Pharmaceutical Ingredients and

Excipients

June 1, 2023 Phar 211 1

 Learning objective
 After completion of this topic students will be able to:

– Define the different pharmaceutical ingredients used in pharmacy

– Discuss the purpose of pharmaceutical excipients in each dosage form

June 1, 2023 Phar 211 2

 Definitions and Types
Pharmaceutical ingredients:
 ingredients added to prepare a dosage form.

 required in preparing the drug substance into a final dosage

form.

 for each dosage form:

• contribute to the physical form, texture, stability, taste

and over all appearance.

June 1, 2023 Phar 211 3

 Definitions and Types, cont’d
Active pharmaceutical ingredients:
 the ingredient (s) of a pharmaceutical product
responsible for its pharmacologic activity ( also
medicament, drug substance, active pharmaceutical
ingredients

June 1, 2023 Phar 211 4

 Excipients

Definition:
 Excipients are pharmaceutical additives, the inactive
ingredients used to make up a medication.
 They include colorant, flavors, binders, emollients, fillers,
lubricants, preservatives, and many more classifications.
 Excipients, cont’d

 Pharmaceutical additives must:

 be safe in the amount used in the drug

 not affect the bioavailability

 Not affect performance of the drug

 be manufactured in accordance with good standards

June 1, 2023 Phar 211 6

 Excipients, cont’d

 Some excipients help a drug to disintegrate into particles small

enough to reach the bloodstream more quickly.
 Others protect the stability of the product so it will be at
maximum effectiveness at time of use.
 Excipients may prevent a drug from dissolving too early,
protecting against stomach upset.

June 1, 2023 Phar 211 7

 Excipients, cont’d
 Drug products contain both drug substance (commonly referred
to as active pharmaceutical ingredient or API) and excipients.
 The resultant biological, chemical and physical properties of the
drug product are directly affected by the excipients chosen and
their concentration
 consistency of drug release and bioavailability,

 stability including protection from degradation,

 ease of administration.

June 1, 2023 Phar 211 8

 Excipients, cont’d

• Excipients are sub-divided into various functional classifications,

depending on the role that they are intended to play in the resultant
formulation.
• Certain excipients can have different functional roles in different
formulation types,

e.g. lactose; widely used as:

• a diluent, filler or bulking agent in tablets and capsules

• a carrier for dry powder inhalation products.

June 1, 2023 Phar 211 9

 Excipients, cont’d
 Excipients commonly used (particularly in oral dosage forms)

 Tablet Excipients

• Diluents (fillers, bulking agents), Disintegrants, Binders,

Lubricants, Glidants

 Liquid / Suspension Excipients

• Solvents/co-solvents , Buffering agents, Preservatives, Anti-

oxidants, Wetting agents, Anti-foaming agents, Thickening
agents, Sweetening agents, Flavouring agents, Humectants

June 1, 2023 Phar 211 10

 Tablet Diluents (Fillers)
 Bulking agent

To make a tablet weight practical for the patient:

• minimum tablet weight is typically ~50mg

• actual API doses can be as low as ~20µg, eg. for oral

steroids

e.g. lactose, microcrystalline cellulose

 Compression aid

• Deforms readily to facilitate robust bonding in tablet

compacts, e.g. microcrystalline cellulose.
June 1, 2023 Phar 211 11
 Tablet disintegrantes, cont’d

 Disintegration of the tablet compact upon exposure to

moisture, de-aggregation of compacted tablets.

e.g. sodium starch glycolate, croscarmellose sodium

 Generally, disintegration is viewed as the first stage in the
dissolution process, although dissolution does occur
simultaneously with disintegration.

June 1, 2023 Phar 211 12

 Tablet disintegrantes, cont’d
 Mode of action:
• In many cases water uptake alone will cause disintegration,
by rupturing the intra-particle cohesive forces that hold the
tablet together and resulting in subsequent disintegration.
• If swelling occurs simultaneously with water uptake, the
channels for penetration are widened by physical rupture and
the penetration rate of water into the tablet increased.

June 1, 2023 Phar 211 13

 Tablet Binders
 Binders hold the ingredients in a tablet together.

 Binders ensure that tablets and granules can be formed with

required mechanical strength
 Binders are usually:

 Saccharides and their derivatives:

 Disaccharides: eg, sucrose, lactose;

June 1, 2023 Phar 211 14

 Tablet Binders, cont’d
 Polysaccharides and their derivatives: eg,
• starches,
• cellulose or modified cellulose such as microcrystalline
cellulose and
• cellulose ethers such as hydroxypropyl methyl cellulose
(HPMC)
• Sugar alcohols such as xylitol, sorbitol or maltitol;
 Protein: eg, gelatin;
 Synthetic polymers:
eg, polyvinylpyrrolidone (PVP),
polyethylene glycol (PEG)

June 1, 2023 Phar 211 15

 Tablet Binders, cont’d
 Binders are classified according to their application:

i. Dry binders are dissolved in a solvent

Eg, water or alcohol can be used in wet granulation

processes

Eg, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone,

starch, sucrose and polyethylene glycol.

June 1, 2023 Phar 211 16

 Tablet Binders, cont’d

ii. Dry binders are added to the powder blend, either after

a wet granulation step, or as part of a direct powder

compression formula.

Eg, cellulose, methyl cellulose,

polyvinylpyrrolidone , polyethylene glycol.

June 1, 2023 Phar 211 17

 Tableting Lubricants

 Lubricants prevent adherence of granule/powder to punch/ die

faces and promote smooth ejection from the die after compaction
• Magnesium stearate is by far the most extensively used
tableting lubricant.
• There are alternatives, e.g. stearic acid, sodium stearyl
fumarate, sodium behenate

June 1, 2023 Phar 211 18

 Tableting Lubricants, cont’d
 Most lubricants are hydrophobic, so their levels (typically 0.3
– 2%) need to be optimised:
• Under-lubricated blends tend to flow poorly and show
compression sticking problems
• Over-lubricated blends can adversely affect tablet hardness
and dissolution rate

June 1, 2023 Phar 211 19

 Tablet Glidants
 Glidants improve flow by adhering to particles and so
reducing inter-particulate friction.
 Good bulk powder flowability is especially important
during high speed processing.
 Tablet glidants are commonly used in dry powder
formulations
• direct compression tablets
 Can also be added to granules to improve flow prior to
compression

June 1, 2023 Phar 211 20

 Tablet Glidants, cont’d
 Starch is a popular glidant since its additional value of
disintegrant
 Concentration of starch is common up to 10%,

 colloidal silicon dioxide (traditionally, talc) has superior

activity than starch
 its conc. should be limited because of its retardant effect on
disintegration profile

 NB: can get undesirable “flooding” if flow is too good

June 1, 2023 Phar 211 21

 Excipients for Suspension Products

 In Liquid / suspension products, the possible types of

excipients include:
 Solvents/co-solvents e.g. Aqueous Vehicle, Propylene
Glycol, Glycerol
 Buffering agents, e.g. Citrate, Gluconates, Lactates

 Preservatives, e.g. Na Benzoate, Parabens (Me, Pr and Bu),

benzalkonium chloride ( BKC)

June 1, 2023 Phar 211 22

 Excipients for Suspension Products...
 Anti-oxidants, e.g. butylated hydroxytoluene (BHT),
Butylated hydroxyanisole (BHA), Ascorbic acid
 Wetting agents, e.g. Polysorbates, Sorbitan esters
 Anti-foaming agents, e.g. Simethicone
 Thickening agents, e.g. Methylcellulose or
Hydroxyethylcellulose
 Sweetening agents, e.g. Sorbitol, Saccharin, Aspartame,
etc
 Flavouring agents, e.g. Peppermint, Lemon oils, etc.
 Humectants, e.g. Propylene Glycol, Glycerol, Sorbitol

June 1, 2023 Phar 211 23

 Pharmaceutical solvents/vehicles
 A medium in which ingredients of a dosage form are
dissolved or dispersed.
 Examples of solvents are water, alcohol, isopropyl alcohol,
glycerol, propyl glycol, acetone, syrups, …..
 Water is the solvent most widely used as a vehicle due to:
• Lack of toxicity, non irritant,
• physiological compatibility,
• Inexpensive and readily available,

June 1, 2023 Phar 211 24

 Solvents/Co-Solvents
 good solubilising power

Drawback
• Likely to cause instability of hydrolytically unstable drugs

• Good vehicle for microbial growth

 Water-miscible co-solvents are used to:
• Enhance solubility, taste, anti-microbial effectiveness
• Optimise insolubility (if taste of API is an issue)
Eg: propylene glycol, glycerol, ethanol, low mwt PEGs
 Water-immiscible co-solvents,
e.g. Emulsions / microemulsions using coconut oils
June 1, 2023 Phar 211 25
 Types of water

1. Potable water, tap water

• fit for drinking
• freshly drawn from the public mains supply
• water obtained from local storage tank is not used for
pharmaceutical purpose.

June 1, 2023 Phar 211 26

 Types of water, cont’d
2. Purified water
• Water obtained from potable warer by purification methods
such as distillation, treatment with ion exchange resins, …
• Distillation is a method of separating substances based on
boiling point
• The dissolved solids are removed
• Purified water must be freshly boiled and cooled.
• Distilled water is not sterile

June 1, 2023 Phar 211 27

 Types of water, cont’d
3. Water for preparation
• Freshly boiled and cooled purified water
• Free of hardness
• Used for preparing medicines which do not require
sterility
4. Water for injection
• Is distilled, sterile and pyrogen free water.
• Used for preparation of injections and other sterile
preparations.

June 1, 2023 Phar 211 28

 Alcohol
Ethanol
 Is flammable and volatile organic solvent that can solublize
most substances.
 Used for both internal and external preparations but in the
former in small amounts due to its physiological effects.
 Has a preservative effect at 20% and more.
 Expensive

June 1, 2023 Phar 211 29

 Alcohol, cont’d
 Since it is volatile it rapidly evaporates from the skin and thus
produce a cooling sensation thus relieve pain.

 For topical products, it may be substituted with IMS because it

is cheaper than ethanol.

 IMS is a denatured alcohol and not fit for oral consumption.

June 1, 2023 Phar 211 30

 Isopropyl alcohol

2-propanol
 For external preparations in combination.
 Two times toxic than ethanol
 Has unpleasant taste

June 1, 2023 Phar 211 31

 Glycerol
 Colorless, viscous, sweet liquid used in both internal and
external preparations usually in combinations.
 Has demulcent effect, e.g., in cough preparations such as
linctuses.
 Moisturizes the skin
 Stimulates peristalsis therefore used in enemas as laxative.
 As a sweetening agent.

June 1, 2023 Phar 211 32

Propylene glycol
• Viscous, sweet liquid similar to glycerol
• Similar application to glycerol,
• Can serve as a preservative.

Acetone
• Highly flammable and volatile solvent
• May be used as a vehicle for external preparations in combination.
• Reacts with iodine and results in the formation of volatile
substances that may be irritant to the eye.

June 1, 2023 Phar 211 33

 Preservatives
 Added to prevent microbial growth.

 Liquid and semisolid pharmaceutical preparations must be

preserved against microbial contamination.
 Preparations that provide excellent growth media for microbes
include aqueous preparations such as syrups, emulsions,
suspensions and semi solid preparations particularly gels.

June 1, 2023 Phar 211 34

 Preservatives, cont’d
 Preservatives used in multi-use cosmetic/pharmaceutical products
(including paediatric formulations)
• prevents an increased risk of contamination by opportunistic
microbial pathogens (from excipients or introduced externally)
 Ideally targeted for microbial cells - showing no toxicity/irritancy
towards mammalian cells
 Pharmaceuticals such as elixirs, spirits, and tinctures are self
sterilizing and do not require additional preservation.

June 1, 2023 Phar 211 35

Preservative Selection
 Considerations in selecting preservative in pharmaceutical
preparations:

1. prevents the growth of the type of microorganisms

( contaminants of the preparations)

2. soluble enough in water to achieve adequate

concentrations in aqueous phase with two or more

phase systems

June 1, 2023 Phar 211 36

 Preservative Selection, cont’d
3. proportion of preservative remaining undissociated at

the pH of preparation (can penetrate the microorganism

& destroy its integrity).

4. concentration of the preservative does not affect the

safety / comfort of the patient.

June 1, 2023 Phar 211 37

Preservative Selection, cont’d

5. with adequate stability and not reduced in concentration

by chemical decomposition / volatilization.

6. compatible with all other formulation ingredients

7. does not adversely affect the preparation’s container

or closure( Container and closure compatibility).

June 1, 2023 Phar 211 38

Preservative utilization
 Examples of commonly employed preservatives :

• Alcohol, Phenol, Cresol,

• Benzoic acid / sodium benzoate

• Phenylmercuric nitrate / acetate

• Chlorobutanol

• Benzalkonium chloride

• Methylparaben / propylparaben, and Others

June 1, 2023 Phar 211 39

 Anti-Oxidants
 Used to control oxidation of:

API, e.g. lovastatin

Preservative, e.g. potassium sorbate

Vehicle like oils or fats susceptible to oxidation

e.g. butylated hydroxytoluene (BHT),

Butylated hydroxyanisole (BHA),

Ascorbic acid

June 1, 2023 Phar 211 40

 Anti-Oxidants, cont’d

 Efficacy can be affected by:

• Compatibility with other excipients

• Adsorption onto surfaces (container, thickening agent and

suspended particles)
• Incompatibilities, e.g. with metal ions

June 1, 2023 Phar 211 41

 Wetting Agents
 To aid ‘wetting’ and dispersion of a hydrophobic API,
preservative or antioxidant
• Reduce interfacial tension between solid and liquid during
manufacture or reconstitution of a suspension
• Not all are suitable for oral administration

Examples include:

Surface active agents,

Hydrophilic colloids

June 1, 2023 Phar 211 42

 Wetting Agents...
 Surface active agents

Examples:
• Oral: polysorbates (Tweens), sorbitan esters (Spans)

• Parenteral: polysorbates, poloxamers, lecithin

• External: sodium lauryl sulphate

… but these can cause excessive foaming and can lead to

deflocculation and undesirable physical instability
(sedimentation) if levels too high.

June 1, 2023 Phar 211 43

 Wetting Agents...

 Hydrophilic colloids that coat hydrophobic particles.

e.g. bentonite, tragacanth, alginates, cellulose derivatives

 Also used as suspending agents, these can encourage
deflocculation if levels are too low.

June 1, 2023 Phar 211 44

 Anti-Foaming Agents
 The formation of foams during manufacturing processes or
when reconstituting liquid dosage forms can be undesirable
and disruptive.
 Anti-foaming agents are effective at discouraging the
formation of stable foams by lowering surface tension and
cohesive binding of the liquid phase.

June 1, 2023 Phar 211 45

 Anti-Foaming Agents, cont’d
 A typical example is Simethicone (polydimethylsiloxane-
silicon dioxide), which is used at levels of 1-50 ppm.

 Of course, a foam is also a very valid dosage form option for

certain situations, e.g. for topical administration and in wound
dressings.

 In addition, granulation using a foam rather than aqueous

granulation fluid is gaining popularity.

June 1, 2023 Phar 211 46

 Thickening Agents
 Suspension stabilisers:

 prevent settling/sedimentation

 They usually modify viscosity and are often thixotropic (where

viscosity is dependent on applied shear and exhibits ‘shear
thinning’)
• Easily poured when shaken

• Quickly reforms ‘gel-like’ structure

June 1, 2023 Phar 211 47

 Thickening Agents...
 Work by entrapment of solid particles,

e.g. API, in a viscous or even ‘gel-like’ structure

• Can be either water-soluble, e.g. methylcellulose or
hydroxyethylcellulose
• Or water-insoluble, e.g. microcrystalline cellulose

June 1, 2023 Phar 211 48

 Surfactants and emulsifying agents

Emulsifier:- An emulsifier (also known as an emulgent) is a

substance that stabilizes an emulsion by increasing its
stability.
 A wide variety of emulsifiers are used in pharmacy to
prepare emulsions such as creams and lotions.
 Common examples include emulsifying wax, cetearyl
alcohol, polysorbate 20, and ceteareth 20.

June 1, 2023 Phar 211 49

 Surfactants and emulsifying agents…
 One class of emulsifiers is known as surface active substances,
or surfactants.

 Surfactant: -An ingredient that helps two substances that

normally do not mix to become dissolved or dispersed in one
another. Also called a surface active agent.

June 1, 2023 Phar 211 50

Surfactants and emulsifying agents…
Surfactant(s) as cleansing agent(s)
 Surfactants that clean skin and hair by helping water to mix
with oil and dirt so that they can be rinsed away.
 Detergents are another class of surfactant, and will physically
interact with both oil and water, thus stabilizing the interface
between oil or water droplets in suspension.
 This principle is exploited in soap to remove grease for the
purpose of cleaning.

June 1, 2023 Phar 211 51

Surfactants and emulsifying agents…

Surfactant(s) as emulsifying agent(s)

 Surfactants that help to form emulsions by reducing the surface

tension of the substances to be emulsified.

Surfactant(s) as foam Booster(s)

 Surfactants that increase foaming capacity or that stabilize

foams.

June 1, 2023 Phar 211 52

Surfactants and emulsifying agents…

Surfactant(s) as hydrotrope(s)

• Surfactants that have the ability to enhance the water solubility

of another surfactant.

Surfactant(s) as solubilizing agent(s)

• Surfactants that help another ingredient to dissolve in a solvent
in which it would not normally dissolve.

June 1, 2023 Phar 211 53

 Surfactants and emulsifying agents…
Surfactant as suspending agents
 function by modifying a solid's surface characteristics by
adsorption.
 Changing the surface properties of a solid, keeps the particles
from coming together and falling out of solution.

June 1, 2023 Phar 211 54

 Sweetening Pharmaceuticals
 are used to make the product more palatable, to mask unwanted
taste.

Egs, Dextrose, Mannitol, Saccharin, Sorbitol, Sucrose

 used in foods and pharmaceuticals:

– natural sweeteners such as sucrose

– artificial sweetening agents

June 1, 2023 Phar 211 55

 Sweetening Agents, cont’d
Natural sweeteners
 Sucrose: commonly used
• soluble in water (vehicle),
• colourless,
• stable (pH 4-8),
• increases viscosity;
• arguably the best taste/mouthfeel overall but cariogenic
(causing tooth decay) & calorific
 avoid in paediatrics.

June 1, 2023 Phar 211 56

 Sweetening Agents, cont’d
 Sorbitol
• non-cariogenic, non-calorific

• appropriate for paediatric formulations,

• but lower sweetness intensity than sucrose so you need

more and that may cause diarrhoea.

June 1, 2023 Phar 211 57

Sweetening Agents, cont’d
Artificial sweeteners
• Much more intense sweeteners compared with sucrose
• As a consequence the levels are much lower (<0.2%)
• Can impart a bitter or metallic after-taste
• hence used in combination with natural sweeteners)
 Examples of artificial sweeteners
– Saccharin, and it’s salts, Aspartame
– Acesulfam potassium
– Sucralose – excellent sweetness, non-cariogenic, low
calorie, wide & growing acceptability but relatively
expensive

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 Sweetening Pharmaceuticals, cont’d

 Saccharin & cyclamate - used in foods

- “generally recognized as safe (GRAS)” (before the

amendment’s passage)

- use on rats: developed incidence of bladder tumors(cancer)

- continued availability but warning labels be used

 cyclamates (banned) - possible carcinogenicity, genetic

damage, testicular atrophy

June 1, 2023 Phar 211 59

 Sweetening Pharmaceuticals, cont’d
 Aspartame – the first artificial sweetener (1958 amendment
of food additives)
- with requirement for pre-marketing proof of
safety.
 Acesulfame potassium (nonnutritive sweetener)
• structurally similar to saccharin (USP approved)
• 130 times as sweet as sucrose, excreted unchanged in
the urine;
• more stable than aspartame

June 1, 2023 Phar 211 60

 Sucrose Saccharin Aspartame

Source Sugar cane; Chemical synthesis; Chemical synthesis;

sugar beet phthalic Anhydride, Methyl ester
a petroleum product dipeptide of
phenylalanine and
aspartic acid
Relative sweetness 1 300 180-200

After taste None Moderate to strong; none

sometimes metallic or
bitter
Calories 4/g 0 4/g

Acid stability good Excellent fair

Heat stability good Excellent poor

June 1, 2023 Phar 211 61

 Coloring Pharmaceuticals
 are added for esthetics; to enhance attractiveness,

• Dyes – added to pharmaceutical preparations in the form

of diluted solutions

June 1, 2023 Phar 211 62

 Coloring Pharmaceuticals, cont’d
 90% of the dyes used in the products - synthesized from
derivative of benzene (aniline).
 FDA - regulates use of color additives in foods, drugs, and cosmetics
(Federal Food, Drug, and Cosmetic Act of 1938)
FD&C color additives - foods, drugs, and cosmetics
D&C color additives - drugs, some in cosmetics &
medical devices
External D&C color additives - restricted to external
parts of the body (not including the lips and other
parts that are covered by mucous membrane)

June 1, 2023 Phar 211 63

 Factors in selecting dyes
 Lighter shades preferred

 Solubility of prospective dye

 pH & pH stability of the preparation to be coloured

 photostablity

June 1, 2023 Phar 211 64

 Flavouring Agents
 Supplement and complement a sweetening agent

• Ensures patient compliance (especially in paediatric

formulations – a big issue)
• Can be natural, e.g. peppermint, lemon oils; Or

• artificial e.g. Butterscotch (whose primary ingredients are

brown sugar and butter)
• Instability can be an issue – combinations can be used to cover
intended product shelf-life

June 1, 2023 Phar 211 65

 Flavouring Agents, cont’d
 flavour appreciation is not globally consistent…

– Genetic element: one person’s acceptable taste is another’s

unacceptable taste
– Territorial (cultural) differences in preference;

e.g. US vs. Japan vs. Europe

 Regulatory acceptability of flavours needs to be checked

– Different sources, different compositions, different flavour,

e.g. there are >30 different “strawberry flavours”

June 1, 2023 Phar 211 66

 Humectants
• Their function is to retard evaporation of aqueous vehicle of
dosage formFunctions of humectants:
• To prevent drying of the product after application to the
skin,
• To prevent drying of product from the container after first
opening,
• To prevent cap-locking caused by condensation onto neck of
container-closure of a container after first opening,
• Examples include: propylene glycol, glycerol ,PEG

June 1, 2023 Phar 211 67

 Buffers and PH adjusting agents
What are Buffers? :
 A buffered solution is one that resists changing pH when
acid or bases is added.
 A buffered solution contains a weak acid and its salt or a
weak base and its salt.
 The resistance to a change in pH is known as buffer action.

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 Buffers & PH adjusting agents…
 A buffering agent is added to an already acidic or basic
solution, which it then modifies and maintains a new pH.
 The function of a buffering agent is to drive an acidic or basic
solution to a certain pH state and prevent a change in this pH.
 Buffering agents have variable properties—some are more
soluble than others; some are acidic while others are basic

June 1, 2023 Phar 211 69

 Buffering Agents
 Can be necessary to maintain pH of the formulation to:

• Ensure physiological compatibility

• Maintaining/optimising chemical stability

• Maintaining/optimising anti-microbial effectiveness

• Optimise solubility (or insolubility if taste is an issue)

• But, optimum pH for chemical stability, preservative

effectiveness and solubility (or insolubility) may not be the same
 Compromises need to be made

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 Summary

 Solvents are used to dissolve the drug substance.

 Flavors and sweeteners are used to make the product

more palatable.
 Colorants are added to enhance appeal.

 Preservatives may be added to prevent microbial growth.

 Stabilizers (antioxidants and chelating agents) - to

prevent decomposition.

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 Summary
 Diluents or fillers - to increase the bulk of the formulation.

 Binders – to cause adhesion of the powdered drug and

pharmaceutical substances.
 Antiadherents or lubricants to assist smooth tablet formation.

 Disintegrating agents - promote tablet break up after

administration and coatings to improve stability, control

disintegration or enhance appearance.

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