Preformulation

• Introduction:
• It is essential to know the fundamental physico-chemical properties
of the potential drug molecules before formulation.
• This information further help to develop a good formulation.
• This first learning phase is term as Preformulation.
• Definition: “The steps to be undertaken before formulation”.
• Significance/ Importance:
• 1. It give detail information on feasibility of the various possible
dosage forms.
• 2. It also give detail information about any potential problems of
instability & poor in-vivo dissolution & ultimately Bio-availability.
• 3. It also gives guidance regarding suitability of excipients to be used
in formulation.
 Principle areas of preformulation

• 1. Bulk characterization
• i. Crystallinity
• ii. Polymorphism
• iii. Fine particle characterization.
• iv. Bulk density
• v. Powder flow properties.
• 2. Solubility analysis
• i. Ionization constant (pKa)
• ii. pH solubility profile
• iii. Common ion effect (Ksp)
• iv. Thermal effects
• v. Solubilization
• vi. Partition coefficient
• Vii. Dissolution
 Principle areas of preformulation

• 3. Stability analysis
• i. Stability in toxicology formulations
• ii. Solution stability-
• - pH rate profile
• iii. Solid state stability
• - Bulk stability
• - Compatibility
I. Bulk Characterization
 1. Crystallinity & polymorphism
• Crystal habit & internal structure of a drug can affect bulk &
physicochemical properties which range from simple flowability to
complicated chemical stability.
• Habits refers to the outer appearance of a crystal whereas internal
structure is the molecular arrangement within the solid.
• The different habits of crystals are shown in fig. 1
• The internal structure can be classified as as shown in fig. 2
• The first major classification is whether the solid is crystalline or
amorphous.
• Crystal:- Fixed geometric pattern arrangement of atoms or molecules
in a 3-D array.
• Amorphous:- randomly placed atoms or molecules like in liquid.
Fig: 1- Different habits of crystals
Fig: 2- Classification of internal structure
 1. Crystallinity & polymorphism

• Amorphous forms can be obtained by rapid precipitation,

lyophilization, or rapid cooling.
• Amorphous forms offers advantages over crystalline solid like higher
solubility & dissolution.
• Disadvantage: But being thermodynamically instability, it convert
into stable crystalline form in bulk processing or within dosage form.
• Crystalline compounds are further classified into stoichiometric or
nonstoichiometric depending on amount of crystallization solvent.
• Stoichiometric: the ratio of amount or contribution of the atoms or
molecules remains constant.
• Nonstoichiometric: this ratio of amount or contribution of the atoms
or molecules is not constant.
• The adducts is undesirable due to its lack of reproducibility.
• In case of stoichiometric, this adduct referred as solvate.
 1. Crystallinity & polymorphism

• When the incorporated solvent is water, it is referred as hydrate.

• So that terms like hemihydrates, monohydrates, dihydrate, trihydrate,
tetrahydrate, pentahydrate & so on used describe molar equivalents
of water corresponding to half, one, two, three, four, five respectively.
• The compound which not contains any water within its crystal
structure is termed as anhydrous.
• Application: To increase the efficacy of the drug.
• Example Ampicillin when administered as a suspension, in two
forms, one as a anhydrous & second as a trihydrate, the in vivo data
shows that, Ampicillin anhydrate produced higher & earlier peaks in
blood serum levels than trihydrate form.

Fig. 4: Citric acid monohydrate

Fig: 3- Effect of solvate forms
 2. Polymorphism

• Polymorphism is the ability of a compound to crystallize as more than

one distinct crystalline species with different internal lattices.
• Changes in Chemical stability & Solubility with polymorphism have
great impact on product development & bio-availability.
• Example
• Chloramphenicol palitate exists in three crystalline polymorphic forms
as A, B, C, & in amorphous form.
• When the peak serum levels of all has been studied, it was observed
that peak serum level for B form is more than for the rests.
• Many physicochemical properties vary with the change in internal
structure like melting point, density, hardness, crystal shape, optical
properties, electric properties, & vapor pressure.
 2. Polymorphism
• Polymorphs can be classified into two types
• 1. Enantiotropic (one polymorph can be reversibly changed into
another by varying temperature or pressure) e.g. Sulphur
• 2. Monotropic (one polymorphic form is unstable) e.g. glyceryl
stearates.
• During preformulation it is important to identify the polymorphs that is
stable at room temperature & whether polymorphic transitions are
possible within the temperature range used for stability studies &
during processing like drying, milling etc.
• A polymorphic compound is best characterized by a complete
pressure-temperature phase diagram showing melt-vapor, solid-
vapor, & solid-melt curves.
• In pharmaceutics, a free energy-temperature curve should be
constructed at 1 atm pressure since temperature is more critical
variable than pressure.
• Example, Chloramphenicol palmitate has three polymorphic forms.
 2. Polymorphism
• The three polymorphic forms can be described by Van’t Hoff plot of
free energy versus temperature.
• A transition temperatures of three forms are shown by intersection of
the extrapolated lines; 50 0C for A & C forms, & 88 0C for B.
• Form A is more stable at a temperature less than 50 0C.
• This method suffers from drawback of large error in estimation.
• The more difficult task in the study of polymorphism is determination
of the relative stability of metastable polymorphs & prediction of its
rate of conversion within a dosage form.
 2. Polymorphism

• Methods for characterization of solid forms

• 1. Microscopy
• 2. Fusion method (Hot stage microscope)
• 3. Differential Scanning Calorimetry (DSC)
• 4. Differential Thermal Analysis (DTA)
• 5. Infrared Spectroscopy (IR/FTIR)
• 6. X- ray powder diffraction (XRPD)
• 7. Scanning electron microscopy (SEM)
• 8. Thermogravimetric Analysis (TGA)
• 9. Dissolution/ Solubility analysis
 2. Polymorphism
• 1. Microscopy
• The crystals are observed under microscope.
• A train optical crystallographer is required to characterize the crystal axis
whether it is uniaxial or biaxial.
• The polarizing microscope fitted with a hot stage is a useful instrument for
investigating polymorphism, melting points, transiton temperature, & rates of
transition at controlled rate of heating.
• The differentiation between anhydrous & hydrous can also be carried out by
hot stage microscope.
• Sample is heated in degassed immersion oil (Silicone oil).
• So hydrates with evolve a gas causing bubling of the oil while that of
anhydrous form bubling will not observed & it will simply melts & forms a
second globular layer.
• The temperature at which bubling will occurs is corresponding to boiling point
of that solvent. From that identification can be done.
• The major disadvantage is, certain organic compound may undergo
degradation when it melts & recrystallization of the melt may not occur,
because of the presence of contaminant degradation products.
 2. Polymorphism

• 2. TGS, DSC, & DTA

• Principle: all measure the heat loss or gain resulting from physical or
chemical changes within a sample as function of temperature.
• It having wide applications in preformulation studies including purity,
polymorphism, solvation, degradation, & excipient compatibility.
• 3. X-Ray
• Each crystal will diffract the X-ray light at one particular angle.
• This angle is specific for each compound & hence can be used to
checked batch to batch reproducibility.
 3. Hygroscopicity

• Many drugs substances, particularly water soluble salt forms, have

tendency to adsorb atmospheric moisture.
• Adsorption & equilibrium moisture content can depend upon the
atmospheric humidity, temperature, surface area, exposure, & the
mechanism for moisture uptake.
• Due to adsorption of moisture, many influence chemical stability,
flowability, & compactibility.
• The measurement of moisture by sample determined by exposing a
thin layer of bulk drug in an open container to controlled humidity &
then moisture level determined by gravimetry, TGA, Karl Fischer
titration, or gas chromatography.
• If drug is susceptible to moisture, then special type of packaging
material or use of desiccant & direction of storage that store in low
humidity condition should be mentioned.
 4. Fine particle characterization

• Bulk flow, formulation homogeneity, & surface area controlled

process like dissolution & chemical reactivity are directly affected by
size, shape, & surface morphology of the drug particles.
• So that particle size of bulk drug by using microscopy, Coulter
counter etc is determined.
• The surface area of the powder sample is determined by BET
(Brunauer, Emmett, & Teller) isotherm.
• As each molecule of nitrogen occupy area of 16 A2 one may compute
the surface area per gram for each preweighed sample from amount
of nitrogen adsorb by sample.
• Surface morphology is observed by SEM.
 5. Bulk Density
• It is more important which selecting the size of capsule to deliver high
doses.
• The bulk density & tapped density for a bulk drug is determined.
• By knowing the tapped density we can select a appropriate size of
capsule by using the figure.
 6. Powder flow properties

• Pharmaceutical powders are broadly classified as free flowing or

cohesive (non-free flowing).
• The flow property of powder mostly affected by particle size, density,
shape, electrostatic charge, & adsorbed moisture.
• Flow properties of powder can be measured by
• 1. Carr's Index
• 2. Hausner ratio
• 3. Angle of repose: It is useless because of its lack of precision.
 Carr's index or % Compressibility index

• % CI = [Tapped density – bulk density / tapped density] x 100

Sr. No. Flow % CI

character

1 Excellent < = 10

2 Good 11-15

3 Fair 16-20

4 Passable 21-25

5 Poor 26-31

6 Very Poor 32-37

7 Very very poor > 38

 Hausner ratio

• Hausner ratio = Tapped density / Bulk density

Sr. No. Hausner ratio Flow character

1 < 1.25 Good

2 1.25 – 1.5 Fair

3 > 1.5 Poor

II. Solubility Analysis
 7. Solubility analysis

• It is very essential to know the solubility of a drug in particular

solvents that further helps in product development.
• The preformulation study generally include
• 1. Determination of pKa
• 2. pH solubility profile & common ion effect
• 3. Temperature dependence
• 4. Solubility product
• 5. Solubilization mechanisms
• 6. Rate of dissolution
• Analytical methods that are used for measurement of solubility
include HPLC, UV spectroscopy, Fluorescence spectroscopy, & gas
chromatography.
 8. Partition coefficient
• It is a measurement of lipophilicity & an indication of its ability to
cross cell membranes is the oil/water partition coefficient.
• It defined as the ratio of un-ionized drug distributed between the
organic & aqueous phase a equilibrium.
• Although the partition coefficient data alone does not provide
understanding of in vivo absorption, it does provide a means of
characterizing the lipophilic/hydrophilic nature of the drug.
 9. Dissolution

• Dissolution of a drug particle is controlled by several physicochemical

properties, including chemical form, crystal habits, particle size,
solubility, surface area, & wetting properties.
• During compression, all the properties mentioned above of the active
drug may change which ultimately affects on dissolution.
• Dissolution with excess drug can be used to characterized
metastable polymorphs or solvates.
• The figure shows the conversion of the metastable form II to form I is
occur in an organic solvent medium.
• Which clearly indicate that, form I is thermodynamically stable & II is
unstable.
III. Stability profile
 10. Stability in Toxicology Formulations

• Although the toxicology studies commence early in drug

development phase, it is often advisable to evaluate samples of the
toxicology preparation for stability & potential homogeneity problems.
• Usually large amount of drug is administered to the animal in the
feed, or by oral gavage of a solution or suspension of the drug in an
aqueous vehicle.
• As the water, enzymes, vitamins, minerals etc reduces the stability of
the drug in feed.
• So that fresh sample of the feed to be used in the toxicology test
provides the most relevant stability data.
 11. Solution stability
• The objective of preformulation research is identification of conditions
necessary to form stable solution.
• These include the effects of the pH, ionic strength, cosolvent, light,
temperature, & oxygen.
• The stability of solution starts with evaluating the stability at extreme
conditions of pH & temperature like 0.1 N HCl, water, 0.1 N NaOH all
at 90 0C.
• This will help to assay specificity as well as maximum rate of
degradation.
• Then the stability in all pH range should be checked in order to
identify the pH of maximum stability.
• Only pH will change & keep all the things constant.
• Stability in cosolvents is also determined.
• The sample also subjected to light stability study, in which a sample
is place in amber or yellow-green color glass container while the
control sample stored in cardboard packages or wrapped in
aluminum foil.
• Some drugs may be susceptible to oxidation. Then stability in
presence of oxygen is also determined.
• In this testing, sample should be subjected to
• 1. With an excessive head-space of oxygen
• 2. With a head-space of an inert gas such as nitrogen or helium
• 3. With an inorganic antioxidants like sodium metabisulfite
• 4. With an organic antioxidants like BHT or BHA.
• To generate a pH-rate profile, stability data generated at each pH &
temperature condition are analyzed kinetically to yield the apparent
degradation rate constant.
• Then all the rate constants at a single temperature are plotted as a
function of pH.
• The minimum of this curve is the pH of maximum stability.
Fig: The pH rate profile for ampicillin degradation in solution at
35 0C & at constant ionic strength
Fig: The pH rate profile for penicillin degradation
 12. Solid state stability
• The primary objective of this study is to identify stable storage
conditions for drug in the solid state & identification of compatible
excipients for a formulation.
• In general, solid state reactions are much slower & more difficult to
interpret than solution state reactions.
• In solid sate, purity & crystallinity severely affects on stability.
• The change polymorphic change can be detected by DSC or
quantitative IR analysis.
• To determine the solid state stability profile of a new compound,
weighed samples are placed on open screw can vials & are exposed
directly to a variety of temperature, humidities, & light intensities for
up to 12 weeks.
• The set of samples should be prepared to checked whether the
degradation in solid state occurs by oxidation or humidity or by both.
 Dosage Form Design
• Principles of dosage form design:
• Drugs are rarely administered as pure chemical substances
alone.
• It is almost always given as formulated preparations or
medicines.
• The pharmaceutical formulations are vary from a simple
solutions to complex drug delivery systems through the use of
appropriate additives or excipients in the formulation.
• The excipients have specialized pharmaceutical functions like
solubilization, suspending, thickening, preserving, emulsifying,
dissolution modifier, improve the compactability, flavouring,
sweetening, diluents, glidants, lubricants, antiadherants,
colouring, disintegrant, environmental protection, to improve
the stability of formulation etc.
 Dosage Form Design
• The principle objective of dosage form design it to achieve a
predictable therapeutic response to a drug that can be
formulated on large scale with reproducible quality.
• For reproducible results, numerous features are required like
chemical & physical stability, preservation against microbial
contamination, uniformity of dose of drug, suitable packaging
etc.
• Ideally it is expected that the dosage form should also be
independent of patient to patient variation, but in practice it is
remains difficult task to achieve.
• With advancement in technology now it is possible to
controlled the drug release example, sonophoresis in which the
drug release trigger by applying, magnetic field.
• Implants, iontophoresis, osmotic devices etc.
 Dosage Form Design
• So that special consideration given on differences in
bioavailability between apparently similar formulations & the
possible causative reasons.
• So that to optimize the bioavailability of drug substances, it is
often necessary to carefully select the most appropriate
chemical form of the drug.
• Drug can be formulated in numerous dosage forms for
convenience & efficacious treatment of a disease.
• Therefore drug can be formulated & administered by
alternative routes to maximize therapeutic response.
• So that drug can be taken orally or injected or applied on skin
or inhaled.
 Dosage Form Design
• However, it is necessary to relate the drug substance to the
clinical indication being treated before the correct combination
of drug & dosage form can be made since each disease or
illness often requires a specific type of drug therapy.
• Along with that, the influence of route of administration &
specific requirement of that particular route take into
consideration while designing dosage form.
• For example paracetamol can be formulated as a tablet,
dispersible tablet, suppositories, oral suspension, paediatric oral
solution, paediatric soluble tablet, sugar free oral solution.
 Dosage Form Design
• Therefore before formulating a drug into a successful dosage
form, many factors must be take into consideration.
• These factors can be broadly classified into three categories.
• 1. Biopharmaceutical consideration, including factors affecting
the absorption of the drug substance from different
administration route.
• 2. Drug factors such as physical & chemical properties of drug
substances.
• 3. Therapeutic considerations, including consideration of the
clinical indication to be treated & patient factors.
 Biopharmaceutical aspects of dosage form
design
• Biopharmaceutics is the study of the relationship between the
physical, chemical, & biological sciences applied to drugs, dosage
forms, & drug actions.
• All these related to drugs absorption, distribution, metabolism &
excretion.
• Whatever the route of administration, drug substance must be in the
solution form before it can be absorbed.
• Drugs are absorbed by two general pathways
• 1. Passive diffusion
• 2. Specialized transport mechanism
• a. Active transport
• b. Facilitated
• Once get absorb drug may act locally or at specific site in which it is
transported from site of administration to site of action.
Fig. no.1:- Pathways a drug may take following the
administration of a dosage form by different route.
 Continue...
• Drug design to delivered by buccal, respiratory, rectal, intramuscular,
or subcutaneous routes, the drug directly passes into the blood
circulation from absorbing tissue.
• While in case of intravenous route drug directly goes into blood
circulation.
• While in case of oral route, drug absorption is slow due to transit
time in GIT tract, absorption, & hepatoenteric blood circulation,
therefore the drug action will be delayed.
• The physical form of the drug will also influence the absorption rate
& onset of action.
• Like solutions acting faster than suspensions, which act faster than
capsules & tablets.
• Then drug gets distributed, metabolized, & eliminated after
absorption from body via urine, faeces, saliva, skin or lungs in
unchanged or metabolized form.
 Routes of administration
• 1. Oral Route
• It is used more frequently for systemic drug delivery & sometimes
for local effect.
• The dosage form first gets dissolve in GIT fluid, then gets absorb
through various epithelia & mucosa of the GIT tract.
• Advantages:-
• Simplest
• Most convenient
• Safest means of drug administration.
• Disadvantages:-
• Slow onset of action
• Irregular absorption
• Degradation of drug due to enzymes, pH conditions etc in GIT tract.
 Routes of administration
• 1. Oral Route
• Example: Insulin containing preparations are inactivated by the
action of stomach fluids.
• Change in the solubility of drug results in decrease in solubility.
• Like tetracyclines forms a complex with calcium which is insoluble
complex, results in decrease in absorption.
• Also pH of the GIT tract also influence on the absorption of drugs,
like unionized drugs are permeable than the ionized & most of the
drugs are either weak acids or weak bases.
• Weakly acidic drugs, being largely unionized, are well absorbed from
the stomach.
• In stomach both weak acids & weak bases are well absorbed.
• Example Tablets, capsules, suspensions, solutions, & emulsions.
 Routes of administration
• 2. Rectal route
• For local action rather than systemic effects.
• Drugs are given in solution, suppository or emulsion form.
• This route indicated for drugs inactivated for GIT fluids or when oral
administration is not possible like in case of vomiting or patient is
unconscious.
• Advantages:
• After absorption, drugs directly enters into the systemic circulation
route of choice for drugs which are significantly inactivated by the
liver.
• Disadvantage:
• Inconvenient
• Irregular drug absorption & difficult to predict the extent of
absorption.
 Routes of administration
• 3. Parenteral route
• Drugs administered via a hollow needle into the body at various sites
& to varying depths.
• Like Subcutaneous (SC), Intramuscular (IM), Intravenous (IV) are
more common than the others.
• Advantages:
• In case of emergency
• When drugs are destroyed, inactivated or poorly absorbed following
oral administration.
• Rapid absorption takes place with predicted pattern.
• Disadvantage:
• Special technique & skillful person is required to administer.
• High cost.
 Routes of administration
• 4. Topical route
• Indicated for mainly for local action.
• Can be used for systemic delivery.
• Formulations like ointments, creams, pastes, gels, lotions, solutions,
• Advantages:
• For local delivery as well as systemic delivery of drug.
• Termination of drug therapy possible in case of emergency.
• Both hydrophobic & hydrophilic drugs can be given.
• Disadvantage:
• Slow onset
• Poor drug absorption pattern
 Routes of administration
• 5. Respiratory route
• Drugs can be given for local as well as systemic effects.
• Drugs are administered by aerosols.
• Advantages:
• High surface area for drug absorption
• Rapid absorption
• Low degradation
• Useful in case of emergency like asthmatic attack
• Disadvantage:
• High cost.