PHARMACEUTICAL NECESSITY

Pharmaceutical necessity

 Traditionally the ingredients of a formulation “other than active

ingredient” were known as inactive ingredients. In the present day,
where these inactive ingredients are known to play a crucial role in
designing a formulation and to provide desirable characteristics, the
term excipient is more commonly used.

 According to the definition given by the International Pharmaceutical

Excipients Council (IPEC),
“Excipients are substances, other than the active drug substance or
finished dosage form, which have been appropriately valuated for
safety and are included in drug delivery systems for specific
functions.”
Selection of excipients depend
on various factors:
1. Origin, source, and availability
2. Functional category
3. Quality and purity
4. Impurity levels and extent of characterization
5. Batch-to-batch consistency
6. Stability in the pure form and in the formulation
7. Compatibility with the active ingredient and packaging material
8. History of prior human use
9. Safety and toxicological issues
10. Cost considerations
11. Biological activity(ies), if any
12. Regulatory and compendial status
13. Patent status.
Antioxidant: Antioxidants are used to reduce the oxidation
of active substances and excipients in the finished product.

 Ideal Antioxidants
1. No harmful physiological effects.\
2. Not contribute an objectionable flavor, odor, or color .
3. Effective in low concentration
4. Fat-soluble
5. Carry-through effect à No destruction during processing
6. Readily-available
7. Economical
8. Not absorbable by the body
Classification of antioxidant

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)sodium edetate
SOLVENT
 Solvents are chemical substances that can dissolve,
suspend or extract other
materials usually without chemically changing eithe
r the solvents or the other materials. Solvents can
be organic, meaning the solvent contains carbon as
part
of its makeup, or inorganic, meaning the solvent do
es not contain carbon. For example, “rubbing”
alcohol is an organic solvent and water is an
inorganic solvent. Hydrocarbon and oxygenated
solvents are examples of types of organic solvents
that can effectively dissolve many materials.
How do solvents work in pharmaceuticals?
 Solvents can serve one or more functions in
pharmaceutical manufacture. They
provide molecules to build some drugs.
 For other drugs, solvents are used for extraction
and purification. Solvents also can provide a
reaction medium. Solvents work in a variety of
ways to contribute too many of the medicines
people use today.
 As helpers in the formulation of many health care
products such as penicillin, aspirin, cough syrup,
and topical ointments, solvents play an important
role in the medicine cabinet.
SUSPENDING AGENTS
 Definition
• 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.

11
List of Suspending Agents

• Alginates
• Methylcellulose
• Hydroxyethylcellulose
• Carboxymethylcellulose
• Sodium Carboxymethylcellulose
• Microcrystalline cellulose
• Acacia, Tragacanth, Xanthan gum
• Bentonite
• Carbomer
• Powdered cellulose
12
• Gelatin
OINTMENTS
DEFINITION:
 “Ointments are semisolid preparation intended for
application to the skin with or without injection”.
 They may be oleaginous e.g., white ointment; they
may be entirely free of oleaginous substances e.g.,
polyethylene glycol ointment, or they may be
emulsions of fatty or wax like material containing
relatively high proportion of water e.g., hydrophilic
ointment.”
IDEAL OINTMENT BASE:
According to BEELER, ideal ointment base should
have following physicochemical properties:
1. Stability
2. Neutral in reaction
3. Non greasy
4. Non degreasing
5. Non irritating
6. Non dehydrating
7. Non hygroscopic
8. Water removable
9. Compatible with all medicaments
10.Free from odors
Cont…

11. Non staining

12. Efficient on all skin type
13. Composed of readily available component of
known chemical composition
14. Capable of holding 50% of water
15. Easily compounded
16. Melting & softening at body temperature
17. smoothness
18. ease of application
19. Suitable base
20. Properly distributed medicament
CLASSIFICATION OF OINTMENT/ OINTMENT
BASES
ACCORDING TO PENETRATION:
1.EPIDEMIC OINTMENT :
 Slight penetration power
 Therapeutic effect on diseased epithelium
 e.g. petrolatum, waxes and 1+2.
2.ENDODERMIC OINTMENT:
 Power of deeper penetration
 e.g. veg oils, lards, lanolin and 1+2+3
3.DIADERMIC OINTMENT:
 Penetrate skin effectively. better absorption
 e.g., emulsion type & water soluble.
Cont…

CLASSIFICATION ACCORDING TO CHEMICAL

COMPOSITION:
(PHYSICAL CLASSIFICATION ):
They may be classified into four main groups:
 Hydrocarbon Bases
 Absorption Bases
 Water Miscible Bases
 Water Soluble Bases
 HYDROCARBON BASES:
(a) Properties.
1.Anhydrous
2.Do not absorb water readily (Hydrophobic)
3. Insoluble in water
4.Not washable
(b) Examples. Fats and fixed oils such as lard, olive
oil, cottonseed oil, petrolatum(soft paraffin), white
ointment, Yellow Ointment (Bees Wax) and silicon
bases.
(c) Advantages. Highly compatible; occlusive; good
emollients.
(d) Disadvantages. Difficult to remove from skin and
clothing; uncertain as to yield of medicament.
May go rancid .
 ABSORPTION BASES:
They may be:
 Non emulsified: they absorb water and aqueous
solutions to produce w/o emulsions. Examples are
wool fat (anhydrous lanolin), wool alcohols, bees
wax and cholesterol.
 w/o emulsions: they are similar in properties to the
previous group and are capable of absorbing more
water. Examples are hydrous wool fat B.P. (lanolin)
and oily cream B.P.
(a)Properties.
 Anhydrous
 will absorb water( hydrophilic)
 Insoluble in water
 most are not washable.
(b)Example. Hydrophilic Petrolatum, USP;
Anhydrous Lanolin, USP.
(c) Advantages. Highly compatible; relatively stable
to heat; can be used in anhydrous form or water
can be added when emolliency is desired.
(d)Disadvantage. Greasy. Less occlusive.
 EMULSION BASES:
A. Emulsion Ointment Base (W/O):
• Hydrous
• Will absorb water
• Insoluble in water
• Not washable
• Water-Oil-Emulsion
• Examples—Lanolin, Rose water Ointment, Cold Cream

B. Emulsion Ointment Base (O/W):

• Hydrous
• Will absorb water
• Insoluble in water
• Washable
• Oil-in-Water Emulsion
• Hydrophilic Ointment
 Emulsion Bases. Emulsion ointment bases consist
of an aqueous phase, an oleaginous phase, and an
emulsifying agent. They are true, solid emulsions.
 Emulsion bases may be either oil-in-water (o/w) or
water-in-oil (w/o), usually depending upon the
phase in which the emulsifier is more soluble. The
water phase varies from 10 percent to 80 percent
of the completed ointment base.
 They can be anionic, cationic, nonionic.
 Combination:30:soft paraffin50: liquid paraffin20.
 Summary of emulsion bases. We can sum up the
important aspects of emulsion bases as follows:
(a) Properties. The w/o emulsion bases are insoluble
in water and are not washable; the o/w emulsion
bases are washable and nongreasy.
(b) Example:
 Lanolin, USP (w/o);
 Hydrophilic Ointment, USP (o/w);
 Vanishing creams (o/w).
(c)Advantages:
 Washable and non greasy if oil-in-water (o/w).
(d) Disadvantages:
 Subject to water loss if o/w,
 greasy and unwashable if water-in-oil (w/o),
 unless, a preservative is added, the
emulsion bases are subject to mold growth.
Water-Soluble Bases.
 The polyethylene glycol polymers, or Carbowaxes,
are of great importance in ointments.
 The names of the Carbowaxes include numbers
that roughly indicate their average molecular
weight.
 Carbowaxes with a molecular weight in the area of
1,000 are soft, ointment-like substances.
 As the molecular weight increases, they become
harder and they finally become waxes. They are
water-soluble, nonvolatile, and do not deteriorate
or support mold growth.
Properties:
 Anhydrous
 but will absorb water and dissolve in water;
 Washable
 Non-greasy.
Examples. Carbowax compounds such as the
polyethylene glycol bases containing pectin,
cellulose, Bentonite, and gelatin.
c) Advantages:
• Wide range of compatibility;
• do not become rancid or support microbial
growth;
• nonirritating (to the same degree as lanolin,
petrolatum, etc);
• adhere well to skin;
• easily washed off;
• low incidence of sensitization.
(d) Disadvantages:
Sometimes undergo gradual discoloration with
certain drugs. Unless cetyl alcohol is added, an
aqueous solution can be added only to the extent
of 5 percent.
 LANE & BLANK CLASSIFICATION:
According to physicochemical action of vehicle on
skin:
1. VEHICLE ACTED AS AQEOUS MIXTURE
2. VEHICLE ACTED AS OILS
3. VEHICLE ACTED AS POWDERS
4. VEHICLE ACTED AS ORGANIC SOLVENT
 CHEMICAL CLASSIFICATION:
1. Hydrocarbon
2. Alcohol
3. Acid
4. Ester
5. Soaps
6. Miscellaneous
ACCORDING TO USES OR THERAPEUTIC
CLASSIFICATION:
1. Emollient
2. Protective
3. Anti Infectives
4. Anti Eczematic
5. Keratolytic
6. Anti Prespirants
7. Anti Sebhorrics
Emulsifying Agents
 Stable suspensions of liquids constituting the
dispersed phase, in an immiscible liquid constituting
the continuous phase is brought about using
emulsifying agents such as surfactants.
 Surfactants must exhibit the following
characteristics to be effective as emulsifiers
- Good surface activity
- Should be able to form a condensed interfacial film
- Diffusion rates to interface comparable to emulsion
forming time.
 Common Emulsifying Agents
Surfactants
Anionic – Sodium stearate, Potassium laurate,
Sodium dodecyl sulfate, Sodium sulfosuccinate
Nonionic – Polyglycol, Fatty acid esters, Lecithin
Cationic – Quaternary ammonium salts,
Amine hydrochlorides.
Solids
Finely divided solids with amphiphilic properties
such as soot, silica and clay, may also act as
emulsifying agents (Pickering Emulsions:
Attribute of high stability)
DISINTEGRANTS
 Disintegrants are agents added to tablet
(and some encapsulated) formulations to
promote the breakup of the tablet (and
capsule “slugs’) into smaller fragments in
an aqueous environment thereby
increasing the available surface area and
promoting a more rapid release of the drug
substance.
There are three major mechanisms and factors
affecting tablet disintegration as follows:
 A Swelling:
 B Porosity and Capillary Action (Wicking):
 C Deformation:
SUPER DISINTEGRANTS
 Because of the increased demands for faster
dissolution requirements, there are now available,
a new generation of “Super Disintegrants” in
addition to the disintegrants discussed earlier.
 Three major groups of compounds have been
developed which swell to many times their original
size when placed in water while producing minimal
viscosity effects:
1. Modified Starches- Sodium Carboxy methyl Starch
(Chemically treated Potato Starch.
i.e. Sodium Starch Glycolate (Explotab, Primogel)
 Mechanism of Action: Rapid and extensive swelling
with minimal gelling.
 Effective Concentration: 4-6%. Above 8%,
disintegration times may actually increase due to
gelling and its subsequent viscosity producing
effects.
2. Cross-linked polyvinylpyrrolidone- water
insoluble and strongly hydrophilic.
i.e. crospovidone (Polyplasdone XL, Kollidon CL)
 Mechanism of Action: Water wicking, swelling and
possibly some deformation recovery.
 Effective Concentration: 2-4%
3. Modified Cellulose- Internally cross-linked form of
Sodium carboxy methyl cellulose. i.e. Ac-Di-Sol
(Accelerates Dissolution), Nymcel
 Mechanism of Action: Wicking due to fibrous
structure, swelling with minimal gelling.
 Effective Concentrations: 1-3% (Direct
Compression), 2-4% (Wet Granulation)
ADVANTAGES:
 Effective in lower concentrations than starch
 Less effect on compressibility and flow ability
 More effective intra granularly
DISADVANTAGES:
 More hygroscopic (may be a problem with moisture
sensitive drugs)
 Some are anionic and may cause some slight in-
vitro binding with cationic drugs (not a problem in-
vivo.)
PRESERVATIVES
MODE OF ACTION FOR PRESERVATIVES
Preservatives interfere with microbial growth,
multiplication, and metabolism through one or
more of the following mechanisms
1. Modification of cell membrane and leakage of cell
constituents (partial lysis)
2. Lysis and cytoplasmic leakage
3. Irreversible coagulation of cytoplasmic constituents
(protein precipitation)
4. Inhibition of cellular metabolism as through interference
with enzymes systems or inhibition of cell synthesis
5. Oxidation of cellular constituents
6. Hydrolysis
Probable Modes Of Action Of Some Preservatives
1. Benzoic acid, boric acid, p-hydroxybenzoates:
Denaturation of proteins.
2. Phenols, chlorinated phenolic cmpds: lytic,
denaturation action on cytoplasmic embranes and
for chlorinated preservatives, also by oxidation of
enzymes.
3. Alcohols: lytic and denaturation action on
membranes. Quaternary compounds: Lytic action
on membranes
4. Mercurials: Denaturation of enzymes by
combining with thiol (-SH) groups
Considerations to be taken in selecting
preservations:
1. The preservatives is effective in preventing the
growth of the type of organism which is the most
contaminants of the formulation.
2. Soluble in water to achieve adequate
concentrations in the aqueous phase of a 2 or more
phase system.
3. The proportion of preservative remaining
undissociated at the pH of the preparation makes it
capable of penetrating the microorganism and
destroying it.
4. The required concentration of the preservative
does not affect the safety or comfort of the
patient upon administration.
5. Preservative should be stable.
6. Preservatives should be compatible with all other
ingredients of the formulation.
7. Should not adversely affect the preparations
container or closure.
Examples:
Benzoic acid (0.1 to 0.2%),
Sodium benzoate (0.1 to 0.2%),
Alcohol (15 to 20%),
Phenol (0.1 to 0.5%),
Cresol (0.1 to 0.5%),
Chlorobutanol (0.5%),
Benzalkonium Chloride (0.002 to 0.01%),
combination of methylparaben and
propylparaben (0.1 to 0.2%)
 FLAVORING AGENTS
To mask effectively the unwanted or disagreeable taste
of drugs
In general, low molecular weight are salty, like
NaCl, KCl, NH4Cl, NaBr and higher molecular salts are
bitter except some lead salts.
Examples: Anise oil, Cinnamon, Peppermint, and
Orange
With organic compounds, an increase in the
number of OH group seems to increase the sweetness
of the compound. Sucrose which has 8 OH groups is
sweeter than glycerin which has 3 OH groups.
Certain flavoring materials have been found through
experience
1. Cocoa - flavored vehicles effective for masking bitter
taste
2. Fruits or Citrus flavors for masking sour or acid
tasting drugs
3. Orange, Cinnamon, Strawberry for improving taste
of salty drugs
Different Types of Flavors
1. Natural Flavor: Essential oil, oleoresin, essence or
extractive, protein, hydrolysate, distillate, or nay
product of roasting, heating or enzymolysis, which
contains the flavoring constituents derived from a
spice, fruit, or fruit juice, vegetables, edible yeast,
herb, bark, bud, root, leaf or similar plant
material, meat, seafood, poultry, eggs, dairy
products or fermentation products there of whose
significant function in food is flavoring rather than
nutritional.
2. Artificial Flavor: Any substance used to impart
flavor that is not derived from a spice, fruit,
vegetables or anything mentioned above.
3. Spice: Any aromatic vegetable substance in
whole, broken, or ground from, except substances
traditionally regarded as foods, such as onions,
garlic, celery; whose significant function in food is
seasoning rather than nutritional; that is true of
any volatile oil or other flavoring principle has
been removed.
 Comparison Of Sweetness
Sucrose Saccharin Aspartame
Source sugar cane; chemical synthesis; chemical synthesis;
sugar beet phthalic anhydride, methyl ester, dipeptide
petroleum product of phenylalanine and
aspartic acid
Relative Sweetness 1 300 180-200
Bitterness none moderate strong none
Aftertaste none moderate strong; none
sometimes metallic
or bitter
Calories 4/g 0 4/g
Acid Stability good excellent fair
Heat Stability good excellent poor
Sweetening Pharmaceuticals
Saccharin = metabolized and excreted by the kidneys virtually
unchanged
Cyclamate = metabolized or processed in digestive tract and its
by product are excreted by the kidneys
Aspartame = breaks down in the body into three basic
components: the amino acids phenylalanine and aspartic acid,
and methanol because of its metabolism to phenylalanine, the
use of aspartame by persons with phenylketonuria (PKU) is
discourages, and diet foods and drinks must bear appropriate
label warning. saccharin and cyclamate were “generally
recognized as safe” or what is known as GRAS
Acesulfame = is more stable than aspartame at elevated
temperature; it is use in candy, chewing gum,
confectionery, and instant coffees and teas
Stevia powder = Stevia rebaudiana bertoni. It is natural,
nontoxic, safe, and about 30 times as sweet as cane
sugar, or sucrose.
Coloring Agents
Uses:
1. For aesthetic value
2. Sensory adjuncts to the flavors employed Distinction
between agent and coloring agent
 Ideal properties of a colorant

I. Nontoxic and have no physiological activity.

II. Free from harmful impurities
III. Unaffected by light, tropical temperatures, hydrolysis and
micro‐organisms and, therefore, be stable on storage.
I. Unaffected by oxidizing or reducing agents and pH changes.
II. Compatible with medicaments and not interfere with them.
III. Ready solubility in water is desirable in most cases but some
IV. oil‐soluble and spirit‐soluble colors are necessary.
V. Does not interferes with the tests and assays to which the
preparations containing it are subject. Should not be
 Sources Of Coloring Agents
Most pharmaceutical colorants are synthetic
origin, few are naturally occurring principles obtained
from mineral, plants and animal source
Example: red ferric oxide is mixed in small portions with
ZnO powder to prepare calamine giving the latter a
characteristic pink color intended to match the
skin done upon application.
Chlorophyll in green plants impart its color to
many products
The synthetic coloring agent come mostly from
coal tar (pix carbonis) black, viscid liquid which is
a by product in the destructive distillation of coal.
Approved Color Additives Are Classified
Into 3 Groups
1. FD & C dyes - legally used in food, drugs
and cosmetics
2. D & C dyes - legally used in drugs and
cosmetics
3. External D & C dyes - legally used only
to color externally applied drugs and
cosmetics
FACTORS TO BE CONSIDERED IN THE
SELECTION OF COLORANT OR DYE
1. Certified dye
2. Gives aesthetic value
3. Physical and chemical properties
4. pH or pH stability of the preparation
CERTIFICATION
Synthetic dyes used internally should be
certified
Characteristics of a dye before gaining
certification
1. Must be safe
2. Must not interfere with the therapeutic efficacy of
the product
3. Must not interfere with the assay procedure for the
preparation
AESTHETIC VALUE
Liquid preparations - the amount is ranging from
0.0005 to 0.001% depending upon the colorant and
intensity desired
Solid or powdered, Compressed Tablets -
generally larger proportion is required (0.1%)
Ointments, suppositories, ophthalmic and
parenteral -no color additives
FACTORS TO BE CONSIDERED IN THE SELECTION
OF COLORANT OR DYE
1. PHYSICAL AND CHEMICAL PROPERTIES
Solubility of the dye should be the first to be studied -
in the solvent or vehicle used.
Dyes may be grouped into
a. Water soluble
b. Oil soluble
2. pH
Dyes can change color with a change of
pH. The color must be chemically stable in the
environment of the other formulative
ingredients for the shelf life.
Examples of color formulation
1. Orange Yellow and Red
2. Cherry Red and Blue
3. Strawberry Red
4. Grape Red and Blue
5. Lemon Yellow
6. Chocolate Red, Yellow and Blue
7. Sulfur yellow
8. Riboflavin yellow
9. Rupric sulfate blue
10.Ferrous sulfate bluish green
11.Cyanocobalamin red
12.Red mercuric iodide vivid red
Categories of Evidence of Carcinogenic Activity For
Color Additives
1. Clear evidence of carcinogenic activity
2. Some evidence
3. Equivocal evidence - indicating uncertainty
4. No evidence - indicating no observable effect
5. Inadequate study - for studies that cannot be
evaluated because of major flaws