Excipients

Information about excipients and their properties.

1. Pharmaceutical Excipients

2. 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

3. 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 bioavailability Stability including protection from degradation Ease of administration to the target patient population(s) by the intended route Excipients 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 .

4. Ideal properties of excipient No interaction with drug Cost effective Pharmacologically inert Stable for handling Feasible

5. Excipients are inactive ingredients used as carriers for the active ingredients in a pharmaceutical product. These may be classified into the following categories: Antiadherents Binders Coatings Disintegrants Fillers and Diluents Coloring Agents Glidants Lubricants Preservatives Sorbents Sweeteners

6. 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 d iluent 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 d iluent since calcium interferes with absorption of the antibiotics from the GI tract.

7. Classification : Diluents Chemical nature Solubility Organic materials Inorganic materials Insoluble Soluble Dextrose Lactose Mannitol Sorbitol Starch sucrose Calcium phosphate (II) Calcium phosphate (III) Calcium sulphate Calcium carbonate Dextrose Lactose Mannitol Sorbitol sucrose Calcium phosphate (II) Calcium phosphate (III) Calcium sulphate Calcium carbonate Starch

8. Example- Calcium phosphate (10-15%) Starch (5-10%0 Calcium 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

9. LACTOSE : solubility – water soluble Forms Hydrous 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

10. 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 ) .

11. Examples of Binders Carboxymethylcellulose , 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

12. 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)

13. 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

14. 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.

15. 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

16. Lubricant and Glidants Lubricants 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.

17. 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

18. 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

19. G lidants G lidants 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

20. 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.

21. 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/cm 3 ) Difficult to work with (very voluminous) – not a standard excipient , only added if needed Issues with dust exposure