This document discusses coloring agents used in pharmaceuticals. It notes that color is important for identification during manufacturing and distribution, and that patients use color to recognize medications and dosages. It describes types of colorants approved in different regions, including FD&C and D&C colorants in the US. FD&C colorants can be dyes or lakes, with lakes being insoluble pigments and dyes being water-soluble. The document also discusses considerations for colorant selection, including stability, particle size, and shade. Preservatives are discussed as substances that prevent microbial growth in pharmaceutical preparations. Common preservatives and their appropriate uses and concentrations are provided.

1. Coloring Agents for Use in Pharmaceuticals
1

2. Coloring Agents for Use in Pharmaceuticals
The Need for Color in Pharmaceuticals:
 The psychological effects of color have long been recognized
 The coloring of pharmaceutical dosage forms is extremely useful
for identification during manufacturing and distribution.
 Many patients rely on color to recognize the prescribed drug
and proper dosage.
 Unattractive medication can be made more acceptable to the
patient by the careful selection of color.
 Color, in combination with flavoring agents, can be used to
provide taste masking of disagreeable components of a
pharmaceutical preparation.
2

3. TYPES OF COLORANTS APPROVED IN VARIOUS REGIONS
U.S. Certified Synthetic Colorants
The FD&C Act divided the synthetic colors into three categories:
colors for foods, drugs, and cosmetics (FD&C), colors for drugs
and cosmetics (D&C), and colors for externally applied drugs and
cosmetics (external D&C). All synthetic colorants approved for
use today must meet the specifications, uses, and restrictions as
described in Title 21 of the CFR (Parts 74, 81, and 82). Certified
synthetic colorants are the primary source of colorants used in
the pharmaceutical industry.
3

4. FD&C colorants
The present list of FD&C certified colorants consists of both dyes
and lakes. Lakes are pigments. They are insoluble materials that
color by dispersion and reflected light. FD&C dyes are water-
soluble and exhibit their color by transmitted light.
FD&C dyes: Today, FD&C dyes are synthetic organic molecules
produced from highly purified intermediates derived from
petrochemicals and other sources. They are marketed in a
number of physical forms, such as powder, granular, pastes,
liquids, and dispersions. Many of these forms are customized for
specific uses and are selected by the user for their particular
application.
4

5. They are marketed in a number of physical forms, such as
powder, granular, pastes, liquids, and dispersions. Many of these
forms are customized for specific uses and are selected by the
user for their particular application.
Dyes are relatively unstable because of their chemical structures.
They are subject to instability as a result of: 1) light energy; 2)
oxidizing and reducing agents; 3) microorganisms; 4) trace
metals; 5) pH; and 6) high temperatures.
FD&C lakes: The only lakes permitted for use in all three
categories—foods, drugs, and cosmetics—are the aluminum
lakes. These are manufactured through the adsorption of an
aluminum salt of an FD&C dye on a base of alumina hydrate.
5

6. The properties of these lakes can be controlled by variations in
process conditions during manufacturing (for example, starting
materials, order of additions, pH, and temperature). The most
important attributes of aluminum lakes are the shade and
particle size.
The shade of the lake may be influenced by the quantity of dye
adsorbed onto the alumina hydrate and the particle size
distribution. The particle size also affects the tinting strength
(that is, coloring power) of the pigment. Smaller particles result
in increased surface area, which allows for an increase in
reflected light and hence more color.
6

7. D&C and external D&C colorants
D&C and external D&C colorants may be used to color drugs and
cosmetics with certain restrictions. A basic regulatory difference
between FD&C, D&C, and external D&C colorants is that D&C
and external D&C colorants have specific uses and restrictions.
The classifications of D&C and external D&C mean little today,
because many of the colorants listed as D&C are restricted to
external uses.
D&C and external D&C colorants may also exist in either the dye
or lake form; however, the majority of the commercially
significant D&C and external D&C colorants are lakes.
7

8. D&C and external D&C dyes: The starting materials used in the
manufacture of this class of colors are similar to those used for
FD&C colors. D&C and external D&C dyes may or may not be
soluble in water. Some are insoluble metal salts, and others are
insoluble because they contain no water solubilizing groups.
Several, however, are soluble in organic solvents.
Analogous stability problems exist between D&C, external D&C,
and FD&C dyes, although there are a few D&C colors that are
considerably more stable than the FD&C colorants.
8

9. D&C and external D&C lakes: These lakes are usually
manufactured by precipitating a soluble dye onto an approved
substrate. In the case of D&C colors, the substrate may be
alumina, blanc fixe, gloss white, titanium dioxide, zinc oxide,
talc, rosin, aluminum benzoate, calcium carbonate, or any
combination of these materials.
A notable difference between FD&C and D&C lakes is that FD&C
lakes must be manufactured using previously certified dyes,
whereas D&C lakes are not restricted by this requirement.
The important physical properties of the FD&C lakes, such as
particle size and shade, are equally important characteristics of
the D&C and external D&C lakes.
9

10. Color Additives Approved for Use in Drugs
Title 21 of the Code of Federal Regulations
Part 73, Subpart B: Color additives exempt from batch certification
Alumina (dried aluminum hydroxide), Caramel, β-Carotene, Cochineal
extract, Potassium sodium copper chlorophyllin (chlorophyllin-copper
complex), Synthetic iron oxide, Chromium hydroxide green, Talc,
Titanium dioxide etc.
Part 74, Subpart B: Color additives subject to batch certification
FD&C Blue No. 2, D&C Blue No. 4, FD&C Green No. 3, D&C Green No. 5,
D&C Orange No. 4, D&C Orange No. 5, FD&C Red No. 3, D&C Red No. 36,
D&C Violet No. 2, FD&C Yellow No. 5, Ext. D&C Yellow No. 7 etc.
10

11. PRESERVATIVES
11

12. A preservative is a substance that prevents or
inhibits the growth of microorganisms and is
added to pharmaceutical preparation to avoid
consequent spoilage of the preparation by
microorganism.
e.g. Methyl paraben
Ethyl Paraben
Propyl paraben
Benzoic acid
12

13. Some Definitions
Disinfectants: Chemical agents or formulations that are too
irritant or toxic on body surfaces, but are used to reduce the
level of microorganisms from the surface of inanimate
objects to one that is safe for a defined purpose.
Preservatives: Chemical agents or formulations that are
capable of reducing the number of viable microorganisms
within an object or field to a level that is safe for its
designated use and will maintain the numbers of viable
microorganisms at or below a level for the use/ shelf-life of
the product.
13

14. Bacteriostatic: A chemical antimicrobial agent that can
prevent the growth of microorganisms within an otherwise
nutritious environment. This term is meaningless without
specifying the concentration at which this effect is
achieved. Bacteriostatic concentrations do vary between
different species of microorganisms.
Bactericide: A chemical antimicrobial agent that reduces
the viability of a population of microorganisms exposed to
it. This term is meaningless without specifying the
concentration range over which this effect is obtained; such
concentration ranges will vary between different species of
microorganisms.
14

15. Sources of microbial contamination in pharmaceutical
products
Raw materials
Packaging materials
Manufacturing environment
Manufacturing equipments
Personnel
Pharmaceutical water
Vehicles
External air
15

16. Types of dosage form
Preservative required Not required
Liquid dosage form Solid dosage form Tablet, capsule)
Injectables Very hypertonic liquid dosage form
Topical On time use Injectables
Semisolid 100% non aqueous liquid dosage form
Aerosols
Name of dosage form where preservatives required

17. Example of widely used preservatives
Dosage form Name of Preservatives Concentration(%)
For oral use
Benzoic acid 0.1
Sodium benzoate 0.1-0.2
Methyl Paraben and salts 0.1
Propyl Paraben and salts 0.05
Butyl Paraben and salts 0.02
Alcohol 15-20
Glycerin 45
Sorbic acid and salts 0.1
Propionic acid and salts
Dehydroacetic acid

18. Dosage form Name of Preservatives Concentration(%)
For Injectables
and ophthalmic
Benzalkonium chloride 0.01
Benzothonium chloride 0.01
Benzyl alcohol 2
Chlorobutanol 0.5
Phenyl ethyl alcohol 0.5
Cresol 0.3-0.5
Chlorocresol 0.1-0.2
Methyl paraben 0.1
Propyl paraben 0.02
Phenol 0.5
Phenyl mercuric nitrate 0.002
Phenyl mercuric acetate 0.002
Thiomerosal 0.01
Polymyxin-B-Sulfate 1000 USP unit

19. Dosage form Name of Preservatives
Topical use
Benzoic acid
Phenol
Sorbic acid
Alcohols (ethyl and Propyl)
Quaternary ammonium salts
Mercurals

20. Classification of antimicobial preservatives
A. On the basis of their action in bacteria
I. Bacteriostatic
II. Bactericidal
B. On the basis of their chemical structure
II. Ester group
Methyl paraben
Ethyl paraben
Propyl paraben
III. Phenol group
Phenol
Cresol
Chlorocresol
Benzyl alcohol
I. Acid group
Benzoic acid
Sorbic acid
Propionic acid

21. VII.85% concentrated sugar solution
IV. Aldehyde group
Formaldehyde
V. Mercurials group
Phenyl mercuric acetate
Phenyl mercuric nitrate
VI. Quaternary ammonium compound
Cetyl trimethyl ammonium bromide
Benzalkonium chloride

22. VII.85% concentrated sugar solution
IV. Aldehyde group
Formaldehyde
V. Mercurials group
Phenyl mercuric acetate
Phenyl mercuric nitrate
VI. Quaternary ammonium compound
Cetyl trimethyl ammonium bromide
Benzalkonium chloride

23. I. Modification of membrane permeability
II. Denaturation of enzymes or other cellular proteins
III.Oxidation and reduction of cellular constituents
IV.Hydrolysis
V. Interference with essential metabolites
Basic mechanism of action of preservatives

24. 1. A wide spectrum of activity against all bacteria, yeasts
and moulds.
2. Bactericidal rather than Bacteriostatic .
3. Freedom from toxic, irritant or sensitizing activity.
4. Compatibility with other ingredients and with the
container.
5. High water solubility.
6. Stability and effectiveness over a wide range of pH and
Temp.
7. Freedom from color and odor.
8. Well within its solubility to avoid crystallization at low
temperature
9. Stable during sterilization and storage
10. Should be effective at low concentration
11. Should be non volatile
Desirable features of a preservative

25. Phenol
 Chemistry: It is also called carbolic acid.
Structure:
OH
• Physical Properties:
Description: Colorless to light pink,
needle shaped crystals, characteristic
odor.

26. Solubility: 1g in 15 ml water, very soluble in
alcohol, glycerin, chloroform & ether.
Use: It is used as a preservative for
injectable preparations at 0.5% w/v.
Phenol

27. Chlorobutanol
Chemistry:1,1,1-trichloro-2-methyl-2-propanol
Structure: (CCl3)C(CH3)2OH
Physical Properties:
Description: Colorless to white crystals,
camphoraceous odor and taste, anhydrous
melts at 950C ; hydrous melts at 760C.

28. Solubility: 1g in 125 ml water; 1 ml
alcohol or 10 ml glycerin; freely soluble
in chloroform, ether or volatile oils.
Use: It is primarily used as preservative
in ophthalmic and parenteral
preparations as it has antimicrobial &
germicidal properties.
Chlorobutanol

29. Methyl Paraben
Chemistry: It is the methyl ester of parahydroxybenzoic
acid.
CH3
Physical properties
Description: Colorless crystals or white powder.
Solubility: soluble in water, ethanol, slightly
Uses: It is used as preservative in pharmaceutical
formulation to inhibit the growth of
microorganisms.
Structure:

30. ANTIOXIDANT

31. Antioxidants
The chemical compounds which can delay the start or
slow the rate of lipid oxidation reaction in food
systems.

32. Characteristics of Antioxidants
The major antioxidants currently used in foods are
monohydroxy or polyhydroxy phenol compounds with
various ring substitutions. These compounds have low
activation energy to donate hydrogen. The resulting
antioxidant free radical does not initiate another free radical
due to the stabilization of delocalization of radical electron.
The resulting antioxidant free radical is not subject to rapid
oxidation due to its stability.
The antioxidant free radicals can also react with lipid
free radicals to form stable complex compounds

33. Ideal Antioxidants
No harmful physiological effects
Not contribute an objectionable flavor, odor, or color to the fat
Effective in low concentration
Fat-soluble
Carry-through effect  No destruction during processing
Readily-available
Economical
Not absorbable by the body

34. Choices of Antioxidants
Different antioxidants show substantially different
antioxidant effectiveness in different fats and oils and food
systems due to different molecular structures.
We should consider the following:
Safety
Antioxidant effectiveness
Off-odor
Off-color
Convenience of antioxidant incorporation to foods
Carry-through effect
Stability to pH and food processing
Availability
Cost
Non-adsorbable, if possible

35. Factors Affecting the Efficiency of
Antioxidant
1. Activation energy of antioxidants to
donate hydrogen should be low
2. Oxidation potential should be high
3. Reduction potential should be low
4. Stability to pH and processing.
5. Solubility in oil.

36. Kinds of Antioxidants
Natural antioxidants:
1.Tocopherols (delta>gamma>beta>alpha)
2.Nordihydroguaretic Acid (NDGA)
3.Sesamol
4.Gossypol
Synthetic antioxidants:
1.Butylated Hydroxy Anisole (BHA)
2.Butylated Hydroxy Toluene (BHT)
3.Propyl Gallate (PG)
4.Tertiary Butyl Hydroquinone (TBHQ)

37. Preventive Antioxidants
 Superoxide dismutase
 Catalase
 Glutathione peroxidase
 Singlet oxygen quencher
 Transition metal chelators (EDTA)
Preventive antioxidants minimize the formation
of initiating radicals

38. Radical Scavenging Antioxidant
• Vitamin C
• Tocopherol
• Quercetin
• Anthocyanin
Radical scavenging antioxidants break free radical chain
reaction by donating hydrogen to free radicals

39. Mechanism of Antioxidants
Hydrogen donation to free radicals by
antioxidants.
Formation of a complex between the lipid radical
and the antioxidant radical (free radical acceptor).

40. Reaction of antioxidants with radicals
R·
+ AH RH + A
RO + AH ROH + A
ROO + AH ROOH + A
R + A RA
RO + A ROA
ROO + A ROOA
Antioxidant + O2 Oxidized Antioxidant
·
· ·
·
·
· ·
·
··
·

41. Minimization of Lipid Oxidation
If a compound inhibits the formation of free alkyl radicals in
the initiation step, or if the chemical compound interrupts
the propagation of the free radical chain, the compound
can delay the start or slow the chemical reaction rate of
lipid oxidation.
The initiation of free radical formation can be delayed by the
use of metal chelating agents, singlet oxygen inhibitors, and
peroxide stabilizers.
The propagation of free radical chain reaction can be
minimized by the donation of hydrogen from the
antioxidants and the metal chelating agents.

42. Antioxidants
OH
C(CH3)3
OCH3
C(CH3)3(CH3)3C
CH3
OH
ButylatedHydroxy TolueneButylated Hydroxy Anisole

43. OH
OHOH
COOC3H7
PropylGallate
OH
C(CH3)3
OH
TBHQ
CH
CHO OH
OH
OH
CH3CH3
OH CHO
OH
CH
OH
CH3 CH3
CH3 CH3
Gossypol
Antioxidants

45. Defination:
 Flavor is a complex effect of taste, odour, and feeling factor
i.e., touch, sight, and sound, to produce physicochemical and
psychological actions that influence the perception of a
substance.
 Taste- primary effects of taste are sweet, sour, and salty.
There is a close co-relation ship between chemical structure
and taste.
 Sour taste is due to acidic nature. Examples: Lemon, Vinegar,
Citric acid, Malic acid, Apple.

46. Salty taste is due to cationic species, halide salts. Example:
Sodium chloride, sodium bromide, sodium iodide.
Increase in molecular weight of halide results in increase in bitter
taste. example: potassium bromide, Ammonium salts.
Sodium chloride is salty, whereas , potassium chloride is bitter.
Sweet taste is due to polyhydroxy compounds.
Example: sugar, glycerin, alpha amino acids, etc.
Odour- Odour is defined as ‘Taste from a distance’, it is very
closely allied to taste. Without odour most of substances lack in
taste appeal.

47. Odourous volatile substances generate vapors these interact
with olfactory cells and elicit receptors and exit. The brain
receives impulses from group of microscopic olfactory
receptors in the nose which it co-ordinates with the gustatory
stimuli to produce the mingled sensation that is recognized as
the flavour of the substance.
Feeling factor :-feeling factor is combination of sight, sound,
and touch i.e., texture(soft/hard) , Viscosity, cooling / warmth ,
irritation sensation, etc.
Examples: flavored viscous multi-vitamin liquid gives
mouthfeel effect, Menthol in mouthwash gives cooling effect.

48. Purpose:
 To mask unpleasant taste or odour.
 To make it more palatable.

49. Products and there preferred flavors:
 Cough syrup- anise , raspberry, mint, liquorice.
 Liver preparation- Apricot, raspberry, Stawberry.
 Protien hydrolysate- Honey, butterscotch,
pineapple, banana.
 Antacid-Mint menthol, ginger
 VitaminA- Caramel, butterscotch, orange
 Laxative- Vanilla, Strawberry
 Papain pepsin- cardamom, pineapple

50. Types of flavoring agents:
 Natural Flavoring agents
 Nature Identical Flavoring Agents
 Artificial flavoring agents
 Flavors are combined with the sweetening agents
like sucrose, sorbitol, invert syrup, saccharine, etc.
to enhance the flavoring effect.

51. Natural flavors:
 Volatile oils such as anise, caraway, cinnamon, clove, dill, ginger, lemon, orange
and peppermint are used as flavoring agents in a variety of forms.The vehicles
of mixtures are often aromatic waters while alcoholic or hydroalcoholic
solutions of oils(tinctures or, more often, spirits) provide convenient
concentrated preparations for flavoring purposes (lemon, peppermint and
compound orange spirits, and strong ginger tincture are examples)
 Flavors containing aromatic oils(except lemon and orange) are more suitable
than fruit syrups for neutral preparations. Fruit flavors are prepared from fruit
juices, peel of citrus fruits. Lemon and orange oils keep badly and develop an
unpleasant turpentine-like taste. By removing most of the terpenes, terpeneless
oils are produced which, compared with the natural oils, are about 20 times
stronger in flavor and odour, are more readily soluble and have better stability.
 For solid dosage form- vanillin crystals,dried lemon extract
 For liquid dosage form- Alcoholic , aqueous, hydroalcoholic (tinctures and spirits
are used.
 Limitations of natural flavors:
 These are chemically and microbiologically unstable.
 Extracts vary in nature or composition.
 Removal of water, resinous material, terpenes and sesquiterpenes improves stability of
flavors.(fractional distillation required)

52. Nature-identical flavoring substances:
Nature identical substances means flavoring substances that
are obtained by synthesis or isolated through chemical
processes, which are chemically identical to flavoring
substances naturally present in products intended for human
consumption. They cannot contain any artificial flavoring
substances.

53. Synthetic flavors:
 These are prepared by chemical reactions. Inaddition to synthetic
sweeteners other synthetic chemicals are used in flavoring. These are
often preferred to natural materials because of their more constant
composition, More ready availability,lower cost, greater stability, and
more predictable incompabilities.
 Examples: Ester (methylsalicylate), Aldehydes( Synthetic vanillin,
benzaldehyde, cinnamaldehyde) fatty alcohols, ketones , lactones and
alcohols are used. Chloroform has an agreeable, warm, sweet taste
and used as a vehicle Chloroform water BP.
 For emulsified products, Soft flavors like benzaldehyde and vanillin are
most suitable. Benzaldehyde has the odour of bitter almonds and is a
substitute for wild cherry syrup and volatile bitter almond oil. Vanillin
is useful when, as with liquid paraffin emulsions , the medicament has
bland taste. Fractionated coconut oil, a non-aqueous vehicle for oral
preparations, is difficult to flavor because of its oily nature; imitation
ground almond oil and olive oil are suitable flavors.
 Exact duplication of natural flavor is impossible because it is not
possible to detect and prepare all components which are present in
natural flavor and hence it is blended with natural flavors.

54. Taste-Masking Agents
The flavoring industry has many proprietary products purported to
have excellent taste-masking properties, which have been used with
some success. Yet, there are a number of natural and artificial flavors
that can be generally described to possess similar taste-masking
effects. Of the many tastes that must be masked in pharmaceuticals,
bitterness is most often encountered; to mask it completely is
difficult. A tropical fruit has been used for centuries in central Africa
to mask the bitter taste of native beers. This so-called ‘‘miracle
berry’’ contains a glycoprotein that transiently and selectively
binds to bitter taste buds. Due to stability challenges, attempts to
isolate the compound for commercial exploitation have been
unsuccessful. Yet, many fruit syrups are relatively stable in
pharmaceuticals if formulated with antimicrobial preservative
agents, e.g. syrups of cinnamon, orange, citric acid, cherry, cocoa
etc.