Pharmaceutical Excipients

Course content

Chemistry, physical properties and uses of the following excipients-

acidifying agents, air displacement agents, alkalizing agents,
antifoaming agents, antimicrobial preservatives, antioxidants, buffering
agents, chelating agents, colors, complexing agents, emulsifying agents,
flavoring agents and perfumes, humectant, ointment bases, solvents,
stiffening agents, wetting and solubilizing agents.
References

• Ansel H.C., Allen L.V., and Jr., Popovich N.G. Pharmaceutical Dosage
Forms & Drug Delivery Systems
• Aulton M.E. Pharmaceutics – The Science of Dosage Form Design
• Lachman L., Lieberman H.A. and Kaing J.L. The Theory And Practice of
Industrial Pharmacy
• Arthur H. Kibbe/ Raymond C Rowe, Paul J Sheskey and Siân C Owen
- Handbook of Pharmaceutical Excipients
• E.A. Rawlins- Bentley’s Textbook of Pharmaceutics
Objective of a medicinal product

The objective of a medicinal formulation development project is to

deliver drug to the patient in the required amount, at the required rate,
consistently within a batch, from batch to batch, and over the product’s
shelf life.
What are pharmaceutical excipients?

• ‘An excipient is any component, other than the active substance(s), present
in a medicinal product or used in the manufacture of the product. The
intended function of an excipient is to act as the carrier (vehicle or basis) or
as a component of the carrier of the active substance(s) and, in so doing,
to contribute to product attributes such as stability, biopharmaceutical
profile, appearance and patient acceptability and to the ease with which
the product can be manufactured. Usually, more than one excipient is used
in the formulation of a medicinal product’- European Pharmacopoeia.
 Continued…

• ‘Excipients are all substances contained in a dosage form other than the
active substance or finished dosage form, which have been appropriately
evaluated for safety and are included in a drug delivery system to either aid
the processing of the drug delivery system during its manufacture, protect,
support, enhance stability, bioavailability, or patient acceptability, assist in
product identification, or enhance any other attributes of the overall safety
and effectiveness of the drug delivery system during storage or use’-
International Pharmaceutical Excipients Council (IPEC, 1995)
Why are they added?
• To modulate solubility & bioavailability of APIs,

• To increase the stability of active ingredients in dosage forms,

• To help active ingredients maintain preferred polymorphic forms or conformations,

• To maintain the pH and /or osmolarity of the liquid formulations,

• To prevent aggregation or dissociation (e.g. of protein and polysaccharide actives),

• To modulate immunogenic responses of active ingredients (e.g. adjuvants),

• To provide bulk in the formulation.

• For product identification

• For improving patient compliance

Ideal characteristics of excipients

• Pharmacologically inactive

• Should not interact with active ingredients/other excipients

• Available

• Non-toxic

• Cost-effective

• Impart no odor or flavor other than required

• Stable on handling

• Should not support microbial growth

Solvents

• A substance that dissolves a solute (a chemically different solid, liquid

or gas) resulting in a solution or used for the extraction or suspend
other materials.

• Usually liquid but can be solid or gas.

• Should not change any properties of the solute or the solvent itself.
Selection criteria
• Solubility
• Intended use
• Clarity
• Viscosity
• Toxicity
• Compatibility
• Palatability
• Odor
• Color
• Chemical inertness
• Economy
• Non-volatile
Types of solvent
On the basis of chemical nature:
1. Organic solvent
2. Inorganic solvent

On the basis of polarity:

1. Polar solvents: High dielectric constant, e.g. water
2. Semi-polar solvents: medium dielectric constant, e.g. methanol
3. Non-polar solvents: Low dielectric constant, e.g. benzene

On the basis of use:

• Solvents used for oral preparations
• Solvents used for external applications
• Solvents used for injectables
• Water
• Alcohol
• Isopropyl alcohol
• Glycerol
• Propylene glycol
• Corn oil
• Cottonseed oil
• Peanut oil
• Olive oil
• Benzene
• Acetone
• Petroleum ether
Co-solvents
Co-solvents are defined as water-miscible solvents that are used in liquid drug formulations
to increase the solubility of poorly water soluble substances or to enhance the chemical
stability of a drug.

Properties of co-solvent:

• Co-solvents increase the solubility of a drug.

• An ideal co-solvent 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.

• should not cause toxicity or irritancy when administrated for oral or parental use.

• Examples: Ethanol, sorbitol, glycerol, propylene glycol, PEG, dimethyl sulfoxide

Advantages and disadvantages of co-solvents

Advantages

1. Improved solubility

2. Simple and rapid mixing

Disadvantages

1. Toxicity and tolerability

2. Undesired and uncontrolled precipitation

3. For injectables, risk of embolism and adverse effects

Buffering agents
Definition
Buffers are compounds or mixtures of compounds that by their presence in the solution
resist changes in the pH upon the addition of small quantities of acid or alkali.

Necessity of buffers:
The preservation of a solution with a defined pH is more difficult than its preparation. If
solution comes in contact with air, it will absorb CO2 and becomes acidic. On the other
hand, if solution is stored in a glass bottle, alkaline impurities from the glass may alter its
pH.
Due to these reasons, pharmaceutical solutions are buffered as the buffer solutions are
capable of maintaining pH at some fairly constant value when even small amounts of
acid or base are added.
Applications

• In biological systems:

The pH of blood is maintained at about 7.4 by two buffer systems.

a) primary buffers : The plasma contains carbonic acid / carbonate & acid
/alkali sodium salt of phosphoric acid.

b) secondary buffers: These are present in erythrocytes: oxy-

haemoglobin / haemoglobin & acid / alkali potassium salts of
phosphoric acid.
Applications (continued….)

• In pharmaceutical systems
Buffers are widely used in the field of pharmacy as ingredients in most of the
pharmaceutical formulations in order to adjust the pH of the product to that
required for maximum stability:
a) In parenteral preparations (i.e. injections): The ideal pH of a parenteral
product is 7.4, which is pH of blood. The most commonly used buffers in
parenteral products (injections) are acetate, phosphate, citrate and glutamate.
b) In ophthalmic preparations (i.e. eye preparations): Buffers are generally used
in ophthalmic preparations to maintain the pH within the physiological pH
range of lacrimal fluid (i.e. eye fluid). The lacrimal fluid has a pH in range 7 – 8 ,
but it has good buffering capacity and can tolerate preparations having pH
values between 3.5 – 10.5 with little discomfort. The buffering agents most
commonly used in ophthalmic preparations include borate, carbonate and
phosphates.
Applications (continued….)

• In ointments and creams: Topical products such as ointments and creams

are also buffered to ensure stability of the formulation. The most commonly
used buffers in ointments and creams are citric acid / its salts & phosphoric
acid / its salts.
Type of buffers

Acidic buffers

Basic buffers

Acidic Buffers: Combination of weak acid and its salt with a strong base.
i.e. Weak acid & salt with strong base (conjugate base). Examples:
CH3COOH/CH3COONa, H2CO3/NaHCO3, H3PO4/ NaH2PO4 and HCOOH /
HCOONa.
Types of buffer
Basic Buffers:

Combination of weak base and its salt with a strong acid. i.e. Weak base & salt with
strong acid (conjugate acid). Examples: NH4OH / NH4Cl, NH3/NH4Cl and NH3/
(NH4)2CO3.

Phosphate Buffers (Double salt buffers):

Besides the two general types of buffers (i.e. acidic & basic), a third appears to exist.
This is buffer system composed of two salts:

Monobasic potassium phosphate (KH2PO4)

Dibasic potassium phosphate (K2HPO4).

Mechanism of action of buffers
Humectants
• A humectant is a hygroscopic substance that attracts & retains the moisture in the nearby air via
absorption, drawing the water vapor into and/or beneath the organism/object's surface.

• Humectants absorb water vapours from atmosphere till a certain degree of dilution is attained.

• They reduce the loss of water from the products.

• They prevent the product from drying out after application to the skin or from the packaging.

• Chemically these are polyhydric alcohols as well as amines and carboxylic compounds sometimes
esterified.

• Enhance skin penetration and increase skin hydration.

• Used at ∼5% concentrations in aqueous suspensions and emulsions for external application.

• High concentrations may actually remove moisture from the skin.

Ideal properties of humectants :
• Must absorb moisture from atmosphere & retain the same under
normal conditions of atmospheric humidity.
• should be colorless or not of too intense color.
• should have good odor and taste.
• should be nontoxic and nonirritant.
• should be noncorrosive to packaging materials
• should not solidify under normal conditions.
• should not be too costly.
Classification of humectants:

1. Natural humectants:
Hyaluronic acid, Aloe, Glycerine, Honey.
2. Synthetic humectants:
Propylene glycol, PEG, Urea, Silicones
Classification of humectants:
1. Inorganic humectants:
e.g. Calcium chloride. It has compatibility problems and corrosive in
nature, so not frequently used in cosmetics.
2. Metal organic humectants:
e.g. Sodium lactate. It has limited used because of compatibility
problems, corrosive nature and pronounced taste.
3. Organic humectants:
• These are the widely used humectants.
• They include polyhydric alcohols, their esters and ethers.
• The most commonly used organic humectants are glycerol, ethylene
glycol, polyethylene glycol (PEG), diethylene glycol, tri ethylene glycol,
propylene glycol, dipropylene glycol, glycerin, sorbitol, mannitol,
glucose.
Viscosity enhancing agents :
Agents used to increase the viscosity of a liquid either to improve palatability or
pourability. They are also called thickening agents. They help retain the dosage form
(e.g. topical and eye preparations) in place as well as to resist the rate of sedimentation
of suspensions.
Most commonly used viscosity imparting agents are :
Hydroxy ethylcellulose Hydroxy propylmethylcellulose
Methyl cellulose Polyvinyl alcohol
Carbomer Alginic acid
Advantages of viscosity imparting agents:
• Improve palatability
• Improve pourability
• Increase contact time of topical and eye products
• Resist the quick sedimentation of particles in suspension

Disadvantages of viscosity imparting agents:

• Precipitation of these agents may occur in the presence of
ions e.g. Al+++, Fe+++ and Ca++.
• Can salt out from the solutions
• Can form molecular complexes with a variety of organic and
inorganic compounds.
• High viscosity may impede drug release and absorption.
Chelating agents:
They tend to form complexes with the trace amount of heavy metal ions
inactivating their catalytic activity in the oxidation of medicaments. They
are also used in heavy metal poisoning.
Examples are EDTA and its salts, dihydroxyethyl glycine, citric acid, tartaric
acid.
Isotonicity modifiers
Tonicity adjustment agents are necessary for

• ophthalmic preparations and

• sterile solutions to be given intravenously.

• Non-isotonic intravenous solutions, particularly if given in quantities larger than 100 ml, can cause
hemolysis or crenation of red blood cells due to hypotonic or hypertonic solution, respectively.

• Non-isotonic ophthalmic preparations cause eye irritation which results in the production of excessive tears
and thus drug is washed away leading to lesser drug-eye contact.

• Dextrose and sodium chloride or potassium chloride are commonly used to achieve isotonicity in sterile
formulations.

• https://www.physiology.org/doi/pdf/10.1152/advan.00080.2016

• http://thepharmacistpharma.blogspot.com/2011/03/active-pharmaceutical-ingredientdrug.html
Organoleptic agents
Organoleptic agents are the components used in pharmaceutical
formulation that have no medicinal value but promote appearance, taste,
color, flavors of the dosage forms.
a) Coloring agents
b) Flavors
c) Sweeteners
Colors or coloring agents
Coloring agents-
• Impart color to the pharmaceuticals.
• Have no direct therapeutic benefits.
• Extremely useful for product identification during manufacturing and
distribution.
• Patient compliance of an unattractive medication can be improved by
careful selection of colors.
• Sometimes an indicator of degradation and loss of potency over time.
Desired physico-chemical properties:
• Non-toxic and have no physiological activity.
• Free from harmful impurities.
• Its Tinctorial (coloring) power should be high so that only small quantities are
required.
• Unaffected by light, temperatures, hydrolysis and micro‐organisms and, therefore,
be stable on storage.
• Unaffected by oxidizing or reducing agents and pH changes.
• Compatible with medicaments and not interfere with them.
Desired physico-chemical properties (cont..):

• Ready solubility in water is desirable in most cases but some oil‐soluble and

spirit‐soluble colors are also necessary.

• Should not interfere with the analytical tests and assays.

• Should not be appreciably adsorbed on to suspended matter.

• Free from objectionable taste and odour.

Dyes
Dyes are synthetic organic molecules which impart color when dissolved in water.
Water soluble dyes are available in powder, granular, liquid, dispersion and paste
forms. The granular dyes are recommended because dust problem are reduced, but
it may cause slow dissolution rates compared to powder forms.
Example: Brilliant blue (FD&C blue #1), Indigotine (D&C blue #6), Erythrosine (FD&C
red #3), etc.
Pigments
Pigment is an insoluble material that tints by dispersion.
Example: Titanium dioxide, ferric oxide etc.
Lake:
A lake pigment is a pigment manufactured by precipitating a dye with an inert
binder, or "mordant", usually a metallic salt. Properties that make the lake more
suitable for coloring dosage forms are their relative opacity, stability with regard
to relative light and heat, and ability to be used dry when coloring tablets are
made by direct compression. They are oil dispersible (but usually not oil soluble).
They can be mixed with oils, fat and lipid formulation as well as dispersed in
other carriers like propylene glycol, glycerine and sucrose. Only aluminum lakes
are permitted for use in foods, drugs and cosmetics.
Example: Indigo lake, Carmine lake, Rose madder lake, etc.
Classification of colors:
Colors can be natural or synthetic.
a) Natural colors
Natural colors are obtained from animals, plants, or minerals. They are expensive,
difficult to produce, cause batch to batch variation in color and possess low grade
coloring properties.
From animals - Tyrian purple (purple dye) - Murex brandaris; Carmine (or cochineal )-
Coccus cacti
From plants – Yellow/orange pigments (b-carotene, lutein)- Carrot;
Yellow dye-turmeric, saffron, annatto
Alizarine (red dye)-Madder plant
Indigo (blue dye)- Indigofera tinctoria
From minerals (without treatment) - Minerals colors are termed as pigments
and can be compounds of copper, iron, lead, mercury, titanium, carbon &
cadmium. Eg. Titanium dioxide, red ferric oxide, yellow iron oxide, carbon
black etc.

Examples of some natural colors approved for ingested drugs:

Paprika. Paprika oleoresin, Mica-based pearlescent pigments, riboflavin,
saffron, tomato lycopene extract, turmeric, turmeric oleoresin.
b) Synthetic color
Less expensive, easier to produce, superior in coloring properties and
small amounts are needed. Most of the synthetic colors are toxic and
hazardous to health. The Federal Food, Drug and Cosmetics (FD&C)
Act of 1938 made certification of the synthetic colorants mandatory.
The FD&C act divided the synthetic colors into three categories: colors
permitted for food, drugs, and cosmetics (FD&C), Colors permitted for
drug and cosmetics (D&C), colors permitted for externally applied
drugs and cosmetics (external D&C).
 Certified colorants

Color Common name Color index number

FD&C blue #1 Brilliant blue 42090
FD&C red #3 Erythrosine 45430
D&C red #7 Lithol rubin B Ca 15850.1
D&C violet #2 Alizurol purple SS 60725
Ext. D&C yellow #7 Napthol yellow S 10316
Ext. D&C red #2 Alizarine violet 60730
Sweeteners
Sweeteners are indispensible components of any liquid oral dosage forms and
chewable medications, specially those containing bitter or unacceptable
tastes. Sweeteners are classified as caloric and non-caloric, where non-caloric
are preferred for diabetic patients. The commonly used sweeteners in the
pharmaceuticals industry are sucrose, glucose, fructose, sorbitol, glycerin,
mannitol, xylitol ,etc.
Artificial sweeteners: Saccharin (non-nutritive, 500X sweeter than
sucrose; it is banned as food additive by the FDA in 1977); Sodium
cyclamate (30X than sucrose, form metabolite cyclohexylamine,
carcinogenic, banned in USA); Aspartame (200X sweeter than sucrose,
contraindicated in phenylketone urea patients); Sucralose (non-caloric,
600X than sucrose); Acesulphame (200X).
 Flavors
Flavour refers to a mixed sensation of taste, touch, smell, sight and sound,
all of which involve a combination of physio-chemical and physiological
actions that influence the perception of substances.
Flavoring agents have been used to flavor foods and make medicine
palatable. The suitable flavours are selected through the results of
elaborate taste – panel studies. Unpleasant taste masking problem can
best be resolved by use of blends of distinctive flavours.
A well constructed flavor system is crucial to oral drug formulations
because it influences patient acceptability and compliance.
The specific therapeutic agents and associated flavours with unique names
individuals certain formulations:
• Orange-mint flavour for disguising diphenhydramine in an expectorant
formulation.
• Spice vanilla flavour for phenylephrine and chloropheniramine maleate
preparation.
• Strawberry is well suited to tranquilliser formulations.
• Maple combined with butterscotch to improve the taste of adsorbents
such as kaolin and pectin as well as for aminophylline and theophylline.
• Mint is preferred in antacid preparation.
Our taste buds are sensitive to basic tastes including sweet, sour, bitter,
salt, metallic and alkaline. Taste responses can be modified by-
Temperature
Physical nature
Special characteristics
Age
Length of administration time
Disease conditions
 Some drugs with their preferred flavors

Cherry, maple, pineapple, orange, raspberry, banana-vanilla,

Antibiotics
butterscotch, coconut-custard, fruit-cinnamon, strawberry, vanilla
Apricot, cherry, cinnamon, grape, honey, lime, peach-orange, peach-
Antihistamines
rum, raspberry, wild cherry.
Banana-pineapple, banana-vanilla, cinnamon-peppermint, orange,
Barbiturates
peach-orange, grenadine-strawberry.
Decongestants& -- Anise, apricot, butterscotch, cherry, coconut-custard, custard-mint-
Expectorants strawberry, grenadine-peach, strawberry-lemon, gooseberry, orange-
lemon, coriander, pineapple, raspberry.
Electrolyte-solutions
Cherry, grape, lemon-lime, raspberry, wild cherry syrup, grenadine-
geriatrics
strawberry, lime, portwine, cherrywine, wild-strawberry.
 Flavourants are also selected on the basis of the taste of the drug to be
incorporated.

Taste of drugs Masking flavour

Salt - Butterscotch, maple
Bitter - Wild cherry, walnut, chocolate-mint, licorice
Sweet - Fruit, berry, vanilla
Acid - Citrus
Flovours used in he formulation must be non-toxic, soluble (if for a clear product
like syrup elixir) and stable and compatible with the preparation.
Flavoring agents composed of aroma (10%) and carrier (90%). The
choice of carrier determines the physical form of the flavor. Carriers
can be syrup or mucilages. Liquid flavors are most widely used because
they diffuse readily into the substrate.
Dry flavor: Crystalline vanillin, cinnamon powder, dried lemon fluid
extract.
Liquid flavor: Essential oils, fluid extracts, tinctures, etc.
Flavoring agents are classified as natural, artificial, or natural and
artificial flavors.
Natural flavors: Natural compounds are the first source for flavors. Modern use of
natural flavors in pharmaceuticals is very limited, because of their instability,
unpredictable quality from season to season.
Example. Terpeneless citrus oil, Anise (Pimpenella anisum), Cardomon (Elettaria
cardomomum), Wild cherry (Prunus serotine), Lemon (Citrus limonum), Orange bitter
(Citrus aurantium), Oranger sweet (Citrus sinensis), Peppermint (Mentha piperita), etc.
Artificial flavors: Artificial flavors are mixtures of individuals synthesized aroma
chemicals that may be identical to natural flavors. Unlike natural flavoring, artificial
flavors are usually stable, have greater consistency, decrease impact from raw materials
changes.
Natural and artificial flavors: In N&A flavor systems, natural flavors are
combined with artificial flavors to enhance flavor balance and fullness.
N&A flavors have broad spectrum flavoring properties from which
formulator can develop an entirely new flavor system.
Example. Allyl benzoate, Cinnamaldehyde, Anethol, Eugenol, Nerol,
Rhodinol, Terpenyl butyrate, Diacetyl, Citral, etc.
 Preservatives
Preservatives are the chemical substances used to improve or amplify shelf life of
drugs by decreasing or lowering the oxidation of active and excipients and by
reducing or preventing microbial contamination, deterioration and spoilage.
Normally preservatives are used in multidose drug products rather than single dose
drug products. Preservatives can increase the product stability by:

1. Reducing and preventing the growth of microorganisms (Antimicrobial

preservatives)

2. Reducing or preventing the oxidation of drug products (Antioxidants)

3. By chelating heavy metals (Chelating agents).

Pharmaceuticals that cannot be autoclaved and provide idea growth
media for microorganisms need preservatives in their formulation.
These include most aqeuoes preparations and some semisolids.
Additional preservation is not required for hydroalcoholic/alcoholic
solutions, eg. Elixir, tinctures, spirits. Microorganisms cannot grow
below pH 3 or above 9. Acidic preservatives are most effective and
stable in acidic media and vice versa.

Large volume parenterals should not contain any preservative due

to high concentrations of the preservatives. Also products
containing incompatible drugs with preservatives should not be
chosen. Sometimes synergistic effect can also be obtained by
combining preservatives (e.g. benzalkonium chloride and EDTA,
benzyl alcohol; combination of parabens)
Ideal characteristics of preservatives:
• Compatible with drug components, other excipients (to maintain availability) and
packaging
• Should maintain activity throughout the product manufacture, shelf life and storage.
• Non-toxic and non reactive
• Stable over wide pH range (should remain undissociated)
• A broad spectrum of antimicrobial activity at lower concentrations which is non-
interfering with other ingredients.
• Cost effective
• Tasteless and odorless
• Highly soluble in the aqueous phase
Preservatives can be acidic, alkaline or non-ionic. They can be microcidal or microstatic.
Preservatives can modify the cell membrane permeability, cause lysis of cells, coagulation of
cytoplasmic constituents, inhibit cellular metabolism, hydrolysis and oxidation of cellular
constituents of the microorganisms which may also affect human cells.
There are other three classes of preservatives as ophthalmic, nasal, and parenteral those are
neutral, volatile. Their volatility introduces problems of odor and loss of preservation on aging in
multidose preparations.
http://www.americanpharmaceuticalreview.com/Featured-Articles/38886-Antimicrobial-
Preservatives-Part-One-Choosing-a-Preservative-System/
https://www.americanpharmaceuticalreview.com/Featured-Articles/38885-Antimicrobial-
Preservatives-Part-Two-Choosing-a-Preservative/
Preservatives used in oral formulation are benzoic acid (0.1-0.3), benzyl alcohol
(0.75-10), butyl paraben (0.001-0.2), ethyl paraben (0.001-0.2), methyl paraben
(0.05-0.18), propyl paraben (0.01-0.1), and sodium benzoate (0.1-0.3).

Preservatives used in parenteral formulation are thimerosal (0.003-0.012),

sodium benzoate (0.1-0.3), propyl paraben (0.01-0.1), phenyl mercuric nitrate
(0.001), phenol (0.-0.5), phenoxyethanol (0.50), methyl paraben (0.05-0.18), cresol
(0.1-0.35), chlorobutanol (0.25-0.5), benzoic acid (0.1-0.3), benzalkonium chloride
(0.02), benzithonium chloride (0.01), butyl paraben (0.001-0.2).
Preservatives used in topical formulation are benzalkonium chloride (0.02),
benzithonium chloride (0.01), benzoic acid (0.1-0.3), benzyl alcohol (0.75-10), bronopol,
butyl paraben (0.001-0.2), cretimide (0.01-0.02), chlorohexidine, chlorobutanol (0.25-
0.5), chlorocresol (0.1-0.35), ethyl paraben (0.001-0.2), methyl paraben (0.05-0.18),
phenoxyethanol (0.50), phenylethyl alcohol (0.2-1.0), phenyl mercuric nitrate (0.001),
thimerosal (0.003-0.012), sodium benzoate (0.1-0.3), propyl paraben (0.01-0.1).

Preservatives used in ophthalmic formulation are benzalkonium chloride (0.02),

benzithonium chloride (0.01), cretimide (0.01-0.02), chlorohexidine, chlorobutanol
(0.25-0.5), methyl paraben (0.05-0.18), phenylethyl alcohol (0.2-1.0), phenyl mercuric
nitrate (0.001), thimerosal.
Mercurials (Thimerosal, vaccine) are readily reduced to free mercury and quarternary
ammonium compounds are inactivated by anionic substances. Newly marketed
preservative is cis-isomer I-(3-chloroallyl)-3,5,7-triaza-I-azoniaadamantane chloride
(Dowicil 200, Dow chemical company).
Antioxidants

• Chemically they are reducing agents.

• They oxidize themselves and prevent oxidation of API.
• A substance that inhibits oxidation is called antioxidants.
• The effectiveness of antioxidant can depend on the concentration used and pH of
solution.
• Examples:
• Ascorbic acid,
• butylated hydroxy anisole (BHA),
• butylated hydroxyl toluene (BHT)
• Oxidation is a chemical reaction involving the loss of electrons or an
increase in oxidation state.
• Oxidation reactions can produce free radicals. In turn, these
radicals can start chain reactions.
• Antioxidants terminate these chain reactions by removing free
radical intermediates, and inhibit other oxidation reactions.
• Alternatively, reducing agents possessing lower redox potential
than the API prevent oxidation by being oxidised.
Ideal characteristics of antioxidants

• It should be readily soluble or dispersible in the medium.

• It should be effective in low concentration.

• It should be non-toxic.

• It should be non-irritant.

• It should be compatible with other ingredients of the formulation.

• It should be colorless, odorless and tasteless.

• Unreactive (does not adsorb, penetrate, or interact) with containers or

closures.
Classification of antioxidants

On the basis of the source antioxidants are 2 types. They are,

Natural antioxidants:

• Tocopherol (Vitamin E),

• Ascorbic acid

• polyphenols

• Mehionine.
Synthetic antioxidant:

• BHA,

• BHT,

• Tertiary butyl hydroquinone.

• Propyl gallate
• On the basis of solubility antioxidants are 2 types. They are,

Water soluble antioxidant:

• Citric Acid,
• Tartaric Acid,
• Phosphoric Acid,
• Ascorbic Acid,
• Sodium Metabisulfite and
• thiol derivatives.
Oil soluble antioxidant:
• BHA
• BHT
• Vitamin E
• Propyl gallate
Read:
• Evaluation of preservatives by PET or AET methods
• Side effects/toxicity of common preservatives
• Examples of synergistic combination of antimicrobial preservatives
• Acidifying agent- e.g. Citric acid, acetic acid, nitric acid, fumaric acid,
hydrochloric acid.

• Alkalinizing agent- e.g. ammonia solution, ammonium carbonate, potassium

hydroxide, sodium bicarbonate, sodium hydroxide.

• Air displacement agent- e.g. nitrogen, carbon dioxide.

• Stiffening agent- e.g. cetyl alcohol, cetyl esters wax, microcrystalline

wax,paraffin, stearyl alcohol.

• Ointment bases- e.g. petrolatum, lanolin, polyethylene glycol.

Surface active agents

A surface active agent (= surfactant) is a substance which lowers the

surface tension of the medium in which it is dissolved, and/or the
interfacial tension with other phases, and, accordingly, is positively
adsorbed at the liquid/vapour and/or at other interfaces. The term
surfactant is also applied correctly to sparingly soluble substances, which
lower the surface tension of a liquid by spreading spontaneously over its
surface.