PARENTERALS

INTRODUCTION:

 The term is derived from the Greek word Para which means Outside and Enterone means
intestine
 According to I.P “parenterals are injectable preparations, sterile products intended for
administration by injection, infusion or implantation in to the body.”
 Parenterals are sterile Sol's or suspension of drug in an aqueous or Oily vehicle.
 Parenteral drugs are administered directly into veins, muscles, or under the skin, or more,
specialized tissues such as the spinal cord.
 The term parenteral is used for any drug or fluid whose delivery does not utilize the
alimentary Canal for entering the body tissues. Transfusion fluids and injections are
parenteral Preparations.
 Injections should be sterile, isotonic & free from foreign particles like dust and fibers.
 They should be administered through the same route for which they are intended.
Ex: An oily Suspension meant for intramuscular injection may be very dangerous if it is
administered by Iv injection. Similarly, those potent drugs to be given through
intramuscular injection may prove very if it is given by IV route

ADVANTAGES:

1. Rapid Onset of Action- Provides quick therapeutic effects, especially useful

in emergencies.

2. Complete Absorption- Ensures 100% bioavailability as it bypasses the

gastrointestinal tract.

3. Avoids First-pass Metabolism

4. Allows for controlled, sustained, or continuous release of medication.

5. Beneficial for patients who are unconscious, uncooperative, or unable to take

medications orally.

6. Suitable for localized treatment such as injections into joints or tissues.

7. Dosing can be adjusted more precisely compared to oral medications.

8. Enables the administration of drugs that are poorly absorbed, unstable, or

ineffective when taken orally.

9. Nutrition Support- Used for delivering total parenteral nutrition (TPN) in

patients who cannot consume food orally.

10. Can be administered through various routes (e.g., intravenous,

intramuscular, subcutaneous) to suit different clinical needs.

DISADVANTAGES:

1. It can be painful and uncomfortable due to needles.

2. There is a higher risk of infections.
3. It is more expensive than oral medication.
4. Requires trained professionals to administer.
5. Can cause complications like tissue damage or bruising.
6. Hard to reverse once given, making adjustments difficult.
7. Needs special storage, like refrigeration.
8. Patients often can’t give it to themselves at home.
9. Mistakes in administration can be serious or harmful.

GENERAL REQUIREMENTS FOR PARENTERAL DOSAGE FORMS

The formulation of parenteral products involves careful consideration of the following

requirements:

1) Stability: The stability of parenteral preparation is very important. The physical as well as
chemical stability of parenteral preparation must be maintained during storage.

2) Sterility: The parenteral preparations should be free from all types of microorganisms.
Aseptic conditions are required to be maintained during the preparation of parenteral products
and its administration. The parenteral product must pass the test for sterility

3) Free from pyrogens: The parenteral preparations should be free from toxin and pyrogens.
It is necessary that the parenteral products roust pass the test for pyrogen, because
contaminated parenteral product causes rise in body temperature after its administration.
4) Free from foreign particles: The parenteral products should be free from foreign particles
such as dust and fibres. To ensure this, the parenteral products must pass the clarity test.

5) Isotonicity: The parenteral preparations should be isotonic with blcod plasma and body
fluids. It is very important, in order to avoid any complications on the administration of
parenteral products.

6) Specific gravity: The parenteral products meant for intra-spinal injections should have the
same specific gravity as that of spinal fluid into which the same are to be injected.

7) Chemical purity: The parenteral products should be free from chemical impurities or it
should be within certain limit as specified in the monograph of that preparation in the
pharmacopoeia.

ROUTES OF ADMINISTRATION OF PARENTERAL PRODUCTS:

The various routes of administration of parenteral preparations are as follows:

1) Intradermal (intracutaneous) injections: These are given in between dermis and

epidermis. Skin of the left forearm is usually selected for giving the injection. Generally, 0.1
to 0.2 ml of parenteral solution is injected by this route. The route is used for diagnostic
purposes and for testing the sensitivity of the injectables.

2) Hypodermic (subcutaneous) injections: These are made under the skin, into the
subcutaneous tissue. The volume of 1.0ml or less is usually injected into the upper arm. This
is the most popular route, because it is convenient for the patient and the doctor.

3) Intramuscular injections: These injections are given into the muscular tissues. The
muscles of the shoulder, thigh or buttock are usually selected. Generally, volume up to 2.0 ml
is administered by this route and should not exceed 4.0 ml at one site. Aqueous or oily
suspensions and oily solutions can be administere by this route.

4) Intravenous injections: These injections are made into a vein and therefore introduced
directly into the blood stream. The median basilic vein near the anterior surface of the elbow
is usually selected, because it is easily located and connects with the major veins of the arm.
Large volume of parenteral solutions ranging from 1ml to 500ml or more than that can be
injected. The parenteral solution should be isotonic with blood if the volumes of more than
15ml should be injected. The suspensions and oily injections cannot be injected by this route.
5) Intra-arterial injections: These are similar to intravenous injections and are occasionally
used for an immediate effect in a peripheral area. These injections are given directly into the
artery.

6) Intra-cardiac injections: These are given into the heart muscle or ventricle in an
emergency only; for example, as a stimulant following cardiac arrest.

7) Intrathecal injections: These are made into subarachnoid space that surrounds the spinal
cord. This route is used for giving spinal anaesthesia.

8) Intracisternal injections: These are given in between the first and second cervical
vertebrae. This route is used to withdraw C.S.F. (cerebrospinal fluid) for diagnostic purposes.

9) Peridural injections: These are given between the duramater and the inner aspects of the
vertebra. So it is that portion of vertebral canal not occupied by the duramater and its
contents. This route is sometimes used for giving spinal anaesthesia in special cases.

10) Intra-articular injections: These injections are given into the liquid that lubricate the
articulating ends of bones in a joint.

11) Intra-cerebral injections: These injections are given into cerebrum.

CLASSIFICCATION OF PARENTERALS
1. Small volume parenterals (SVP)

2. Large volume parenterals (LVP)

1. LARGE VOLUME PARENTERALS

 These solutions are usually administered by intravenous infusion to replenish body

fluids or electrolytes or to provide nutrition.
 They are usually administered in volumes of 100ml to 1L or more per day.
 Because of the large volumes administered, these solutions must not contain
bacteriostatic agents or other pharmaceutical additives.
 They are packaged in large single dose containers.
 Electrolytes, vitamins are frequently incorporated into large volume parenteral for
coadministration to the patient.

Common uses may include;

 Correction of electrolyte and fluid balance disturbance

 Nutrition

 Vehicle for administrating other drugs

Container for LVP

Large volume parenteral solutions are packaged in containers holding 100ml or more. LVP
packaged in

 Glass bottle with an air vent tube

 Glass bottle without an air vent tube

 Plastic bags

 Plastic bags are advantages over glass bottles as they are unbreakable light in weight,
take up less storage space.
 Most common sizes are 250, 500 and 1000 mL
 Plastics are majorly used for LVP as a container.
 But some drugs are incompatible with plastic in such case glass in used as a container.

Four types of LVPs

• Hyperalimentation solution

• Cardioplegia solution

• Peritoneal dialysis solution

 • Irrigating solution

i. HYPERALIMENTATION SOLUTION

• Administration of solution containing large amount of nutrients to patients who

unable to take food orally for several weeks at calorie intake levels of 4000
kcal/day or more. Solutions are administered by subclavian vein through
cannulation.

• Commonly consists of mixture of dextrose, amino acids, lipids, electrolytes &

vitamins. It is useful in case of patients in coma or to patients undergoing treatment
for esophageal obstruction, GI disease, ulcer etc.

ii. CARDIOLPLEGIC SOLUTIONS

• Are LVP used in heart surgery to prevent injury to myocardium during the time the
blood flow supply to the heart is stopped.

• These are specially designed electrolyte solutions required to maintains the diastolic
arrest.

• Slightly alkaline to compensate metabolic acidosis,

• USE: To minimize reperfusion injury resulting from tissue edema.

iii. PERITONEAL DIALYSIS SOLUTION

• These are infused continuously into abdominal cavity, to clean peritonium & are
then continuously withdrawn.

• These solutions used to removal of toxic substances from body.

• To aid & accelerate excretion from kidneys.

• To treat acute renal insufficiency

iv. IRRIGATING SOLUTIONS

• To irrigate, flush, & aid in cleaning body activities & wounds.

• Certain IV solution (normal saline) may be used as irrigating solution, but solution
designed as irrigating soln should not be used parenterally.

• Use: Treatment of serious wounds infused in to blood stream

2. SMALL VOLUME CONTAINERS:

USP defn: An injection that is packed in containers labeled as containing 100 ml or less.

May be given single dose or multiple dose. Mostly given as multiple doses.

Different types are:

• Solution

• Suspension

• Emulsion

• Dry powders

Solutions

 Typically used for delivering medications at a controlled infusion rate

 Most commonly solutions of 5% dextrose, normal saline, 45% normal saline, or 5%
dextrose with normal saline.
 Dextrose contributes glucose to meet energy needs and saline contributes sodium, an
electrolyte that maintains fluid balance and cellular functions.

Suspensions:

 They should be sterile, pyrogen free, stable, re-suspendable, syringeable, injectable,

isotonic & non-irritating.
 They are usually administered by either subcutaneous (S.C.) or intramuscular (I.M.)
route.
 These suspensions usually contain between 0.5% and 5.0% solids & should have particle
size less than 5 micrometer for I.M. or S.C. administration.
 Certain antibiotic preparations (For example procaine, Penicillin G) may contain up to
30% solids

Advantages of Parental suspension

■ It is better for the therapeutic use of drugs that are insoluble in convention solvents.
■ In this dosage from there is increased resistance to hydrolysis & oxidation as drug is
present in the solid form.

■ Formulation of controlled released drug is possible in this dosage form.

■ There is elimination of hepatic first pass effect.

Injectable Emulsion

 An emulsion is a heterogenous dispersion of one immiscible liquid in another.

 This inherently unstable system is made possible through the use of an emulsifying
agent, which prevent coalescence of the dispersed droplet.
 Parenteral emulsion are rare because it is necessary (and difficult) to achieve stable
droplet of less than 1 micron to prevent emboli in blood vessels and it is not usually
necessary to achieve an emulsion for drug administration.

Dry Powders

• Dry powder formulations are lyophilized or freeze-dried powders that must be

reconstituted with some suitable solvent to make a liquid formulation before being
withdrawn from the vial.

• Some drugs are not stable in liquid form and so these drugs are put into the powder form
and reconstituted just prior to use.

• There are several solvents that might be used to reconstitute the dry powders;

• The most common solvents are Sterile Water for Injection, Bacteriostatic Water for
Injection, Sodium Chloride Injection etc.

FORMULATION OF SUSPENSION:

1.Vehicles:

• Aqueous vehicle

• Non aqueous vehicle

2 .Adjuvants:

• Solubilising agents
 • Stabilizers

• Buffering agents

• Antibacterial agents

• Chelating agents

• Suspending agents

• Emulsifying agents

• Wetting agents

• Tonicity factors

1. VEHICLE

Two types of vehicle commonly used

a) Aqueous vehicle

b) Non aqueous vehicle

(a) Aqueous vehicle

The aqueous vehicle used are

• Water for injection

• Bacteriostatic water for injection

• Water for injection free from carbondioxide

• Water for injection free from dissolve air

Water for injection:

• It is a sterile water, which is free from volatile, non volatile impurities and also from
pyrogen.

• Pyrogens are byproduct of bacterial metabolism

• They are polysaccharide, thermostable, soluble in water, unaffected by bactericide and

can pass through bacteria proof filters.

• They are removed from water by simple distillation process.

 • WFI contaminated with pyrogen may cause increase in body temperature if injected.

• Method of preparation a) Distillation b) Reverse osmosis

• Total solid content in WFI-10ppm

(b) Non aqeous vehicle

Commonly used non aqueous vehicle are

• Oils- fixed oils

• Alcohols –ethyl alcohol, propylene glycol

FIXED OIL

• Eg: arachis oil, cotton seed oil, almond oil, sesame oil

• Used when drug or medicament are insoluble or slightly soluble in water

ALCOHOL

• Ethyl alcohol- preparation of hydrocortisone injection

• Propylene glycol ; preparation of digoxin injection

2. ADJUVANTS

These are substance added to increase the stability or quality of the preparation

 Solubilising agents

• Used to increase the solubility of drugs which are slightly soluble in water

• Eg: surfactants like tweens and polysorbates

 Stabilizers

• They are added to prevent oxidation and hydrolysis

• Oxidation can be prevented by adding antioxidants

• Eg :thiourea, ascorbic acid, sodium meta bisulphite

• Hydrolysis can be prevented by using nonaqueous vehicle or adjusting the pH of the

preparation
 Buffering agents

• The degradation of preparation which is due to change in pH can be prevented by

adding suitable buffer to maintain desired pH

• Eg: citric acid, sodium citrate, acetic acid, and sodium acetate

 Antibacterial agents

• They prevent the growth of microorganisms during storage

• They act as preservatives

• Eg; phenyl mercuric nitrate, methyparaben

 Chelating agents

• They chelate the metallic ions present in the formulation

• To remove trace elements

• Eg: EDTA Sodium or pottasium salt of citric acid

 Suspending agent

• Improve the viscosity of the preparation

• Eg: methycellulose, CMC, gelatin, acacia

 Emulsifying agent

• They are used in sterile emulsion

• Eg;lecithin

 Wetting agents

• Reduce the interfacial tension between the solid particles and liquid

• Prevent the formation of lumps

• Act as antifoaming agents

 Tonicity adjusters

• Should be isotonic with blood plasma and other body fluids

• Thus avoid destruction of RBC, irritation and tissue damage

 • Reduce the pain on injection

• Eg; sodium chloride, dextrose, boric acid

MANUFACTURING OF PARENTERALS

1. Cleaning of containers ,closures and equipments

• Rubber closure are washed with hot solution of 0.5% sodium pyrophosphate in water

2. Collection of materials

• Should be pure

• WFI free from pyrogens and microorganism

3. Preparation of parenteral product

• Under aseptic condition

4. Filtration

 Parenteral solution passed through bacteria proof filters such as filter candle,
membrane filter, and sintered glass filter
 Primary objective of filtration is to clarify the solution by removing foreign particles

5. Filling the preparation in final containers

• Ampoule are used for filling single doses

• Vials used for filling multiple doses

• Both are used for filling transfusion fluids

6. Sealing of containers

• Ampoules are sealed by rotating the neck in the flame of bunsen burner

• Transfusion bottle and vials by closing with rubber closure

7. Sterilisation

• For thermostable medicament

• Autoclave can be used

 • Temperature 115oC to116oC for 30minutes

OR

121oC for 20minutes

• Hot air oven 160oC for 2hr

• For thermolabile preparations

• Using bacteria proof filters

CONTAINERS:

Ampules

• Sealed glass containers with an elongated neck that must be broken off.

• Most ampules are weakened around the neck for easy breaking; these will have a colored
band around the neck.

• A 5 micron filter needle should be used when drawing the contents of an ampule into a
syringe since glass particles may have fallen inside the ampule when the top was snapped
off.

Vials

• Drugs and other additives are packaged in vials either as liquids or lyophilized powders.

• Made of glass or plastic and are sealed with a rubber stopper.

• A needle is used to add contents to or withdraw contents from the vial.

• Before withdrawing contents from a vial, an equal volume of air is usually injected into
the vial to pressurize the vial and aid in withdrawing the contents.

• Vials may be designated for single-dose or multi-dose use.

• Multi-dose vials contain a preservative to inhibit bacterial contamination once the vial has
been used
STERILITY TESTING FOR PARENTERALS:

1. Sterility Test

2. Clarity Test

3. Leakage Test

4. Pyrogen Test

 STERILITY TEST:

• Sterility is defined as free from the presence of viable microorganisms.

• Sterility testing is a procedure carried out to detect and conform absence of any viable
form of microbes in or on pharmacopeia preparation or product. Sterility test is
performed to check the presence of aerobic and anaerobic viable forms of bacteria,
fungi and yeast in parenteral products

• Types of media used

a) Fluid thioglycollate media- for anaerobic bacteria

b) Soya-bean casein digest media-for fungi and aerobic bacteria

Methods of sterility testing

i. Membrane filtration method

ii. Direct inoculation method

(i) Membrane filtration method

• It is more popular and widely used method over direct incoulation method. It require
more skill and knowledge than direct inoculation method.

Procedure:

This method involves filtration of sample through membrane filters of porosity 0.22 microns
and diameter 47mm with hydrophobic characteristics. The filtration is assisted under vaccum.
After filtration completion, the membrane is cut into two halves and one halve is placed in
two test tubes containing FTM,SCDM

ii ) Direct transfer/inoculation method

 • It is a traditional sterility test method which involves a direct inoculation of required
volume of a sample in two tests tube containing a culture medium that is Fluid
thioglycolate medium and soya bean casein digest medium.

Procedure:

• Suitable amount of material under test is transferred into sterile nutrient media and
incubated for suitable period of time at optimum temperature. After incubation, media
is examined for the presence or absence of any microbes.

• Interpretation: If not, any growth of microbes seen, product considered to be sterile.

• If growth of microbes occurs, test is repeated 2 nd and 3rd time to account for any
accidental contamination .

• If test fails after 2nd and 3rd time, product is declared nonsterile and discarded.

 CLARITY TEST:

• Clarity test is performed to detect presence of any particulate matter.

• Also called particulate matter monitoring. Particular matter is defined as unwanted

mobile insoluble matter other than gas bubble present in the given product.

• By clarity test apparatus-This method involves direct lighting on container against

black and white background to check presence of any particulate matter.

• Other methods: light absorption, light scattering, change in electrical resistance is also
used to detect particulate matter.

 LEAKAGE TEST:

The sealed ampoules are subjected to small cracks which occur due to rapid temperature
changes or due to mechanical shocks.

Filled & sealed ampoules

Dipped in 1% Methylene blue solution

 Under negative pressure in vacuum chamber

Vacuum released

colored solution enter into the ampoule, Defective sealing

Vials & bottles are not suitable for this test because the sealing material used is not rigid

 PYROGEN TEST:

• Pyrogenic - means producing fever

• Pyrogens - fever inducing substances

• This test is used to detect the presence of pyrogenic substances in parenteral

preparations .

• In this test, rabbits are used as test animals because they show same physiological
response to pyrogenic substances like that of man.

• If pyrogenic substance present in the product, it causes increase in body temperature

of test animal.

• Procedure: Test sample is injected into ear vein of three rabbits.3 hours after injection,
body temperature of test animals are measured by rectal thermocouple inserted into
rabbits and temperature is measured by employing electronic thermometer.

Interpretation:

• If no single rabbit shows rise in temperature, product is declared as nonpyrogenic

• But if any one rabbit shows the rise in temperature of 0.6ºC or more above the normal
temperature, then the test is repeated on 5 additional rabbits.

• Test requirements are met if not more than 3 of 8 rabbits show an individual rise in
temperature of 0.6°C and sum of maximum rise in temperature of 8 rabbits is not
more than 3.7ºC