LO-1

PHARMACEUTICAL DOSAGE FORMS

1.1. Introduction
1.1.1 Definition of pharmaceutics
 Pharmaceutics is the general area of study concerned with the formulation, manufacture,
stability and effectiveness of pharmaceutical dosage forms.
 Pharmaceutics deals with the formulation of a pure drug substance into a dosage form.
 The word pharmaceutics is used in pharmacy and pharmaceutical sciences to encompass
many subject areas which are all associated with the steps to which a drug is subjected
towards the end of its development i.e. it is the stages that follow its discovery or synthesis,
its isolation and purification and testing for advantageous pharmacological effects and
absence of serious toxicological problems
1.1.2 Pharmaceutical Dosage Forms
 Definition: - Dosage form is the form of the preparation of a certain drug to be given to the
patient.
 There are different dosage forms of pharmaceutical drugs. E.g. liquids, solids, semisolids
gases.
 Drugs are rarely administered as pure chemical alone; but require additives to make them
in to dosage forms and this in turn introduces the concept of formulation
 There are three major considerations in the design of dosage forms
1. The physicochemical properties of the drug itself
2. Biopharmaceutical considerations such as how the route of administration of a
dosage form affects the rate and extent of drug absorption in to the body
3. Therapeutic considerations of the disease state to be treated, which in turn decide the
most suitable type of dosage form, possible routes of administration and the most
suitable duration of action and dose frequency for the drug in question.
In addition:
 The physicochemical and biological characteristics of all of the
pharmaceutical ingredients to be used in fabricating the product.
 The drug and pharmaceutical materials utilized must be compatible with one
another to produce a drug product that is stable, efficacious, attractive, easy to
administer and safe.
 The product should be manufactured under appropriate measures of quality
control and packaged in containers that contribute to product stability.
The Need for Dosage Forms
 The main reason of preparing different dosage forms is to provide the mechanism for the safe
and convenient delivery of accurate dosage of drugs.
 The specific reasons are:
 For the protection of a drug substance form the destructive influences of
atmospheric oxygen or humidity e.g. coated tablets, sealed ampoules

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  For protection of a drug substance from the destructive influence of gastric acid
after oral administration e.g. enteric coated tablets
 To conceal the bitter, salty or offensive taste or odor of a drug substance e.g.
capsules, coated tablets, flavored syrups
 To provide liquid preparations of substances that are either insoluble or unstable
in the desired vehicle e.g. suspension
 To provide clear liquid dosage forms of substances. e.g. syrups, solutions
 To provide rate controlled drug action e.g. various controlled release tablets,
capsules and suspension
 To provide optimal drug action from topical administration sites e.g. ointments
creams, etc
 To provide for the insertion of a drug in to one of the body orifices e.g. rectal and
vaginal suppositories
 To provide for the placement of drug directly in to the blood stream or in to body
tissues e.g. injections
 To provide for optimal drug action through inhalation therapy e.g. Inhalation
aerosols, etc
Components of Dosage forms
 Drug substances are seldom administered alone but rather as part of a formulation in
combination with one or more non-medical agents that serve varied and specialized
pharmaceutical functions.
 Generally, the components of a dosage form are divided in to two groups
a) The active ingredient:
 is the drug substance of a dosage form that produces medicinal effect
b) Excipients, additives or pharmaceutical ingredients:
 Are non-medicinal agents or components of a dosage form for their non-
medicinal effects like to solubilize, suspend, thicken, dilute, emulsify, stabilize,
preserve, colorize, flavor, and fashion medicinal agents in to efficacious and
appealing dosage forms
 for instance, the preparation of pharmaceutical solutions, one or more solvents are
used to dissolve the drug substance,
o Flavors and sweaters are used to make the product more palatable,
o colorants are added to enhance product appeal,
o preservatives may be added to prevent microbial growth and
o stabilizers, such as antioxidants and chelating agents may be used to
prevent drug decomposition
 In the preparation of tablets, diluents or fillers are commonly added to increase
the bulk of the formulation, binders to cause the adhesion of the powdered drug
and pharmaceutical substances. Antiadherents or lubricants to assist the smooth
tabletting process, disintegrating agents to promote tablet break up after

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 administration and coatings to improve stability, control disintegration or to
enhance appearance
Types of Pharmaceutical Dosage Forms
 Generally, there are 4 types of dosage forms:- solid, semisolid, liquid and gaseous
1.1.3 Raw Materials testing and handling
 Raw material is a precursor of pharmaceutical drug product either act as active or inactive
(excipient).
 Good raw material specifications
 must be written in precise terminology,
 must provide specific details of test methods, type of instruments, and manner of
sampling,
 must be properly identified
 The following table lists general test, limits and other physical or chemical data for raw
materials related to identity, purity, strength and quality.
Raw Material Quality Assurance Monograph
A. (Raw material Name)
1. Structural formula, molecular weight
2. Chemical name (S)
3. Item number
4. Date of issue
5. Signature of writer
6. Signature of approval
7. Date of superseded, if any or new material
B. Samples
1. Safety requirement
2. Sample plan and procedure
3. Sample size and sample container to be used,
4. Preservation sample required.
C. Retest program
1. Retesting schedule
2. Reanalysis is to be performed to assure identity, strength, quality and purity.
D. Specifications
1. Description
2. Solubility
3. Identity
 Specific chemical tests such as related alkaloids, Na, K, Cl etc. test
 Infrared absorption
 UV absorption
 Melting range
 Boiling point or range

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  Thin-layer, paper, liquid, or gas chromatography
4. Purity and quality.
 General completeness of solutions, PH, water content,
 Special quality test, particle size, polymorphism forms
 Special purity tests,
5. Assay, calculated either on anhydrous or hydrous basis
6. Microbial limits, especially for raw materials from natural sources
E. Test procedures
1. Compendia, USP, or NF, references
2. Non compendia, detailed analytical procedure, weights, dilutions, extractions, reagents,
instrumentation
F. Approved suppliers
1. List of prime suppliers and other approved alternative suppliers, if any
 The FDA current good manufacturing practices (CGMP) covering raw materials handling
procedures are found in the code of federal regulations.
 It simply states that” components” be received, sampled, tested, and stored in a
reasonable way, that rejected material be disposed of , that samples of tested components
be retained, and that appropriate records of these steps be maintained.
 In practice, the manufacturer physically inspects and assigns lot numbers to all raw
materials received and quarantines them until they are approved for use. Each raw
material is sampled according to standard sampling procedures and is sent to the quality
control laboratory for testing according to the written procedures.
 If acceptable, it is moved to the release storage area, after being properly stickered to
indicate the item number, name of material, lot number, date of release, reassay date, and
signature of the quality assurance inspector.
 It is retested as necessary according to an established schedule to assure that it still
conforms to specifications at time of use.
 Quality assurance personnel should keep preservation samples of active raw materials
that consist of at least twice the necessary quality to perform all tests required, to
determine whether the material meets the established specifications.
 These preservation samples should be retained for at least 7 years. Approved materials
should be rotated so the oldest stock is used first. Any material not meeting the
specifications must be isolated from the acceptable materials, stickered as rejection and
returned to the supplier or disposed of promptly.
 To verify the supplier’s conformance to specifications, further supporting assurance by
means of on – site periodic inspections are pertinent to the total quality of raw materials
 This procedures assures that cross-contamination does not take place because of
improperly cleaned equipment or poor housekeeping practices, otherwise contaminants
could go undetected because specification generally are not designed to control the
presence of unrelated materials.
1.1.4 Quality assurance of raw materials
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 Quality assurance: is a concept of embracing a wide variety of activities. These starts with
product design and follow through all stages of manufacture to and beyond the final release
of the product for use.
 The aim of quality assurance is to ensure that each batch of medicinal product complies with
its specification and it fit for its intended use in terms of safety, efficacy and acceptability.
 An important aspect of quality assurance is the use of the appropriate quality of ingredients
from authenticated suppliers.
 Quality must be built into a drug product during product and process design.
 The product and process design begins in research and development
- It considers materials, in process and product control, including specifications and tests
for the active ingredient( assay), the excipients and the product itself, specific stability
procedures for the product, freedom from microbial contamination (limit test) and
proper storage of the product and containers, packaging labeling.
 In general raw materials can be classified in to two groups.
i. Active or therapeutic
ii. inactive (inert)
1. Active or therapeutic materials
A. antibiotics
 Testing for antibiotics is usually performed chemically, microbiologically, biologically, or by
all three methods.
 Caution must be exercised in testing antibiotic raw material to assure that it is not altered
during the sampling procedure.
- The sample must be taken in a relatively dry atmosphere, relatively free from dust, and
free of both chemical and microbial air borne contamination, and exposure must be
reduced to minimal time of sampling.
- Special attention should be given to the assay for potency of antibiotic raw materials.
B. Other active materials
 Since there is such a wide variance in the nature of the active ingredients used in
manufacturing, it is impossible to summarize briefly the testing those raw materials.
 One of the most important decisions to be made in raw materials control is the degree of
purity to be maintained for each material.
 It is not uncommon find an appreciable variation in the degree of purity between samples of
the same raw material purchased from different commercial sources.
 The selection must then result in the highest purity and efficacy of the final dosage form.
 Raw materials cannot be adequately evaluated and controlled without special instrumentation
such as GLC, paper, thin- layer and high- pressure liquid chromatography (HPLC).
• No less demanding are the tests required form microbiologic assay, pharmacologic assay
and safety testing.

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 • For certain products, even when highly purified and well characterized raw materials are
involved, specifications should include additional critical tests, such as particle size,
crystal shape, and crystalline versus amorphous forms.
• Any of these characteristics could affect the safety or effectiveness of the dosage form.
2. In active or inert materials
 Inactive or inert materials usually make up the major portion of the final dosage form.
 Therefore, their physical characteristics such as color, odor, and foreign matter, are as
important as their chemical purity.
 Among other important specifications of inactive or inert materials are particles size, heavy
metal content, water content, microbial limit, pH-
 If a flavored oral DF is desired, flavors or volatile oils are usually tested for refractive index,
solubility, and alcohol content.
 Sweetening agents are tested for unwanted impurities, water content and the presence of
heavy metals.
1.1.5 Water as raw materials
 Water is used to clean containers and equipment, and is the main constituent in the majority
of pharmaceuticals. -
 Water is the preferred injection vehicle since aqueous preparations are well tolerated by the
body and easy to administer.
 Water has a large solvent capacity for a wide range of materials, but it is difficult to purify
and difficult to keep clean.
I. Drinking water
 Can affect most substance which it contacts
 Contains varying amounts of dissolved inorganic salts e.g. sodium, potassium, calcium,
magnesium and iron.
 Can contain micro-organisms.
 Drinking H2O should be clear, colorless, odorless and neutral
 Ordinary drinking H2O obtained from the tap is not generally acceptable for the
manufacture of most pharmaceutical preparations or for the extemporaneous
compounding of prescriptions because of the chemical incompatibilities they may result
from the combinations of dissolved solids present and the medicinal agents being added.
 Signs of drinking water incompatibilities for extemporaneous compounding are
precipitation, discoloration and occasionally effervescence
 Drinking water can be economically used to clean pharmaceutical machinery and
equipment even through purified water is used as final rinse of residue of solids.
 To use water as a raw material for pharmaceutical purpose, it should undergo certain
purification of treatment either by demineralization, distillation, removal of particulate
matter or reverse osmosis.
II. Purified water
 It is obtained by distillation, ion-exchange treatment, and reverse osmosis.
 It is free of solids impurities
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  It must not yield greater than 0.001% of residue when evaporated (1mg of total solids per
100ml of sample evaporated).
 It is intended for used in the preparation of aqueous dosage forms, except for parnteral
administration (injections).
 Pure water is a poor conductor of electricity. It has a conductivity of 0.055 S/cm
(microsiemens) at the standard measuring temperature of 250C. Even low concentration
of dissolved solids will cause a substantial change in conductivity, so conductivity
measurement represents a useful means of checking the degree of impurity in a sample of
water. There are three general methods of purifying water, by distillation, deionization or
reverse osmosis.
1.1.5.1 Water treatment
1. Distillation method- by partial vaporization of the mixture
 The separation of one liquid from nonvolatile impurities.
 The feed H2O to the boiler is heated to de-gas it.
2. Deionization
 Deionization, or ion exchange, removes all inorganic ions and some weak organic ions from
the water by exchanging them with hydrogen or hydroxide ions, depending on the charge on
the contaminant. The process uses two types of polymeric bead, one bearing anionic reactive
groups and the other cationic reactive groups. The resins are known respectively as cation
and anion exchange resins:
1. R – H + NaCl = R – Na + HCl
2. R – OH + HCl = R – Cl + H2O
 In stage 1 above an ionic impurity sodium chloride interacts with the resin to produce the salt
of the acidic resin and free hydrochloric acid.
 In step 2 the acid reacts with the basic resin to produce the chloride salt of the basic resin and
water.
 The net result of passing through both resins is therefore the exchange of a molecule of ionic
impurity with an equivalent molecule of water. Two kinds of anion exchange resin are
commonly used; weakly and strongly basic.
 Weakly basic resins are economical in use and can yield a product with conductivity
better than 50 μ S/cm.
 Strongly basic resins, such as that shown in the above example, remove chlorides and
sulphates as well as weakly ionized species such as silica, carbon dioxide and organic
contaminants. They yield a product with conductivity of 1 μ S/cm or less but cost more
to run.
 Ultra-pure water with conductivity below 0.1 μ S/cm can be produced using mixed-bed
systems and these are the type found in most laboratories.

3. Reverse osmosis

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 Reverse osmosis is a technique in which pure water and feed water are separated from one
another by a semi permeable membrane, and pressure is applied to the feed water sufficient
to overcome the osmotic pressure exerted by its contaminants. As a result, water is forced
from the feed waterside of the membrane to the pure waterside leaving the bulk of the
contaminant load behind.
 Depending on their pore size, cross-flow filter membrane, can remove particles defined in the
range of
i) Micro filtration (0.1 to 2 microns e.g. bacteria)
ii) Ultra filtration (0.01 to 0.1 “ e.g. virus)
iii) Nano filtration (0.001 to 0.01 microns e.g. organic compounds in the M.Wt range of
300 to 1000).
 Reverse osmosis removes virtually all virus, bacteria, pyrogens, organic molecules and & 90-
99% of all ions.
1.2 LIQUID PHARMACEUTICAL DOSAGE FORMS

1.2.1 SOLUTIONS
 Pharmaceutical solutions may be generally defined as liquid preparations in which the
therapeutic agent and the various excipients are dissolved in the chosen solvent system.
 A solution is a homogenous one-phase system consisting of two or more components. The
solvent, or mixture of solvents, is the phase in which the dispersion occurs, and the solute is
the component which is dispersed as molecules or ions in the solvent.
 For most pharmaceutical solutions the solvent system is likely to be liquid, and the solute
will be either a liquid or a solid.
 Generally, water is chosen as the vehicle in which medicaments are dissolved, since it is non-
toxic, non-irritant, tasteless, relatively cheap and many drugs are water-soluble.
 There are certain drugs, which can only be administered in liquid dosage forms. e.g. castor
oil
 They are more quickly effective than the same amount of drug in a tablet & capsule
Advantages and disadvantages of pharmaceutical solutions for oral administration
 Advantages
 Liquids are easier to swallow than solids and are therefore particularly acceptable for
pediatric and geriatric use
 The therapeutic agent is dissolved in the formulation and is therefore immediately available
for absorption. Providing the drug does not precipitate within the GIT, the bioavailability of
pharmaceutical solutions is greater than that of oral solid-dosage forms.
 A solution is a homogenous system and therefore the drug will be uniformly distributed
throughout the preparation.
 No need to shake container
 Irritation is reduced by the administration of a solution of a drug because of the immediate
dilution by the gastric contents.

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 Disadvantages
 Pharmaceutical solutions for oral administration are unsuitable for therapeutic agents that
are chemically unstable in the presence of water.
 The poor solubility of certain therapeutic agents may prohibit their formulation as
pharmaceutical solutions.
 The shelf-life of a liquid dosage form is often much shorter than that of the
corresponding solid preparation
 The chemical stability of some ingredients can, however, be improved by the use of a
mixed solvent system.
 Pharmaceutical solutions are expensive to ship and are bulky for the patient to carry due
to the associated mass of the product.
 Technical accuracy needed to measure dose on administration
 Solutions often provide suitable media for the growth of microorganisms and may
therefore require the incorporation of a preservative.
1.2.1.1 Solubility
Factors Affecting Solubility of Solute
i. Temperature
 Endothermic reaction – The process of solution where heat is applied and
absorption of the heat takes place in the solutes, this increase in
temperature will cause more of the solute to go into solution.
 Exothermic reaction – solute gives off heat during the process of solution;
solubility is decreased with an increase in temperature.
Example: more soluble in cold than hot water
Methyl cellulose and calcium salts such as Ca(OH)2
ii. Particle size – an increase in surface area to the solvent will increase rate of
solution.
 So the particle size should be reduced by comminution before it is
dissolved
iii. Solvent nature
 The general rule: “like dissolves like”
iv. Effects of other substance
 Example: Iodine is very slightly soluble in water but when added to a
concentrated solution of KI dissolves immediately.
v. pH – Many of the organic substances which are used medicinally are either
weak acids or weak bases. And their aqueous solubility depends upon the pH of
the solvent.
vi. Agitation – increases the rate of solution by removing from the surface of the
solute.
Relative Terms of Solubility
Descriptive Term Parts of Solvent required

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 Very Soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10,000
Practically soluble From 10,000 and over
or Insoluble

Methods of increasing solubility of poorly soluble drug

a. pH: -
 a large No of modern chemotherapeutic agents are either weak acids or weak bases. The
solubility of these agents can be markedly influenced by the pH of their environment.
And can be optimized by selecting an optimum pH that dose not conflict with other
product requirements, such as stability and physiologic compatibility.
 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 addition, if pH is critical to maintaining drug solubility, the system must be adequately
buffered. The selected buffer should be:
 Biologically safe for use
 Have adequate capacity in the desired PH range
 Allow acceptable flavoring and coloring of the product.
 Have little or no deleterious effect on the stability of the final product.
b. Cosolvency:-
 Weak electrolytes and non polar molecules frequently have poor water solubility.
 Their solubility usually can be increased by the addition of a water-miscible solvent in
which the drug has good solubility. This process is known as cosolvency and the solvents
used in combination to increase the solubility of the solute are known as cosolvents.
 A cosolvent system works by reducing the interfacial tension between the predominately
aqueous solutions and the hydrophobic surface of solute.(proposed mechanism)
 A cosolvent is a solvent that is both miscible with water and in which the compound is
also soluble.
 Ethanol, sorbitol, glycerin, propylene glycol, and several members of the polyethylene
glycol polymer series represent the limited number of co solvents that are both useful and
generally acceptable in the formulation of aqueous liquids
 Cosolvents are employed not only to affect solubility of the drug, but also to improve the
solubility of volatile constituents used to impart a desirable flavor and odor to the
product.
 The choice of suitable cosolvent is somewhat limited for pharmaceutical use b/c of
possible toxicity and irritancy, particularly if required for oral or parenteral use. Ideally,

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 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 include sorbitol, glycerol, propylene glycol and syrup.
c. Solubilization:-
 Solubilization has been defined as the spontaneous passage of poorly water soluble solute
molecules into an aqueous solution of a soap or a detergent, in which a
thermodynamically stable solution is formed.
 The mechanism for this phenomenon involves the property of surface-active agents to
form colloidal aggregates known as micelles.
 When surfactants are added to a liquid at low concentration, they tend to orient at the air-
liquid interface. As additional surfactant is added, the interface becomes fully occupied,
and the excess molecules are forced into the bulk of the liquid. As still higher
concentrations, the molecule of surfactant in the bulk of the liquid begin to form oriented
aggregates or micelles; this change in orientation occurs rather abruptly, and the
concentration of surfactant at which it occurs is known as the critical micelle
concentration (CMC).
 Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed
onto the micelle.
 Thus, the ability of surfactant solutions to dissolve or solubilize water-insoluble materials
starts at the critical micelle concentration and increase with the concentration of the
micelles.
 This phenomenon of micellar solubilization has been widely used for the formulation of
solutions of poorly soluble drugs. In aqueous systems, non-polar molecules will dissolve
in the interior of the micelle, which consists of the lipophillic hydrocarbon moiety.
 The amount of surfactant to be used for this purpose must be carefully controlled.
 A large excess is undesirable
o because of cost, possible toxicity and its effect on product aeration during
manufacture.
o Because it may also reduce the bioavailability of a drug if it is strongly
adsorbed within the micelle.
 An insufficient amount of surfactant
o may not solubilize all the drug, or
o may lead to precipitation either on storage or on dilution of the product.
 The surfactant chosen must be
 non-toxic and non-irritant
 miscible with the solvent system, compatible with the other ingredients,
 free from disagreeable odor and taste and be non-volatile.
 Polyoxyethylene Sorbitan, fatty acid esters and sucrose monoesters are some of the
solubilizing agents used in pharmaceutical systems.
d. Complexation

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  Complexation refers to the interaction of a poorly soluble therapeutic agent with an
organic molecule, e.g. surface-active agents, hydrophilic polymers to generate 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.
 examples
o the complexation of iodine with a 10-15% solution of polyvinylpyrrolidone to
improve the aqueous solubility of the active agent.
o the interaction of salicylates and benzoates with xanthenes, such as theophylline
or caffeine, or with carbazochrome
e. 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 chloramphenicol sodium succinate
has no antibacterial 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.
f. Particle size
 The size and shape of very small particles, if less than 1 µm diameter, can affect their
solubilities.
 As particle size decreases solubility will increase, and molecular dispersions of drugs in
solid/solid solutions can exhibit improved bioavailability owing to the increase in
solubility of the dispersed drug.
In practice, however, this phenomenon has little application in the formulation
of solutions, but is of particular relevance in suspension formulation.
1.2.1.2 Solvents for Liquid Preparations
A. Water – has the widest range of usefulness of all the solvents employed in
pharmaceutical dispensing or manufacturing. It is a good solvent for most
inorganic and organic compounds
 Characteristics of water
o Tasteless
o Freedom from irritating qualities
o Lack of pharmacologic activity
 Disadvantages

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 o Favorable medium for many chemical reactions
o Support growth of microorganisms when contaminated
 Purified water:- as compared with ordinary drinking water it is more free of
solid impurities
o intended for use in the preparation of aqueous dosage forms except
those intended for parental administrations (injections)
 Water for injection or Sterile Water for Injection is used for injections.
B. Alcohol USP (Ethyl Alcohol, Ethanol) – good solvent for many organic substances
both natural and synthetic next to water
 Alcohol USP is 94.9 – 96% C2H5OH by volume when determined at 15.560c.
 Alcohol is often preferred because of its miscibility with water and its ability
to dissolve many water insoluble
 Alcohol is also utilized with glycols and glycerin to reduce the amount of
alcohol required.
 It is used in liquid preparation as an antimicrobial preservative alone or as co-
preservative with parabens, benzoatesm, sorbates and others
 Limitation: - undesired pharmacologic and potential toxic effects of alcohol
when ingested in pharmaceutical products, particularly by children.
C. Glycerin USP ( Glycerol) – clear syrupy liquid with sweet taste. It is miscible both
with water and alcohol.
 Excellent solvent for tannins, phenol and boric acid. It has a preservative
quality.
 As a solvent it is comparable with alcohol but because of its viscosity, solutes
are slowly soluble in it unless it is rendered less viscous by heating
D. Propylene Glycol – miscible in water, acetone, alcohol and chloroform
 a useful solvent with wide range of application and is frequently substituted
for glycerin
E. Polyethylene glycol 400 – miscible in water, acetone alcohol and other glycols
F. Chloroform – miscible with alcohol, ether, benzene, hexane and both fixed and
volatile oils
G. Acetone – miscible with water, alcohol, ether, chloroform and most of the volatile
oils.
1.2.1.3 Preparation of oral solutions
Methods of Preparing Solutions
1. Simple Solution – prepared by dissolving the solute in the solvent
Examples: Calcium hydroxide solution USP (lime water),
Sodium Phosphate solution and Strong Iodine solution USP (lugol’s)
2. Solution by Chemical reaction – prepared by reacting two or more solutes with
each other in a suitable solvent.

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 o Examples: Aluminum subacetate – prepared by reacting aluminum
sulfate sol. with calcium carbonate and acetic acid forming magma.
o Magnesium Citrate = prepared by reacting official magnesium
carbonate with citric acid, flavoring and sweetening agents, filtering
talc and carbonating it by potassium or sodium bicarbonate.
o Sodium Citrate and Citric acid oral solution = contains 100 mg
sodium citrate and 67 mg citric acid in each ml od aqueous solution.
3. Solution by Extraction – vegetables or animal origin are often extracted with
suitable solvent. Preparation of this type may be classified as solutions but
more often extractives
1.2.1.3.1 Syrups
 Syrups are concentrated solutions of sugar (such as sucrose) in water or other aqueous
liquids with or without added flavoring agents and medicinal substances
 3 Types of syrups
1) Simple syrup – concentrated solution of sucrose in purified water alone.
2) Non-medicated/Flavored syrup – contained various aromatic and pleasantly
flavored substances and is intended as a vehicle or flavor for preparations.
 Pharmaceutical Classification-- Based on their basic formula
o sugar based syrups – syrups which are concentrated solutions
 sucrose and dextrose are usually employed in the preparation
of syrups
o artificial sweeteners and non-nutritive syrups – formulated with
artificial sweetening agents and viscosity builders
 sugar-free syrups which are intended as substitute for sugar-
based syrups and are intended to be administerd to persons
who must regulate their sugar/calorie intake
 Examples of Flavoring syrups
o Orange Syrup, Raspberry syrup, Cocoa syrup, Cherry syrup, . Acacia
syrup, Citric acid syrup
3) Medicated syrup – aqueous solution of sucrose containing other substances as
polyols (glycerin and sorbitol)
 Examples Of Medicated Syrups By Category
 Analgesic:-Meperidine HCl Syrup
 Anticholinergics:-Dicyclomine HCl Syrup and Oxybutynin Chloride
 Antiemetics :- Chlorpromazine HCl Syrup, Dimenhydrinate syrup,
Prochlorperazine Edisylate, Promethazine HCl
 Anticonvulsant:- Sodium Valproate syrup
 Antipsychotic:- Lithium Citrate Syrup
 Antihistamines:- Chlorpheniramine Maleate, Cyproheptadine HCl,
Hydroxyzine HCl

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  Antitussives:- Dextromethorphan, Diphenhydramine Liquid
 Antiviral:- Amantadine HCl
 Bronchodilators:- Albuterol Sulfate, Metaproterenol Sulfate syrup
 Cathartic:- Lactulose syrup
 Cholinergic:- Pyridostigmine Bromide syrup
 Decongestant:- Pseudoephedrine Hydrochloride
 Expectorant :- Guaifenesin syrup
 Fecal Softener:- Docusate Sodium
 Gastrointestinal stimulant:- Metoclopramide syrup
 Hemostatic:- Aminocaproic Acid
 Hypnotic/Sedative:- Chloral Hydrate syrup
Components Of Syrups
1) Sugar - usually sucrose and other substitutes for sweetness and viscosity
2) Antimicrobial preservatives
3) Flavorants
4) Colorants
5) Miscellaneous - special solvents, solubilizing agents, thickeners or stabilizers

Sucrose and Non sucrose Based syrups

 Sucrose is the sugar most frequently employed in syrups although in special
circumstances it may be replaced in whole or in parts by other sugars, as dextrose, or
non-sugars as sorbitol, glycerin, saccharin sodium and propylene glycol.
Antimicrobial Preservatives
 The amount of preservatives required in syrup varies with the proportions of
water available for microbial growth.
 Among the preservatives
 Benzoic acid-0.1% to 0.2%
 Sodium benzoate – 0.1 to 0.2%
 Combination of methyl, propyl, butyl parabens totaling 0.1%
Flavorants for syrup
 Most syrups flavored with synthetic flavorants (chloroform, vanillin) or with
naturally occurring materials, such as volatile oils (e.g. orange oil, anise oil,
cinnamon water) to render the syrup pleasant tasting. Since syrups are
aqueous preparations, these flavorants must be possess sufficient water
solubility
 However, sometimes a small amount of alcohol is added to a syrup to ensure
the continued solution of a poorly water soluble flavorant.

Colorants for Syrup

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  To enhance appeal of the syrup, a coloring agent is generally used which
correlates with the flavorant employed.
 The colorant used is generally water-soluble, non-reactive with other
components, and color stable at the pH range and under intensity of light that
the syrup is likely to encounter during its shelf life.
Sweeteners
 Non-nutritive, synthetic sweetening agents required in the formulation
o Saccharin sodium is 300 - 550 times as sweet as sucrose. It may be
used in concentration of 0.1 to 0.2% but characterized by a bitter after
taste.
o Aspartylphenylalanine methyl ester is a potential low calories – 160
times sweeter than sucrose in aqueous solution.
Sweeteners and Viscosity Builders-Sorbitol Based Syrup
 Sorbitol, A hexahydric alcohol, C6H14O6, made by hydrogenation of glucose
is used mostly in the 70% aqueous solution USP
 Characteristics of Sorbitol
o Sorbitol solution is not irritating to the membrane of the mouth and
the throat
o Unlike sucrose, it does not contribute to the formation of dental caries
o Although it is metabolized and converted into glucose it is not
absorbed from the GIT as rapid as sugars, so no significant
hyperglycemia is formed
o Although it is 60% as sweet as sucrose and half as viscous as simple
syrup, it has excellent “mouth feel” and lacks acrid characteristics.
o Sorbitol is compatible with other polyol and simple syrup
o Sorbitol is chemically stable and practically inert
o Sorbitol inhibits the sticking and locking of bottle caps which occurs
with high concentration of sucrose so they are usually combined
o Many drugs are more stable in sorbitol than in sucrose solution thus
may have extended shelf-life
o As much as 10% v/v of alcohol can be added before crystallization is
observed same as sucrose
Uses Of Syrups
1. Due to sweetness, can mask the taste of salty and bitter drugs and therefore
serve as pleasant tasting vehicle
2. Used as vehicle for pediatric use due to their high viscosity and the
“smoothness” and mouth feel qualities.
3. Due to the wide variety of flavors of syrups such as orange, lemon,
peppermint, these are widely acceptable.
Preparation Of Syrups

16 | P a g e
  Syrups are most frequently prepared by any one of the four methods depending
upon the physical and chemical characteristics of the ingredients.
A. Solution of the ingredients with the aid of heat
B. Solution of the ingredients by agitation without the use of heat or the
simple admixture of liquid components
C. Addition of sucrose to a prepared medicated liquid or to a flavored liquid
D. By percolation of either the sucrose of the medicating substance or of the
sucrose.
1. Solution of ingredients with the aid of heat
 Syrups are prepared by this method for the following reasons:
o When desired to prepare the syrup as quickly as possible
o When the syrups components are not damaged or volatilized by heat
 Procedure
1. Add the sugar to the purified water and heat until solution is affected.
2. Heat stable components are added to the hot syrup
3. Cool and made up to volume.
4. If other components are heat labile, they are added after cooling like
alcohol and oil.
 Caution: Do not apply excessive heat - inversion of sucrose causing
discoloration due to caramelization
 Examples : Acacia syrup, NF; Cocoa Syrup, NF; Syrup USP (85% sugar,
made by cold and hot process, percolation)
2. Solution of ingredients by agitation without the aid of heat
 To avoid heat-induced inversion of sucrose, a syrup maybe prepared
without heat by agitation
 Procedure:
1. Sucrose and other formulative agents maybe dissolved in purified water
2. Place the ingredients in a bottle of greater capacity than the volume of
syrup.
3. Agitate the mixture
 Examples: Ferrous Sulfate Syrup, Ephedrine Sulfate, Citric acid Syrup
3. Percolation
 In this method, either sucrose maybe percolated to prepare the syrup or
the sucrose of the medicinal component may be percolated to form an
extractive preparation to which sucrose or syrup may be added
 Procedure:
1) Purified water or aqueous solution of a medicating or flavoring
liquid is allowed to pass slowly through a column of crystalline
sucrose to dissolve it.

17 | P a g e
 2) The percolate is collected and returned to the percolator as required
until all of the sucrose has been dissolved.
3) Percolator with a pledget of cotton at the bottom is used
 Example: Tolu Balsam syrup - flavor for cough syrup
4. Addition of Sucrose to a Medicated liquid or to a flavored liquid
 Occasionally, a medicated liquid, as a tincture of fluid extract is
employed as the source of medication in the preparation of a syrup.
 Many such tinctures and fluid extract contain alcohol-soluble
constituents and are prepared with alcoholic vehicles.
 Examples: Senna Syrup, NF and Cherry Syrup
Preservation and Storage of Syrups
 Generally, syrups are stored at room temperature in tightly closed bottle and well-
filled bottles.
1.2.1.3.2 Elixirs
 Elixirs are clear, sweetened; hydro-alcoholic solution intended for oral use and is usually
flavored to enhance their palatability.
 They are pleasantly flavoured and usually attractively coloured
 More stable than mixtures but some require preparation immediately before issue to the
patient, by adding a solvent to dry granules
 Most elixirs are stable and, if properly packed and stored, can be assumed to have a shelf
life of about two years
Advantages of elixirs
i. Because of their hydroalcoholic character, elixirs are better able than the
aqueous syrups to maintain both water soluble and alcohol soluble components
in the solutions
ii. More preferred than syrups due to the stability character
iii. Easy to prepare which is by simple solution
iv. Pleasant flavor
Characteristics of Elixir
a) The main ingredient of elixirs are ethanol and water but glycerin sorbitol,
propylene glycol, flavoring agents, preservatives and syrups are often used in
preparation of the final product
b) The alcohol content vary from 3 to 41% depending on the water alcohol solubility
of the ingredients
c) Although many elixirs are sweetened with sucrose, some utilize sorbitol, glycerin,
and artificial sweeteners such as saccharin for this purpose.
d) Elixirs having a high alcoholic content usually use as artificial sweeteners as
saccharin which is used in small quantities only.

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 Formulation
i. Vehicle
 About 10 to 20 % of alcohol is useful for keeping oils in solution, while the
inclusion of glycerol, also a good solvent for flavouring oils, prevents the
precipitation of some ingredients of vegetable extracts; e.g. tannins and their
oxidation products in Cascara elixir
 It is preferable to use a mixture of solvents to prepare a potent medicament of
low solubility
 E.g. in paracetamol elixir a mixture of alcohol, propylene glycol and
glycerol is used as the vehicle
 The main constituents of many elixirs is syrup or a flavoured syrup
ii. Adjuncts
 Chemical stabilizers are sometimes needed
 E.g. citric acid is used in Neomycin elixir preparation in order to
minimize the darkening that occurs on storage
 Coloring agents
 E.g. amaranth---- paracetamol and streptomycin elixir
 Flavouring agents
 Sweetening agents and fruit flavours are used more than aromatic
vehicles and liquorice extract
o E.g. of fruit flavours includes concentrated raspberry juice, lemon
spirit, compound orange spirit
 Sweetening gents
 E.g. syrups, glycerol, sorbitol solution, invert syrup and saccharin
sodium
 Preservatives
 The use of preservatives may be limited if the vehicle contains more than
20 % alcohol, propylene glycol, or glycerol
 Chloroform is the most common additional preservative
 Other--- benzoic acid and methyl ester of parahydroxybenzoic acid
Preparation of Elixirs
1) Simple solution with agitation
2) By the admixture of two or more liquid ingredients
Classes of Elixirs
1. Non-medicated - used in the extemporaneous filling of prescriptions involving
 The addition of a therapeutic agent to a pleasant tasting vehicle
 The dilution of an existing medicated elixir
 Example: Aromatic elixirs, Compound Benzaldehyde Elixir, Iso - alcoholic
Elixir

19 | P a g e
 2. Medicated Elixirs – are employed for the therapeutic benefit of the medicinal agent
present.
Example:
Phenobarbital elixir
Phenobarbital 4g;
Orange oil 0.25mL;
Propylene Glycol 100mL;
Alcohol 200mL;
Sorbitol Solution 600m;
Color q.s
purified water to make 1000mL.
Examples of medicated Elixirs by Category
 Adrenocortical steroid:- Dexamethasone elixir
 Analgesic/Antipyretic:- Acetaminophen elixir
 Anticholinergic/Antispasmodic:- Hyoscyamine Sulfate elixir
 Antiasthma:- Diphenhydramine elixir
 Antipsychotic:- Fluphenazine HCl elixir
 Cardiotonic :- Digoxin elixir
 Sedative/Hypnotics:- Butabarbital Sodium elixir, Phenobarbital elixir
1.2.1.3.3 Tinctures
 Are defined as alcoholic preparation containing the active principles of vegetable drugs
or from chemical substances
 Disadvantages of Tinctures
 Unpleasant tasting
 Physician will prefer single drug instead of preparation from plants
 High alcohol content
 Variations of Official Tinctures are on:
 Method of Preparation
 Strength of their active constituent
 Alcohol content
 Intended use in medicine or pharmacy
Method of Preparation of Tinctures
1) By simple solution - tinctures prepared from chemical substances
Example: Iodine, Thimerosal, Nitromersol green soap tinctures
2) By extraction - by maceration or percolation
 Maceration
Examples: Compound Benzoin Tinctures; Sweet Orange Peel Tincture and
ToLu Balsam Tincture
 Percolation
Examples: Belladona Tincture and Vanilla Tincture

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 Alcohol Content
 Depending on the preparation, tinctures contain alcohol in amounts ranging from
approximately 15% to 80%.
 Tinctures are considered to be stable preparation containing alcohol to protect against
microbial growth.
Pharmaceutical Uses
 As flavoring tinctures like vanilla, sweet orange peel, Tolu balsam tinctures.
Medicinal use
 Iodine Tincture, Thimerosal, Nitromersol Tinctures - Anti-infective;
 Compound Benzoin Tincture - Topical protectant;
 Green soap Tincture - Topical detergent;
 Paregoric Tincture - Antiperistalsis;
 Belladona Tincture - Anticholinergic
1.2.1.3.4 Miscellaneous solutions
1.2.1.3.4.1 Aromatic waters
 Aromatic water is also called medicated water, defined in the USP as clear, saturated
aqueous solutions of volatile oils or other aromatic or volatile substances.
 These are to be free from
 Smoke like odor and other odors
 Must have odor and taste similar to those oil or drugs from which they are
prepared.
 Components
1. Volatile oil
2. Water
Official Processes of Preparation
1. Distillation
 Cohobation – is the process of obtaining aromatic water by distillation one or more times
from delicate drugs with small quantities of volatile principles.
Examples: Stronger Rose (Aqua Rose Fertier, Triple Rose Water)
2. Solution Method
A. Simple Solution Method
Example: Peppermint water Concentrate
Synonyms: Aqua Mint, American Mint
Latin name: Aqua Menthae Piperitae
Formula:
Peppermint oil 20mL
90%Ethanol 600mL
Purified Talc 50g
Purified Water q.s.to make 1000mL
Uses: Vehicle for internal aqueous sol. Carminative, flavoring diluent

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 Description: Clear, saturated solution
B. Alternate Solution by Intervention
 The volatile material is mixed thoroughly with 15g of purified talc.
 The mixture is agitated with purified water for ten minutes prior to filtration.
 The disadvantage of this method is the fineness of the filter aid which passes
through the filter paper.
 Aromatic water are not permanently stable preparations
 Preservation of Aromatic Water
 Protect from excessive light and heat. Deterioration may due to volatilization.
Decomposition or mold growth producing cloudy preparation or disagreeable
odor.
1.2.1.3.4.2 Diluted Acids
 Diluted acids are aqueous solutions prepared by diluting the corresponding concentrated
acids with purified water.
 To prepare a diluted acid from a concentrated one, it is necessary first to calculate the
amount of solute required in the diluted product.
 Then the amount of concentrated acid required to supply the needed amount of solute can
be determined.
 There is very little use of diluted acids in medicine today. However, because of its
antibacterial effects, acetic acid finds application as a 1% solution in surgical dressings,
as an irrigating solution to the bladder in 0.25% concentration, and as a spermatocidal in
some proprietary contraceptive preparations.
1.2.1.3.4.3 Spirits
 alcoholic or hydroalcoholic solutions of volatile substances
 Formerly called “Essences”
 Generally the alcoholic content is high (>60%)
 Because of the greater solubility of volatile substances in alcohol than in water, spirits
can contain a greater concentration of these materials than the corresponding aromatic
water.
 Uses:
1. as flavoring agents pharmaceutically
2. For therapeutic value of the aromatic solute medicinally
spirits may be taken orally, applied externally, or used by inhalation
depending on the particular preparation
To be taken orally, spirits are mixed with a portion of water to reduce their
pungency.
Preparation of Spirits
1. Simple Solution
 Majority of spirits are prepared by dissolving the solute in alcohol by agitation.
 Filtration is generally desirable to obtain a sparking clear product.

22 | P a g e
  Example: Aromatic Spirit - 62 to 68% hydroalcoholic solution of ammonia and
ammonium carbonate flavored and perfumed with lemon, lavender and myristica oil.
2. Solution with Maceration
 Macerate the vegetable materials in a suitable solvent to remove the undesired
constituents or to extract one which is desired.
 Example: Peppermint Spirit – 79 to 85% hydroalcoholic solution containing 10%
peppermint oil (Use: digestive aid or carminative)
3. Distillation
 No spirits currently official are prepared by distillation; however, two products of
historical significance which is official in NF are prepared by distillation.
 Examples: Brandy and whisky
1.2.1.3.5 Non-Aqueous solutions
1.2.1.3.5.1 Liniments
 Are alcoholic or oleaginous solutions or emulsions of various medicinal substances
intended for external application to the skin, generally with rubbing
 Types Of Liniments
i. Alcoholic liniments
 used as rubefacient ( induce mild irritation with reddening of the skin),
counterirritant, mildly astringent, and penetrating effect
ii. Oily liniments
 milder in action and less irritating to the skin than the alcoholic, used as
protective coating and use as rubefacient for muscular pain
 Factors to be considered in using solvents or vehicle
1. Type of action desired, whether rubefacient, counterirritant or just massage - alcohol
or oil
2. Solubility of the desired components in the various solvents. For oleaginous liniments
the solvents may be fixed oil (almond oil, peanut oil, sesame oil or cotton seed oil) or
volatile oil (such as wintergreen or turpentine oil) or combination of fixed or volatile oil.
 Methods of Preparation
 Liniments are prepared in the same manner as solutions, emulsions or suspensions
 All liniments Must Bear A Label Indicating
1. For external use only
2. Store in tight containers and at cool place
3. Not to be applied to bruises or broken skin areas
1.2.1.3.5.2 Collodions
 Are liquid preparation composed by pyroxylin dissolved a solvent mixture. Usually
composed of alcohol and ether with or without added substances
 Pyroxylin (nitrocellulose soluble gun cotton, collodion cotton) is obtained by the action
of mixture of nitric acid and sulfuric acids on cotton and consists chiefly of cellulose
tetranitrate.

23 | P a g e
  The vehicle is volatile and evaporates on application to the skin, leaving a flexible ,
protective film covering the site.
 The volatile solvents are ether and alcohol, the film-producing ingredient is
pyroxylin and the substance giving the flexibility is castor oil.
 Uses of Collodion
a) As a protective coating to the skin
b) As medication where a thin layer of the medication is firmly placed against the
skin
 Direction Of Use
 Collodions are applied to the skin by means of a soft brush or other suitable
applicators.
 Example Of Official Collodion
I. Which provides protective coating
a) Collodion, USP is a clear or slightly opalescent viscous liquid prepared by
dissolving 4% W/V pyroxylin in 3:1 mixture of ether and alcohol.
b) Flexible Collodion, USP is prepared by adding 2% of Camphor and 3%
castor oil to the Collodion
II. Which provides medication
a) Salicylic acid Collodion, USP is 10% solution of salicylic acid in flexible
collodion. Used as keratolytic effect ( topical drug that softens the
superficial keratin-containing layer of the skin and promotes its
desquamation) especially in the removal of corns from the toes
 Collodions are stored in small light-resistant, well-closed containers and labeled
 For external use only
 Sore in a cool place
 Highly inflammable
1.2.2 Disperse systems
1.2.2.1 Suspensions
A Pharmaceutical suspension is a coarse dispersion in
which internal phase is dispersed uniformly throughout the external phase.
The internal phase consisting of insoluble solid
particles having a specific range of size which is maintained uniformly throughout the
suspending vehicle with aid of single or combination of suspending agent.
The external phase (suspending medium) is generally
aqueous in some instance, may be an organic or oily liquid for non oral use.
Taken orally or by parenteral route or external application.
Classification
 Based On General Classes
 Oral suspension- e.g.: Paracetamol suspension antacids, Tetracycline HCl
 Externally applied suspension e.g.: Calamine lotion.

24 | P a g e
  Parenteral suspension e.g.: Procaine penicillin G, Insulin Zinc Suspension
 Based On Proportion Of Solid Particles
 Dilute suspension (2 to10%w/v solid) e.g.: cortisone acetate, predinisolone
acetate
 Concentrated suspension (50%w/v solid) e.g.: zinc oxide suspension
 Based On Electrokinetic Nature Of Solid Particles
 Flocculated suspension
 Deflocculated suspension
 Based On Size Of Solid Particles
 Colloidal suspension (< 1 micron)
 Coarse suspension (>1 micron)
 Nano suspension (10 ng)
Advantages
 Suspension can improve chemical stability of certain drug. E.g. Procaine penicillin G
 Drug in suspension exhibits higher rate of bioavailability than other dosage forms.
 bioavailability is in following order,
Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
 Duration and onset of action can be controlled. E.g. Protamine Zinc-Insulin
suspension
 Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol
palmitate
Disadvantages
 Physical stability, sedimentation and compaction can causes problems.
 It is bulky; sufficient care must be taken during handling and transport.
 It is difficult to formulate
 Uniform and accurate dose cannot be achieved unless suspension are packed in unit
dosage form
1.2.2.1.1 Reasons for suspension
when the drug is insoluble in the delivery vehicle
To mask the bitter taste of the drug.
To increase drug stability.
To achieve controlled/sustained drug release
1.2.2.1.2 Features Desired In Pharmaceutical Suspensions
The suspended particles should not settle rapidly and sediment produced, must be easily re-
suspended by the use of moderate amount of shaking.
It should be easy to pour yet not watery and no grittiness.
It should have pleasing odour, colour and palatability.
Good syringeability
It should be physically, chemically and microbiologically stable.
Parenteral/ophthalmic suspension should be sterilizable.
Theory of Suspensions
25 | P a g e
 A knowledge of the theoretic considerations pertaining to suspension technology ultimately
help formulator to select ingredients that are
 Appropriate for suspension preparation
 That available for milling
 Some theoretic considerations are :
 Particle size control.
 Wetting
 Sedimentation
1) Particle size control:
Particle size of any suspension is critical and must be reduced within the range as
determined during the preformulation study.
Too large or too small particles should be avoided.
o Larger particles will:
 settle faster at the bottom of the container
 particles > 5 um impart a gritty texture to the product which may cause
irritation if injected or instilled to the eye
 particles > 25 um may block the needle
o Too fine particles will easily form hard cake at the bottom of the container.
2) Wetting of the particles
Hydrophilic materials (talc, ZnO, Mg2CO3) are easily wetted by water while hydrophobic
materials (sulphur, charcoal) are not due to the layer of adsorbed air on the surface. Thus,
the particles, even high density, float on the surface of the liquid until the layer of air is
displaced completely.
The use of wetting agent allows removing this air from the surface and to easy
penetration of the vehicle into the pores.
However hydrophobic materials are easily wetted by non-polar liquids.
wetting agents include:
A. Surfactants
o Surfactants decrease the interfacial tension between drug particles and liquid and
thus liquid is penetrated in the pores of drug particle displacing air from them and
thus ensures wetting.
o Surfactants of HLB value 7 – 9 are used as wetting agents.
o Disadvantages of surfactants are:
 that they have foaming tendencies
 they are bitter in taste
 Some surfactants such as polysorbate 80 interact with preservatives such as
methyl paraben and reduce antimicrobial activity
o Polysorbate 80 is most widely used surfactant both for parenteral and oral
suspension formulation.
 It is non-ionic so no change in pH of medium

26 | P a g e
  No toxicity.
 Safe for internal use.
o Sodium lauryl sulphate is used for external application.
B. Hydrophilic Colloids
o Hydrophilic colloids coat hydrophobic drug particles in one or more than one layer.
This will provide hydrophillicity to drug particles and facilitate wetting.
o Disadvantage: They cause deflocculation of suspension because force of attraction
is declined.
o e.g. acacia, tragacanth, alginates, gelatin, wool fat, egg yolk, bentonite, Veegum,
Methylcellulose etc
C. Solvents
o The most commonly used solvents used are alcohol, glycerin, polyethylene glycol
and polypropylene glycol.
o The mechanism by which they provide wetting is that solvent flows into the voids
between particles to displace air and it coats and separates the material so that
water can penetrate and wet the particles.
3) Sedimentation Behaviour
• Sedimentation means settling of particle or floccules occur under gravitational
force in liquid dosage form.
Theory of Sedimentation
• Velocity of sedimentation expressed by Stoke’s equation
V= 2r2 (ρ s- ρ o ) g or V= d2 (ρ s- ρ o ) g
9h 18h
Where, vsed. = sedimentation velocity in cm / sec
d = Diameter of particle r = radius of particle
ρ s= density of disperse phase ρ o= density of disperse media
g = acceleration due to gravity η = viscosity of disperse medium in poise
Factors Affecting Sedimentation
Particle size diameter (d)
 Sedimentation velocity (v) is directly proportional to the square of diameter of
particle. (V α d 2)
Density difference between dispersed phase and dispersion media (ρs - ρo)
 V α (ρ s - ρo)
 Generally, particle density is greater than dispersion medium but, in certain cases
particle density is less than dispersed phase, so suspended particle floats & is
difficult to distribute uniformly in the vehicle.
 If density of the dispersed phase and dispersion medium are equal, the rate of
settling becomes zero.

27 | P a g e
  The density of the vehicle of a suspension can be increased by adding the
following substances either alone or in combination: polyethylene glycol,
polyvinyl pyrolidone, glycerin, sorbitol, and sugar.
Viscosity of dispersion medium (η )
 Sedimentation velocity is inversely proportional to viscosity of dispersion
medium. (V α 1/ ηo)
 So increase in viscosity of medium, decreases settling, so the particles achieve
good dispersion system but greater increase in viscosity gives rise to problems
 Advantages and Disadvantages due to viscosity of medium
 Advantages
o High viscosity inhibits the crystal growth.
o High viscosity prevents the transformation of metastable crystal to stable
crystal.
o High viscosity enhances the physical stability.
 Disadvantages
o High viscosity hinders the re-dispersibility of the sediments
o High viscosity retards the absorption of the drug.
o High viscosity creates problems in handling of the material during
manufacturing.
Sedimentation Parameters:- Two important parameters are considered:
a. Sedimentation volume (F) or height (H) for flocculated suspensions
o F = V u / VO -------------- (A)
Where, Vu = final or ultimate volume of sediment
VO = original volume of suspension before settling
o Sedimentation volume is a ratio of the final or ultimate volume of sediment
(Vu) to the original volume of sediment (VO) before settling.
o Sedimentation volume can have values ranging from less than 1 to greater
than1; F is normally less than 1.
o F=1,such product is said to be in flocculation equilibrium, and show no clear
supernatant on standing

28 | P a g e
 Fig.1: Suspensions quantified by sedimentation volume (f)
b. Degree of flocculation (β)
o It is a very useful parameter for flocculation

The Sedimentation Behavior of Flocculated and Deflocculated Suspensions:

I. Flocculated Suspensions
In flocculated suspension, formed flocks (loose aggregates) will cause increase in
sedimentation rate due to increase in size of sedimenting particles. Hence, flocculated
suspensions sediment more rapidly.
Here, the sedimentation depends not only on the size of the flocs but also on the
porosity of flocks.
In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to
preserve in the sediment, which contains an appreciable amount of entrapped liquid.
The volume of final sediment is thus relatively large and is easily redispersed by
agitation.

29 | P a g e
 Even the smallest particles are involved in flocs, so the supernatant appears clear.

II. Deflocculated suspensions

In deflocculated suspension, individual particles are settling, so rate of
sedimentation is slow which prevents entrapping of liquid medium which makes
it difficult to re-disperse by agitation. This phenomenon also called ‘cracking’ or
‘claying’.
In deflocculated suspension larger particles settle fast and smaller remain in
supernatant liquid so supernatant appears cloudy whereby in flocculated
suspension, even the smallest particles are involved in flocs, so the supernatant
does not appear cloudy.

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 A comparison of properties of flocculated and deflocculated suspension particles

FORMULATION OF SUSPENSIONS
 The formulation of a suspension depends on whether the suspension is flocculated or
deflocculated.
 Three approaches are commonly involved
 Use of structured vehicle
 Use of controlled flocculation
 Combination of both of the methods :
 Structured vehicles
 Structured vehicles also called thickening or suspending agents.
 They are aqueous solutions of natural and synthetic gums.
 These are used to increase the viscosity of the suspension.
 It is applicable only to deflocculated suspensions.
 E.g. methyl cellulose, sodium carboxy methyl cellulose, acacia, gelatin and
tragacanth.
 These structured vehicles entrapped the particle and reduces the sedimentation of
particles. Thus, the use of deflocculated particles in a structure vehicle may form
solid hard cake upon long storage.

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  Too high viscosity is not desirable as:
It causes difficulty in pouring and administration.
It may affect drug absorption since they adsorb on the surface of particle and
suppress the dissolution rate.
 Structured vehicle is not useful for parenteral suspension because they may create
problem in syringeability due to high viscosity.
 Controlled flocculation
 Controlled flocculation of particles is obtained by adding flocculating agents, which
are: (1) electrolytes (2) surfactants (3) polymers
 Flocculation in structured vehicles
 Sometimes suspending agents can be added to flocculated suspension to retard
sedimentation
 Examples of these agents are: Carboxymethylcellulose (CMC), Carbopol 934,
Veegum, and bentonite
Ingredients used for the Formulation of Suspensions

Ingredients Use
Wetting agents They are added to disperse solids in continuous liquid phase.
Flocculating agents They are added to floc the drug particles
Thickeners They are added to increase the viscosity of suspension.
Buffers and pH adjusting agents They are added to stabilize the suspension to a desired pH range.
Osmotic agents They are added to adjust osmotic pressure comparable to
biological fluid.
Coloring agents They are added to impart desired color to suspension and improve
elegance.
Preservatives They are added to prevent microbial growth.
External liquid vehicle They are added to construct structure of the final suspension.

 Suspending agent
 are also known as hydrophilic colloids which form colloidal dispersion with water
and increase the viscosity of the continuous phase
 form film around particle and decrease interparticle attraction
 Most suspending agents perform two functions i.e. besides acting as a suspending
agent they also imparts viscosity to the solution.
 Preferred suspending agents are those that give thixotropy to the media such as
Xanthan gum, Carageenan, Na CMC/MC mixers, Avicel RC 591, Avicel RC 581 and
Avicel CL 611.
 most commonly used suspending agents
Alginates, Methylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose,
Hydroxypropyl methylcellulose, Carboxymethylcellulose, Sodium

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 Carboxymethylcellulose, Microcrystalline, cellulose Acacia, Tragacanth,
Xanthan gum, Bentonite, Colloidal silicon dioxide, Carbomer, Carrageen
Powdered cellulose Gelatin
 Buffers
 Buffers are the materials which when dissolved in a solvent will resist any change in
pH when an acid or base is added.
 To encounter stability problems all liquid formulation should be formulated to an
optimum pH. Rheology, viscosity and other property are also dependent on the pH of
the system.
 Generally pH of suspension is preferably at 7.4-8.4
 Most commonly used buffers are salts of weak acids such as carbonates, citrates,
gluconates, phosphate and tartrates.
 Osmotic Agents
 added to produce osmotic pressure comparable to biological fluids when suspension
is to be intended for ophthalmic or injectable preparation
 Most commonly used osmotic agents are dextrose, mannitol sorbitol, sodium
chloride, sodium sulfate glycerol.
 Preservatives
 Naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are
susceptible to microbial contamination. This leads to:
 loss in suspending activity of suspending agents,
 loss of color, flavor and odor,
 e.g. Propylene glycol, disodium EDTA, benzalkonium chloride, benzoic acid, butyl
paraben
 Flavoring And Coloring Agents
 They are added to increase patient acceptance.
 Only sweetening agents are not capable of complete taste masking of unpleasant
drugs therefore, flavoring agents are incorporated.
 E.g. Acacia, Ginger, Sarsaparilla syrup, Anise oil, Glucose, Spearmint oil
Benzaldehyde, Glycerin, Thyme oil
 Color aids in identification of the product. The color used should be acceptable by the
particular country.
 Colors are obtained from natural or synthetic sources. Plant colors are most widely
used for oral suspension. The synthetic dyes should be used within range of (0.0005
% to 0.001%)
 Most widely used colors :- Titanium dioxide (white) · Brilliant blue (blue) ·
Indigo carmine (blue ), Amaranth (red), Tartarazine (yellow ), Annatto seeds
(yellow to orange)
 Sweetening Agents
 used for taste masking of bitter drug particles
 A bulk sweeteners is used at concentration of 15-70 %
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  Bulk sweeteners sugars such as xylose, ribose, glucose, and mannose.
 Sugar alcohols such as sorbitol, xylitol, mannitol
 Artificial sweetening agents:- Sodium cyclamate, Sodium saccharin, Aspartame
 Humectants
 Humectants absorb moisture and prevent degradation of API by moisture.
 Examples of humectants most commonly used in suspensions are propylene glycol,
glycerol.
 Total quantity of humectants should be between 0-10 % w/w.
 Antioxidant
 Ascorbic acid derivatives such as ascorbic acid, erythorbic acid,
 Thiol derivatives such as thio glycerol, cytosine, acetylcysteine,
 Tocopherols, Butylated hydroxy anisole (BHA), Butylated hydroxytoluene (BHT),
Sodium bi sulfite, Sodium sulfateacetone
 Flocculating agents:
 Reasons:- in order to improve the dispersibility of insoluble drug particles by
reducing the surface tension and minimizing the flocculation
 Examples:
 Neutral electrolytes such as KCl, NaCl
 Surfactants
 Polymeric flocculating agents (Starch, alginates, cellulose derivatives,
carbomers, tragacanth )
 Sulfate, citrates, phosphates salts
1.2.2.1.3 Preparation of suspensions
Following consideration are important for manufacturing pharmacist
 Selection of right material that go into the manufacture.
 The step involved and their sequence in the manufacture.
 Preservation and storage of the product.
Small scale preparation of suspensions:
Step 1: Suspensions are prepared by grinding (or) levigating the insoluble materials in
the mortar to a smooth paste with a vehicle containing the wetting agent.
Step 2: All soluble ingredients are dissolved in same portion of the vehicle and added to
the smooth paste to step1 to get slurry.
Step 3: The slurry is transformed to a graduated cylinder; the mortar is rinsed with
successive portion of the vehicle.
Step 4: Decide whether the solids are suspended in a structured vehicle, flocculated,
flocculated and then suspended. Add the vehicle containing the suspending agent (or)
flocculating agent
Step 5: Make up the dispersion to the final volume. Thus suspension is prepared.

1.2.2.1.4 Methods of Dispensing Suspensions

1. Suspensions containing diffusible solids
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 2. Suspensions containing indiffusible solids
3. Suspensions containing precipitate forming liquids
4. Suspensions produced by chemical reactions

1. Suspensions containing diffusible solids

 Contains insoluble drug particles which are light in weight and readily mix with water and
remain suspended throughout the liquid for sufficient period of time after shaking
 Example: calcium carbonate, magnesium trisilicate, rhubarb powder, light kaolin
 General method of dispensing
Powder all the solid ingredients and add enough vehicle to form a smooth cream

Add more of vehicle to make it pourable

Remove if any foreign particle present by passing through muslin cloth

Rinse the mortar and pestle with successive volume of vehicle until they are quite clean

Add if any liquid ingredients

Add more of vehicle to adjust the final volume and mix thoroughly by shaking the bottle
 Example: Kaolin mixture
2. Suspensions containing indiffusible solids
 Contain substances which do not dissolve in water and do not remain evenly distributed in
the vehicle for sufficient period of time
 Example: calamine, zinc oxide ,hydrocortisone, aspirin, phenobarbitone
 General method of dispensing
Powder and mix all the solid ingredients and add compound tragacanth powder

Measure ¾ th of the vehicle and triturate to form a smooth cream

Remove if any foreign particle present by passing through muslin cloth

Rinse the mortar and pestle with successive volume of vehicle until they are quite clean

Add if any liquid ingredients

Add more of vehicle to adjust the final volume

 Example: succinyl sulphathiazole mixture
3. Suspensions containing precipitate forming liquids
 Contains liquid substances that are precipitated on addition of water.

35 | P a g e
 These liquid substances are insoluble and indiffusible and it is difficult to redisperse on
shaking.
 Example: compound benzoin tincture, myrrh tincture
 General method of dispensing(using tragacanth powder)
Powder and mix all the indiffusible and diffusible solid ingredients

add compound tragacanth powder and mix

measure half of the vehicle and incorporate small amount of it to the powders to
form a smooth cream and add remaining part of the vehicle

Add precipitate forming liquid in a slow stream in the centre of the cream with rapid stirring

Dissolve the soluble ingredient if present in the vehicle and add slowly with constant stirring

Remove if any foreign particle present by passing through muslin cloth

Rinse the mortar and pestle with successive volume of vehicle until they are quite clean

Add if any liquid ingredients

Add more of vehicle to adjust the final volume

 General method of dispensing(using tragacanth mucilage)
 Tragacanth mucilage is used when the vehicle is water or chloroform water
Mix the tragacanth mucilage with an equal volume of the vehicle

Add precipitate forming liquid in a slow stream in the centre of the mucilage with
constant stirring

Dissolve the solid substance if any, in about ¼ th of the vehicle and mix it with
the above mixture

Remaining steps are same as that of dispensing for suspension containing

precipitate forming liquid using compound tragacanth powder
4. Suspensions produced by chemical reactions
 Some of the suspensions are prepared by the chemical reactions between the ingredients used
in the formulations.
 In this reactants are highly diluted and mixed together to form very finely divided
precipitates that can be easily distributed throughout the liquid by shaking.
 The precipitate so formed is diffusible in nature. Hence there is no need of adding any
suspending agent
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 Example: sulphurated potash and zinc sulphate mixture
1.2.2.1.5 Packaging and storage of suspensions
Packaging of Suspensions
 Pharmaceutical suspensions for oral use are generally packed in wide mouth container
having adequate space above the liquid to ensure proper mixing.
 Parenteral suspensions are packed in either glass ampoules or vials.
Storage:
 Suspensions should be stored in cool place but should not be kept in a refrigerator
 Freezing at very low temperatures should be avoided which may lead to aggregation of
suspended particles
 Stored at controlled temperature from 20-250 C
Labeling
 Shake well before use
 Do not freeze
 Protect from direct light(for light sensitive drugs)
 In case of dry suspensions powder the specified amount of vehicle to be mixed may
indicated clearly on label.
1.2.2.1.6 Dry Powders For Oral Suspension
 Preparations may consist of dry powder mixtures or granules that are intended to be
suspended in distilled water or some other vehicle prior to oral administration.
 these preparations have “for Oral Suspension” in their official title to distinguish them from
prepared suspensions
 Most drugs prepared as a dry mix for oral suspension are antibiotics
 The dry products are prepared commercially to contain the antibiotic drug, colorants
(FD&C dyes), flavorants, sweeteners (e.g., sucrose or sodium saccharin), stabilizing
agents (e.g., citric acid, sodium citrate), suspending agents (e.g., guar gum, xanthan
gum, methylcellulose), and preserving agents (e.g., methylparaben, sodium benzoate)
that may be needed to enhance the stability of the dry powder or granule mixture or
the liquid suspension.
 E.g. amoxicillin oral suspension, Ampicillin for oral suspension, Cefaclor for oral
suspension, Cefixime for oral suspension, Cephalexin for oral suspension,
Dicloxacillin sodium for oral suspension, Doxycycline for oral suspension,
Erythromycin Ethylsuccinate for oral suspension
 To reconstitute these products the label-designated amount of purified water, usually in
portions should be added, and shakes the slurry until all of the dry powder has been
suspended
 the use of purified water rather than tap water is needed to avoid the possibility of adding
impurities that could adversely affect the stability of the resulting preparation
1.2.2.2 Emulsion

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 An emulsion is a thermodynamically unstable system consisting of at least two immiscible
liquid phases, one of which is dispersed as globules in the other liquid phase, stabilized by
the presence of an emulsifying agent.
 Emulsions are also called heterogeneous systems or biphasic systems

Phase A

Phase B

B
A

C D

A.: Two immiscible liquids not emulsified

B. An emulsion of phase B dispersed in Phase A
C. Unstable emulsion slowly separates.
D. The emulsifying agent (black film) places itself on the interface between phase A and phase B
and stabilizes the emulsion.
 The characteristics of an acceptable pharmaceutical emulsions
 Physical stability (no phase separation).
 The flow properties of the emulsion should enable the formulation to be easily
removed from the container.
 The formulation must be aesthetically and texturally pleasing.

1.2.2.2.1 Pharmaceutical application of emulsions

To mask the taste
O/W is convenient means of orally administration of water-insoluble liquids
O/W emulsion facilitates the absorption of water-insoluble compounds comparing to their
oily solution preparations (e.g. vitamins)
Oil-soluble drugs can be given parenterally in form of oil-in water emulsion. (e.g. Taxol)

38 | P a g e
 Emulsion can be used for external application in cosmetic and therapeutic uses.
1.2.2.2.2 Types of emulsions
Simple emulsions (Macro emulsions)
 Oil-in-water (O/W)
 Water-in-oil (W/O)
Multiple emulsions
 Oil-in-water-in-oil (O/W/O)
 Water-in-oil-in-water (W/O/W)
 However, the pharmaceutical uses of multiple emulsions are extremely limited due to
their possible reversion to the parent primary emulsion. For example, an o/w/o emulsion
may revert to a w/o emulsion.
Identification of emulsion
there are four methods to differentiate between o/w or w/o emulsions
1) Dilution test:
In this test the emulsion is diluted either with oil or water.
If the emulsion is o/w type and it is diluted with water, it will remain stable as water is the
dispersion medium; but if it is diluted with oil, the emulsion will break as oil and water are
not miscible with each other.
Generally o/w emulsion can be diluted with water and w/o emulsion can be diluted with oil.
2) Conductivity test:
water is good conductor of electricity whereas oil is non-conductor.
Therefore, continuous phase of water runs electricity more than continuous phase of oil.
3) Dye test
Water-soluble dye will dissolve in the aqueous phase.
 Water Soluble Dye Ex. Amaranth Dye

water is continuous phase

Oil is dispersed phase

o/w emulsion

oil is continuous phase

water is dispersed phase

W/O EMULSION

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 Oil-soluble dye will dissolve in the oil phase.
 Oil Soluble Dye Ex. scarlet
water is continuous phase

Oil is dispersed phase

O/W EMULSION

oil is continuous phase

water is dispersed phase

W/O EMULSION
4) Fluorescence test:
Oils give fluorescence under UV light, while water doesn’t. Therefore, O/W emulsion shows
spotty pattern while W/O emulsion fluoresces.
However, all oils do not exhibit fluorescence under UV light and thus the method does not
have universal application.
It is necessary that the results obtained by one method should always be confirmed by means
of other methods
1.2.2.2.2 Emulsifying agents
They are the substances added to an emulsion to prevent the coalescence of the globules of
the dispersed phase. They are also known as emulgents or emulsifiers.
They help in formation of emulsion by three mechanisms.
 Reduction in interfacial tension – thermodynamic stabilization
 Formation of a rigid interfacial film – mechanical barrier to coalescence
 Formation of an electrical double layer – electrical barrier to approach of particles.
Classification of emulsifying agents
 Surface active agents (monomolecular film)
 Hydrophilic colloids (multimolecular film)
 Finely divided solid particles (Particulate film)
i. Synthetic emulsifying agents (Surfactants):
Reduce interfacial tension and make the emulsion thermodynamically more stable.
Form protective monomolecular film
This group contains surface active agents which act by getting adsorbed at the oil water
interface in such a way that the hydrophilic polar groups are oriented towards water and
lipophillic non polar groups are oriented towards oil, thus forming a stable film.
This film acts as a mechanical barrier and prevents coalescence of the globules of the
dispersed phase.
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 Oil

They may be subdivided into anionic, cationic and nonionic surfactants.

a. Anionic Surfactants :
 These agents are primarily used for external preparations and not for internal use as they
have an unpleasant bitter taste and irritant action on the intestinal mucosa. e.g., alkali
soaps, polyvalent soaps (metallic soaps), organic soaps, sulphated alcohols and alkyl
sulphonates.
I. Monovalent soaps: E.g. potassium, sodium, ammonium salts of lauric and oleic acid.
 They are soluble in water and are good o/w emulsifying agents.
 Disadvantages: They have disagreeable taste and are irritating to the GIT. So
they are useful only for external use emulsions.
 They have a high pH. They get precipitated below pH 10 because the
unionized fatty acid is formed which has a low aqueous solubility. So
emulsions formed with alkali soaps are not stable at pH less than 10.
II.Polyvalent soaps: The calcium, magnesium and aluminum salts of fatty acids (metallic
soaps) are water insoluble and give w/o emulsion.
III.Organic soaps: Triethanol amine soaps of fatty acids give o/w emulsion.
 They are used for external use emulsions. They are less alkaline as compared to
monovalent soaps. They can act till pH 8.00
IV.Sulfated alcohols: They are neutralized sulfuric acid esters of such fatty alcohols as
lauryl and cetyl alcohol. They can be used as auxiliary emulsifying agents.
V.Sulfonates: In these compounds the sulfur atom is connected directly to the carbon
atom, giving the general formula; CH3(CH2)n CH2SO3 – Na+
 e.g. sodium lauryl sulphate , dioctyl sulphosuccinate

b. Cationic Surfactants:
 The positive charge cations produced on dissociation are responsible for emulsifying
properties. They are mainly used in external preparations such as lotions and creams.
 Quaternary ammonium compounds such as cetrimide, benzalkonium chloride and
benzethonium chloride are examples of important cationic surfactants.
 These compounds besides having good antibacterial activity are also used in combination
with secondary emulsifying agents to produce o/w emulsions for external application.
 The pH of an emulsion prepared with cationic emulsifier is in pH 4 -6 range. This is the
range of normal pH of skin. So they are suitable for skin.

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  They are comparatively weak emulsifying agents, so they are used along with auxiliary
emulsifying agents such as cetostearyl alcohol. They are incompatible with anionic
surfactants.
c. Nonionics:
 They are the class of surfactants widely used as emulsifying agents. They are extensively
used to produce both oil in water and water in oil emulsions for internal as well as
external use.
 Advantages: They are not susceptible to pH change and presence of electrolytes.
 They also show low irritancy as compared to other surfactants.
 Most commonly used nonionics are glyceryl esters, polyoxyethylene glycol esters and
ethers, sorbitan fatty acid esters (spans), polyoxyethylene derivatives of sorbitan fatty
acid esters (Tweens or polysorbates), polyoxyethylene/polyoxypropylene block polymers
(Poloxamers)
 Glyceryl esters: e.g. glyceryl mono stearate. It is too lipophillic to be used as a
primary emulsifying agent. It is used as auxiliary emulsifying agent.
 Sorbitan fatty acid esters: e.g. sorbitan mono oleate. They are oil soluble
nonionic surfactants and give w/o emulsions.
ii. Hydrocolloid Emulsifying agents
Provide a protective sheath (Multimolecular films) around the droplets
Impart a charge to the dispersed droplets (so that they repel each other)
Swell to increase the viscosity of the system (so that droplets are less likely to change.)
Classification of Hydrocolloid emulsifying agents
 Semi-synthetic
 Natural
 Plant origin
 Animal origin
a. Semi-synthetic polysaccharides
 Includes mainly cellulose derivatives like sodium carboxy methyl cellulose, hydroxyl
propyl cellulose and methyl cellulose.
 They are used for formulating o/w type of emulsions.
 They primarily act by increasing the viscosity of the system.
b. Natural emulsifying agents
I. Natural emulsifying agents from vegetable sources
 These consist of agents that are carbohydrates and include gums and mucilaginous
substances. Since these substances are of variable chemical composition, these exhibit
considerable variation in emulsifying properties.
 They are anionic in nature and produce o/w emulsions.
 They act as primary emulsifying agents as well as secondary emulsifying agents
(emulsion stabilizers).

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  Since carbohydrates acts a good medium for the growth of microorganism, therefore
emulsions prepared using these emulsifying agents have to be suitably preserved in order
to prevent microbial contamination.
 E.g. tragacanth, acacia, agar, chondrus (Irish moss), pectin and starch.
o Acacia: It is a carbohydrate gum which is soluble over a wide pH range. It can be
used as emulsifying agent in the following ratio to prepare primary emulsions:
o Tragacanth, pectin and starch are used as auxiliary emulsifying agents.
II. Natural emulsifying agents from animal source
 The examples include gelatin, egg yolk and wool fat (anhydrous lanolin).
 Gelatin:
 It is a protein. It has two isoelectric points, depending on the method of preparation.
o Type a gelatin derived from acid treated precursor, has an isoelectric point
between pH 7 and 9. It acts best as an emulsifier around pH 3 where it is
negatively charged. It is generally used for preparing o/w emulsion
o Type B gelatin obtained from an alkaline precursor has an isoelectric point around
pH 5. It is suitable as emulsifier at pH 8 where it is negatively charged. It is used
for o/w emulsions of pH 8 and above.
 Lecithin:
 It is an emulsifier obtained from both plant (soybean) and animal (e.g. egg yolk)
sources and is composed of phosphatides.
 used for formulating o/w emulsions
 Lecithins are good emulsifying agents for naturally occurring oils such as soy, corn,
or sunflower.
 Purified lecithin from soy or egg yolk is used for IV emulsions.
 cholesterol:
 It forms w/o emulsion. It is because of cholesterol that wool fat absorbs water and
form a w/o emulsion It is also present in egg yolk.
 Wool fat
 It is mainly used in w/o emulsions meant for external use. They absorb large
quantities of water and form stable w/o emulsions with other oils and fats.

iii. Finely dispersed solids :

They form particulate films around the dispersed droplets, producing emulsions which are
coarse grained but stable.
Colloidal clays like bentonite, veegum are the examples of finely divided solids used as
emulsifying agents.
Bentonite: It is a gray, odorless and tasteless powder which swells in the presence of water to
form a suspension with a pH of about 9.

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  Depend on the order of mixing, both o/w or w/o emulsion can be formed with
bentonite.
 For o/w emulsion, bentonite is first dispersed in water and allowed to hydrate
to form magma. Then oil phase is gradually added with constant agitation.
 To prepare w/o emulsion, bentonite is first dispersed in oil and then water is
added gradually.
Veegum (Magnesium Aluminium silicate): Used as stabilizer in concentration of 1% for
cosmetic lotions and creams. Prepared with anionic or non ionic emulsifying agents.
Other e.gs.- Magnesium trisilicate, Metallic hydroxides, Magnesium hydroxide, Aluminium
hydroxide,
Auxiliary emulsifying agents:
These are those compounds which normally cannot form an emulsion on their own but can
function as thickening agents and stabilize the emulsion.
Sometimes they increase the viscosity of the external phase and help restricting the collisions
of droplets.
Some of them prevent coalescence by reducing van de Waals forces between particles or by
providing a physical barrier between droplets.
Proteins, semi-synthetic polysaccharides (methyl cellulose, carboxy methyl cellulose), clays
can be used as auxiliary agents.
Preservation:
a relatively mild antimicrobial agent is sufficient to protect the product against microbial
contamination
The preservative system must be effective against invasion by a variety of pathogenic
organisms and protect the product during use by consumer.
The preservative must be :
 Less toxic, Stable to heat and storage, Chemically compatible
 Reasonable cost, Acceptable taste, odor and color.
 Effective against fungus, yeast, bacteria.
 Available in oil and aqueous phase at effective level concentration.
Antimicrobial agents includes
• Acids and acid derivatives - Benzoic acid - Antifungal agent
• Aldehydes – Formaldehyde - Broad spectrum

• Phenolics - Phenol - Broad spectrum

Cresol, Propyl p-hydroxy benzoate
• Quaternaries -Chlorhexidine and salts - Broad spectrum
Benzalkonium chloride, Cetyl trimethyl ammonium bromide
• Mercurials -Phenyl mercuric acetate - Broad spectrum
Antoxidants:

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 Many organic compounds are subject to autoxidation upon exposure to air. And emulsified
lipids are particularly sensitive to attack. Many drugs commonly incorporated into emulsions
are subject to autoxidation and resulting decomposition.
Upon autoxidation, unsatuarated oils, such as vegetable oils, give rise to rancidity with
resultant unpleasant odor, appearance, and taste. On the other hand mineral oil and related
saturated hydrocarbons are subject to oxidative degradation only under rare circumstances.
Autoxidation is a free. radical chain oxidation . It can be inhibited, by the absence of oxygen,
by a free radical chain breaker or by a reducing agent.
Some of antioxidants used
 Gallic acid, Propyl gallate - pharmaceuticals and cosmetics - Bitter taste
 Ascorbic acid – Suitable for oral use products
 Sulphites - Suitable for oral use products
 L-tocopherol - pharmaceuticals and cosmetics -Suitable for oral preparations e.g.
those containing vit A
 Butylated hydroxylanisol - pharmaceuticals and cosmetics
Formulation of emulsions – Chemical factors
The formulator must determine the physical and chemical characteristics of the drug, which
includes the structural formula, melting point, solubility in different media, stability, dose
and specific chemical incompatibilities.
Then the required emulsifying agent(s) along with other additives and its (their)
concentration(s) should be identified.
The choice of materials to be used largely depends on the purpose for which the emulsion is
to be used. While selecting the additives the chemical stability and safety must be kept in
mind :
Chemical stability:
 Chemical inertness of all the ingredients is very important.
 Soap cannot be used as emulsifiers in a system having a pH of less than 5.
 Some lipids may undergo chemical changes due to oxidation (rancidity),
 Sometimes the hydrolytic changes may take place more easily due to micellar
catalysis. This type of catalysis is observed when the reactive species is present on or
near the micellar surface. e.g. hydrolysis of alkyl sulphates
Safety :
 The formulator should be sure about the toxicological clearance of the components
used in emulsion.
Lipid Phase: Selection of lipid phase:
 Choose from Lipids of natural or synthetic origin depends upon the release rate
needed
 For topical preparations – feel of the product
Phase ratio:
 The ratio of the internal phase to the external phase is determined by

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  the solubility of the active ingredient which must be present at a
pharmacologically effective level
 Desired consistency: Low level of consistency results from less % of internal
phase.
o It is generally difficult to formulate emulsions containing less than
25% of internal phase due to their susceptibility to creaming or
sedimentation problems. However, a combination of proper
emulsifying agents and suitable processing technology makes it
possible to prepare emulsions with only 10 % dispersed phase.
o Similarly products containing more than 70% dispersed phase may
exhibit phase inversion.
Selection of emulsifying agent:
o An ideal emulsifying agent should posses the following characteristics:
 It should be able to reduce the interfacial tension between the two immiscible liquids.
 It should be physically and chemically stable, inert and compatible with the other
ingredients of the formulation.
 It should be completely non irritant and non toxic in the concentrations used.
 It should be organoleptically inert i.e. should not impart any colour, odour or taste to
the preparation.
 It should be able to form a coherent film around the globules of the dispersed phase
and should prevent the coalescence of the droplets of the dispersed phase.
 It should be able to produce and maintain the required viscosity of the preparation.
o Choice of emulsifying agent depends upon
 Shelf life of the product
 Type of emulsion desired
 Cost of emulsifier
 Compatibility
 Non toxicity
 Taste
 Chemical stability.
1.2.2.2.4 The HLB systems
o HLB method for selection of emulsifying agent :
 Emulsifying or surface-active agents may be categorized on the basis of their
chemical makeup as to their hydrophilic–lipophillic balance, or HLB.
 By this method, each agent is assigned an HLB value or number indicating the
substance’s polarity.
 Each surfactant is given a value between 1-20.
 The molecules that are water soluble have high HLB value; those which are
oil soluble have low HLB value.

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  Generally, surface active agents having an assigned HLB value of 3 to 6 are
greatly lipophillic and produce w/o emulsions and agents with HLB values of
about 8 to 18 produce o/w emulsions.
 Fundamental to the utility of the HLB value concept is the fact that the HLB values
are algebraically additive. Thus calculations can be done to find the correct ratio of
combination of low HLB value and high HLB value surfactant for particular oil for a
particular type of emulsion.
 Example:
 Liquid paraffin ( Required HLB 10.5) 15 gm
 Emulsifying agents : 5 gm
(A) Sorbitan monooleate (HLB 4.3)
(B) Polyoxyethylene 20 sorbitan mono oleate (HLB 15.0)
 Water
By allegation method, it can be found that (A) and (B) should be mixed in the
ratio of 4.5 and 6.2 to get the required 10.5 HLB value. Because the formula
calls for 5 gm of emulsifying agent, the required weights are 2.1 and 2.9 gm.
respectively.
The formulator can chose a single emulsifying agent which can yield HLB
value of 10.5. But more often in case of o/w emulsions, stable emulsion can be
produced by utilizing a combination of a hydrophilic and hydrophobic
surfactant.
 Such combination appears to produce mixed interfacial phases of high
surface coverage as well as of sufficient viscosity to prevent creaming
and promote stability.
 HLB values of combination may be determined by taking weighted
average of the individual surfactant HLB values. Many combinations
can be tried to choose the best emulsifying agent.
Selection of preservative:
 The concentration of preservative to be used depends upon its ability to react with
microorganisms. It is preferred to use combination of preservatives depending upon
the preservative is available in both oil and water phase.
 Combination of methyl p-hydroxy benzoate (water soluble) and propyl –p-
hydroxy benzoate ( oil soluble)
 If there is interaction between the emulsion ingredients and the preservative, extra
preservative must be added to compensate for the loss due to interaction.
 pH also plays a role on the ability of acidic or phenolic preservatives
 Other factors include the phase ratio, degree of aeration during preparation presence
of flavors and perfumes, some of which have antimicrobial activity.
Selection of antioxidant:
 The choice of antioxidant depends upon its safety, acceptability for a particular use
and is efficacy. Antioxidants are normally used at conc. ranging from 0.001 to 0.1%.
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  Almost all antioxidants are subject to discoloration in the presence of light, trace
metals and alkaline solutions.
 Combinations of two or more antioxidants have been shown to produce synergistic
effects.
Selection of viscosity imparting agents:
 Once the emulsifying agent is selected, a consistency that provided the desired
stability and yet has the appropriate flow characteristics must be attained.
 Viscosity of emulsion can be altered by manipulating the composition of the liquid
phase, by variations in the phase ratio and the surfactants and by addition of gums.
 A newly formed emulsion should be allowed to rest undisturbed for 24 -48 hrs to
build up viscosity.
1.2.2.2.5 Methods of Emulsion Preparation
Emulsification Techniques:
To prepare an emulsion, first the internal phase has to be broken up into droplets and they
have to be stabilized. These two steps must be carried out before the internal phase can
coalesce.
The breakup of internal phase is rapid (by physical means) but the stabilization and the rate
of coalescence are time and temperature dependent.
So in designing the emulsification process it is important to select physical and chemical
parameters which favor emulsion formation.
Each method requires that energy be put into the system in some form. The energy is
supplied in a variety of ways: trituration, homogenization, agitation, and heat.
Physical parameters affecting the stability of emulsion:
 Location of the emulsifier, method of incorporation of the phases, the rates of
addition , the temperature of each phase and the rate of cooling after mixing of the
phases considerably affect the droplet size distribution , viscosity, and stability of
emulsion.
Preparation Techniques:
The preparation techniques for emulsion can be divided into laboratory scale productions and
large-scale productions.
Laboratory Scale Techniques (Extemporaneous Method of Preparation Of Emulsions)
 Emulsification process can be carried out by four methods :
 Addition of internal phase to the external phase, while subjecting the system to shear
or fracture.
 Phase inversion technique: The external phase is added to the internal phase. E.g. if
o/w emulsion is to be prepared, the aqueous phase is added to the oily phase. . First
w/o emulsion is formed. At the inversion point the addition of more water results in
the inversion of the emulsion system and formation of an o/w emulsion. This phase
inversion technique allows the formation of small droplets with minimal mechanical
action and heat. A classical example is the dry gum method

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  Mixing both phases after warming each: This method is used for creams and
ointments.
 Alternate addition of two phases to the emulsifying agent: In this method, the water
and oil are added alternatively, in small portions to the emulsifier. This technique is
suitable for food emulsions.
Techniques used on laboratory scale
Continental or dry gum method
Wet gum method
Bottle or Forbes bottle method
Auxiliary method
In situ soap method
1.2.2.2.5.1 Dry gum method (Continental method)
 The continental method is used to prepare the initial or primary emulsion from oil, water and
a hydrocolloid or “gum” type emulsifier (usually acacia).
 The primary emulsion or emulsion nucleus is formed from 4 parts of oil, 2 parts of water and
one part of gum. The 4 parts of oil and 1 part of gum represent their total amount for the final
emulsion.
 In a mortar the 1 part of gum (acacia) is levigate with 4 parts of oil until the powder is
thoroughly wetted; then the 2 parts of water is added all at once and the mixture is vigorously
and continuously triturated until the primary emulsion formed is creamy white.
 Additional water or aqueous solutions may be incorporated after the primary emulsion is
formed.
 Solid substances (e.g. active ingredients, preservatives, color, flavors) are generally dissolved
and added as a solution to the primary emulsion; oil soluble substances in small amounts may
be incorporated directly into the primary emulsion.
 Any substance which might reduce the physical stability of the emulsion, such as alcohol
(which may precipitate the gum) should be added as near to the end of the process as possible
to avoid breaking the emulsion.
 When all agents have been incorporated, the emulsion should be transferred to a calibrated
vessel, brought to final volume with water, then homogenized or blended to ensure uniform
distribution of ingredients.
1.2.2.2.5.2 Wet gum method (English method)
 In this method the proportion of oil and water and emulsifier (gum) are the same as in dry
gum method (4:2:1), but the order and technique of mixing are different.
 The 1 part of gum is triturated with 2 parts of water to form a mucilage; then 4 parts of oil is
slowly added in portions, while triturating.
 After all the oil is added, the mixture is triturated for several minutes to form the primary
emulsion. Then other ingredients are added as in continental method.
 Generally speaking, the English method is more difficult to perform successfully, especially
with more viscous oils, but may result in a more stable emulsion.
(Reading assignment; - Bottle method, Auxiliary method, In situ soap method)
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 Large scale production
 Commercially, emulsions are prepared in large volume mixing tanks and refined and
stabilized by passage through a colloid mill or homogenizer.
 The internal phase can be reduced to small droplets by application of energy in the form of
heat, mechanical agitation, ultrasonic vibration or electricity.
 Application of energy: Energy may be supplied in the form of heat, homogenization or
agitation
♣ Heat:
 Emulsification by Vaporization (Condensation method):
 Vaporization is an effective way of breaking almost all bonds between
molecules of a liquid, so emulsions may be prepared by passing vapor of a
liquid into an external phase that contains suitable emulsifying agent. This
process is called condensation method.
 Disadvantages:
Slow
Limited to the preparation of dilute emulsions of materials having a
relatively low vapor pressure
 Emulsification by Change in temperature (Phase inversion technique):
 Change in temperature can be used as an effective way of making emulsion
by phase inversion technique.
 In this method first the emulsion is prepared at a higher temperature. On
cooling phase inversion takes place and a stable inversion with finely divided
internal phase is produced.
 Change in temperature due to cooling brings about phase inversion. The
temperature at which phase inversion takes place is called phase inversion
temperature (PIT).
 PIT is generally considered to be the temperature at which the hydrophilic
and the lipophillic properties of the emulsifier are in balance and is therefore
also called the HLB temp.
 Low energy emulsification:
 In low energy emulsification, all of the internal phase, but only a portion of
the external phase is heated.
 After emulsification of the heated portions , the remainder of the external
phase is added to the emulsion concentrate, or the preformed concentrate is
blended into the continuous phase.
 In those emulsions in which a phase inversion temperature exists, the
emulsion concentrate is preferably prepared above PIT which results in
emulsion having extremely small droplets size.
♣ Mechanical equipment for emulsification ( Agitation)
Some sort of agitation is needed to break internal phase into droplets.

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 To break up the internal phase into droplets the liquid jet at high speed through a
small diameter nozzle may be introduced into a second liquid or liquid may flow into
a second liquid which is being agitated vigorously.
Once the initial break up into droplets gas occurred, the droplets continue to be
subjected to additional forces due to turbulence, which causes further breakdown
into smaller droplets.
The amount work depends on the length of time during which energy is supplied;
thus timing becomes another physical parameter.
Timing:
 During the initial period of agitation required for emulsification, droplets are
formed. However as agitation continues, the chance for collision between droplets
becomes more frequent and coalescence can occur.
 It is advisable, therefore to avoid excessive period of agitation during and after the
formation of emulsion.
 Timing also affects the speed with which the two immiscible liquids are blended.
In the case of o/w emulsions, the rate at which the oil phase is added to the
aqueous phase can affect the particle size and hence the stability of emulsion.
 There is also a relationship between temperature and timing i.e. the cooling /
heating cycle. It is common to prepare emulsions at high temp. . The cooling rate
of the initially formed emulsion also has a profound influence on the ultimate
characteristics of the emulsion.
Various types of equipment are available to bring about droplet break up and
emulsification either in laboratory or in production. Such equipment can be divided
into four categories:
1 Mechanical stirrers, 2. Homogenizes, 3. Ultrasonifiers, 4. Colloid mills
 Mechanical stirrers:
– An emulsion may be stirred by means of various impellers mounted on shafts,
which are placed directly into the system to be emulsified.
– Impellers may be of following types:
 Propeller type mixers:- Simple top entering propeller mixers are adequate
for routine development work in the laboratory and production if the
viscosity of the emulsion is low
 Turbine type mixers:- If more vigorous agitation is required or viscosity is
more, turbine type mixers can be used.
 Homogenizers:
– the dispersion of two liquids is achieved by forcing their mixture through a
small inlet orifice at big pressures
– Generally consists of a pump that raises the pressure of the dispersion to a
range of 500 to 5000 psi and an orifice through which this fluid impinges upon
the homogenizing valve held in place on the valve seat by a strong spring.

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 – As the pressure builds up, the spring is compressed, and some of the
dispersion escapes b/n the valve and the valve seat. At this point, the energy
that has been stored in the liquid as pressure is released instantaneously and
subjects the product to intense turbulence and hydraulic shear.
– Homogenizers can be made with more than one emulsifying stage, and it is
possible to recycle the emulsion through the homogenizer more than one time.
– Homogenization raises the temperature of the emulsion, and subsequent
cooling may be required
 Colloid mills:
– Operate on the principle of high shear, which is normally generated b/n the
rotor and the stator of the mill.
– Used primarily for the comminution of solids and for the dispersion of
suspensions containing poorly wetted solids but are also useful for the
preparation of relatively viscous emulsions.
 Ultrasonifiers:
– Useful for the laboratory preparation of fluid emulsions of moderate viscosity
and extremely low particles size.
1.2.2.2.5.2 Stability of Emulsion
Physical stability:
♣ The term emulsion stability refers to the ability of an emulsion to resist changes in the
properties over time; i.e. the more stable is the emulsion, the more slowly its properties
change.
♣ Stability ( Instability) of the emulsion is related to four major phenomenon :
– Flocculation
– Creaming or sedimentation
– Aggregation or coalescence
– Phase inversion
A. Flocculation:
Flocculation is defined as the association of particle within an emulsion to form large
aggregates. However these aggregates can easily be redispersed upon shaking.
It is considered as a precursor to the irreversible coalescence. It differs from
coalescence mainly in that interfacial film and individual droplets remain intact.
Flocculation is influenced by the charges on the surface of the emulsified globules.
The reversibility of flocculation depends upon strength of interaction between
particles as determined by
– the chemical nature of emulsifier,
– the phase volume ratio,
– the concentration of dissolved substances, specially electrolytes and ionic
emulsifiers
B. Creaming and sedimentation:

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 The upward or down ward movement of dispersed droplets is termed creaming or
sedimentation respectively.
In any emulsion, creaming or sedimentation takes place depending on the densities of
disperse and continuous phases. Creaming or sedimentation is undesirable as it may
lead to coalescence.
Factors affecting rate of creaming:
Rate of creaming is governed by Stoke’s law.
a. Droplet size:
 As per Stoke’s law, rate of creaming is directly proportional to the
square of radius or diameter of the droplet size. Smaller is the diameter
of the droplet, lesser will be the rate of creaming. So reduction in
droplet size helps in reducing creaming or sedimentation.
b. Difference in densities of dispersed and continuous phase:
 As per Stoke’s law no creaming is possible if densities of the two
phases are equal. So Creaming can be avoided by adjusting the density
of dispersed phase.
c. Viscosity of the continuous phase :
 As per Stoke’s law, rate of creaming is inversely proportional to
viscosity of the continuous phase. So increase in viscosity of the
continuous phase by adding thickening agents can reduce the rate of
creaming.
C. Coalescence (Cracking ):
Coalescence is the process in which the emulsified particles join to form larger
particles. Whereas aggregation is the process in which dispersed particles come
together but do not fuse.
The major factor which prevents coalescence is the mechanical strength of
electrical barrier. That is why natural gums and proteins are so useful as auxiliary
emulsifiers when used at low level , but can even be used a primary emulsifiers at
high concentration.
Reasons for Coalescence:
Globule size: If globule size is big (more than 1-3 µm), emulsion may first
cream and then crack. A homogenizer can reduce the size of globules.
Storage temperature: Extremes of temperature can lead to cracking.
 When water freezes, it expands, so undue pressure is expected on
dispersed globules and the emulsifying film which may lead to
cracking. On the other hand, increase in temperature decreases the
viscosity of the continuous phase and disrupts the integrity of
interfacial film. An increasing number of collisions between droplets
will also occur, leading to increased creaming and cracking.
D. Phase inversion
An emulsion is said to invert when it changes from an o/w to w/o or vice versa.
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 Causes
 Addition of electrolyte :
 Addition of CaCl2 into o/w emulsion by sodium soaps can be inverted
to w/o.
 Changing the phase volume ratio
1.3 Semisolid pharmaceutical dosage forms
♣ Semi solids are the topical dosage form used for the therapeutic, protective or cosmetic
function. They may be applied to the skin, or used nasally, vaginally, or rectally.
♣ The semisolid pharmaceutical dosage forms include ointments, creams, jellies, pastes,
plasters
♣ Their common property is the ability to cling to the surface of application for reasonable
duration before they are washed or worn off.
♣ Ideal properties of semisolid dosage forms
 Physical properties
 Smooth texture, Elegant in appearance, Non dehydrating, Non greasy and non
staining, Non hygroscopic
 Physiological properties
 Non irritating, Do not alter membrane / skin functioning, Miscible with skin
secretion, Have low sensitization index
 Application properties
 Easily applicable with efficient drug release, High aqueous washability.
♣ Advantages
 Avoid of first pass metabolism.
 Site specific action of drug on affected area.
 Convenient for unconscious patient or patient having difficulty on oral administration.
 Suitable dosage form for bitter drugs.
 More stable than liquid dosage form.
♣ Disadvantages
 May cause staining.
 They are bulky to handle.
 Application with finger may cause contamination.
 Physico-chemically less stable than solid dosage form.
 May cause irritation.
 Allergic to some patients.
1.3.1 Ointments
♣ Homogeneous, translucent, viscous, semi-solid preparation, most commonly a greasy, thick
oil (oil 80% - water 20%) with a high viscosity.
♣ Applied to the skin or mucous membranes.
♣ Ointments, in general, are composed of fluid hydrocarbons meshed in a matrix of higher
melting solid hydrocarbons.

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♣ Either medicated or non-medicated
 Medicated
 Either dissolved or dispersed in a vehicle as fine powder e.g. steroids
 Unmedicated
 Unmedicated ointments are used for physical effects such as protectants or
lubricants
1.3.1.1. Ointment Bases
1.3.1.1.1 Oleaginous (hydrocarbon) bases
♣ They consist of a combination of more than one oleaginous material such as water-insoluble
hydrophobic oils and fats.
♣ They are highly compatible; occlusive; good emollients.
♣ They are anhydrous, do not absorb water, readily insoluble (hydrophobic) in water, not
washable.
♣ Constituents of hydrocarbon bases:- soft paraffin, hard paraffin and liquid paraffin
♣ Uses: protectants, emollient, and vehicle for solid drugs.
1.3.1.1.2 Absorption bases
♣ Have capacity to absorb considerable quantities of water or aqueous solution and turn to w/o
without marked changes in consistency.
♣ These bases are not easy to remove from skin since the external phase of emulsion is
oleaginous
♣ Difficult to water washing
♣ Fall into two classes
i. Non-emulsified bases
 Absorb water and aqueous solutions producing w/o emulsions
 Have good emollient but poor occlusive property
 Assist oil-soluble medicaments to penetrate the skin
 Easier to spread
 E.g. wool fat (anhydrous lanolin), wool alcohols, hydrophilic petrolatum
ii. Water in oil emulsions:- capable of absorbing more water and have the properties of
the previous group
 E.g. hydrous wool fat (lanolin),
1.3.1.1.3 Water removable bases (emulsifying bases)
♣ They are oil in water emulsions having an emulsifier which makes them readily miscible
with water.
♣ Because of their surface active property they facilitate contact between skin and medicament
♣ They may be diluted with water or aqueous solutions
♣ Readily water washable
♣ E.g. emulsifying ointments B.P., Cetrimide emulsifying ointment B.P., Cetomacrogol
emulsifying ointment B.P.

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 1.3.1.1.4 Water soluble bases
♣ These include both anhydrous and hydrous dermatological non-emulsion bases which are
water soluble and contain no oil phase.
♣ Water soluble, water washable, greaseless.
♣ Because they soften with the addition of water, large amounts of aqueous solutions are not
effectively incorporated into these bases.
♣ Examples:- PEG Ointment
1.3.1.2. Selection of appropriate base
♣ Depends upon
 purpose for which ointment is going to be applied
 desired release of drug substance from ointment base
 desirability of topical or percutaneous drug absorption
 desirability of occlusion of moisture from skin
 stability of drug in ointment base
 Characteristics of surface to which it is to be applied
 Effect, if any, of the drug on the consistency or other features of the ointment base
 Desire for a base easily removed by washing with water
♣ furthermore a base should fulfill the following criteria
 Equally efficient on dry and oily skin
 Should have a suitable pH
 No dehydrating effect
 Nonirritant and non-sensitizing
 Compatible with a large number of drugs
 Miscible with skin secretions and excretions e.g. sebum, sweat etc.
1.3.1.3 Preparation of ointments
♣ A well-made ointment is
a) Uniform throughout, i.e. it contains no lumps of separated high melting point
ingredients of the base, there is no tendency for liquid constituents to separate and
insoluble powders are evenly dispersed
b) Free from grittiness, i.e. insoluble powders are finely subdivided and large clumps of
particles are absent
♣ Methods of preparations must try to satisfy these criteria.
♣ Depending primarily on nature of ingredients and physical properties of constituents of base
there are two general methods of preparation of ointments
 Incorporation
 Fusion
I. FUSION
♣ By the fusion method, all or some of the components of an ointment are combined by being
melted together and cooled with constant stirring until congealed.
♣ Components not melted are added to the congealing mixture as it is being cooled and stirred.

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♣ Naturally, heat-labile substances and any volatile components are added last, when the
temperature of the mixture is low enough not to cause decomposition or volatilization of the
components.
♣ Substances may be added to the congealing mixture as solutions or as insoluble powders
levitated with a portion of the base.
♣ Once congealed, the ointment may be passed through an ointment mill (in large-scale
manufacture) or rubbed with a spatula or in a mortar to ensure a uniform texture.
♣ On a small scale, fusion is generally carried out in an evaporating basin over a water bath.
♣ On a large scale, it is carried out in large steam jacketed kettles.
♣ Medicated ointments and ointment bases containing components such as beeswax, paraffin,
stearyl alcohol, and high-molecular-weight PEGs, which do not lend themselves well to
mixture by incorporation, are prepared by fusion.
♣ By this general process, the materials with the highest melting points are heated to the lowest
required temperature to produce a melt. The additional materials are added with constant
stirring during cooling of the melt until the mixture is congealed.
o In this way, not all of the components are subjected to the highest temperature.
♣ Alternative methods entail simply melting all of the components together under slowly
increasing temperature.
o By these methods, a lower temperature is usually sufficient to achieve fusion because
of the solvent action exerted by the first melted components on the others.
II. INCORPORATION
♣ By the incorporation method, the components are mixed until a uniform preparation is
attained.
a. Incorporation of solids:
 On small scale as in extemporaneous compounding the components are mixed using
pestle and mortar or spatula may be used to rub ingredients on an ointment slab
 Medicament is mixed with small amount of base and remainder is mixed gradually and
triturated continuously
 If material to be incorporated is solid then first the solid is triturated to fine powder and
then should be incorporated
 It is often desirable to reduce particle size of crystalline material so that final product will
not be gritty
 This is done by Levigating or mixing substance in a vehicle in which it is
insoluble so that a smooth dispersion is formed
 Levigating agent should be in equal volume to solid material
 If material to be incorporated is soluble in one of ingredients of base, first dissolve in that
ingredient and then incorporate
 Twin-roller mills are available for preparation of small quantities of ointments by hand
 If ingredients of ointments are reactive with stainless steel spatula (as does iodine for
example) hard rubber spatula may be used

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 b. Incorporation of liquids:
 Liquids are added only after due consideration of an ointment base capacity to accept
volume required
 Only small amount of aqueous solution is incorporated into oleaginous ointment
 Hydrophilic ointments readily accept large volumes
 When it is necessary to add aqueous preparation to hydrophobic base, solution first may
be incorporated into minimum amount of hydrophilic base and then added to
hydrophobic base
 All liquids have their limits to retain liquids beyond which they become too soft or semi-
liquid
1.3.1.4 Compendial requirements for ointments
♣ Ointments and other semisolid dosage forms must meet USP tests for microbial content,
minimum fill, packaging, storage and labeling
♣ Ophthalmic ointments must also meet test for sterility and metal particles content.
i. Microbial content
 Ointments and other semisolids with the exception of ophthalmic preparations are not
required to be sterile, however, they must meet acceptable standards for microbial content
and preparation which is prone to microbial growth must be preserved with antimicrobial
preservative.
 Microbial limits are stated in pharmaceutical products except the absence of some like S.
aureus, Peudomonal aeruginosa,
 Among the antimicrobial preservatives used to inhibit microbial growth in topical
preparations are:
 Methylparaben, Propylparaben, Phenols, Benzoic acid, Sorbic acid
ii. Minimum fill
♣ The USP’s minimum test involves the determination of the net weight or volume of the
content of filled containers to assure proper contents compared with the labeled amount.
iii. Packaging, storage and labeling
♣ Ointments and other semisolid preparations are packaged either in large mouth ointment jars
or in metal or plastic tubes
♣ Semisolid preparations must be stored in a well closed container to protect against product
separation due to heat.
♣ When required light sensitive preparations are packaged in opaque or light resistant
containers.
♣ In addition to the usual labeling requirements for pharmaceutical products, the USP directs
that the labeling for certain ointments and creams include the type of base used (e.g. water
soluble or water insoluble)

 Additional standards included in USP are

 Viscosity

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  Uniformity of batches
 Drug release tests

1.3.2 Creams
♣ Viscous semisolid emulsion system with opaque appearance as contrasted with translucent
ointments.
♣ Defines as “a semisolid dosage form containing one or more drug substances dissolved or
dispersed in a suitable base” semisolid emulsions of either O/W or W/O type.
♣ Creams may be:
 Medicated:- For specific action e.g. for application on burns
 Non-medicated:- Emollient
♣ Two types:
a) Water in oil or oily creams:
 Contain w/o emulsifier e.g. wool fats and wool alcohol
 aid in the retention of moisture
 Examples: Cold cream, Zinc cream
b) Oil in water or aqueous creams:
 Contain o/w emulsifier e.g. emulsifying wax alkali salt of a fatty acid
 Oil in water emulsions contain large percentage of water, stearic acid and other
oleaginous components
 After application water evaporates and leaves behind a thin residue film of stearic
acid and oleaginous component
 So it is protectant in nature
 more comfortable and cosmetically acceptable as they are less greasy and more easily
washed off using water
 Examples: Vanishing cream, Hydrocortisone cream
♣ Their consistency and rheologic character depend on whether the emulsion is a water-in-oil
or oil-in-water type and on the nature of the solids in the internal phase.
♣ Advantages over ointments
 Aqueous creams are easy to wash than all ointments
 Creams are easier to spread than ointments

1.3.2.1 Anionic emulsifying wax creams

♣ Made by fusion
♣ The wax and oily ingredients are melted together & cooled to about 600C
♣ The wax or aqueous solution is warmed to the same temperature and added to the oily
mixture with constant stirring which is continued until the preparation is cold
♣ Results are less reliable if admixture takes place above 600C and, therefore, a thermometer
should be used
1.3.2.2. Cationic emulsifying wax creams

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♣ These are made in the same way as anionic emulsifying wax creams.
♣ However, the formulae contain the ingredients of cationic emulsifying wax (i.e. cetostearyl
alcohol and cetrimide) and only liquid paraffin
1.3.2.3 Creams emulsified with non-ionic surfactants
♣ These are prepared in essentially the same way as anionic and cationic creams
♣ These creams or cream bases prepared with
 Self-emulsifying monostearin
 A sorbitan ester
 A macrogol ester
 A sorbitan ester with a polysorbate
1.3.2.4 Dilution of creams
♣ Sometimes dilutions of proprietary creams are requested
♣ The diluent must not impair the activity or stability of the cream; for example-
 Diluents containing no antimicrobial agent reduce the overall concentration of the
preservative in the preparation, leaving it with inadequate protection
 Release of a water-soluble medicament will be impaired if the o/w cream in which it was
formulated originally is reversed by using a w/o preparation as diluent
 Diluents that alter the pH of the product may cause precipitation or degradation of
medicaments
 Creams containing anionic emulgents, such as soaps and sodium lauryl sulphate, may
crack if mixed with preparations in which the medicament is cationic (e.g. neomycin
sulphate, crystal violet, acridine dyes and chlorhexidine salts)
 Use of a wrong diluent may cause a medicament to change into a more stable crystalline
form that is poorly released to the body
 Binding or complex formation with unsuitable diluents may reduce the activities of
medicaments and preservatives
 Use of a fatty diluent for a preparation containing a lipid-soluble drug (e.g. a topical
steroid) may reduce the release rate of the medicament
♣ In general it is best to use a neutral, non-ionic cream, such as cetomacrogol cream B.P.C., for
diluting o/w products.
♣ Dilutions are performed with strict hygienic precautions, without heat, and should always be
freshly prepared
1.3.3 Jellies
♣ Jellies are transparent or translucent non-greasy semisolid and contain more water than gels.
♣ Used for medication, lubrication and carrier for spermicidal agents to be used intra vaginally
with diaphragms.
1.3.3.1 Medicated jellies
♣ contain a considerable amount of water

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 Therefore, they are quite suitable as a vehicle for water soluble medicaments such as
local anesthetics, spermicides and antiseptics,
but not used for insoluble medicaments which are difficult to incorporate and do not
produce a uniform and smooth product
♣ easy to apply and produces a pleasant cooling effect
♣ the residual film, after evaporation, usually adheres well and gives protection but is easily
removed by washing when treatment is complete
♣ medicaments presented in this form include
 ephedrine sulphate, pramoxine hydrochlorides and phenylmercuric nitrate
1.3.3.2 Lubricant jellies
♣ they are very acceptable for lubrication purpose b/c of their water solubility, transparency,
blandness, smoothness and lubricity
♣ Jellies used for lubricating articles to be inserted in to sterile regions of the body should be
sterile.
♣ They are chiefly used on mucous membranes for their Lubricating, antiseptic or spermicidal
purposes. Jellies are also use for lubricating surgical gloves, catheters and rectal
thermometers.
1.3.3.3 Formulations of Jellies
♣ Jellies are usually prepared by adding a gelling agent such as tragacanth, carboxy methyl
cellulose to an aqueous solution in which the drug has been dissolved
♣ The mass is triturated in a mortar until a uniform product is obtained
♣ Jelling agents are usually organic hydrocolloids, but occasionally a hydrophilic inorganic
substance is more appropriate.
♣ The gelling agents used in the preparation of jellies are the following
a) Tragacanth
 Tragacanth jellies are also called bassorin paste
 the amount of gum required is determined by the use of the jelly,
 For lubricant -----2.5%
 For dermatological vehicles ------5%
 All formulations contain alcohol and/or glycerol and /or a volatile oil to disperse gum
and prevent lumpiness when the water is added.
 For instance, 5% tragacanth, 10% alcohol, 2% glycerol and water to 100ml
have been used as a vehicle for ichthamol, resorcinol, salicylic acid and other
medicaments.
 Tragacanth jellies have become less popular because;
 They vary in viscosity, due to the natural origin of gum and variations in
milling and storage
 The film left on skin tends to flake

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  Viscosity is rapidly lost outside the PH range 4.5-7 e.g. if benzoic acid is used
as preservative
 They are susceptible to microbial degradation
b) Sodium Alginate
 Sodium alginate may be used as lubricant (1.5 -2%) and dermatological vehicles (5-
10%),
 a trace of soluble calcium salt may be added to increase viscosity and most
formulation contain glycerol as a dispersing agent
 Sodium alginate has an advantage over tragacanth that it is available in several grades
of standardized viscosity
 The disadvantage is their off-white or buff color and several substances affect their
viscosity adversely
c) pectin
 valuable gelling agent for acid products and has been used, often with glycerol as a
dispersing agent and humectant, in dermatological jellies
 Pectin act as a very good medium for bacterial growth and therefore jellies prepared
with pectin must be preserved and stored in well closed container to prevent the loss
of moisture by evaporation
d) Starch
 It was used with other like gelatin and glycerin to prepare jellies
 Starch mucilages prepared with water alone lead to bacterial growth, therefore, a
suitable preservative must be added (glycerin up to 50% )
 The water is necessary for gelatinization to occur
 Starch jellies should be freshly prepared and packed in well closed container,
e) Gelatin
 A hot solution containing only 2% gelatin forms a jelly on cooling.
 Very stiff medicated jellies can be prepared by incorporating about 15% gelatin.
 Have been used for protection and support in various dermatological disorders
such as varicose ulcers
 Such jellies are melted before use and after cooling to desired temperature are
applied with a brush to the affected area. The area is covered with bandage
and the dressing may be left in place for several weeks. e.g. Zn gelatin jelly
 It is included in some ointments, pastes and gels as an adhesive to confine the
preparation to the area under treatment and prevent easy removal, e.g. by saliva

f) Cellulose Derivatives
 Widely used b/c they produce neutral jellies of very stable viscosity, good resistance
against bacterial growth, high clarity and good film strength when dried on the skin
 Example: - cellulose and sodium carboxy methyl cellulose

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  Sodium carboxyl methylcellulose is used for the preparation of lubricating jellies
as well as used for sterile jellies such as lignocaine gel because it can withstand
autoclaving without deterioration.
Preservation of jellies
♣ Since all the jellies contain large amount of water there must be a suitable antimicrobial
preventative unless they are to be used immediately.
♣ In selecting a suitable preservative allowance must be made for incompatibility with the
gelling agent
 Methyl p-hydroxyl benzoate (0.1 – 0.2% w/v) is commonly used preservative for
medicated jellies.

1.3.4 Pastes
♣ Pharmaceutical pastes are generally composed of ointment bases that contain a high
concentration (frequently> 50% w/w) of dispersed drug.
 The viscosity of pharmaceutical pastes is greater than that of pharmaceutical ointments.
♣ pastes are advantageous for the following reasons
 They have good adhesion on skin and less greasy.
 protecting and soothing inflamed itchy conditions
 allowing perspiration of skin after application because of its powder content
making it porous
 absorbing exudates by powders and are less macerating the skin compared to
ointments with a similar base
♣ Disadvantage
 less attractive cosmetically than ointments
 Difficult to remove from hairy skins
♣ The methods of preparing pastes are similar to those for ointments.
 When the base is semi-solid, fusion and/or trituration are used while trituration alone
is suitable if the vehicle is a liquid
♣ Bases used for pastes
a) Hydrocarbon bases: e.g. soft and liquid paraffin.
o Zinc paste and compound zinc and salicylic acid paste are prepared with soft
paraffin to be applied for treating eczema and psoriasis either alone or with coal
tar and dithranol
Coal tar paste is used for treating eczema whereas dithranol paste is
used for ring worm and psoriasis
o Liquid paraffin is used as base in compound Aluminium paste as skin
protectant.
b) Water miscible bases

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 o E.g. emulsifying ointment is the base for resorcinol and sulphur paste for
treatment of dandruff therefore it should be easily removed from hair; hence
emulsifying emulsion base is used.
c) Water soluble bases
o Examples- PEG of mixture of low and high molecular weight to get a product of
desired consistency, which soften or melt when applied to the skin.

1.4 Solid pharmaceutical dosage forms

1.4.1 Powders
Powders are the solid dosage form of medicament, which are meant for internal and external
use.
The term may be used to describe the physical form of the material that is dry substance
composed of a finely divided particles or it may be used to describe a type of pharmaceutical
preparation that is a medicated powder intended for internal (i.e. oral powder ) or external
(i.e. topical powder) use.
Advantage
 When it is not possible to dispense a drug as a solution or a suspension, because of its
insolubility or because it is susceptible to microbial contamination if it is wetted, then
it is a good idea to dispense it as a powder.
 Flexibility of compounding;-easy to prepare
 More stable than liquid dosage forms
 Rapid dissolution due to small particle size
 Fast action and better bioavailability
Disadvantage
 Time consuming
 Bulky to carry
 Inaccuracy in dose
 Unsuitable for many unpleasant tasting, volatile, oxidizing, hygroscopic and
deliquescent drugs
Classification
 Based on Usage-
 powders for external use
 powders for internal use
 Based on quantity
 bulk powders
 divided powders

1.4.1.1 Particle size

 The particles of pharmaceutical powders may range from extremely coarse about 10mm in
diameter to extremely fine approaching colloidal dimensions of 1mm or less.

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 In order to characterize the particle size of a given powder, the BP uses the descriptive terms
coarse, moderately coarse, fine and very fine which are related to the proportion of powder
that is capable of passing through the openings of standardize sieves of varying dimensions
in a specified time period under shaking, generally in a mechanical sieve shaker.
Table: - showing grades of powders according to BP standards
Grading of powder sieve through which sieve no through w/c
All particles must pass not more than 40% of
particle size pass
(10/44) coarse 10 44
(22/60) moderately coarse 22 60
(44/85) moderately fine 44 85
Fine (85) 85 not specified
Very fine 120 not specified

 The purpose of particle size analysis in pharmacy is to obtain quantitative data on the size
,distribution and shapes of drug and non-drug components to be used in pharmaceutical
formulation
 Particle size can influence a variety of important factors including the following.
i. Dissolution of particles
 Drug micronization can increase the rate of drug dissolution and bioavailability
ii. suspendability of particles intended to remain undissolved but uniformity
dispersed in a liquid vehicle
iii. uniform distribution of drug substance in a powder mixture or solid dosage form
to ensure dose to dose content uniformity
iv. penetrability of particles intended to be inhaled for deposition deep in the
respiratory tract
v. Non-grittiness of solid particles in dermal ointments cream and ophthalmic
preparations
1.4.1.2 Pharmaceutical Technology involved in the Manufacturing of Powders
a) Comminution of Drugs (Particle Size reduction of drugs)
b) Blending of Powders
a) Comminution of Drugs (Particle Size reduction of drugs)
 On a small scale, the pharmacist reduces the size of chemical substances by grinding with
a mortar and pestle.
 Grinding a drug in a mortar to reduce its particle size is termed trituration or
comminution.
 On a large scale, various types of mills and pulverizers may be used to reduce particle
size. e.g. FitzMill
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  Levigation is commonly used in small-scale preparation of ointments and suspensions to
reduce the particle size and grittiness of the added powders.
 A paste is formed by combining the powder and a small amount of liquid
(levigating agent) in which the powder is insoluble. The paste is then triturated to
reduce particle size. The levigated paste may be mixed with base well with help
of a spatula and tile. Mineral oil and glycerin are generally used levigating agent.
b) Blending of powders
 When two or more powdered substances are to be combined to form a uniform mixture, it
is best to reduce the particles size of each powder individually before weighting and
blending.
 Depending on the nature of the ingredients, the amount of powder to prepare and the
equipment available, powders may be blended by spatulation, trituration and tumbling.
 Spatulation:-
Mixing is done using spatula and tile or sheet
useful for solid substances that liquefy or form eutectic mixtures (i.e., mixtures
that melt at a lower temperature than any of their ingredients) when in close,
prolonged contact with one another e.g. phenol, camphor, menthol, thymol,
 To diminish contact, a powder prepared from such substances is
commonly mixed in the presence of an inert diluent, such as light
magnesium oxide or magnesium carbonate, to separate the troublesome
agents physically.
It is not suitable for large quantities of powders or for powders containing potent
substances because homogenous blending is not as certain as other methods
 Trituration
employed both to comminute and to mix powders
If simple admixture is desired without the special need for comminution, the glass
mortar is usually preferred.
When a small amount of a potent substance is to be mixed with a large amount of
diluent, the geometric dilution method is used to ensure the uniform distribution
of the potent drug.
 This method is especially indicated when the potent substance and other
ingredients are the same color and a visible sign of mixing is lacking.
 By this method, the potent drug is placed with an approximately equal
volume of the diluent in a mortar and is mixed thoroughly by trituration.
 Then, a second portion of diluent equal in volume to the mixture is added
and the trituration repeated.
 This process is continued by adding an equal volume of diluent to the
powder mixture and repeating this until all of the diluent is incorporated.
 Tumbling
mixing powders in a large container rotated by a motorized process

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 Mixing by this process is thorough but time consuming
1.4.1.3 Medicated powders
 Some medicated powders are intended to be used internally and others externally
 most powders for internal use are taken orally after mixing with water
 Some powders are intended to be inhaled for local and systemic effects
 Other dry powders are commercially packaged for constitution with a liquid solvent or
vehicle, some for administration orally, others for use as an injection, and still others for use
as a vaginal douche.
 powders for external use are applied on the affected area from a stiffer type container or from
a powder aerosol
1.4.1.3.1 Aerosolized powders
 They are administered by inhalation with the aid of dry powder inhalers which deliver
micronized particles of medication in metered quantities for the treatment of asthma and
other bronchial condition
 the particle size of the micronized medication is prepared in the range of 1 to 6 μm in
diameter
 In addition to the therapeutic agent, these products contain inert propellants, and
pharmaceutical diluents, as crystalline alpha lactose monohydrate, to aid the formulations
flow properties, metering uniformity and to protect the powder against effect of humidity
1.4.1.3.2 Bulk powders
 The bulk powders are available in prepackaged amount from which the patient takes by
mixing the powder in an appropriate vehicle according to the instruction
 Examples: -
Antacids bulk powder (NaHco3)
Laxative powders (psyllium)
medicated powders for external application to the skin, usually topical anti- infectives
(e.g., bacitracin zinc and polymyxin B sulfate) or antifungals (e.g., tolnaftate);
 Dispending powder medication in bulk quantities is limited to non-potent substances
 Generally, these products are stored at room temperature in a clean, dry place.
 Patients should be instructed how to measure the appropriate amount of the powder and be
told the type of liquid or vehicle to use to deliver the medication consistent with package
and/or physician instructions.
1.4.1.3.3 Divided powders
 These are dispensed in individual doses, usually in folded papers.
 After the powder has been properly blended, it may be divided in to individual dosing units
based on the amount to be taken or used at single time in folded paper /packets.
 It is applied for substances that are potent and needs controlled dosage
1.4.2 Granules
Granules are prepared agglomerates of smaller particles of powder
They are irregularly shaped but may be prepared to be spherical

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 Granulation is a pharmaceutical process that attempts to improve the flow of powdered
material by forming sphere like or regularly shaped aggregates called granules
Has some advantage over powder
 have better flow property than powders
o Because of their flow properties, granulations are commonly used in tablet
making to facilitate the free flow of material from the feeding container (or
hopper) into the tablet presses.
 usually more stable to the effects of atmospheric humidity and are less likely to cake
or harden upon standing
 Granules are easily wetted unlike powders that float on fluid surface and are often
preferred for dry products intended to be constituted in to solutions or suspensions.
1.4.2.1 Effervescent granules
These are granules containing a medicinal agent in dry mixture usually composed of sodium
carbonate, citric acid and tartaric acid.
When added to water the acids and bases reacts to liberate CO2 resulting in effervescence
the resulting carbonated solution masks an undesirable taste of any medicinal agent present
By using granules or coarse particles of the mixed powders rather than small powder
particles, the rate of solution is decreased and violet and uncontrollable effervescence is
prevented.
By using a combination of citric and tartaric acids rather than either acid certain difficulties
are avoided
 When tartaric acid alone ---granules lose their firmness readily and crumble
 When citric acid alone ---results in a sticky mixture difficult to granulate
1.4.2.2 Method of preparation of granules
Effervescent granules are prepared by two general methods: (a) the dry or fusion method and
(b) the wet method.
1.4.2.2.1 Dry or Fusion method
In the fusion method, the one molecule of water present in each molecule of citric acid act as
the binding agent for the powder mixture
Before mixing the powders, citric acid crystal are powdered and then mixed with the other
powders of the same sieve size to ensure uniformity of mixture.
the sieves and the mixing equipment should be stainless steel or other that resist the effect of
acids
The mixing of the powders is performed as rapidly as is practical, preferably in an
environment of low humidity to avoid absorption of moisture and a premature chemical
reaction.
After mixing, the powder is placed on a suitable dish in an oven at temperature between
34oC and 40oC

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 The heat cause the release of the water of crystallization from citric acid which in turn
dissolves a portion of the powder mixture, setting of the chemical reaction and consequent
release of CO2
this makes the softened mass of powder to become somewhat spongy, and when
it has reached the proper consistency, it removed from the oven and rubbed
through a sieve to produce granules of desired size
The granules are dried at a temperature not exceeding 54 oc and immediately placed in
containers and tightly sealed.
1.4.2.2.2 Wet Method
In this method, the binding agent is not water of crystallization from Citric acid, but water
added to alcohol as the moistening agent- forming the pliable mass for granulation
In this method, all of the powders may be anhydrous as long as water is add to the
moistening liquid
Just enough liquid is added (in portions ) to prepare a mass of proper consistency, then
granules are prepared and dried in the same manner as described in fusion method.
1.4.3 Tablets
 a solid dosage form prepared by compression of medicaments with a variety of excipients
 Most of the time intended for oral use and usually swallowed with water.
 Oral tablets are designed to release the medicament within the gastro-intestinal tract for
absorption in to the circulation, or more rarely for local effect.
 At least 90% of all drugs used to produce systemic effects are administered by the oral route.
 The oral route of drug administration is the most important method of administering drugs
for systemic effects
 Of drugs that are administered orally, solid oral dosage forms represent the preferred class of
product.
 The reasons:-
 tablets and capsules represent unit dosage forms in which one usual dose of the
drug has been accurately placed
 Liquid oral dose forms: - like syrup, emulsion, suspension, are usually designed to
contain usually the total dose of one course of therapy in a single container.
 Liquid D.F – are much more expensive to ship. (1 L.D.F weighs 5gm Vs 0.25 to
0.40g for over tab).
 Drugs are less stable in liquid form than in dry state and shelf-life tend to be shorter.
 Desired characteristics of tablets
 Should be elegant product having its own identity, free from defects as chips, cracks,
discoloration.
 Should have strength to withstand mechanical shock during production, packaging or
shipping
 Should be chemically, physically and microbiologically stable.
 Must be able to release the medicament in predictable and reproducible manner.

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 1.4.3.1 Advantage and Disadvantage of Tablets
 Manufacturing of tablets have more advantages than capsules.
1. Their cost is lowest of all oral dosage forms
2. They are the lightest and more compact of all oral dosage forms.
3. Tablets are the easiest and cheapest to package and ship of all oral dosage forms
4. Product identification is potentially the simplest and cheapest, requiring no additional
processing steps if stamped or mono gammed punch face is used.
5. Provide the greatest ease of swallowing with the least tendency for “Hang-up” above the
stomach, especially if coated and disintegration is not excessively rapid.
6. They lend themselves to certain special release profile products, such as enteric or
delayed-release products.
7. They are better suited to large-scale production than other unit oral forms.
8. They have best combined properties of chemical, mechanical and microbiological
stability than other unit oral forms.
 Disadvantages of tablet as dosage form
1. Some drugs resist compression into dense compacts, owing to their amorphous nature or
flocculent, low density character.
2. If a drug has low or poor wetting and slow dissolution properties, it is difficult to prepare
as tablet.
3. Special coating is required for bitter testing drugs, drugs with an objectionable odor or
drugs that are sensitive to oxygen or atmospheric moisture. In such cases capsules may
offer the best and lowest cost approach.
4. Difficult to swallow in case of children and unconscious patients.
1.4.3.2 Types of Tablets
A. Tablets ingested orally:
 Conventional Compressed tablet – are manufactured with tablet machines capable of
exerting great pressure in compacting the powder.
 Multiple compressed tablets: Multilayer tablets are made primarily to separate
incompatible drugs from each other, i.e. incompatible drugs can be incorporated into the
same tablet.
 Delayed release table:- release the drug slowly over a prolonged period of time e.g.
enteric coated Bisacodyl tablet
 Coated tablets
Sugar coated tablet: - beneficial in covering up drug substances possessing
objectionable tastes or odors, and in protecting materials sensitive to oxidation.
e.g. Multivitamin tablet
Film coated tablet:- compressed tablets which are covered with a thin layer or
film of a water-soluble material. e.g. Metronidazole tablet
Enteric-Coated Tablets: - These are compressed tablets coated with substances
that resist solution in gastric fluid but disintegrate in the intestine.

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  Chewable tablets: - chewed and thus mechanically disintegrated in the mouth. The drug
is, however, normally not dissolved in the mouth but swallowed and dissolves in the
stomach or intestine. e.g. Antacid tablet
B. Tablets used in oral cavity:
 Buccal: - used for drug release in the mouth followed by systemic uptake of the drug
small, flat, oval tablets
 Sublingual: - placed under the tongue e.g. nitroglycerin
 Lozenge: are tablets that dissolve slowly in the mouth and so release the drug dissolved
in the saliva. Lozenges are used for local medication in the mouth or throat, e.g. with
local anesthesia, antiseptic and antibiotic drugs. They can thus be described as slow
release
C. Tablets used to prepare solution:
 Effervescent tablets: Effervescent tablets are dropped into a glass of water before
administration, during which carbon dioxide is liberated. This facilitates tablet
disintegration.
D. Tablets administered by other route:
 Implantation tablet
 Vaginal tablet, e.g. Clotrimazole tablet
1.4.3.3 Method of Tablet Preparation
Formulation considerations
Tablet Excipients
 are chemical substances which are added or mixed with the active ingredient to enhance the
therapeutic effectiveness of drugs
 Examples of tablet excipients are:-
 Diluents: - are fillers designed to make the necessary bulk to a formulation to prepare
tablets of the desired size. E.g. starch, sorbitol, lactose, sucrose, mannitol, dicalcium
phosphate, microcrystalline cellulose, dextrose
 Tablets formulations may contain diluents for secondary reasons: to provide better
tablets properties such as improved cohesion, to permit use of direct compression
manufacturing or to promote flow.
 The dose of some drugs is sufficiently high that no filler is required (E.g. Aspirin
and certain antibiotics).
Note -Reading assignment- ideal properties of diluents
 Binders: - substances used to cause adhesion of powder particles in tablet granulations
e.g. Acacia, tragacanth, alginic acid, carboxy methyl cellulose, sodium ethylcellulose,
gelatin, sugars such as sucrose, glucose, dextrose, and lactose.
 Disintegrants: - which promote the breakup of the tablet after administration to smaller
particles for more ready drug availability. It may function either by increasing the
porosity and wettebility of the tablet (e.g. Starch, MCC) or by swelling in the presence of
aqueous fluids (increasing internal pressure) E.g. Pregelatinised starch

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  Lubricants: are intended to reduce the friction during tablet ejection between walls of
the die cavity in which the tablet was formed. E.g. Stearic acid, talc, PEG
 Glidants: act to enhance the flow properties of the powders within the hopper and into
the tablet die in the tablet press by filing the space between the particles or granules. E.g.
Talc, colloidal silicon dioxide.
 Colorant: - used to impart color to liquid and solid (e.g. tablets and capsules)
pharmaceutical preparations
 The use of colors and dyes in tablet has three purposes:- to disguising off-color
drugs, product identification and to produce more elegant product
 E.g. Ferric oxide, red, charmel FD & C Red No 3, 20 FD & C yellow No 6 FD & C
blue No 2
 Antiadherents: - agents that prevent the sticking of tablet formulation ingredients to
punches and dies in a tablet machine during production. E.g. magnesium stearate, Talc
 Antioxidant: - agents that inhibits oxidation and thus is used to prevent the deterioration
of preparations by the oxidative process. E.g. Ascorbic acid
 Flavoring agents: For chewable tablet or tablets intended to dissolve in the mouth
 Generally, water-soluble flavors have poor stability; hence, flavor oils or dry
powders usually are used
 Sweetening agents: For chewable tablets:.
 E.g. Sugar, mannitol
Saccharine (artificial): 500 times sweeter than sucrose
 Disadvantage: Bitter aftertaste and carcinogenic
Criteria for use as excipients
1. They must be non toxic.
2. They must be commercially available in an acceptable grade in all countries where the
product is to be manufacture.
3. Their cost must be acceptably low.
4. They must not be contraindicated by themselves (e.g. sucrose) or because of a component
(e.g. sodium) in any segment of the population.
5. They must be physiologically inert.
6. They must be physically and chemically stable by themselves and in combination with the
drug(s) and other tablet components.
7. They must be free of any unacceptable microbiologic “load”.
8. They must be color-compatible (not produce any off-color appearance)
9. If the drug product is also classified as a food, (certain vitamin products), the diluent and
other excipients must be approved direct food additives.
10. They must have no deleterious effect on the bioavailability of the drug (s) in the product.
 Example: TTC, product made with calcium phosphate filler had less than half the
bioavailability of the standard product.

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  The interaction of certain amine drugs with the commonly used diluent lactose, in
the presence of magnesium stearate; the resulting tablets were gradually discolored
with time.
 Anhydrous lactose has the advantage over lactose in that it does not undergo
reaction, which can lead to browning and discoloration with certain drugs.
 However the anhydrous form picks up moisture when exposed to elevated
humidity.
Methods of tablet manufacturing
 There are three methods of tablet manufacturing: direct compression, dry granulation and
wet granulation.
 The choice of method for the manufacture of tablets depend on:
 The physical and chemical stability of the therapeutic agent.
 The availability of the necessary processing equipment.
 The cost of the manufacturing process.
 The excipient used to formulate the product.
Tablet Granulations
 The characteristics of a tablet that make it a popular dosage form is due to primary by the
qualities of the granules, such as compactness, physical stability, rapid production capability,
chemical stability and efficacy.
 Granulation is a process by which primary powder particles are made to adhere to form
larger, multi particulate entity for manufacturing of tablet.
 Granulation is in part the pharmaceutical process that attempts to improve the flow of
powdered materials by forming spherelike or regularly shaped aggregates called granules.
 Pharmaceutical granules size range from 0.2 – 4.0mm
 For tablet and capsules 0.2 – 0.5mm granules are needed.
Reasons for granulation
1. To prevent powder particles segregation, this may be caused by variation in size distribution.
2. To improve flow properties of a powder mix because finally enhance uniform dosing.
3. To improve compaction characteristic of powder mix because granulation increases attraction
between practices.
4. Reduces toxic nature of powders which are released as dust to affect the environment.
5. For hygroscopic substances cake formation is minimized by granulation.
6. Easy to store and transport than primary powder particles.
1. DIR ECT COMPRESSION
 As its name implies, direct compression consists of compressing tablets directly from
powdered material without modifying the physical nature of the material itself.
 There is no formation of granules.
 There are a few crystalline substances that posses free flowing and cohesive properties that
enable them to be compressed directly in a tablet machine without need of wet or dry
granulation, such as sodium chloride, sodium bromide, and potassium chloride and can be
compressed directly.
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 For tablets in which the drug itself constitutes a major portion of the total tablet weight, it is
necessary that the drug possess those physical characteristics required for the formulation to
be compressed directly.
 this method is important for
 Highly crystalline substances (b/c they are self lubricating and self disintegrating)
 Small doses of drugs
 Potent medicament of moderate dose.
 Most large dose drugs don’t lend themselves to this process. Also for many other drugs
having small doses, uniform blends of the drug and coarser cannot be achieved, which makes
the process impractical.
 However, the use of compressible diluents with many moderate-dose drugs makes the
process the most stream lined method of tablet manufacturing.
 The directly compressible diluents are microcrystalline cellulose, Dicalcium phosphate
dehydrates.
 The procedures used in direct compression are basically screening or milling and mixing
 Advantages of direct compression
 Fewer unit operation
 low labor input
 It obviates heating (costly unit operation)- dry process.
 Limitations of direct compression
 It is limited only to directly compressible materials
 The final tablets tend to be softer than those by wet granulation.
 It is not used if a colorant is required in the formulation.
 Not employed for most large –dose drug preparations.
 Static charge builds up b/c of the dry nature of the process.
2. DRY (COMPRESSION) GRANULATION
 When tablet ingredients are sensitive to moisture or are unstable to withstand elevated
temperatures during drying and when the tablet ingredient have sufficient inherent binding or
cohesive properties, slugging may be used to form granules. This method is referred to as dry
granulation.
 The powder is compacted into large piece and subsequently broken down or sized in to
granules. In this method particle-particle interaction occur due to electrostatic force, vander
waals interaction or by melting of components within the formulation.
 It is a valuable technique in situations where:-
 The effective dose of a drug is too high for direct compaction.
 The drug is sensitive to heat, moisture or both which precludes wet granulation. E.g.
Aspirin and vitamin formulations are prepared by this method.
 It eliminates a number of steps but still include weighing, mixing, slugging, dry
screening/milling, lubrication and compression. The active ingredient, diluents and part of
the lubricant are blended.
 It involves the use of:-
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  Tablet press or
 Roller compactor.
Procedures of dry granulation
A. compression granules involving use of tablets press or slugging method
 Slugging: - after weighing and mixing the ingredients, the powder mixture is “slugged” or
compressed by flat faced punches. The compacted masses are called slugs.
 The slugs then are broken up by a mill and passed through a screen of desired mesh for
sizing. Lubricant is added in the usual manner and tablets are prepared by compression.

" Slug " crushed " milled " compressed to tablet

 The two or more times that the material is subjected to compaction pressures cause a
strengthening of the bonds that hold the tablet together. The resultant granules also increase
the fluidity of these powder mixtures, which by themselves do not flow well enough to fill
the dies satisfactorily.
 Advantage: require less equipment and space and eliminates the addition of moisture and the
application of heat as found in wet massing and drying steps of the wet granulation method.
B. compression of granules involving use of roller compactor
 Roller compactor is especially designed machinery employed on large scale production of
tablets by compression granulation.
 In roller compaction instead of slugging, powder compactors may be used to increase the
density of a powder by pressing it between high pressure rollers.
 Roller compactors utilize two rollers that revolve toward each other. By means of a hydraulic
ram forcing one of the rollers against the other, the machine is capable of exerting known
fixed pressures on any powdered material that flows between the rollers.
 Powdered material is fed between the rollers by a screw conveyor system. After passing
through the rollers, the compacted mass resembles a thin wide ribbon that has fallen apart
into large segments. These are equivalent to the slugs produced by the slugging process. The
segments are then screened or milled for the production of granules.
 The compaction force of the roller compactor is controlled by three variables: (1) the
hydraulic pressure exerted on the compaction rolls, (2) the rotational speed of the compaction
rolls, and (3) the rotational speed of the screws.
 The roll speed and the feed-screw speed have the greatest effect on the compaction process.
 The feed screws on most modern compaction consist of a variable – speed horizontal and
vertical screw.
 The horizontal screw picks up the powder from the hopper and maintains a continuous
flow to the vertical screw.
 The vertical screw delivers the power to the compaction rolls. The vertical screw speed
is critical for uniform compaction. It serves to deaerate the powder and maintains a
constant flow onto the compaction rolls. Any variation in dearation or load causes
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 extreme changes in the compact. The vertical feed screw is usually set so that it
delivers more material than the compaction rolls accept, assuring constant loading
during the compaction process.
 The speed of the compaction rolls controls the pressure dwell time, which has a great effect
on the density and hardness of the compact.
 Advantages: increased production capacity (500kg per hour), greater control of compaction
pressure, no need of excessive lubrication of powder and it is a continuous process.

3. WET GRANULATION
 The wet granulation technique uses the same preparatory and finishing steps (screening or
milling, and mixing) as the two previously discussed granulation techniques.
 The unique portion of wet granulation involves the massing of a mix of dry primary powder
particles using a granulating fluid and wet sizing or milling and drying.

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 This technique employs a solution, suspension, slurry containing a binder which is usually
added to the powder mixture or the binder may be incorporated dry into the powder mix and
the liquid may be added by itself.
 It is widely employed method for the production of compressed tablets.
 The steps required are:
a. Weighing and blending the ingredients
 Specified quantities of active ingredient, diluents or filler and disintegrating agent are mixed
by mechanical powder blender or mixer until uniform.
b. Preparing a damp mass
 a liquid binder is added to the powder mixture to facilitate the adhesion of the powder
particles.
 A damp mass resembling dough is formed and is used to prepare the granulation.
 The binding agent contributes to the adhesion of the granules to one another and maintains the
integrity of the tablet after compression.
c. Screening the damp mass in to pellets or granules
 The wet mass is pressed through a screen (No 6 or 8 mesh) to prepare the granules.
d. Drying the granulation
 Granules may be dried in thermostatically controlled ovens which constantly record the time,
To and humidity.
e. Sizing the granulation by dry screening
 After drying, the granules are passed through a screen of a smaller mesh than that used to
prepare the original granulation.
 The degree to which the granules are reduced depends up on the size of the punches to be
used.
f. Adding lubricant and blending
 After dry screening a dry lubricant is dusted over the spread-out granulation through a fine
mesh screen.
 Lubricants
 They improve the flow of the granulation in the hopper to the die cavity.
 They prevent the adhesion of the tablet formulation to the punches and dies during
compression
 They reduce friction between the tablet and the die wall during the tablets ejection.
 They give a sheen to the finished tablet
g. Tabletting by compression

 Advantages of wet granulation

 work well for many drugs
 Useful for fluffy powders that do not flow well or mix well.
 Disadvantage
 not applicable for moisture sensitive or heat sensitive drugs.
 Extra steps require more time, labor, and material than the previous methods.
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Summery
Processing steps commonly required in the various tablet granulation preparation
techniques
Processing step Wet Dry Direct

Raw materials X X X

Weighing X X X

Screening X X X

Mixing X X

Slug formation X

Wet mass X

Mill X X

Drying X

Compress X X X

TABLET COMPRESSION OPERATION

 Powder compression: - the reduction in volume of the powder owing to the application of force. The
bulk volume of the material reduces as a result of the removed gaseous phase.
 Tablets are made by compressing a formulation containing a drug or drugs with excipients on
stamping machines called presses.
 Tablet compression machine are designed with the following basic components
i. Hoppers; - for holding and feeding granulation to be compressed.
ii. Dies:- for defining the size and shape of the tablet
iii. Punches:- for compressing the granulation tablet within the dies
iv. Cam tracks:-for guiding the movement of the punches.
v. Feeding mechanism:- for moving granulation from the hopper into the dies

 Compressing a formulation for tablet has 3 stages

1. Die filling
2. Tablet formation
3. Tablet ejection
1. Die-filling: - is accomplished by gravitational flow of the powder from the hopper to die table (the
portion holding the dies).
2. Tablet formation (powder compression): Is done by the upper punch by entering in to the die.

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3. Tablet ejection: - is performed by lower punch. The lower punch ride up the cam, which brings the
tablet flush with or slightly above the surface of the dies.

Initial step in tablet production (die filling)

The compression stage in tablet production (compression)

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 The final stage in tablet formation (ejection)

Types of compression machines

 There are two basic compression machines for tabletting
1) Single punch presses
2) Rotary multi-station presses
I. Single punch presses (stamping machine)
 Components:-
 A pair of punches (one pair)
 A hopper
 One die
 Mechanism of Tabletting
o Production filing is done by gravity
o Amount of production is controlled by position of lower punch
o Compression force is applied by upper punch
o The force is controlled by displacement of upper punch
o The total tablet production is 200 tablets/min.
 Application
 For new formulation development
 For production of tablets for clinical trials

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 II. Rotary multi-station presses
 Multi-station presses termed rotary, because the bead of machine that holds the punches and dies
in place rotates.
 The portions of the head that hold the upper and lower punches are called the upper and lower
turrets respectively.
 Granulation stored in hopper empties into the feed frame then spread the granulation over a wide
area to provide time for dies.
 The pull down cam guides à the lower punches to the bottom à allowing the dies to over fill.
 A wipe off blade – removes the excess granulation and directs it around turret and back into the
front of the feed frame.
 The lower punch travels over the lower compression roll while simultaneously the upper punch.
 The upper punch enters a fixed distance into the dies, while the lower punches are raised to
squeeze and compact the granulation within the dies.
 After compression the upper punch are withdrawn as they follow the upper punch raising cam.
 The lower punch ride up the cam which brings the tablet flushes with or slightly above the
surface of the dies.
 Application
 For large scale production of tablets. Total tablet production is 10,000 or >/min.
 Components
i. Number of dies and sets of punches
 Small rotary press punches has 3 sets of dies and 3 pairs of punches
 Large “ “ “ “ 60 or > dies and 60 or > pair of punches
 One die is associated with one pair of punch.
ii. Hopper – used to hold powder
iii. Feed-frame – used to feed the powder in to the die
 A tablet machines output is regulated by
1. Number of tooling sets
2. Number of compression stations
3. Rotational speed of the press
Auxiliary equipment
 Their Purpose is to increase efficiency of the tablet compression operation.
 The various Auxiliary equipment include.
1. Mechanical feeder: - increase flow property of granules
2. Hopper feeder: - automatic controller of powders in the hopper.
3. Granulation sensor: - gives sound to operator for feeding the hopper.
4. Electronic tablet weight monitors – senses the weight electronically.
5. Tablet deduster: - removes excess powder on the tablet after production.

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 1.4.4 Capsules
 Capsules are solid dosage forms in which the medicinal agents and inert substances are
enclosed within small shell of gelatins.
1.4.4.1 Advantage and Disadvantage of capsules
 Capsules have become a popular dosage form. Why??????
 Because they provide a smooth, slippery, easily swallowed and tasteless shell for
drugs.
 Capsules are a convenient method by which liquids may be orally administered to patients
as a unit dosage form.
 Is particularly beneficial for drugs having an unpleasant taste or odor.
 It is elegant, easy to use and portable
 They are economically produced in large quantities
 The contents are readily available faster than tablets.
 Require less adjuvant.
 Easy to identify b/c of their color variation.
 The use of capsules avoids many unit operations that are associated with the
manufacture of tablets, e.g. compression, granulation, drying.
 Disadvantages
 the requirement for specialized manufacturing equipment
 potential stability problems associated with capsules containing liquid fills
 Problems regarding the homogeneity of fill weight and content may be associated
with capsule formulations.
 Capsules are not usually used for the administration of extremely soluble materials
such as KCl, KBr, or NH4Cl since the sudden release of such compounds in the
stomach could result in irritating concentrations.
 Capsules should not be used for highly efflorescent (materials that release moisture)
or deliquescent (materials that absorb moisture) materials. Because efflorescent
materials may cause the capsule to soften, whereas deliquescent products may dry the
capsule shell to excessive brittleness.
1.4.4.2 Types of Capsules and their Production
 There are two, types of capsule. These are hard gelatin and soft gelatin capsule depending on
shell composition.
1) Hard Gelatin Capsule
 Hard gelatin capsule is used to formulate solid substances
 Are used to manufacture most of the commercially available medicated capsules.
 These capsules are filled by introducing the powdered material in to the longer end or body
of the capsule and the slipping on the cap.
The cap: the part of the capsule which has greater diameter.
The body: This holds the powder material.

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Materials used in capsules production
 Capsules are made principally of:
 Gelatin blends: Gelatin is a heterogeneous product derived by irreversible hydrolytic
extraction of treated animal collagen.
 Common sources of collagen are- animal bones and frozen pork skin.
 The bone gelatin produces a tough, firm but tends to be hazy and brittle.
 The pork skin gelatin contributes plasticity and clarity to the blend, thereby
reducing haze or cloudiness in the finished capsule
 Plasticizers: glycerol and sorbitol are added to increase the elasticity and decrease
brittleness of gelatin.
 Preservatives: gelatin solutions are an ideal medium for bacterial growth at temperature
below 550C . E.g. benzoic acid, parahydroxy benzoic acid, SO2 etc.
 Certified dyes, opaquing agents and water – 12-16 %.
 Capsules have been made with methyl cellulose, poly vinyl alcohols and denatured
gelatins to modify their solubility or produce an enteric effect.
Types of gelatin
 Type A gelatin is derived from an acid-treated precursor.
 Type B gelatin is derived from an alkali-treated precursor.
 Although capsules may be made from either type of gelatin, the usual practice is to use a
mixture of both types as dictated by availability and cost considerations.
The process of manufacturing gelatin used in capsule
Dry bone 5% HCl 10-15 days Lime 10% 4-8 wks Lime removal pH Adjustment

bone meal Dicalcium phosphate

wash
Calf skin Lime 10%6-12 wks Water wash 10-30 hrs

wash
Pork skin Acid 1-5% HCl 10-30hrs Acid removal

Hot water extraction Filter Vacuum concentration cool to solidify air dry
mill to size

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 Two recent developments have taken place in the gelatin supply area. First “green” (fresh)
bones are being used commercially as a source of type B gelatin. Aside from additional
pretreatment to remove residual tissues and fat, the processing coincides with that used for
aged bones, and the gelatins obtained are indistinguishable from each other in practical use.
 The second development is the processing of an “acid-bone” gelatin prepared from bone by
techniques essentially comparable to those for Type A gelatins. The acid extraction technique
for bones is valuable to processors of gelatin because of the decreased extraction time
required.
Method of production
 Hard gelatin capsule shells are manufactured in 2 sections, the capsule body and a sorter cap.
 The two parts over lap when joined, with the cap fitting supply over the open end of the
capsule body.
 The completely automatic machine most commonly used for capsule production consists of
mechanisms for automatically dipping, spinning, drying, stripping, trimming and joining the
capsules.
 The stainless steel mold pin, on which the capsule is formed, controls some of the final
critical dimensions of the capsule. Pegs on which the caps are formed are slightly larger in
diameter than the pegs on which the bodies are formed.
 Dipping
 These pins are dipped into a gelatin (melted gelatin mixture) to form caps and bodies
simultaneously. The pins sub merged to the desired depth and maintained for the
desired period to achieve the proper length and thickness of coating.
 Spinning
 The pins are rotated to distribute the gelatin over the pins uniformly. During this time
the gelatin may be set or gelled by a blast of cool air.
 Drying
 the pins are moved through a series of controlled air drying kilns for the gradual and
precisely controlled removal of H2O (thermally insulated chamber or oven)
 Stripping
 The dried films are removed from the moulds by bronze jaws.
 Trimming
 Cut to the correct length by stationary knives
 Joining of cap and body and ejection
 The two parts joined together and ejected from the machine.
 The entire cycle of the machine lasts approximately 45 min
 Thickness of the capsule wall is controlled by the viscosity of the gelatin solution and the
speed and time of dipping.
 other factors critical for the final dimension
 mold pin dimension
 precise drying
 machine control relating to cut length
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 Evaluation of empty gelatin capsules

 In process quality control include

 periodic monitoring and adjustment of film thickness
 cut lengths of both cap and body
 Color and moisture content
 Empty-capsules are subject to size variations as a result of moisture content variations.
 this can be caused by exposure to extreme variation in absolute humidity or elevated
temperature
 solution
 unopened shipping containers
 Empty capsules as usually received range in moisture content between 12% and 15%.
 Below 10% moisture content, they become brittle and may shrink to the point of not
fitting into the filling equipment.
 Above 16% moisture content, they may cause size problems in the filling equipment and
a loss of mechanical strength.

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 Recent studies have been made in several areas to provide computer control of viscosity
during either machine operations or gelatin solution make-up.
 Inspection processes takes place to remove imperfect capsules
 Electronic sorting mechanism mechanically orients the capsules and transports them paste a
series of optical scanners, at which time those having detectable visual imperfections are
automatically rejected.
Filling operations of hard gelatin capsules
 Empty capsules are sold by sizes. The ones most commonly employed for human use range
from size o, the largest to size 5 the smallest.
 Size 00 capsules may occasionally be required because of the volume of material to be filled.
 but not used commercially in large volume
 The powder weights listed are approximate and vary with the amount of pressure employed
in hand filling or with the type of equipment utilized in machine filling.
Filling capacity of empty capsules
Capsule size Approx. volume (ml)
000 1.36 (veterinary)
00 0.95 (veterinary)
0 0.67
1 0.48
2 0.37
3 0.27
4 0.20
5 0.13
 The size selected for use is determined by the amount of fill material to be encapsulated.
Preparation of filled hard gelatin capsule
 The large scale or small scale preparation of filled hard gelatin capsules is divided into the
following general steps.
1. Developing and preparing the formulation and selecting the size of capsule
2. Filling the capsule shells
3. Capsule sealing
4. Cleaning and polishing the filled capsules
1. Developing the formulation and selection of capsule size
 The developing of a capsule formation, the goal is to prepare a capsule with accurate dosage, good
bioavailability, eases of filling and production stability and elegance.
 In dry formulation, the active and inactive components must be blended thoroughly to ensure a
uniform powder mix for the capsule fill.
 There are 2 major problems in powder mixing and filling operations of capsule
i. Demixing
 the flow of the resultant mixture must be adequate to ensure delivery of sufficient powder
to the capsules at the time of filling

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 ii. Physical incompatibilities between active ingredients, between additives or b/n active
ingredients and or diluents and the capsule shell may create problems.
 the choice of excipients should be made with a view toward current FDA regulations
 excipients
o bentonite, CaCO3, MgCO3, lactose, mannitol, Mg(OH)2, silica gel, starch
talc
 improve flow characteristics (glidants and or lubricants)
o glycol esters, silicones, silicon dioxide, metallic stearates, stearic acid and
talc
 the determination of amounts of diluents to be used is based on
 the total amount of material that can possibly be put in the capsule in relation to
the amount of active ingredients to be supplied by the capsule
 the amount of lubricants that can be used
 Inserting tablets or small capsules with in capsules is sometimes a useful technique in the
commercial production of capsules and in extemporaneous preparation of capsules. This
may be done to separate chemically incompatible agents or to add premeasured (as tablets)
amounts of potent drug substance. Rather than weighing potent drugs a pharmacist may
choose to insert an available prefabricated tablet of the desired strength in each capsule.
Other less potent agents and diluents may then weighted and added.
2. Filling hard capsule shells
 When filling a small no of capsules, the pharmacists use the “punch” method.
 In this method, the pharmacist takes the precise no of empty capsules to be filled from his
stock container. The product to be encapsulated is placed on a sheet of clean paper or on
a glass. Because of the amount of product packed in to a capsule depends up on the
degree of compression, the pharmacist should punch each capsule in the same manner.
After the body of a capsule has been filled the cap placed on the body.
hand operated capsule filling machines
 have capacities ranging from 24-300 capsules and
 when efficiently operated are capable of producing 200-2000 capsules per hr
Machines developed for industrial use automatically separate the caps form empty capsules,
fill the bodies, scrape off the excess product release the cap, seal the capsules as desired and
clean the outside of the filled capsules at a rate of up to 165,000 capsules per hour.
 Common steps (operations in the process of capsule filling are:
 Rectification: it is a process where the bodies end is kept down ward by the difference in
diameter b/n cap and body.
 Separation: of caps and bodies.
 Dosing of fill materials: here the formulation is filled in to the body. Dosing can be done
by:-
o Direct filling: the capsule body is used for measuring the amount of the
formulation to be filled.

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 o Indirect filling: here the dose to be filled is first measured by an appropriate
dosing meter.
 Replacement of caps and ejection of filled capsules: cap and body are rejoined, pins
are used to push the filled bodies up in to the caps and eject the dosed capsules.
 Capsule filling equipment - There are different types of capsule filling equipment. Such as
 Lilly/parke-Davis
 Farmatic
 Hofliger and karg
 Macofar
 MGZ SP.A
 Zansi
3. Capsule sealing
 One manufacturer makes distinctive – locking capsules by sealing them with a colored band
of gelatin.
 Capsules may also be sealed through a heat welding process that fuses the capsule cap to the
body through the double thickness at their junction.
4. Cleaning and polishing capsules
 are important to – increase patient acceptance, remove dust from the shell and to provide
necessary gloss to the capsules
 dusting/polishing operations vary according to the type of filling equipment used, the type of
powder used for filling, and the individual desires for the finished appearance of the
completed capsules.
 most commonly
 pan polishing
 the accela cota tablet coating pan may be used to dust and polish capsules
 cloth dusting
 On small scale, capsules may be cleaned individually or in small number by
rubbing them with a clean gauze or cloth.
 brushing
 capsules are fed under rotating soft brushes
 the process must be accompanied by a vacuuming for dust removal.
Evaluations of filled capsules
 control procedures must ensure that the finished, filled capsules meet the appropriate current
regulatory test
e.g. weight variation, content uniformity, solubility and/or disintegration
 weight variation test defined by USP XX is a sequential test, in which 20 intact capsules are
individually weighed and the average weight is determined
 The test requirements are met if none of the individual weights are less than 90% or
more than 110%, of the average.

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  If the original 20 do not meet these criteria, the individual net weights are determined.
These are averaged and differences are determined b/n each net content and the
average.
 The test requirements are met (1) if not more than two of the individual differences
are greater than 10% of the average, or (2) if in no case any difference is greater than
25%
 if more than 2 but less than 6 net weights determined by the test deviate by more than
10% but less than 25% , the net contents are determined for an additional 40 capsules,
and the average is calculated for the entire 60 capsules. 60 deviations from the new
average are calculated.
 The requirements are met (1) if the difference does not exceed 10% of the average in
more than 6 of the 60 capsules, and (2) if in no case any difference exceeds 25%.
 capsule weighing machine
o rotoweigh- a high speed machine and operates at 73,000 capsules per hour
o vericap 2000
 content uniformity
 30 capsules are selected, 10 of which are assayed by the specified procedures
 the requirements are met if 9 of the 10 are within the specified potency range of 85 to
115%, and the tenth is not outside 75 to 125%.
 if more than 1, but less than 3, of the first 10 capsules fall outside the 85 to 115%
limits, the remaining 20 are assayed.
 the requirements are met if all the 30 capsules are within 75 to 125% of the specified
potency range and not less than 27 of the 30 are within the 85 to 115% range
 stability
 no broad generalizations about stability can be made
 the test must include
o extended storage at various elevated temperatures with different humidity
levels
2) Soft gelatin capsules
 Soft gelatin capsules are made of gelatin to which glycerin or a polyhydric alcohol such as
sorbitol has been added to render the gelatin elastic or plastic like.
 Soft gelatin capsules contain more moisture than hard capsules.
 Pharmaceutical applications of soft gelatin capsules.
1. As an oral dosage form of ethical or proprietary products for human or veterinary use.
2. as a suppository dosage form for rectal use or for vaginal use
3. As a specialty package in tube form, for human and veterinary single dose application
of topical, ophthalmic and otic preparation and rectal ointments.
 In the cosmetic industry, these capsules may be sued as a specialty package for breath
fresheners, perfumes, bath oils and various skin creams.

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 Methods of manufacturing soft gelatin capsule
 They may be prepared by the plate process, using a set of molds to form the capsules, or by
the more efficient and productive rotary or reciprocating die processes by which they are
produced, filled and sealed in continuous operation.
A) Plate process:-
 the oldest commercial method of manufacture
 is a batch process
 a warm sheet of plain or colored gelatin is placed on the bottom plate of the mold
 application of vacuum to draw the sheet in to the die pockets and the liquid containing
medication is evenly poured on it
 Then a 2nd sheet of gelatin is carefully placed on top of the medication and the top plate
of the mold is put into place.
 Pressure is then applied to the mold to form fill and seal the capsules simultaneously.
 The capsules are removed and washed with a solvent harmless to the capsules.
B) Rotary die process:-
 most soft gelatin capsules are prepared by this method
 reduced manufacturing loses to a negligible figure and content variations to less than ±
3%
 the gelatin mass is fed by gravity to a metering device (spreader box) which controls the
flaw of the mass onto air-cooled rotating drums
 gelatin ribbons of controlled (±10%)thickness are formed. and the thickness of the
shell ranges from .025-.032 inch
 product cost is directly proportional to shell thickness
 the ribbons are fed through a mineral oil lubricating bath, over guide rolls, and then down
b/n the wedge and the die rolls
 The material to be capsulated flows by gravity into a positive displacement pump. The
pump accurately meters the material through the leads and wedge into the gelatin ribbons
between the die rolls.
 the bottom of the wedge contains small orifices lined up with the die pockets of the die
rolls
 the capsule is about half sealed when the pressure of the pumped material forces the
gelatin into the die pockets, where the capsules are simultaneously filled, shaped,
hermetically sealed and cut from the gelatin ribbon
 the sealing of the capsule is achieved by mechanical pressure on the die rolls and the
heating (37 to 400C) of the ribbons by the wedge
 during manufacture, capsule samples are taken periodically for seal thickness and feel
weight checks
 immediately after manufacture, the capsules are automatically conveyed through a
naphtha wash unit to remove the mineral oil lubricant
 the washed capsules may be automatically subjected to a preliminary infrared drying
step, which removes 60-70% of the water that is to be lost
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  after drying, the capsules are transferred to the inspection department and held until
released by the quality control department
 control tests
 seal thickness determination
 total or shell moisture tests
 capsule fragility or rupture tests
 determination of freezing and high temperature effects

C) Reciprocating die
 process is similar to the rotary process in that ribbons of gelatin are formed and used to encapsulate the
fill, but it differs in the actual encapsulating process
 The gelatin ribbons are fed b/n a set of vertical dies that continually open and close to form rows of
pockets in the gelatin ribbons.
 These pockets are filled with the medication and are sealed, shaped and cut out of the film as they
progress through the machinery.
 As the capsules are cut from the ribbons, they fall into refrigerated tanks which prevent the capsules
from adhering to one another.

The nature of the capsule shell

 capsule shell composed of
 gelatin, plasticizer and H2O

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  preservatives, coloring and opacifying agents, flavorings
The nature of the capsule content
 The formulation of the capsule content for each product is individually developed to fulfill the
specification and end use requirement of the product.
 The content of a soft gelatin capsule is a liquid, or a combination of miscible liquids, a solution of a
solid in a liquid, or a suspension of a solid in a liquid.
 Liquids
 an essential part of the capsule content
 Those liquids that are both water – miscible and volatile cannot be included as major
constituents of the capsule content since they can migrate into the hydrophilic gelatin
shell and volatilize from its surface. e.g. H2O, ethyl alcohol and emulsions
 As minor constituents (5%of the capsule content) H2O and alcohol can be used as
cosolvents.
 Gelatin plasticizers (glycerin and propylene glycol) cannot be major constituents due
to their softening effect on the gelatin shell, which thereby makes the capsule more
susceptible to the effects of heat and humidity. (up to 10% glycerin and propylene
glycol can be used as cosolvents with polyethylene glycol or other liquids that have a
shell-hardening effect when capsulated alone)
 The most widely used liquids for human use are oily active ingredients (clofibrate),
vegetable oils (soybean oil), mineral oil, non ionic surface active agents (polysorbate
80) & polyethylene glycols (400 & 600), either alone or in combination.
 All liquids, solutions and suspensions for capsule should be homogeneous and air free
and preferably should flow by gravity at room. To but not at temperature exceeding
350C at the point of capsulation
 the sealing temperature of the gelatin films is usually in the range of 37 to
400C
 a solution is more easily capsulated and exhibits better uniformity, stability, and
biopharmaceutical properties than does a suspension
 combinations of miscible liquids often are used to
 Produce desired physiological results E.g. increased or more rapid absorption
of active ingredients (Vit. A and polysorbate 80)
 produce desired physiochemical results- e.g. improved flow properties
(dilution or partial substitution with a thinner liquid) and improved solubility
(steroid with oil and benzyl alcohol)
 Solids: - that is not sufficiently soluble in liquids or in combination of liquids
are capsulated as suspensions

 Solids:-
 that are not sufficiently soluble in liquids or in combination of liquids are capsulated
as suspensions

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  Mostly compounds cannot be capsulated, owing to their solubility in H2O and thus
their ability to affect the gelatin shell. e.g. strong acids (citric), strong alkalis (Na salts
of weak acids), salts of strong acids and bases (NaCl) and ammonium salts.
 Any substance that is unstable in the presence of moisture (e.g. Aspirin) would not
exhibit satisfactory chemical stability in soft gelatin capsules.
Micro encapsulation
 is a means of applying relatively thin coatings to small particles of solids or droplet of liquids
and dispersions.
 Microencapsulation provides means of environmental protection and of controlling the
release.
 provides a means of converting liquids to solids
 Micro encapsulation may enhance absorption by diminishing localized drug concentration
 An example of a drug commercially available in a micro encapsulated extended release
dosage form is KCl.

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