Pharmaceutical Excipients

Excipient An excipient is an inactive substance

formulated alongside the active ingredient of a medication, for the purpose of bulking-up formulations that contain potent active ingredients.

Drug products contain both drug substance (commonly referred to as active pharmaceutical ingredient or API) and excipients. Formulation of API with excipients is primarily to ensure an efficacious drug product with desired properties and a robust manufacturing process

The resultant biological, chemical and physical properties of the drug product are directly affected by the excipients chosen, their concentration and interactions with the API:Consistency of drug release and bioavailabilityStability including protection from degradationEase of administration to the target patient population(s)

by the intended routeExcipients determine the bulk of the final product in

dosage forms such as tablet, capsule, etc., the speed of disintegration, rate of dissolution,release of drug, protection against moisture, stability during storage, and compatibility . Excipients should have no bioactivity, no reaction with the drug substance, no effect on the functions of other excipients, and no support of microbiological growth in the product .

Ideal properties of excipientNo interaction with drug Cost effective Pharmacologically inert Stable for handling Feasible

Excipients are inactive ingredients used as carriers for the active ingredients in a pharmaceutical product. These may be classified into the following categories:

AntiadherentsBindersCoatingsDisintegrantsFillers and DiluentsColoring AgentsGlidantsLubricantsPreservativesSorbentsSweeteners

DILUENTS Diluents increase the volume to a formulation to prepare tablets of

the desired size. Widely used fillers are lactose, dextrin, microcrystalline cellulose, starch, pregelatinized starch, powdered sucrose, and calcium phosphate.

The diluent is selected based on various factors, such as the experience of the manufacturer in the preparation of other tablets, its cost, and compatibility with other formulation ingredients. For example, in the preparation of tablets or capsules of tetracycline antibiotics, a calcium salt should not be used as a diluent since calcium interferes with absorption of the antibiotics from the GI tract.

Classification :Diluents

Chemical nature Solubility

Organic materials

Inorganic materials Insoluble Soluble

DextroseLactoseMannitolSorbitolStarchsucrose

Calcium phosphate (II)Calcium phosphate (III)Calcium sulphateCalcium carbonate

DextroseLactoseMannitolSorbitolsucrose

Calcium phosphate (II)Calcium phosphate (III)Calcium sulphateCalcium carbonateStarch

Example-Calcium phosphate (10-15%)Starch (5-10%0Calcium sulphate (5-10%)Microcrystalline cellulose (5-15%)

Purpose of diluents :•to enhance bulkiness•to provide improved cohesion•to enhance flow

•to allow direct compression manufacturing

LACTOSE :

• solubility – water soluble

FormsHydrous

Anhydrous

used in wet granulation

shows fast disintegration, good friability, practically no sticking, binding and capping

• most widely used diluent

hydrous form undergoes maillard reaction discoloration of certain drugs

( amine drug )

• Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the presence of basic amine drugs and catalyzed by tartarate, citrate and acetate ions

BINDERS Binders promote the adhesion of particles

of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. Commonly used binding agents include: starch, gelatin and sugars (sucrose, glucose, dextrose, and lactose).

Examples of BindersCarboxymethylcellulose, sodium Karaya gum

Cellulose,microcrystalline(Avicel®) Starch, pregelatinized

Ethylcellulose Tragacanth gum

Hydroxypropyl methylcellulose Poly(acrylic acid)

Methylcellulose Polypvinylpyrrolidone

Acacia gum Gelatin

Agar Dextrin

Algin acid Glucose

Guar gum Molasses

Binders

Binders add mechanical strength to the tablet or granules.

Starch(1,4-alpha-glycosidic linkages)

Cellulose(1,4-beta-glycosidic linkages)

Gellatin Polyethylene glycol (PEG)

Disintegrants ( Added to a tablet formulation to facilitate its breaking or

disintegration when it contact in water in the GIT).

• Example: Starch- 5-20% of tablet weight.

• Starch derivative – Primogel and Explotab (1-8%) • Clays- Veegum HV, bentonite 10% level in colored tablet only

• Cellulose

• Cellulose derivatives- Ac- Di-Sol (sodium carboxy methyl cellulose)

• Alginate

• PVP (Polyvinylpyrrolidone), cross-linked

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 dosage form increased.

Superdisintegrants• Swells upto ten fold within 30 seconds when contact water.

• Example: Crosscarmellose- cross-linked cellulose, Crosspovidone- cross-linked povidone (polymer), Sodium starch glycolate- cross-linked starch.

• These cross-linked products swell upto ten fold within 30 seconds when in contact with water.

• A portion of disintegrant is added before granulation and a portion before compression, which serve as glidants or lubricant. Evaluation of carbon dioxide in effervescent tablets is also one way of disintegration

Lubricant and GlidantsLubricants are intended to prevent adhesion of the tablet

materials to the surface of dies and punches, reduce inter particle friction and may improve the rate of flow of the tablet granulation.

Glidants are intended to promote flow of granules or powder material by reducing the friction between the particles.

Example: Lubricants- Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate, Talc, PEG (Polyethylene glycols), Surfactants

Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas such as Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.

Compression 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 Lubricants tend to be 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

Lubricants can also be used when compression isn’t involved, e.g. In powder blends for filling into capsules to prevent

adherence of granule/powder to equipment surfaces and dosator mechanisms

Coating the surface of multi-particulate dosage forms (including intermediate product) to inhibit agglomeration of individual particles

GlidantsGlidants promote flow of the tablet

granulation or powder materials by reducing friction between particles.

The commonly used glidants are talcum, starch, colloidal silica, silicates, stearates, calcium phosphate etc.

The effect of glidants on the flow of the granules depends on the shape and size of the particles of the glidants and the granules

As a general rule hydrophilic materials act better on hydrophilic granules and lipophilic ones on the lipophilic granules.

The glidants in a particular formulation ensure increasing flow of granules up to a certain optimum concentration . If the concentration of the glidant is taken beyond this, a drag action may come into operation

bringing down the rate of flow.

Most commonly; colloidal silicon dioxide (traditionally, talc was used)

Good bulk powder flowability is especially important during high speed processing

Glidants improve flow by adhering to particles and so reducing inter-particulate friction Most common in dry powder formulations, e.g. direct

compression tablets Can also be added to granules to improve flow prior to

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

Very low levels required (ca. <0.2%) Control can be challenging with blends sensitive to levels

Very low bulk density (0.03 – 0.04g/cm3) Difficult to work with (very voluminous) – not a standard

excipient, only added if needed Issues with dust exposure