIGN  Specially designed equipment used in the
Highest and lowest strength/size is tested stability testing of pharmaceutical products.
 Used to maintain specified environmental
conditions of temperature, humidity and
light.
 Range in size from the smallest 182 liter (6.5
[Link]) when demand for test space is small,
to the largest standard Walk-in Room.
 Stability chambers are used for accelerated
and long-term testing.
 A stability test chamber must perform
reliably and accurately throughout this time.
[Link] M ATRIXING DESIGN  Fitted with recording, safety and alarm
All strength are tested at all point devices
 Maintenance or service interventions during
the testing are disruptive and costly
 For photostability: Combination of visible
light and near UV, on separate shelves
(important for maximum light uniformity)
 Provide circulation of air for more uniform
distribution of temperature and humidity.

[Link] S AMPLING P LAN

 Number of samples
 Plan of sampling
o Represent whole batch
o Unbiased
o nth container

[Link] T EST S TORAGE C ONDITIONS

 Product
 Zone

[Link] T EST P ARAMETERS

 Type of dosage form
 API and sometime degradation products

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 Stability Studies 104

 eg Aspirin, sulphonamide, spiranolactone,

penicillin
 Esters usually undergo hydrolytic reactions
that cause drug instability.
 Formulators are reluctant to incorporate
drugs that have ester functional groups into
liquid dosage forms.
[Link] P REVENTION
 Replace water
 Prepare suspension
 Prepare dry powder

[Link] O XIDATION
 Oxidation is usually mediated through
reaction with atmospheric oxygen under
ambient conditions (auto- oxidation).
 Also due to reversible loss of electron
 Both water and oil soluble drug are degraded
 Aldehyde, alcohol, alkaloids, unsaturated fats
 Riboflavin, adrenaline
[Link] P REVENTION
 Pack in an inert atmosphere (e.g. nitrogen)
to exclude air from their containers.
 Fill the container completely
 Use sod bisulfite, butylated hydroxy toluene,
ethylene diamine tetra acetic acid
22.12 MODES OF PHARMACEUTICAL
DEGRADATION 22.14 PHOTOlYSIS
 Photolysis is the degradation of drug
The decomposition of active ingredient in a dosage
molecules by normal sunlight or UV.
form occurs through several pathways
 Activation energy is needed. Molecules may
absorb the proper wavelength of light and
[Link] C HEMICAL DEGRADATION acquire sufficient energy to undergo
 Solvolysis reaction.
 Oxidation  Photolytic degradation occurs on exposure
 Photolysis to light of wavelengths less than 400nm.
 Dehydration Shorter wavelength are more dangerous
 Isomerization  Once started -- continue even light source is
 Racemization removed
 Decarboxylation  Chlorpromazine, morphine, codeine
[Link] P REVENTION
[Link] P HYSICAL DEGRADATION  An amber glass bottle or an opaque
 Loss of volatile components container acts as a barrier to this light,
 Loss of H2O thereby preventing or retarding photolysis.
 Absorption of H2O For example, sodium nitropruside in aqueous
 Crystal growth solution has a shelf life of only 4 hours if
 Polymorphic changes exposed to light. When protected from light,
 Colour changes the solution is stable for at least 1 year.
 Avoid direct light
22.13 CHEMICAL DEGRADATION
22.15 PHYSICAL DEGRADATION
[Link] S OLVOLYSIS (H YDROLYSIS )
 Hydrolysis is the most common type of [Link] L OSS OF V OLATILE C OMPONENTS
degradation because many medicinal
compounds are esters, amides or lactams.

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 Stability Studies 105

 Volatile components such asAlcohol, ether, [Link] C RYSTAL G ROWTH

Iodine, volatile oils, Camphor, menthol,  In solutions after super saturation crystal
Nitroglycerine evaporates. growth occurs
[Link] P REVENTION  Reason may be the fall in temp and a
 Such product should be placed in well closed consequent ↓ in solubility of solute
container e.g.
 Place at low temperature · Injection of calcium glucconate
 In suspensions crystals settle down and
caking occurs and suspension becomes
[Link] L OSS OF H 2 O unstable.
 Loss of water from o/w emulsions thus its e.g. Ophthalmic preparations.
stability changes. [Link] P REVENTION
 Water evaporates causing the crystalline  Minimum temp. flocculation should be
growth. managed
This will result into ↑ in potency & ↓ in  Incorporation of surface active agent
weight.  By increasing viscosity of suspending
 This tendency depends on temp. and material
humidity of surrounding environment.
e.g. water evaporates from efflorescent salts [Link] P OLYMORPHIC C HANGES
such as Na2SO4, borax  In polymorphic changes crystal forms are
[Link] P REVENTION changed. A stable crystal form loosens.
 Such product should be placed in well closed This may cause alteration in solubility and
container possibly crystalline growth in aqueous
 Use glass containers suspensions
[Link] P REVENTION
[Link] A BSORPTION OF H 2 O  Formulated products should contain a stable
 Hygroscopic drugs absorb the water from crystalline form of the drug.
external atmosphere causing the physical
degradation. [Link] C OLOUR C HANGES
 Depends on temp and humidity of  Colour changes is due to
surrounding material o pH change
e.g. o Presence of reducing agent
· Glycerin suppositories may become opaque o Exposure to light
· Gelatin capsule may soften [Link] P REVENTION
· Some deliquescent salts calcium chloride,  PH should not be changed
potassium citrate. Exposure to light should be avoided
[Link] P REVENTION
 Such product should be placed in well closed
container
 Use moisture absorbent

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 Stability Studies 106

REFERENCE BOOKS
1. Martin, Physical Pharmacy, B I Waverly PVT, Delhi, 5th Ed., 2005.
2. Cooper and Gunns Tutorial Pharmacy, 6th Ed, CBS Publishers & Distributors, New Delhi, 2005.
3. Bentley‘s Pharmaceutics, All India Traveler Book Seller, New Delhi, 1996.
4. Martin P, Bustamante P and Chun, Physical & Chemical Principles of Pharmaceutical Science, AHC, 6th Ed.,
(1999), New York.
5. Martin AMN, Banker G S and Chun AHC Advances in Pharmaceutical Sciences. Vol 7, Academic Press,
London, 1995.
6. Mill C C Casson,N. Rheology of disperse systems. Pergamon Press, New York, 1975.
7. Rienger M and Scott-Blair. G W Rheology. Academic Press, London, 1990.
8. Barry B W Advances in Pharmaceutical Sciences, Academic Press, London, 1990.
9. Sherman P Emulsion Science, Academic Press, London, 1972. 1 [Link] A, Swarbrick J and Cammatra A
10. Physical Pharmacy, 3rd Ed., Lee & Febiger, Philadelphia. 1983.
11 Attwood D and Flocence A T Surfactant [Link] and Hall Ltd, London, 1982.

Pharmacy Exam Guide