Definition

Pharmaceutical excipients are agents which are used other than active ingredients

-to increase stability of the products,

-to enhance patients acceptance

-to ease manufacturing process

For the liquid preparation the following additives are used:

1. Preservative: e.g. Phenol, Boric acid & its salts, Benzoic acid & its salts, Sorbic acid & its salts, Alkyl ester of parahydroxy benzoic acid (PARABEN),

2. Antioxidant: e.g. Sodium Sulphite, Sodium metabisulfite, Ascorbic acid.

3. Sweetening agent: e.g. Sucrose, Liquid glucose, Saccharine, Sorbitol, Glycerin

4.Flavoring agent: e.g Vanilla

5. Coloring agent: e.g. FD&C Red# 3, D&C Red# 8

6. Solvent: Water.

7. Co solvent: e.g. Poly ethylene glycol

8. Viscosity imparting agent: e.g. Poly vinyl pyrrolidone (Povidone), Methyl cellulose

9. Surface active agents: e.g. Tween, Span

10. Chelating agent: e.g. EDTA (Ethylene Diamine Tetra acetic acid)

11. Buffering agent: Phosphate buffer

12. Humectants: e.g. Polyethylene glycol, sorbitol

For solid preparation the following additives are used:

1. Binding agent:

e.g. Acacia, Tragacanth, Starch, cellulose(HPMC), Povidone (Poly vinyl pyrrolidone)

2. Diluents/ Fillers:

e.g. Starch, Lactose, Sucrose, Mannitol, CMC(Carboxymethylcellulose)

3. Lubricant:--A lubricant is a substance (often a liquid) introduced between two moving surfaces to reduce the friction between them, improving efficiency and reducing wear e.g. Mg-Stearate, Talc

4. Glidant:--A glidant is a substance that is added to a powder to improve its flowability e.g. colloidal silica

5. Disintegrating agent: e.g. sodium starch glycolate , Microcrystalline cellulose

Antioxidant:The oxidative decomposition of Pharmaceuticals is responsible for the instability of products. These reactions are mediated by Free radical or by molecular oxygen. The most common form of oxidative decomposition is auto oxidation. Auto oxidation may be defined as the reaction of any material with molecular oxygen. Free radicals are produced by reactions involving homolytic bond fission of a covalent bond. Free radical is odd number electron containing compound. Free radical are highly unstable compound and

readily takes electron from other substance

Free radical reaction mechanism

The auto oxidation of an organic substance RH by a free radical chain process can be simply described as following three steps:1. Initiation:

RH → R. + H.2. Propagation:

R. + O2 → ROO.ROO. + RH → ROOH + R.ROOH → RO. + .OH

3. Termination:ROO. + X → inactive productsROO. + ROO. → 2ROO inactive productsR. + R. → R-R

Where X can be free radical inhibitor.

Classification of antioxidant:

Depending on mode of action Antioxidant can divided into four types:1. Reducing agent:e.g. Sodium Sulfite, Sodium metabiosulfite, Ascorbic

acid. - Reducing agents acts by being prefentially

oxidized. 2. Blocking agent: - Blocking agents acts by blocking the free radical

reaction mechanism.e.g. BHT. BHA, Tocopherol

3. Synergists: (Combine effect)

- They help the reducing agent.

e.g. Ascorbic acid, Citric acid, Tartaric acid.

4. Chelating agent (Complexing agent):

- Acts by formation of complex with metals. So metals are not available for initiation step of free radical reaction. e.g. EDTA ( Ethylene Diamine Tetra acetic acid)

Concentration range used for antioxidant:

Ascorbic acid - 0.02-0.1%

- Sodium bisulfite - 0.1-0.15%

- Sodium metabisulfite - 0.1-0.15%Blocking agent: Butylated hydroxy

toluene (BHT)- 0.005-0.02%Chelating agent: EDTA salt - 0.01-

0.075%

Preservative:

Antimicrobial preservatives are agents which are used to prevent the presence/growth of microorganism.

An ideal preservative should meet the following characteristics:

It must be effective against a broad spectrum of microorganism.

It must be physically, chemically and microbiologically stable for the lifetime of the product.

It must be non-toxic, non-sensitizing, adequately soluble, compatible both with other formulation components acceptable with suspect to taste and odor at the concentration use.

Classification of antimicrobial agents

Antimicrobial agents are classified into four categories:

a. Acidic: e.g. Phenol, Boric acid & its salts, Benzoic acid & its

salts, Sorbic acid & its salts, Alkyl ester of parahydroxy benzoic acid (PARABEN), Methyl-PARABEN, Propyl-PARABEN, Butyl-PARABEN

N.B.- Combination of parabens give synergistic effect.

b. Neutral:

- Chlorobutanol, Benzyl alcohol

c. Mercurials:

- Phenyl mercuric acetate, Phenyl mercuric nitrate, Thimerosal

d. Quartanary amonium compound:

e.g. Benzal Konium chloride.

Sweetening agent:

Sweetening agents are agents, which are used to, sweetened the preparation & make it palatable.

1. Sucrose: (Not for diabetes patient) - It is soluble in aqueous media (85%) - It is available in highly purified form at

reasonable cost. 2. Liquid glucose: (For diabetes patient) - Extremely viscid substance that imparts both

body and sweetness to liquid formulations. - It is prepared by the partial hydrolysis of starch

with strong acid.

3. Saccharine: - It is used to supplement sugars. - It is approximately 250-500 times as sweet

as sugar. 4. Aspartame: - It is synthetic sweetener. - It is 200 times sweeter that sucrose but it

has no after taste of saccharine. 5. Sorbitol: (For diabetes patient) 6. Glycerine: (For diabetes patient)

Viscosity imparting agent:

Sometime it is desirable to increase the viscosity of a liquid either to serve as adjacent for palatability or to improve pour ability.

Example: Poly vinyl pyrrolidone (Povidone) Methyl cellulose(Methocel) Sodium carboxy methyl cellulose Acacia, Tragacanth, Sodium-Alginate. Veegum (Mg-Al-silicate) Carbomer (Carboxy poly methylene)

Flavoring agent:

Flavoring agents add flavor to the pharmaceutical formulation & make it palatable

It has aesthetic value.There are four basic taste sensations:1. salty, 2. Bitter, 3. Sweet, 4. SourA combination of flavoring agent is

usually required to mask these taste sensation.

Menthol & Chloroform are used as flavor adjunct. They impact a flavor & odor of their own to the product. And have a mild anesthetic effect on the sensory receptor organ.

Example of flavoring agent:Sweet flavor: Fruit, Berry, and Vanilla.Sour flavor: Citrus flavor, RaspberrySalty flavor: Wintergreen, MintBitter flavor: Wild cherry, Chocolate.

Coloring agent:

Purpose of using coloring agentProduces aesthetic valueHelps in DifferentiationHelps in Identification

1.Pigment: Mineral color are frequently

termed as pigment and used to color, lotion,

cosmetic, external preparation. Eg, red

Fe2O3, yellow Fe2O3, Tio2, Carbon black

2. Dye:

- Nitrogenous compound used in Textile- Water soluble used in liquid preparationCertain structural element in organic molecule called chromospheres group give color to the molecules.

Chromophore group: Azo group (-N=N-) Nitroso group (-N=O) Nitro group (-NO2) Azoxy group (-N=NO-) Carboxyl group (C=O) Ethylene group (C=C)

Dyes dissolve in water, but are not soluble in oil. Dyes are manufactured as powders, granules, liquids or other special purpose forms. They can be used in beverages, dry mixes, baked goods, confections, dairy products, pet foods, and a variety of other products.

3. Lake: - are formed by the absorption of water soluble dye on a

hydrous oxide especially Al2O3 which result is in insoluble form of the dye.

Dye + Al2O3 → Water insoluble dye (lake)

- Lakes are used to color powders, pharmaceuticals, foods, candies.

Lakes are made by combining dyes with salts to make insoluble compounds. Lakes are not oil soluble, but are oil dispersible. Lakes are more stable than dyes and are ideal for coloring products containing fats and oils

Classification of coloring agent:

Coloring agents are classified into three types.

1.Food, Drug and Cosmetic color

2.Drug and Cosmetic color

3.External Cosmetic color

Permitted color: Approved by FDA (Food & Drug Administration

Surfactants:

Surfactants are wetting agents that lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids.

A shortened form of "surface-active agent", a surfactant is a chemical that stabilizes mixtures of oil and water by reducing the surface tension at the interface between the oil and water molecules. Because water and oil do not dissolve in each other, a surfactant has to be added to the mixture to keep it from separating into layers.

Surfactants in cosmetics provide one or more of six functions:

1. Detergents - for cleansing 2. Wetting agents - in perms 3. Foaming agents - for shampoos 4. Emulsifiers - in creams and lotions 5. Conditioning agents - in skin and hair-care products 6. Solubilizers - for perfumes and flavors

Surfactant (Surface active agent)

A molecule must fulfill specific structural requirement to become a surfactant.

First requirement: A surface acting agent must contain a lipophilic region.

Second requirement: A surfactant must contain a hydrophilic region.

A balance of the hydrophilic & lipophilic region of a surfactant is usually required.

Properties

A micelle - the lipophilic tails of the surfactant molecules remain on the inside of the micelle due to unfavourable interactions. The polar "heads" of the micelle, due to favourable interactions with water, form a hydrophilic outer layer that in effect protects the hydrophobic core of the micelle..

Classification of Surfactant:

1. Anionic surfactant (Here hydrophilic region is anion) e.g. Sodium lauryl sulphate2. Cationic surfactant (Here hydrophilic region is cation) e.g. Cetyl trimethyl ammonium bromide(Cetrimide)3. Non-ionic surfactant: e.g. Tween 80 (Polyoxyethylene sorbitan monooleate)

Span (Sorbitan ester of lauric acid, oleic acid). 4. Amphoteric surfactant e.g. Lecithin, N-dodecyl alanine

HLB

The hydrophilicity and lipophilicity are different among emulsifiers, and the balance between the two is called HLB value. The value ranges from 0 to 20.An emulsifier with higher lipophilicity shows a lower HLB whereas higher hydrophilicity has high HLB, and the behaviors and functions to water depend on this HLB.

Characteristic behaviors related to

water

HLB

ratio

functions hydrophilic part

lipophilic part

not dispersing 0

0 100  

 

anti-foaming agent

slightly dispersing

2 10 90

 

4 20 80 W/O

emulsification

 

6 30 70

 

wetting agent

 

milky dispersion

8 40 60 O/W

emulsification

Wetting agent:

Wetting is the displacement of either a liquid or a gas from a surface by a second liquid. Wetting agents are surfactants with HLB values of 7-9. Wetting agents aid is attaining intimate contact between solid particles and liquids.

Contact angle

The contact angle is a useful indicator of wetting. A low contact angle indicate that adhesive forces between the liquid and the solid predominate and wetting occurs. While a high contact angle indicates the cohesive forces of the liquid predominate. contact angle may vary from 0° to 180°.

If the drop of liquid/gas is completely insoluble, = 180°

If the drop of liquid/gas is completely soluble, = 0°