INTEGRATED PHYSICAL PHARMACY AND

PHARMACEUTICS I
 
Derso. T

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 Chapter I: Introduction

course outline
 Definition of pharmaceutics & physical pharmacy

 Principle of dosage form design

 Types of dosage forms

 Routes of drug administration

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Learning objectives:
Upon completion of this chapter, students will be able to:-
define pharmaceutics and physical pharmacy

explain the principles of dosage form design

List types of dosage forms and common routes of drug

administration

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 Introduction
Pharmaceutics:
The general area of study concerned with the formulation,

manufacture, stability and effectiveness of pharmaceuticals.

The science that deals with the dosage form design.

Pharmaceutics converts a drug (API) into a medicine.

It is concerned with the scientific and technological aspects of

the design and manufacture of dosage forms.

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Pharmaceutics encompasses many subject areas such as

chemistry, physiology, anatomy, mathematics, physics e.t.c

which are all associated with the steps to which a drug is
subjected towards the end of its development.

Physical pharmacy
It is the study of the physicochemical properties of drugs.

It is concerned with the quantitative and theoretical principles

of science as applied to pharmacy.

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Drugs
Chemicals that alter function of living things and are intended for

use in the diagnosis, treatment, cure or prevention of disease in

man or any other animal.
They are rarely administered as pure chemical substances alone

almost always given as formulated preparations or medicines.

Medicines
They are a means of administering drugs to the body in a safe,

efficient, reproducible and convenient manner.

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Principle of Dosage Form Design
 strength
It refers the strength of a medication and tells how much active
ingredient is contained within the medicine.
 Dose - the amount of drug taken at any one time
 Dosage : a set of instruction for how to take the medication.
 the amount and rate of administration of a substance

 Dosage form
It is the pharmaceutical preparation with unique characteristics
and which makes dosage possible.
 Dosage form design
 is the overall process of changing a certain drug in to a
particular DF that is safe, effective, stable, and suitable for
large scale manufacture with reproducible quality
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Stability:
 is the capacity of a drug product to remain within
specifications established to ensure its identity, strength,
quality and purity.
 physical, chemical and microbiological stability
Safety:
 acceptable degree of undesired effect (harm)
Effective:
 capable of maintaining the intended effect.
 Achieving a predictable therapeutic response.
Excipients/Nonmedicinal agent:
 are inactive ingredients used as carriers for the active
ingredients in a pharmaceutical product.

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D

Dosage form

Dosage forms are the means by which drug molecules are

delivered to sites of action within the body

Contains API + inactive pharmaceutical ingredients (excipients)

The pharmaceutical preparations with particular characteristics

presented (given) to the patients

Each type of dosage form is unique in its physical and

pharmaceutical characteristics.

They are designed to facilitate the administration of drug

substances.

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Dosage form

It determines the physical form of the final pharmaceutical

preparation.

It is a drug delivery system which is formed by technological

processing (drug formulation)

It must reflect therapeutic intentions, route of administrations,

dosing , etc

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 To ensure product quality, numerous features are required:

 chemical & physical stability, with suitable preservation

against microbial contamination if appropriate.

uniformity of dose of drug

acceptability to users, including both prescriber & patient

 suitable packaging and labelling.

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Why from simple drug to dosage form?
API handling & accurate dosing can be difficult or impossible

 To protect the drug substance from the destructive influences

of atmospheric oxygen or humidity (coated tablets)

 API administration can be impractical, unfeasible or not

according to therapeutic aims

To provide rate-controlled drug action

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To protect the drug substance from the destructive influence of

gastric acid after oral administration (enteric-coated tablets)

To conceal the bitter, salty, or offensive taste or odor of a drug

substance (capsules, coated tablets, fl avored syrups)

To provide rate-controlled drug action (various controlled-

release tablets, capsules, and suspensions)

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API may cause local irritations or injury when they are present

at high concentrations at the site of administration

To conceal (hide or mask) the bitter, salty, or obnoxious

(hateful) taste or smell of a drug substance

Administration of active substance would mean to have no

chance for modification (improvement) of its PK profile

To provide the drug in the desired dosage form such as solution,

suspension, semisolids, inhalation etc.

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 In the vast majority of cases a single drug substance is prepared
into a number of dosage forms
to satisfy both the particular preferences of the patient or

physician (e,g. Infants- liquid DF, adults- solid DF)

the specific needs of a certain clinical situation e.g

 asthmatic pts use inhalation for rapid emergency relief

 Oral products for chronic asthma therapy.

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Pharmaceutical preparation (PP)
Particular pharmaceutical product containing active and

inactive pharmaceutical ingredients formulated into the

particular dosage form.
 API + Additives (expients)
Two major types of PP according to the origin:

Manufactured in large scales by pharmaceutical industry

Compounded individually in compounding pharmacies

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 The individually compounded PP can be a justified choice

when:

The drug in a particular dosage form is not commercially

available on the market

The extraordinary low or high dose is needed (young

children, elderly people).

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The patient suffers from the allergy on a specific excipients or

another drug appearing in the PP.

Patient is unable to use a PP in its commercially available

dosage form (e.g., children, elderly)

For drugs with a very short shelf life in its manufactured form

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Major considerations in the design of dosage forms

The proper design and formulation of a dosage form requires

consideration of the physical, chemical, and biologic

characteristics of all of the drug substances and pharmaceutical
ingredients to be used in fabricating the product.

The drug and pharmaceutical materials must be compatible

with one another to produce a drug product that is stable,

efficacious, attractive, easy to administer, and safe

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 Major considerations in the design of dosage forms
The physicochemical properties of the drug
 Partition coefficient: Absorption/BA

 Stability and/or degradation rate in the physiologic fluids

 Complexation: BA, solubility, stability

 Crystalline form (polymorph)

 Solubility & dissolution

 BA, stability, flow and compaction
 Density, hardness, crystal shape
 Melting point
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 Particle size

 dissolution rate, BA, content uniformity, texture, color,

stability, flow characteristics and sedimentation rates are

affected by the particle size distribution
 Solubility & Dissolution rate

 dissolution rate can affect the onset, intensity, and duration

of response and control the overall BA of the drug from DF

 Impurities: stability, shelf life, appearance

 Salt form: solubility and dissolution rate

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pKa and pH profile

Both are necessary for optimum stability and solubility of

the final product

Hygroscopicity

Moisture absorption may affect the physical structure as

well as stability of the product.

Excipients interaction

The compatibility of the excipients with the drug and

sometimes trace elements in excipients may affect the

stability of the product.
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II. Biopharmaceutical considerations
 route of adminstration

 By choosing the ROA of drug carefully & properly designing

the drug product, BA of drug can be varied.
 rapid and complete absorption to a slow sustained rate of
absorption or
 even virtually no absorption, depending on the therapeutic
objective

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The rate of drug release from the product and the rate and

extent of drug absorption are important in determining

the distribution

onset

Intensity and

duration of drug action

Anatomical and physiological considerations of GIT

 Stomach; Small intestine , Large intestine; Pathways of

drug absorption
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III. Therapeutic consideration of the disease state to be treated
the age and anticipated condition of the patient

nature of the illness

the need for systemic or local therapy.

the duration of action required

 emergency vs chronic situations

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Types of Dosage Forms
There exists different type of dosage forms which can be classified
according to physical properties (physical state) or according to
the route of administration.

Route of administration Physical state

Oral Solid
Topical Semisolid
Rectal liquid
Parenteral Gaseous
Vaginal
Inhaled
Ophthalmic
Otic

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Liquids
Solutions

 solutions are clear liquid preparations containing one or

more active ingredients dissolved in a suitable vehicle.

Continuous phase
Homogenous phase (Dispersion medium)

Suspensions
Dispersed phase
A dispersion system where solid particles

(dispersed phase) are dispersed in liquid phase

v
(dispersion medium)

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Emulsions

defined as a biphasic system consisting of two immiscible

liquids, one of which (the dispersed phase) is finely and

uniformly dispersed as globules throughout the second
phase (the continuous phase).
thermodynamically unstable system, a third agent, i.e. the

emulsifier is added to stabilize the system

can be o/w or w/o types

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Semisolid dosage forms

Gels
semisolid systems consisting of dispersions of small or large

molecules in an aqueous liquid vehicle rendered jellylike by the

addition of a gelling agent.
Creams
semisolid preparations containing one or more medicinal agents

dissolved or dispersed in either a W/O or O/W emulsion

After application of the cream, the water evaporates, leaving behind

a thin residue film of the stearic acid or other oleaginous component

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Ointments
 Ointments are semi-solid, greasy preparations for application

to the skin, rectum or nasal mucosa

It is viscid and heavier than cream

Pastes -generally composed of ointment bases that contain a

high concentration (frequently >50% w/w) of dispersed drug

The viscosity of pastes is greater than that of ointments.

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Gases
Aerosols
 defined as a two phase system of solid particles or liquid
droplets dispersed in air or other gaseous phase, having
sufficiently small size to display considerable stability as a
suspension.

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solid dosage form

Tablet
• A tablet is a hard, compressed medication in round, oval or
square shape
• The API will be compressed along with other
pharmaceutical excipients
• Used as oral dosage form

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Immediate-release tablets
Immediate-release tablets are designed to disintegrate and

release their medication with no special rate-controlling

features, such as special coatings and other techniques.

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Coated tablet
A coating may be applied to:

1- hide the taste of the tablet's components.

2- make the tablet smoother and easier to swallow .

3- make it more resistant to the environment.

4- extending its shelf life.

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Multiply compressed tablets
Multiply compressed tablets are prepared by subjecting the fill

material to more than a single compression.

The result may be a multiple-layer tablet or a tablet within a tablet,

Each layer may contain a different medicinal agent, separated for

reasons of
 chemical or physical incompatibility,
 staged drug release, or
 simply for the unique appearance of the layered tablet.
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Multiply compressed tablets

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Buccal and sublingual tablet
• Sublingual - under the tongue (sublingual)

• buccal - between the gum and the cheek

• The medications dissolve rapidly and are absorbed through the

mucous membranes of the mouth.

• Avoid the acid and enzymatic environment of the stomach and

first pass metabolism
• e.g. vasodilators, steroidal hormones.
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Effervescent tablets

Effervescent tablets are uncoated tablets that generally contain

acid substances (citric and tartaric acids) and carbonates or

bicarbonates and which react rapidly in the presence of water
by releasing carbon dioxide.
They are intended to be dissolved or dispersed in water before

use providing:
 A- Very rapid tablet dispersion and dissolution.
 B- pleasant tasting carbonated drink.

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Chewable tablet
They are tablets that chewed prior to swallowing.

They are designed for administration to children e.g. vitamin

products.

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Capsules

Capsules are solid dosage form in which one or more

medicaments are enclosed in a water-soluble, biodegradable
shell made up of gelatin.
Gelatin capsule shells may be hard or soft,
depending on their composition

1- hard-shelled capsules, which are normally used for dry,

powdered ingredients, cap

body

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2- soft-shelled capsules, primarily used for oils and for API that
are dissolved or suspended in oil.
API and excipients are enclosed in water soluble container

made of gelatin.

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Implants

Sterile disks inserted surgically into body tissues and

designed to release drug(s) over extended period of time

Transdermal patches

Transdermal drug delivery systems (TDDSs) facilitate the

passage of therapeutic quantities of drug substances through

the skin and into the general circulation for their systemic
effects

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Suppositories –

are solid dosage forms intended for insertion into body

orifices where they melt, soften, or dissolve & exert local

/systemic effects.

 commonly used rectally and vaginally and occasionally

urethrally.

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Route of administration
The absorption pattern of drugs varies considerably b/n

individual drug substances as well as b/n the different

administration routes.
Dosage forms are designed to

provide the drug in a suitable

form for absorption from each

selected route of administration.

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 Route of drug administration
• It refers the route by which the drug is placed (given or
taken).

2. Local route
1. Systemic
Route In this route the drug is
applied on the skin and
mucous membrane for the
local action.

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The ROA is determined by

the physical characteristics of the drug

the speed at which the drug is absorbed and/ or released

the need to bypass hepatic metabolism and

 how much concentration to achieve at particular sites

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Per-oral(po)------Gastro intestinal tract (via mouth)
Sublingual ---Under the tongue
Parenteral -----Other than gastro intestinal tract (by injection)
•Intramuscular-----Muscle
• Intravenous-------Vein

• Intra-arterial -------Artery

• Intracutaneous or intradermal -----Skin

• Subcutaneous ------Beneath the skin

Epicutaneous (topical) -----Skin surface

Intraocular --------Eye
Intranasal-------- Nose
Aural-----------Ear
Rectal ---------Rectum
Vaginal--------- Vagina
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Oral Route (po)
 Drug is placed in the mouth and swallowed

 Advantages

It is most natural route of administration.

It is most easy route for administration of drug for pts.

It is safest, simplest & most convenient ROA

This route can take large variety of dosage forms.

Nursing for administration is not required.

It is economical to the patients.

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 Disadvantages

The onset of action of drug is late

Doses of drug required is more.

It is difficult for non-cooperative patients

The absorption of drug from GIT is not assured by patients

suffering from GIT disorder.

May cause GI disorders like acidity, loss of appetite, etc.

Drug may be destroyed by the enzyme in GIT

First pass effect

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 Hepatic first pass effect
• The hepatic metabolism of a pharmacological agent when it is

absorbed from the gut and delivered to the liver via the portal
circulation.
• The greater the first-pass effect, the less the agent will reach the
systemic circulation when the agent is administered orally

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Sublingual/Buccal route

• Drug is kept in the buccal cavity or under tongue where it

disintegrates and absorption occurs in the mouth

• Buccal -often harder – slower absorption

• Sublingual - softer - faster release

•Examples - nitroglycerin, steriods, nicotine (chewing gum)

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Sublingual/Buccal route
Advantages

• Avoid first pass effect: direct to the blood (liver is by-passed )

• Rapid absorption: good blood supply to the area

• Drug stability: not destroyed by the enzymes and acids

Disadvantages

• Inconvenient

• Holding the dose in the mouth

• Advantages lost if swallowed
• Small size is required to keep the drug in the mouth

• Unpleasant taste of some drugs 53

Rectal Route

The formulation is given through the rectal cavity and

absorption through the rectum

Suppository

Advantages

oBy pass liver:

• Blood from the upper haemorrhoidal vein enters the

portal vein.
• Blood in the middle and lower haemorrhoidal veins

enters the general circulation.

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Rectal route
o It can be given for noncooprative pt (unconscious, children, pt

with NV)
may be successfully employed to provide a local effect

may be employed to provide systemic drug absorption in

situations where oral drug absorption is not recommended

promote evacuation of the bowel by irritating the rectum

o Easy to terminate exposure

administration may be easily performed by the pts/with advice

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 Disadvantages

generally unpopular (USA, UK) whereas the opposite is true in

European countries.
advice is required concerning the administration

Absorption may be variable and slow

development of local side-effects

Upward movement of suppository from local site can increase

first-pass metabolism.
 Suppositories can leak.

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Vaginal route

The administration of drugs to the vagina is principally

performed to achieve a local effect.

systemic absorption of drug may occur following administration

due to the highly vascular nature of the vaginal wall

avoids first-pass metabolism in the liver

specialist advice is required concerning the administration

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 Parenteral

 injected via a hollow needle into the body at various sites and to

varying depths.
 IV, SC, IM

Other routes: intra-arterial, intra-articular, Intra-ceribral

 preferred when rapid absorption is essential,

as in emergency situations

when patients are unconscious

When drugs are destroyed, inactivated in GIT (PO)

for poorly absorbed drugs following oral administration.

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 Parenterals are formulated as

• solutions, suspensions, emulsions,

 PARENTERAL PRODUCTS MUST BE:-
 must be sterile
 Free from pyrogenic (endotoxin) contamination.
 Free from visible particulate matter.
 Isotonic

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Intravenous (IV)
 placing a drug directly into the blood stream
Formulations are usually solutions or emulsions O/W ( size of
disperse phase is small, 1<µm).
Suspensions or solutions that precipitate within the blood stream or
W/O emulsion must not be administered IV due to disruption of
blood flow
suspension physically block blood capillaries
W/O fat embolism blocking blood vessel
 High or low pH or hypertonic solutions will damage the cells
lining the vein and cause localized pain and inflammation
(thrombophlebitis)


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 Advantages

Absorption phase is by passed (100% BA)

Precise, accurate & almost immediate onset of action

Large quantities can be given, fairly pain free

10 ml - up to 500 ml volume formulations may be

administered intravenously

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 Disadvantages

Greater risk of adverse effects

High concentration attained rapidly

Risk of embolism

Training is required for administration

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Intramuscular (IM)
administered into the tissue of a relaxed muscle
Aqueous or oily solutions or suspensions can be administered in
volumes of up to 4 mL.
Very rapid absorption of drugs in aqueous so/n

Advantages
Larger volume than SC (1–3 ml or up to 10 ml in divided doses)
Depot or sustained effect is possible.

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Disadvantages
• Needs trained personnel
• Site affects absorption: deltoid

• Pain at injection sites for certain drugs

Faulty injection technique may lead to

local muscle damage.

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 Subcutaneous (SC)
 injections are administered into the loose connective and adipose
tissues immediately beneath the dermal skin layer
volume of injection is typically up to 1ml may be infused
 aqueous solutions or suspensions of drugs are administered by
this route
Massage or heat, Vasoconstriction
Advantages
• Can be given by the patient e.g. insulin
the route of choice for the administration of insulin.

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Disadvantages
slower onset of action& sometimes less BA than IV & IM

Absorption is limited by blood flow, affected if circulatory

problems exist
Viscous formulations are not generally administered

subcutaneously
Painful

Tissue damage from irritant drugs

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Inhalation route
Absorption through the lungs

Gaseous agents and aerosols

Quick onset of action due to rapid access to circulation

 Large surface area

 Thin membranes separates alveoli from circulation
 High blood flow
 
 

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Topical route
 Mucosal membranes (eye drops, nasal, etc.), skin

Skin
a. Dermal
Preparation is applied for its local action

b. Transdermal
drug is absorbed through the skin (systemic action)

Stable blood levels, no first pass metabolism

Drug must be potent

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Route for administration Time until effect-
Intravenous :30-60 seconds

Inhalation: 2-3 minutes

Sublingual: 3-5 minutes

Intramuscular: 10-20 minutes

Subcutaneous: 15-30 minutes

Rectal: 5-30 minutes

Ingestion (po): 30-90 minutes

Transdermal (topical): variable (minutes to hours)

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Types of drugs
 Drugs are classified on the basis of how they are obtained with
respect to prescription papers as follows.

Legend Drugs:

These drugs may not be dispensed by a pharmacist without a

prescription from a physician.

Controlled Drugs:

In addition to the need for a prescription, these drugs require

additional safeguards for storage, prescription e.t.c.

Refills are also limited.

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Over-the-Counter (OTC) Drugs:

 These drugs do not require a prescription.

Some medicines which are considered safe in general terms

and for which the people is aware of their appropriate use

may be available in general stores, supermarkets, etc.

The rules vary considerably from country to country

 

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1. Define pharmaceutics and physical pharmacy
QUIZ
2. Differentiate -1medicine?
drug and
3. List reasons for the incorporation of drugs into various dosage
forms
4. Which one of the following decreases absorption of drug from
SC drug administration?
a) Massage c) Vasoconstriction
b) Heat d) None

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PHARMACEUTICAL EXCIPIENTS
Inactive ingredients used as carriers for the active ingredients

in a pharmaceutical product
 Excipients provide varied and specialized pharmaceutical
functions.
 facilitate the administration of the dosage form, e.g.
pourability, palatability,
protect the formulation from issues regarding physical and
chemical stability
 enhance the solubility of the therapeutic agent, etc.

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 Ideal characteristics of pharmaceutical excipients
It should be chemically and physically stable
It should be easily available and inexpensive
Compatible with other ingredients
Non-toxic and non irritant, etc

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PHARMACEUTICAL SOLVENTS
Solvents are excipients which are used to dissolve

ingredients during dosage form preparation.

They can be broadly grouped as aqueous or oleaginous

There is a greater choice of solvents available for inclusion

into products for external application than those for internal

use
For parenteral products the choice is limited even further.

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 Water
 Water is the solvent most widely used as a vehicle for
pharmaceutical products, because of
Physiological compatibility
Lack of toxicity
Palatability
Easy accessibility
Inexpensiveness
Solubilize a wide range of substances etc.
 It possesses a high dielectric constant, which is essential
for ensuring the dissolution of a wide range of ionizable
materials.
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Types of pharmaceutical water

Potable water
This is water freshly drawn from the mains system and which

is suitable for drinking and sanitary purpose.

usually contains less than 0.1 % (100 mg in 100 ml) of total

solids./chloride, sulphate, bicarbonate of Na, K, Ca, Mg,

Not acceptable for the manufacture of most aqueous
pharmaceutical preparations due to the possibility of chemical
imcompatibities within the formulation.
reduce drug solubility and stability.
Signs of incompatibilities are
 Precipitation, discoloration, effervescence….

It is not free from ions and microbes.

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Purified Water
Purified water is normally prepared by the distillation or

deionization of potable water, or by the process of reverse

osmosis.
The main methods used in the preparation of purified water are

distillation and ion exchange.

The reverse osmosis process can remove virtually most virus,

bacteria, pyrogens, organic molecules, and 90-99% of all ions

depending on the pore size of the filter membrane
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The solid residue (obtained after evaporation) is less than 1
mg per 100 ml of evaporated sample. (0.001%)

100 times more free of dissolved solids than potable water.

more expensive

Purpose
For production of non-parentral formulation

For cleaning of certain equipment used in nonparentral

product

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 Water for Injections
Pyrogen free distilled water and is used for parenteral

product preparation.
Water for injection could be unsterilized or sterilized but in

both cases it should be pyrogen free

In case of unsterilized water for injection, the final

preparation would be sterilized.

Sterile water for injection is sterilized before it is added to

the formulation.

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Sterile water may contain a slightly greater amount of solids

than the unsterile water for injection due to leaching of solid

matter from the containers during sterilisation

Drugs which are liable to oxidation, such as apomorphine and

ergotamine maleate, require water for Injections free from

dissolved air to be used.

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Bacteriostatic Water for Injections USP .
 sterile and devoid of pyrogens.

 contains an antimicrobial agent, e.g. 0.9% w/v benzyl

alcohol (a bacteriostatic preservative)

Commonly supplied in a multidose container.

 only used whenever the volume of formulation to be
administered is less than 5 ml
to prevent potential toxicity of preservatives

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Aromatic water
It is a saturated aqueous solution of volatile oils or other
aromatic or volatile substances
often used as solvents and vehicles in oral liquids especially
in extemporaneously prepared mixtures.

 used mainly for their flavoring properties

some are mildy therapeutic and or preservative in action.

Examples: Camphor water is used as flavor, carminative
and mild expectorant.

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Approaches to the improve aqueous solubility
Temperature
Although water is very widely used for inclusion in
pharmaceutical preparations, it may not be possible to ensure
complete solution of all ingredients at all normal storage
temperatures.

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Co solvency
The solubility of a weak electrolyte or non-polar compound in
water can often be improved by altering the polarity of the
solvent.

This can be achieved by the addition of another solvent that is

both miscible with water and in which the compound is also
soluble.

Vehicles used in combination to increase the solubility of a drug

are called co solvents, and often the solubility in this mixed
system is greater than solubility in each individual solvent.

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PH control
A large number of drugs are either weak acids or weak bases,
and therefore their solubility in water can be influenced by the
pH of the system.
The solubility of acids and bases increases as the degree of
ionisation increases
The solubility of a weak base can be increased by lowering the
pH of its solution, whereas the solubility of a weak acid is
improved by an increase in pH.

In controlling the solubility of a drug in this way, it must be

ensured that the chosen pH does not conflict with other product
requirements.

86
• The chemical stability of a drug may also depend on pH, and
in many cases the pH of optimum solubility does not
coincide with the pH of optimum stability.
This may also be true for other ingredients, especially colors,
preservatives and flavors.

The pH of solutions for parenteral and ophthalmic use, for

application to mucous membranes or for use on abraded skin
must also be controlled, as extremes can cause pain, irritation
and even tissue damage

This is particularly true for SC, IM and intraspinal injections

because the solutions will not be rapidly diluted after
administration

87
In some instances the BA of drugs may be influenced by the
pH of their solution
changes in pH can also affect a preservative's activity by
altering the extent to which it is ionized.

Often a compromise must be reached during formulation to

ensure that the stability and solubility of all ingredients,
physiological compatibility and bioavailability are all
adequate for the product's intended purpose.

88
Solubilization
The solubility of a drug that is normally insoluble or poorly
soluble in water can often be improved by the addition of a
surface-active agent.
 SAA are chemicals that possess both hydrophilic and
hydrophobic regions.
At dilute concentrations SAA will orient at the interface between
two phases with the hydrophilic and hydrophobic regions of the
molecule being positioned to the hydrophilic and hydrophobic
phases, respectively.
As the concentration is increased, the interface will become
saturated with SAA and the molecules that are present in the bulk
aqueous phase will orient themselves in an attempt to shield the
hydrophobic regions of the surface-active agent

89
This orientation is referred to as a micelle and the concentration of

surface-active agent at this occurs is termed the critical micelle

concentration (CMC).
These molecules form different types of micelles.

This phenomenon of micellar solubilization has been widely used

for the formulation of solutions of poorly soluble drugs.



It may also be possible to combine the beneficial effects of

solubilization and cosolvency in one formulation.

 
90
Complexation
In some cases it may be possible to interact a poorly soluble
drug with a soluble material to form a soluble intermolecular
complex.
Inclusion complexes are formed by insertion of drug molecule

into a cavity formed by the complexing agent.

 In this arrangement the non-polar area of the drug molecule is

excluded from water, due to its insertion in the complexing

agent.
One requirement for the complexing agent in such systems is

that it has a non-polar core and a polar exterior.

91
The most commonly used inclusion complexing molecules are

cyclodextrins.
 The cyclic oligomers of glucose are relatively soluble in water and

have cavities large enough to accept non-polar portions of many drug

molecules.
As most complexes are macromolecular, however, they tend to be
inactive, being unable to cross lipid membranes.

It is therefore essential that complex formation is easily reversible, so

that the free drug is released during or before contact with biological
fluids.
Many complexes are not water soluble and may, in fact, be better
suited for the prolonged release of the drug.
92
Chemical modification
Chemical modification of a drug may be necessary in order to
produce a water-soluble derivative.
There are many examples of poorly soluble acids and bases
being converted to a salt form to increase water solubility.

Examples include the synthesis of the sodium phosphate salts

of hydrocortisone, prednisolone and betamethasone.

The water-soluble derivatives may have no therapeutic

activity of its own but is suitable for parenteral administration
as a solution in order to obtain high blood levels, after which
it is converted back to the less soluble active base.

93
Non-aqueous solvents
If it is not possible to ensure complete solution of the
ingredients at all storage temperatures or if the drug is
unstable in aqueous systems it may be necessary to use an
alternative, non-aqueous solvent.
The use of non-aqueous systems may also have other
advantages.
For example:
The IM injection of solutions of drugs in oils is often
used for depot therapy, and some drugs are specifically
synthesized to improve their oil solubility.
e.g propionate & benzoate esters of testosterone&
estradiol

94
Fixed oils of vegetable origin
These are non-volatile oils that consist mainly of fatty acid
esters of glycerol.
Almond oil, Arachis oil, Olive oil, sesame oil, maize oil,
cottonseed oil, soya oil and castor oil are all suitable for
parenteral use.

95
 Alcohols
Ethyl alcohol is the most widely used solvent next to water,
particularly for external application, where its rapid evaporation
after application to the skin imparts a cooling effect.
Many water insoluble drugs, flavorants, preservatives etc are
alcohol soluble.

 Alcohol is frequently used with other solvents, as glycols and

glycerin to reduce the amount of alcohol needed.

It is also used in liquid preparations as a preservative alone or

as co preservative with parabens, benzoates, sorbets and other
agents.

96
At concentrations greater than 15% ethanol exhibits
antimicrobial activity, but because of its toxicity it is used orally
or parenterally only at low concentrations, usually as a cosolvent
with water.

 It is also particularly useful for the extraction of crude drugs,

being more selective than water.

 An alcohol possessing similar properties is isopropyl alcohol,

which is used externally as a solvent.

Its main advantage is that it is less likely to be abused than

ethanol.
97
Polyhydric alcohols
Alcohols containing two hydroxyl groups per molecule are
known as glycols, but because of their toxicity they are rarely
used internally.
One important exception to this is propylene glycol.
It is used in pharmaceutical preparations as a co-solvent,
generally as a replacement for glycerin.

The lower molecular weight polyethylene glycols (PEG) or

macrogols are often used in conjunction with water or glycerol
as a cosolvent.
It is used, for example, in the formulation of Digoxin Injection.

98
Glycerol
Glycerol ( glycerin) is an odorless, sweet liquid that is miscible
with water and whose co-solvency properties are due to the
presence of three hydroxyl groups.

99
PRESERVATIVES

Antimicrobial preservatives are used to prevent or inhibit the

growth of microorganisms which could present a risk of

infection or degradation of the medicinal product
These microorganisms may arise from

 the raw materials

 during manufacturing
 proliferate during normal storage conditions or
 use of the product by the patients, particularly in
multidose preparations.

100
Some of the natural products, particularly if they are to be
applied to broken skin, should be sterilized before use.
Bentonite, for example, may contain Clostridium tetani
/sterilized by heating the dry powder at 160°C for 1 hour.

Preparations at greatest risk of contamination are those which

contain water such as oral solutions, suspensions and emulsions
to be taken orally, solution for external use, creams, and sterile
preparations used repeatedly (e.g. injectable multidose
preparations and eye drops).
• The product that has not been terminally sterilized

Oil-based parenteral products (solutions and suspensions) do not

generally require the inclusion of a preservative due to the low
water activity of this medium
101
The preservative is required in the aqueous phase of the emulsion
to exert the antimicrobial effect.
Certain hydro alcoholic & most alcoholic preparations may not

require the addition of a chemical preservative when the alcoholic

concentration is sufficient to prevent microbial growth.
Generally 15% or more alcohol concentration prevents microbial

growth.
If products do not contain a preservative and do not have adequate

inherent preservative efficacy they must not be packaged in

multidose presentations without a sound justification.

102
Mode of action of preservatives
Preservatives interfere with the metabolism, growth and
multiplication of microorganisms in one or more of the
following mechanisms:
 Modification of cell membrane permeability
 Irreversible coagulation of cytoplasm constituents
 Examples: protein precipitation

 Interference with metabolic enzymes.

 E.g. inhibition of cell wall synthesis

103
A preservative suitable for use should maintain the following
properties:
Possess a broad spectrum of antimicrobial activity.

Bactericidal rather than bacteriostatic activity.

It should not impart any taste, color or odor to the product.

• should have high water solubility

Compatibility with the other ingredients & with the container.

Stability & effectiveness over a wide range of pH & temperatures.

Nonirritant, nonsesitizing & nontoxic at concentration used

104
It must be realized that no single preservative exhibits all of
the desirable properties outlined earlier.

In many cases a combination is required, the most widely used

being a mixture of methyl and propylhydroxybenzoates at a
ratio usually of 10:1.

Because of the irritancy and toxicity of certain preservatives,

the initial choice will depend on the route of administration of
the product

105
Factors affecting preservative efficacy

The level of efficacy obtained will vary according to the

chemical structure of the preservative, spectrum of activity, its
concentration, the physical and chemical characteristics of the
medicinal product (especially pH), the type and level of initial
microbial contamination, the design of the pack and the
temperature at which the product is stored.

Although few microorganisms can grow below a pH of 3 or

above pH 9, most aqueous pharmaceutical preparations are
within the favorable pH range and therefore must be protected
against microbial growth.

106
Unfortunately, in many formulations, the concentration of
preservative within the formulation may be affected by the
presence of other excipients and by formulation pH.

The antimicrobial properties are due to the unionized form of the

preservative; the degree of ionization being a function of the pH of
the formulation.

The activity of the unionized form of the acid in this respect is due
to the ability of this form to diffuse across the outer membrane of
the microorganism and eventually into the cytoplasm.
The presence of micelles and adsorption of the preservative onto
the container from the product reduces the effective preservative
concentration.

107
The most widely used preservatives include
Benzoic and sorbic acid and their salts,
p-hydroxybenzoic acid esters,
Chlorocresol,
Phenoxyethanol,
Quaternary ammonium compounds and, to a lesser extent,
organic mercurials.
Phenols, methyl paraben, benzalkonium chloride

108
ANTIOXIDANTS
Antioxidants are included in pharmaceutical preparations to
enhance the stability of therapeutic agents that are susceptible
to chemical degradation by oxidation.

Typically antioxidants are molecules that are redox systems

which exhibit higher oxidative potential than the therapeutic
agent and hence antioxidants are oxidized (and hence
degraded) in preference to the therapeutic agent, thereby
protecting the drug from decomposition.

Oxidation may occur due to the action of molecular oxygen

may be facilitated by free radicals

109
These agents either act to prevent the formation of free radicals
or
alternatively oxidized in preference to the therapeutic agent
A further strategy that may be used to enhance the stability of
the therapeutic agent is
to flush the injection container/vial with nitrogen prior to
closure . Oxygen is removed from the headspace within the
packaged product
 Antioxidants may also be employed in conjunction with
chelating agents, e.g. ethylenediamine tetra acetic acid
(EDTA) that act to form complexes with heavy-metal ions
that are normally involved in oxidative degradation of
therapeutic

110
Typically antioxidants are employed in low concentrations

(0.2% w/w) &

 it is usual for the concentration of antioxidant in the

finished product to be markedly less than the initial

concentration, due to oxidative degradation during

manufacture of the dosage form.

 
 
 

111
Both water-soluble and water-insoluble antioxidants are
commercially available, the choice of these being made
according to the nature of the formulation.
Examples of antioxidants that are commonly used for aqueous
formulations include:
Sodium sulphite
Sodium metabisulphite
Ascorbic acid
Examples of antioxidants that may be used in oil-based solutions
include:
Butylated hydroxytoluene (BHT)
Butylated hydroxyanisole (BHA)
 Propyl gallate

112
 Buffer solutions will maintain a constant pH even when small
Buffers

amounts o acid or alkali are added to the solution.

Buffers usually contain mixtures o a weak acid and one of its
salts, although mixtures of a weak base and one of its salts may
be used
The latter suffer from the disadvantage that arises from the
volatility o many bases
Typically pH control is performed:
 To maintain the solubility of the therapeutic agent in the
formulated solution product.
 To enhance the stability of products in which the chemical
stability of the API is pH-dependent.
113
Buffered solutions characteristically have two components: a

weak acid and its conjugate base (soluble salt of the acid), for
example, acetic acid and sodium acetate.

H3O+ + CH3 COO- ↔ CH3COOH + H3O+

Any extra H3O+ will be neutralized by CH3COO− in the buffer

CH3COOH + OH- ↔ CH3COO- + H3O+

Any extra OH− that is added will be neutralized by the acid

114
When a small amount of an acid is added to the solution, it

will convert some of the salt into acetic acid, but if the
concentrations of both acetate ion and acetic acid are
reasonably large then the effect of the change will be
negligible and the pH will remain constant.
Similarly, the addition of a small amount of base will convert

some of the acetic acid into its salt form but the pH will be
virtually unaltered if the overall changes in concentrations of
the two species are relatively small.

115
If large amounts of acid or base are added to a buffer, then

changes in the ratio of ionized to unionized species become

appreciable and the pH will then alter

The ability of a buffer to withstand the effects of acids and

bases is an important property from a practical point of view.

This ability is expressed in terms of buffer capacity (β).

116
The choice of suitable buffer depends on the pH and buffering

capacity required.
Therefore, the pH chosen for product is likely to be a compromise

between the requirements for stability, solubility and physiological

compatibility
It must be compatible with other excipients and have a low

toxicity.

117
As the pH of most body fluids is 7.4, products such as
injections, eye drops and nasal drops should, in theory, be
buffered at this value to avoid irritation.

But to improve solubility, pH different from this may be

needed.
Examples of buffer salts used in pharmaceutical solutions
include:
Acetates (acetic acid and sodium acetate)
Citrates (citric acid and sodium citrate)

118
 VISCOSITY-ENHANCING AGENTS

Viscosity is a measure of resistance to flow.

The viscosity of the formulation must be sufficiently controlled
because it affects
 the stability and appearance of dispersed preparations
 flow from the container for liquid and semisolids

 accuracy of dosing
 ease of spread when applied to skin.
 increasing the viscosity of some formulations may increase
the palatability.
Accordingly there is a viscosity range that the formulation should
exhibit to facilitate this operation.
Certain liquid formulations do not require the addition of viscosity
enhancing agents, e.g. syrups, due to their inherent viscosity

119
 I. Natural Polysaccharides
Acacia
It is a very soluble polyelectrolyte whose solutions are highly
viscous due to the branched structure of the macromolecular
chains.

It is not very effective for dense powders, and for these it is
often combined with other thickeners such as tragacanth, starch
and sucrose in compound tragacanth powder.

Being a natural product, it is contaminated with

microorganisms.
 Hence preservatives should be added to the formulation.

120
Unfortunately, acacia mucilage becomes acidic on storage as a
result of enzyme activity, and it also contains an oxidase enzyme
which may cause deterioration of active agents that are
susceptible to oxidation.
 This enzyme can, however, be inactivated by heat.
*Because of the stickiness of acacia it is rarely used in
preparations for external use.
Tragacanth
Tragacanth is a naturally occurring dried gum.
 It is used as suspending agent as tragacanth mucilage or as
compound tragacanth powder.
The latter contains tragacanth, acacia, starch, and sucrose.
Gum tragacanth partially dissolves in water to give highly
viscous solutions.
121
It is one of the most widely used natural emulsifiers and
thickeners and is an effective suspending agent.
This product will form viscous aqueous solutions even at
relatively low concentration.

It can be used both for internal and external products.

Tragacanth is stable over a pH range of 4-7.5 but takes several
days to hydrate fully after dispersion in water.

The maximum viscosity of its dispersions is not, therefore,

achieved until after this time, and can also be affected by
heating.
 
 
122
Alginates
 Its salts have suspending properties similar to those of
tragacanth.
Alginate mucilage must not be heated above 60°C as
depolymerization occurs, with a consequent loss in viscosity.

They are most viscous immediately after preparation, after

which there is a fall to a fairly constant value after about 24
hours.

Alginates exhibit a maximum viscosity over a pH range of 5-9,

and at low pH the acid is precipitated.

123
Sodium alginate (Manucol) is the most widely used material

in this class but it is, of course, anionic and will be

incompatible with cationic materials and with heavy metals.
It has the advantage of being less variable in composition

than other natural suspending agents.

Starch
Starch is rarely used on its own as a suspending agent but it

is one of the constituents of compound tragacanth powder,

and it can also be used with carmellose sodium.

124
Xanthan gum
This is an anionic heteropolysaccharide.
 It is very soluble in cold water and is one of the most widely
used thickening agents for the extemporaneous preparation of
suspensions for oral use.
It is used in concentrations up to about 2% and stable over a
wide pH range.

II. Semisynthetic polysaccharides

These are derivatives of the natural polysaccharide, cellulose.
Several cellulose derivatives are available that will disperse in
water to produce viscous colloidal solutions suitable for use as
suspending agents.

125
Methylcellulose
 Methylcellulose is a methyl ether of cellulose containing about
29% of methoxyl groups.
It is slowly soluble in water.
It is used as suspending and viscosity increasing agent.
It is non-ionic and stable over a wide range of pH values
High-viscosity grades are used as thickening agents for
medicated jellies and as dispersing and thickening agents in
suspensions.

Microcrystalline cellulose (MCC)

It is widely used as suspending agent in combination with
others.
It is free from heavy microbial contamination
126
Hydroxyethylcellulose (Natrosol)
This compound has hydroxyethyl instead of methyl groups
attached to the cellulose chain and is also available in different
viscosity grades.
It has the advantage of being soluble in both hot and cold water
and will not gel on heating. Otherwise it exhibits the same
properties as methylcellulose.

Carmelose sodium (sodium carboxymethyl cellulose)

It can be used both internally and externally at concentrations
of up to about 5%, and stable over a pH range of 3.5-11. It is
anionic.

127
Clays
They are inorganic materials derived from natural sources. They
are predominantly hydrated silicates.

Bentonite
It is used at concentrations of up to 2 or 3% in preparations for
external use, such as calamine lotion.
As this product may contain pathogenic spores it should be
sterilized before use.

III. Synthetic agents

The quality of synthetic agents tends to be less variable than that
of suspending agents derived from natural sources.
128
Carbomer (Carboxypolymethylene)
 a high-molecular-weight polymer of acrylic acid, containing a high
proportion of carboxyl groups
used as a suspending agent in pharmaceutical preparations,as a
binding agent in tablets, and in the formulation of prolonged-acting
tablets.
It is a polymer of acrylic acid. It is readily oxidized and need the
addition of antioxidants and chelating agents.
Other synthetic agents are: colloidal anhydrous silica, polyvinyl
alcohol, povidone.

129
Quiz
say true or false and justify.
1. pH control of the pharmaceutical preparation is more critical in IV
administration than Sc or IM administration.
2. The solubility of weak bases increases as the pH is
decreased.
3. Purified water can be used for preparation of parentral dosage form.
4. The efficacy of antioxidants may be improved in the presence of
ethylenediaminetetraacetic acid (EDTA).
5. Bactrocidal preservative is preferred than bactrostatic preservative for
preparation of sterile product.
6. Preservative having high water solubility's are better than those having
low water solubility.
7. What is the important of pH controlling in pharmaceutical preparation?
8. How antioxidants prevent oxidation of therapeutic agents ?

130
SWEETENING AGENTS
Sweetening agents are employed in formulations designed for
oral administration specifically to increase the palatability of
the therapeutic agent.
The main sweetening agents employed in oral preparations
are
Sucrose
Liquid glucose
Glycerol
Sorbitol
Saccharin
Aspartame

131
The use of artificial sweetening agents in formulations is increasing

and, in many formulations, saccharin sodium is used either as the

sole sweetening agent or in combination with sugars to reduce the
sugar concentration in the formulation.

The main disadvantage of all artificial sweeteners is their tendency

to impart a bitter or metallic aftertaste, and they are therefore often

formulated with sugars to mask this.
The use of sugars in oral formulations for children and patients with

diabetes mellitus is to be avoided.

132
Advantage of Sucrose

Colorless

Very soluble in water

Stable over a pH range of about 4-8

By increasing the viscosity of fluid preparations, it will

impart to them a pleasant texture in the mouth

It will mask the tastes of both salty and bitter drugs and

has a soothing effect on the membranes of the throat

133
FLAVOURS
The simple use of sweetening agents may not be sufficient to

render palatable product containing a drug with a particularly

unpleasant taste.
In many cases, therefore, a flavoring agent can be included.

This is particularly useful in pediatric formulation to ensure

patient compliance.
The inclusion of flavors has the additional advantage of

enabling the easy identification of liquid products.

134
Flavouring agents are incorporated into a formulation to give
the tablet a more pleasant taste or to mask an unpleasant one
 are often thermolabile and so cannot be added prior to an
operation involving heat.
Flavoring and perfuming agents can be obtained from either
natural or synthetic sources.
Natural products include fruit juices, aromatic oils such as
peppermint and lemon, herbs and spices, and distilled fractions
of these.

They are available as concentrated extracts, alcoholic or

aqueous solutions, syrups , and are particularly widely used in
the manufacture of products for extemporaneous use.

135
Artificial perfumes and flavours are of purely synthetic origin,
often having no natural counterpart.
They tend to be:
 Cheaper

 More readily available

 Less variable in chemical composition and more stable
than natural products
 They are usually available as alcoholic or aqueous
solutions or as powders

136
The fact that personal preferences for flavours and perfumes
often vary with age can also aid the formulator.
Children, in general, prefer fruity tastes and smells, whereas
adults choose flowery odours and acid flavors.

Other suitable materials for the masking of unpleasant tastes

include menthol, peppermint oil and chloroform.
In addition to having their own particular tastes and odors
they also act as desensitizing agents by exerting a mild
anaesthetic effect on the sensory taste receptors.

137
Flavours that may be used to mask a salty taste include:
Butterscotch
Apricot
Peach
Vanilla
Wintergreen mint

138
Flavours that may be used to mask a bitter taste include:
● Cherry
● Mint
● Anise
Flavours that may be used to mask a sweet taste include:
● Vanilla
● Fruit and berry.
Flavours that may be used to mask a sour taste include:
● Citrus flavours
● Raspberry
Usually a combination of flavours is used to achieve the
optimal taste-masking property.

139
EMULSIFYING AGENTS
They prevent coalescence of the dispersed globules in

emulsified systems by forming barriers at the interface.

They may also facilitate the initial dispersion of globules by

reducing the interfacial tension

140
Surfactants
They have two distinct regions in their chemical structure

one of which is water-liking or hydrophilic and

the other of which is water-hating or hydrophobic.

These molecules are referred to as amphiphilic or amphipathic

molecules or simply as surfactants or surface active agents.

Some typical surfactants depending on their charge

characteristics
the surface-active molecules may be anionic, cationic,

zwitterionic (ampholytic) or non-ionic.

141
ASSIGEMNENT

WHAT IS EMULSIFING AGENT

TYPES OF EMULSIFING AGENTS

HLB SYSTEM

CHOICE OF EMULSIFIER OR EMULSIFIER

MIXTURE
DRAW BACK OF HLB SYSTEM

142
 These are ingredients that are added to impart color for the
COLOURANTS

formulation.
Some of the ingredients in a formulation may have color but
not used as colorant.
The reason for the inclusion of colors
increase attractiveness ( improving appearance)
enable easy product identification for the patient and for
the manufacturer.
The presence of a strongly colored degradation product, which
does not affect the use of the product, may occasionally be
masked by the use of a suitable colour.

143
As with flavours and perfumes, there is a range of both natural
and synthetic colors.
The natural tend to be more widely acceptable, can be classified
into:
Carotenoids
Chlorophyll
Anthocyanins
Riboflavines, caramel and extracts of beetroot.

144
They can, however, exhibit the usual problems associated with

natural products, namely variations in availability and chemical

composition, both of which may cause formulation difficulties.

Synthetic or 'coal tar' dyes tend to give bright colors and are

generally more stable than natural materials.

Most of those that are suitable for pharmaceutical use are the

sodium salts of sulphonic acids, and therefore they may be

incompatible with cationic drugs.

145
Care must also be taken to ensure that any dye used is not

adversely affected by pH or by UV radiation, or by the

inclusion of oxidizing or reducing agents or surfactants.

When used in combination with flavours, the selected colour

should ‘match’ the flavor of the formulation,

E.g. Green with mint-flavored solutions, red for

strawberry-flavored formulations.

146
Humectants
Glycerol, PEG and Propylene glycol are examples of

suitable humectants that can be added to an emulsion

formulation in order to reduce the evaporation of the water,
either from the packaged product when the closure is
removed or from the surface of the skin after application.
High concentrations, if used topically, may actually remove

moisture from the skin, thereby dehydrating it.

147
Isotonicity modifiers

An aqueous solution of sodium chloride at a concentration of

0.9% w/v or 9 g per L has a measured osmolarity of 286 mmol

per L and is isotonic
Solutions for injection, for application to mucous membranes,

and large-volume solutions for ophthalmic use must be made

iso-osmotic with tissue fluid to avoid pain and irritation.
The most widely used isotonicity modifiers are dextrose and

sodium chloride.

148
Isotonicity adjustments can only be made after the addition of

all other ingredients, because each ingredient will contribute to

the overall osmotic pressure of a solution.
The osmotic pressure of a solution is the external pressure that

must be applied to the solution in order to prevent it being

diluted by the entry of solvent via a process that is known as
osmosis.

149
Tablet excipients
Tablet antiadherents
They are agents which prevent the sticking of tablet
formulation ingredients to the punches and dies in a tableting
machine.
E.g. Magnesium stearate and talc
Tablet binder
substances used to cause adhesion of powder particles in tablet
granulation.
Acacia, gelatin, starch, ethylcellulose are just some examples

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Tablet and capsule diluent/filler
These are inert substances used as fillers to create the desired
bulk, flow properties, and compression characteristics in the
preparation of tablet and capsule.
These include starch, kaolin, sorbitol, lactose and Mannitol
Tablet coating agents
They are used to coat a formed tablet for different purposes.
 to improve the appearance of the formulation
 to mask the bitter taste of the therapeutic agent.
 to control the rate and duration of drug release or to target drug
release to certain regions of the GIT
 Prevent irritation effect, prevent drug from GI acid attack
 Improving mechanical properties
E.g. Sucrose, hydroxyl ethyl cellulose, cellulose acetate
phthalate
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Tablet disintegrants
They are used in solid dosage forms to promote the disruption of

the solid mass in to smaller particles which are more readily

dispersed or dissolved.eg starch and sodium alginate

Tablet glidants
They are substances used to improve the flow property of

powder mixture.
E.g. Colloidal silica and talc

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QUIZ
1. Which type of water is preffered for preparation of multidose
parentral formulation?
A. Purified water C. Bacteriostastic water
B. Sterilized water for injection D. Potable water
2. Which type of dosage form is absorbed rapidly?
A. solution B. suspension C. tablet D. capsule
3. Which type of DF not administered intraveneously?
A. solution B. suspension C. O/W Emulsion D. W/O emulsion
4. Use of expients
A. Improve shelf-life B. Mask bad taste
C. Improve PK profile D. Improving appearance E. none

4. Flavourant and colourant commonly used in parentral DF rather

than oral DF
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