INTEGRATED PHYSICAL

PHARMACY AND
PHARMACEUTICS I
Course Code: Phar 2091
Course CHRS: 5

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 Chapter I
Introduction to dosage forms
and routes of drug
administration
This chapter covers the following topics.
• Definition of some terminologies
• The need for dosage forms
• Types of dosage forms
• Principle of dosage form design
• Routes of drug administration
• Introduction to pharmaceutical ingredients

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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
• Explain common types of pharmaceutical excipients

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 Definition of Terminologies
Pharmaceutics

• It is the general area of study related with the physical,

chemical and biological factors influencing the
formulation, manufacturing, stability and effectiveness of
pharmaceutical dosage forms.

• It is simply the science of converting a drug in to a

medicine or the science of dosage form design.

• It is concerned with the scientific and technological

aspects of the design and manufacture of dosage forms. 4
• 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.

• It is perhaps the most diverse of all the subject areas in

pharmaceutical science.

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Drugs

• They are chemicals that alter physiological 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 and are almost always given as formulated
preparations or medicines.
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Medicines

• They are drug delivery systems.

• They are a means of administering drugs to the body in a safe, efficient,

reproducible and convenient manner.

• Medicines are rarely drugs alone.

Physical pharmacy

• It is concerned with the quantitative and theoretical principles of science

as applied to pharmacy.

• It is the study of the physicochemical properties of drugs.

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Principle of Dosage Form Design

Before discussing the dosage form design, be clear with the

following related terms.
Dose
• It refers the strength of a medication and tells how much active
ingredient is contained within the medicine.
• Example: Paracetamole 500mg or Magnesium hydroxide
375mg/5ml
Dosage
• A means of giving a medication in a prescribed amount
Dosage form
• It is the pharmaceutical preparation with unique characteristics
and which makes dosage possible.
• Example: Tablet, Syrup 8
• Dosage form design is the overall process of changing a
certain drug in to a particular dosage form that is safe,
effective, stable, and suitable for large scale
manufacture with reproducible quality.

Stability: physical, chemical and microbiological stability

Safety: acceptable degree of undesired effect (harm)

Effective: capable of maintaining the intended effect.

Achieving a predictable therapeutic response.

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Pharmaceutical preparation
(PP)
• Particular pharmaceutical product containing active and
inactive pharmaceutical ingredients formulated into the
particular dosage form.

• 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).

• In this case right dosage strength need not be

readily commercially available for every patient 11

• The patient suffers from the allergy on a specific
excipients (e.g., lactose as a filler, some
colorizing/flavouring or antimicrobial agents -
parabens) 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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• The pharmaceutical preparations with particular characteristics
presented (given) to the patients are called as dosage forms.
• 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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Why from simple drug to dosage form?

• API handling can be difficult or impossible

• Example: Low mg and g doses

• Accurate drug dosing can be difficult or impossible

• Some API can benefit from reducing the exposure to

the environmental factors (light, moisture…), or they
need to be chemically stabilised due to the inherent
chemical instability e.g. coated tablets

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Cont…
• API can be degraded at the site of administration
(e.g., low pH in stomach)

• 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
(e.g. capsules, coated tablets, flavored syrups etc.).
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• 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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Major considerations in the design of
dosage forms
I. The physicochemical properties of the drug

• Particle size and surface area

This may affect the solubility of the drug and therefore the
dissolution rate of the product.

• Solubility and dissolution

• Partition coefficient

This may give some indication of the relative affinity of the

drug for oil and water. A drug that has high affinity for oil may
have poor release and dissolution from the drug product.
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Crystal property: polymorphism

• The ability of a drug to exist in various crystal forms may

change the solubility of the drug.

• Also, the stability of each form is important, because

polymorphs may convert from one form to another.

• Certain classes of drug are particularly susceptible to

polymorphism
• Example, about 65% of the commercial sulfonamides and
70% of the barbiturates used medicinally are known to exist
in several polymorphic forms
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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.

• It is important to have specifications of all raw materials. e.t.c

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II. Biopharmaceutical considerations

• How the route of administration affects bioavailability of the

drug in to the body

• By choosing the route of drug administration carefully and

properly designing the drug product, the bioavailability of the
active drug can be varied from 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

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III. Therapeutic consideration of the disease state to be treated

• the need for systemic or local therapy,

• the duration of action required and

• whether the drug will be used in emergency situations

• There is interdependence of biological aspects of the living

organism (the patient) and the physical–chemical principles
that govern the preparation and behavior of the medicinal
agent or drug product.

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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 (Infants generally prefer liquid dosage forms,
adults generally prefer solid dosage forms, primarily because
of their convenience)
• the specific needs of a certain clinical situation (rapid
bronchial relaxation by inhalational anti asthmatics).

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For example:
• Many asthmatic patients use inhalation aerosols from which
the drug is rapidly absorbed into the systematic circulation
following deep inhalation for rapid emergency relief, and
• Oral products for chronic asthma therapy.

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Types of Dosage Forms
• Classified according to physical properties (physical state) or
according to the route of administration.

• Classification according to physical state

• Gaseous dosage forms
• Liquid dosage forms
• Semisolid dosage forms
• Solid dosage forms

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Gases

Aerosols
• Aerosols are a system of finely

divided liquid or solid particles

dispersed in and surrounded by a gas
• Example: Antiasthmatic inhalations or sprays

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Liquids

• Solutions
• Homogenous phase, prepared by dissolving one or more solutes in a
solvent

• Emulsions
• a dispersion system consisting of two immiscible liquids
• can be o/w or w/o types

• Suspensions
• A dispersion system where solid particles

(dispersed phase) are dispersed in liquid phase

(dispersion medium)

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Semisolid dosage forms

• Gels
• A semisolid systems in which a liquid phase is constrained within 3D
cross-linked matrix.

• Creams
• Semisolid emulsion systems (o/w, w/o)

containing more than 10% of water.

• Ointments
• Semisolid for application onto skin or mucosa.
• It is viscid and heavier than cream

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• Pastes
• Pharmaceutical pastes are generally composed of ointment bases that
contain a high concentration (frequently >50% w/w) of dispersed drug

Solid Dosage Forms

• Powders for external/internal use

• Tablets are compressed product

(API+ excipients – e.g., fillers, desintegrants)

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• Capsules
• API and excipients are enclosed in the hard/soft water soluble container
made of gelatin.

• Implants
• Sterile disks inserted surgically into body tissues and designed to release
drug(s) over extended period of time

• Suppositories
• Solid dosage forms to be

inserted through the rectum or vagina

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• Classification according to the route of administration
• For systemic administration
• Per oral (p.o)
• Sublingual (S.L) and buccal.
• Rectal
• Parenteral
• Transdermal

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• For local administration
• Into/onto - the eye, nose, ear, the oral cavity, the vagina,
rectum, the bronchi, the skin
• Oral (local effect within GIT; antacids, adsorbents)

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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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ROUTES OF DRUG ADMINISTRATION

• It refers the route by which the drug is placed (regulated/given

or taken).

• The possible routes of drug entry into the body may be divided
into two classes:
• Enteral and
• Parenteral.

• Enteral – the formulation is placed directly in the GI tract

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Enteral Routes

Sublingual route

• Placed under the tongue

Advantages
• Rapid absorption

• Drug stability

• Avoid first-pass effect

• Disadvantages

• Inconvenient

• Small doses

• Unpleasant taste of some drugs

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Oral route

• Swallowing (p.o., per os)

Advantages
• It is most natural route of administration.
• It is most easy route for administration of drug for patients.
• It is safest route of administration.
• It is most convenient for patients.
• 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

• As it is absorbed from gastrointestinal tract the quantity of doses of drug

required is more.

• It is difficult route of administration of drug for non-cooperative patients

like babies and children.

• It is also difficult route of administration of drug for unconscious

patients.

• The absorption of drug from gastrointestinal tract is not assured by

patients suffering from gastrointestinal disorder.
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• Oral route of administration may cause gastrointestinal
disorders like acidity, loss of appetite, etc.

• Drug may be destroyed or inactivated by the enzyme in

gastrointestinal tract.

• Some drugs are extensively metabolized by the liver before

systemic absorption( first pass effect)

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Rectal route

• The formulation is given through the rectal cavity and absorption

through the rectum

Advantage
• It can be given for unconscious patients and children

• If patient is nauseous or vomiting

• Easy to terminate exposure

• Good for drugs affecting the bowel such as laxatives

Disadvantages
• Absorption may be variable

• Irritating drugs of the rectal mucosa are contraindicated

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Parenteral Routes

Intravascular(IV, IA)
• Placing a drug directly into the blood stream.

Advantages
• Absorption phase is by passed (100% bioavailability)
• Precise, accurate and almost immediate onset of action,
• Large quantities can be given, fairly pain free

Disadvantages
• Greater risk of adverse effects
• High concentration attained rapidly
• Risk of embolism
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Intramuscular (IM)
• Drug injected into skeletal muscle
• Very rapid absorption of drugs in aqueous solution
• Repository and slow release preparations
• Pain at injection sites for certain drugs

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Subcutaneous
• Absorption of drugs from the subcutaneous tissues
• Slow and constant absorption
• Absorption is limited by blood flow, affected if circulatory
problems exist
• Concurrent administration of vasoconstrictor will slow
absorption

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Cont…

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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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• 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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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 or patch becomes to large

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 2. PHARMACEUTICAL EXCIPIENTS

• Drugs are rarely administered as pure chemical substances

alone and are almost always given as formulated preparations
or medicines.

• Such formulations contain the active pharmaceutical

ingredient (API) and the therapeutically inert ingredients or
commonly called the pharmaceutical excipients or additives.

• Excipients provide varied and specialized pharmaceutical

functions.

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• It is the formulation additives that solubilize, suspend, thicken,
preserve, emulsify, stabilize, modify dissolution (drug release),
improve the compressibility and flavor drug substances to form
various preparations or dosage forms.

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Classification of excipients
1. Excipient based on their origin

• Animal source: - Lactose, Gelatin, Stearic acid, Bees wax, Honey, Musk,
Lanolin etc.

• Vegetable source: - Starch, Peppermint, Turmeric,

Guar gum, Arginates, Acacia etc.

• Mineral source: - Calcium phosphate, Silica, Talc,

Calamine, Asbestos, Kaolin, Paraffin, etc.

• Synthetic: - Boric acid, Saccharin, Lactic acid,

Polyethylene glycols, Polysorbates, Povidone

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Cont…

2. Classification of excipients based on their

functions

• Various excipients used in solid dosage forms

perform various functions like:-

Binders, diluents, lubricants, disintegrating agent’s

plasticizers

• Excipients that are used in liquid dosage forms are:-

Solvents , co- solvents, buffers, anti-microbial agents

emulsifying agents , sweetening agents, flavors

• Some excipients have therapeutic values which are

classified as :-

• Anesthetics :- chloroform, etc

• Laxatives: - bentonite 52
Cont…

• Astringent: - cinnamon, alum, zinc sulphate.

• Carminative: - cinnamon1, dill water, anise water.

• Nutrient sources: - agar

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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
• Low equipment and process sensitive
• Acceptable with regards to organoleptic

characteristics
 Having efficiency in regards with the intended use
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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

• It works by Breaking of bonds and reducing effective charge on

ions thus increasing Solute-Solvent forces of attraction which
are eventually

greater than Solute-Solute and Solvent-Solvent forces of

attraction.

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Cont…
• It will be obvious that there is a greater choice of solvents
available for inclusion into products for external application
than those for internal use, and 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.
57
Types of pharmaceutical water
Potable water

• This is water freshly drawn from the mains system and which is suitable
for drinking and sanitary purpose.

• It is prepared from fresh water or from sea water

• For many preparations potable water can be used.

• It is not free from ions and microbes.

• Water found in most cities and towns where water is purified for
drinking purposes usually contains less than 0.1 %w/v of total solids.

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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.

• In other words purified water is 100 times more free of

dissolved solids than potable water.

• It is more expensive

Water for preparation

• It is freshly boiled and cooled water to destroy vegetative

microorganisms.

• It is used in oral liquid or for external preparations

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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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• This water may contain a slightly greater amount of solids than
the unsterile water for injection (which has 1mg solid per
100ml like the purified water obtained through distillation or by
other means).

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

• They are used mainly for their flavoring properties although

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 improve aqueous solubility

• 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.

• For unionized drugs or for weak electrolytes at a pH that is

unfavorable for extensive ionization, one or more of the
following methods should be used to improve aqueous
solubility.

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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 can be predicted from the material's solubility in each
individual solvent.

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• Choice of suitable co solvents is somewhat limited because of possible toxicity
and irritancy, particularly if required for oral or parenteral use.

• Ideally, suitable blends should possess values of dielectric constant between 25

and 80.

• The most widely used system that will cover this range is a water/ethanol
blend.

• Other suitable solvents for use with water are ethanol, sorbitol, glycerol,
propylene glycol and syrup.

• Example:
• A blend of propylene glycol and water is used to improve the solubility of
co-trimoxazole
• Paracetamol is formulated as an elixir by the use of alcohol, propylene glycol
and syrup.
66
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 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.

• For example:
• 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.

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• 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
68
• In some instances the bioavailability of drugs may be
influenced by the pH of their solutions and 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.

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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.
• Surfactants (surface active agents) are molecules which
have two distinct regions in their chemical structure
• These molecules form different types of micelles.
• Surfactant molecules tend to associate in water into
aggregates called 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.

70
Complexation
• In some cases it may be possible to interact a poorly soluble
drug with a soluble material to form a soluble intermolecular
complex.

• 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.
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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.
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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 solubilities.
• The propionate and benzoate esters of testosterone and estradiol,
respectively, are good examples of this.
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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.

74
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.

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• Alcohol USP is 95-96% Ethanol by volume (i.e. v/v).

• Diluted alcohol NF is prepared by mixing equal volumes of

alcohol USP and purified water USP. Due to contraction of the
liquids upon mixing, the final volume of the mixture is 3% less
than what would normally be expected. So the percentage
strength is higher than the simple expectation.

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

being more selective than water.
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• 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.

• 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.

77
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.
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Glycerol

• Glycerol (also termed 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.

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Dimethylsulphoxide

• This is a highly polar compound and is thought to aid the

penetration of drugs through the skin (penetration enhancer).

• Although used mainly as a solvent for veterinary drugs, it is

used as a carrier for idoxuridine, an antiviral agent, for
application to human skin.

Liquid paraffin

• The oily nature of this material makes it unpleasant to use

externally, although it is often used as a solvent for the topical
application of drugs in emulsion formulations.
80
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 or

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

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• 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 but can
be 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).
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• Certain hydro alcoholic and 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.

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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
84
Preservative suitable for use should maintain the following
properties:

• Possess a broad spectrum of antimicrobial activity encompassing

Gram-positive and Gram-negative bacteria and fungi.

• Bactericidal rather than bacteriostatic activity. A preservative

having a minimal bacteriostatic activity may lose it if any physical
or chemical changes occur in the system;

• At the concentration used in the preparation, the preservative

should be safe and comfortable to the patient such as freedom
from toxic, irritant or sensitizing activity.

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• High water solubility.

- Because the growth of microorganisms occur in the aqueous phase,

it is important that the preservative has high water solubility.

• Compatibility with the other ingredients and with the container.

Certain preservatives are incompatible with particular groups of
emulsifying agent.

• Stability and effectiveness over a wide range of pH and

temperatures.

• Freedom from color and odour.

86
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

87
• 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 propyl hydroxybenzoates 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
88
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.
89
• 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.
90
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.

91
• 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
92
• Typically antioxidants are employed in low concentrations (0.2%

w/w) and 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.

• 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 agents.

93
 BUFFERS

• Buffers are employed within pharmaceutical preparations to control the

pH of the formulated product and, in so doing, optimise the
physicochemical performance of the product.

Typically pH control is performed:

• To maintain the solubility of the therapeutic agent in the formulated

solution product. The solubility of the vast number of currently available
drugs is pH-dependent and, therefore, the solubility of the therapeutic
agent in the formulation may be compromised by small changes in pH

• To enhance the stability of products in which the chemical stability of the

active agent is pH-dependent.
94
• Buffers are materials which, when dissolved in a solvent, will enable the
formulation to resist any change in pH should an acid or an alkali be added.

• The choice of suitable buffer depends on the pH and buffering capacity

required.

• It must be compatible with other excipients and have a low toxicity.

• Most pharmaceutically acceptable buffering systems are based on

carbonates, citrates, gluconates, lactates, phosphates or tartrates.

• Borates can be used for external application, but not to mucous membranes
or to abraded skin.

95
• Although solutions of drugs that are themselves weak
electrolytes will act as buffers, their buffering capacities are not
usually sufficiently robust and should be enhanced by one of
the systems described above.

• 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.

96
• The concentration (and hence buffer capacity) of buffer salts
employed in the formulation of oral solutions should be selected
to offer sufficient control of the pH of the formulation but yet
should be overcome by biological fluids following administration.

• This latter property is particularly appropriate for parenteral

formulations to ensure that there is no irritation or damage
following injection.

Examples of buffer salts used in pharmaceutical solutions include:

• Acetates (acetic acid and sodium acetate)
• Citrates (citric acid and sodium citrate)
97
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 such as suspensions, flow
from the container for liquid and semisolids, accuracy of dosing, as well as ease
of spread when applied to skin.

• Furthermore, 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 specific addition of viscosity-

enhancing agents, e.g. syrups, due to their inherent viscosity

98
 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.
99
• 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.

100
• 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.

101
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.
102
• 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.

103
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.

104
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

105
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.

106
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.

107
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.

108
SWEETENING AGENTS

• Sweetening agents are employed 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
109
• 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 use of sugars in oral formulations for children and patients with
diabetes mellitus is to be avoided.

• 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.

110
• 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

111
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.

112
• 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.

113
• 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

114
• 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.
115
• Flavours that may be used to mask a salty taste include:
• Butterscotch
• Apricot
• Peach
• Vanilla
• Wintergreen mint

116
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
117
• Usually a combination of flavors is used to achieve the optimal
taste-masking property.

• Certain excipients may be added to oral solution formulations,

referred to as flavor adjuncts (e.g. menthol, chloroform) that
add flavor to the formulation but, in addition, act to desensitize
the taste receptors.
• In so doing these agents augment the taste-masking
properties of conventional flavors.

118
 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

• They can be broadly classified into

• Surfactants
• Those derived from natural products
• Finely divided solids

119
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.

120
• An efficient emulsifying agent should have both lipophilic and
hydrophilic properties at a reasonable balance.

• The interfacial film comprises the water, the emulsifying agent,

and the oil in consecutive layers

121
• The film acts as a mechanical barrier to coalescence by physical
or chemical effects due to the adsorbed emulsifying agent, by
repulsive forces of electrically charged groups, or by the
combination of the two.

• Surfactants could be divided in to

• Anionic
• Cationic
• Ampholytic
• Non ionic

122
Anionic surfactants

• Soaps formed from long chain fatty acids (C12-C18), sulphated

alcohols and sulphonates comprise many of the anionic
emulsifying agents in common use.

• On dissociation of the long chain, the anion imparts surface

activity while the cation is inactive.

• Soaps and similar anionic agents are unsuitable for internal use
because of their unpleasant taste and irritation on the GI
mucosa.
123
• Examples
• Fatty acids such as steric acid,
• Alkali metal and ammonium soaps such as sodium stearate
• Soaps of divalent and trivalent metals
• Amine soaps such as from triethanolamine and oleic acid

124
Cationic surfactants
• Cetrimide
• Benzalkonium chloride

Non ionic surfactants

• Account for the majority of surface active agents used to

produce w/o or o/w emulsions for internal and external use.

• Resist the effect of electrolytes and are compatible with other

surfactants, are generally less irritant than the ionic ones

125
• When present in excess, they can bind and inactivate
preservative having phenolic or carboxylic group.

• Examples
• Macrogol esters such as polyoxyl 40 stearate
• Sorbitan esters such as sorbitan monolaurate
• Polysorbates, polivinyl alcohols

Ampholytic surfactants

• Are not widely used as surfactant but used as bactericidal

detergents
126
The HLB system

• The HLB system (hydrophile-lipophile balance) was originally

developed for non ionic surfactants.

• Each emulsifying agent is assigned values from 1-20.

• For non ionic surfactants, the no is assigned based on

hydrocarbon chain length and no of polar groups. For other
surfactants from water solubility, dielectric constant interfacial
tension etc.

127
HLB range Property

• 4-6 Emulsifying agents (w/o)

• 7-9 Wetting agents

• 8-18 Emulsifying agents (o/w)

• 13-15 Detergent

• 10-18 Solubilizing agents

128
Emulsifying agents derived from natural product

• Have microbial contamination

• Examples
• Tragacnth
• Acacia
• Wool fat
• Cholesterol
• Lecithin
• Gelatin etc
129
Finely divided solids

• Colloidal particles accumulate at oil-water interfaces to yield solid

interfacial films.

• A number of colloidal clays and inorganic substances are effective

emulsifying agents in the divided state.

• Although the resulting emulsions are often of coarse texture, they

show good stability and are less prone to microbial spoilage than
many of those made with natural emulsifying agents.

• The addition of a surfactant may improve the texture of the

emulsion.
130
• Examples

• Bentonite

• Aluminium magnesium silicate

• Colloidal anhydrous silica

• More rigid interfacial films can often be formed by using two

emulsifying agents.

• Emulsifying waxes are good examples.

• Emulsifying wax BP contains cetostearyl alcohol and sodium lauryl

sulphate

131
COLOURANTS

• These are ingredients that are added to impart color for the 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,
• 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.

132
• As with flavors 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.

133
• 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.

134
• 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.

135
 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.

136
Isotonicity modifiers

• 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.

• 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.
137
Wetting agents

• Aid wetting and dispersion of hydrophobic active pharmaceutical ingredients.

• It works by reducing interfacial tension between solids and liquids in

suspensions.

Example : Sodium Lauryl Sulphate (SLS), Tween 80,

Spans, Lecithins

Thickening agents

• Prevent settling/sedimentation, modify viscosity.

• It Works by entrapment of solid particles.

Example Methyl cellulose, Hydroxyethyl cellulose,

Microcrystallince cellulose

138
Flocculating agents

• Prevent caking

• Addition of an electrolyte reduces the

magnitude of zeta potential of dispersed particles.

Example: Starch, Sodium alginate, Carbomer

139
Tablet excipients
Tablet antadherents

• 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.

E.g. Acacia, gelatin, starch, ethylcellulose are just some examples

140
Tablet and capsule diluent

• 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.

• E.g. Sucrose, hydroxyl ethyl cellulose, cellulose acetate

phthalate
141
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

142
Lubricants

• Reduce inter-particular friction, prevent adhesion of tablet

material to the surface of dies and punches facilitate easy
ejection of tablet from die cavity and improve the rate of flow
tablet granulation

E.g. Talc, Stearic acid, Magnesium stearate, Calcium stearate,

Polyethylene glycol, Surfactants, vegetable oil

143