Pharmaceutical Excipient In Manufacture Of Drug
Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form. They are not no longer inert materials but they are effective and able to improve the characteristics of the products’ quality, stability, functionality, safety, solubility and acceptance of patients. It can interact with the active ingredients and alter the medicament characteristics.
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| Pharmaceutical excipient |
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The basic requirements for pharmaceutical excipients include safety, functionality and quality. We can conclude that the importance of pharmaceutical excipients encompasses three parts: functions, quality evaluation and safety of pharmaceutical excipients. Toxicity and bioavailability are the main problems of excipients regarding safety and function requirements consequently.
Ideal Properties Of Excipients
1. No interaction with drugs
2. Pharmacologically inert
3. Feasible
4. Cheap
Classes Of Excipient
Excipient can be of animal origin, plant origin, mineral and synthetically produced. They are classified by the functions they perform in a pharmaceutical dosage form. Excipients are added to improve one or more of the three key functional properties of a dosage form: (1) bioavailability, (2) manufacturability, and (3) stability.
Excipient Bioavailability
Excipients facilitate optimum bioavailability, that is, rate and extent of drug absorption from the dosage form, by providing reproducible and optimum rate, extent, and the site of drug release.
Excipient Manufacturability
Excipients facilitate manufacturability by converting the API powder into a powder blend that flows, compresses, and can be manufactured on high-speed equipment.
Excipient Stability
Excipients facilitate stability of the API for the duration of time a product may be stored between the manufacture and the consump-tion (called shelf life).
Others are;
i. Assist in product identification, and enhance any attribute of the overall safety
ii. Assist in the effectiveness and/or delivery of the drug in use
iii. Assist in maintaining the integrity of the drug product during storage
Classification Of Pharmaceutical Excipients
1. Classification of pharmaceutical excipients based on function
i. Binders
Example: PVP, HPMC
ii. Coloring agents
Example: E number colorants
iii. Coating agents
Example: Phthalates
iv. Diluents
Example: Lactose, microcrystalline cellulose
v. Disintegrants
Example: Sodium starch glycolate, croscarmellose sodium
vi. Fillers/bulking agents
Example: Lactose
vii. Glidants
Example: Colloidal SiO²
viii. Lubricants
Example: Magnesium stearate, sodium stearyl fumarate, sodium behenate
ix. Preservatives
Example: Sodium benzoate, thimerosal
x. Sweetener (sweetening agents)
Example: Sorbitol, mannitol, dextrose, aspartame, saccharin, sucralose
xi. Surfactants (surface active agents)
Example: Tweens, spans, polysorbates, poloxamers, lecithins
xii. Solvent and Co-solvent
Example: Ethyl alcohol, benzyl alcohol, propylene glycol, sorbitol, PEGs
Others are;
1. Suspension and viscosity agents (viscosity imparting agents)
2. Flavoring agents
3. Emollient
4. Emulsifying agent
5. Humectant
6. Plasticizer
7. Propellant
8. Protective colloid
9. Sialogogues
10. Viscosifier
11. Sorbents
12. Antiadherent
13. Antioxidants
14. Buffering agents
15. Chelating agents
16. Humectants
2. Classification of pharmaceutical excipients based on origin of source
i. Animal source
Example: Lactose, gelatin, stearic acid
ii. Mineral origin
Example: Silica, calcium phosphate
iii. Plant source
Example: Alginates, starches, sugars, cellulose
iv. Synthetic excipients
Example: Polyethylene glycol, polysorbates, polyvinylpyrrolidone
3. Classification of pharmaceutical excipients based on chemical substituents
i. Alcohols
Example: Ethyl alcohol, benzyl alcohol, propylene glycol
ii. Carboxylic acids
Example: Benzoic acid
iii. Carbohydrates
Example: Monosaccharides, disaccharide and polysaccharides, sucrose, lactose, mannitol
iv. Dyes
Example: Tartrazine, amaranth
v. Esters/ethers
Example: Fatty acid esters or ethers
vi. Glycerides and waxes
Example: Peanut oil, beeswax
vii. Halogenated hydrocarbon derivatives
Example: Freons, chlorbutol, halothane
viii. Organic mercurial salts
Example: Thimerosal
ix. Phenolic compounds
Example: BHA, BHT
x. Proteins
Example: Albumin, gelatin
xi Polymers
Example: HPMC, Eudragits
4. Classification of pharmaceutical excipients based on route of administration
i. Oral excipients
ii. Topical excipients
iii. Parenteral excipients
iv. Other excipients
5. Classification of pharmaceutical excipients based on dosage form
i. Solid
ii. Liquid
iii. Semi solid
iv. Gas
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Diluents
A tablet should weigh at least about 50 mg for ease of handling by the patient. Therefore very low-dose drugs invariably require a diluent (also known as filler) or bulking agent to bring overall tablet weight to at least 50 mg. In addition, enabling manufacturability of powder blends on high-speed equipment requires adequate properties such as flow and compressibility, which are improved by the addition of diluents.
Adsorbents
Adsorbents are substances capable of holding fluids in an apparently dry state. These are the powder particles that can adsorb the liquid while maintaining the ability to be handled as powders. Oil-soluble drugs or fluid extracts can be mixed with adsorbents to bring them to a solid form for compression into tablets. For example, fumed silica, microcrystalline cellulose, magnesium carbonate, kaolin, and bentonite.
Granulating Fluid
Granulating fluids are liquids that are used for wet granulation. Typically, these are water, ethanol, or isopropanol—or the solution of a hydrophilic polymer (binder) in one of these liquids. Addition of granulating fluid while mixing a powder blend of the API with excipients promotes surface adhesion of particles.
Glidants
A substance (as colloidal silica) that enhances the flow of a granular mixture by reducing interparticle friction and that is used in the pharmaceutical production of tablets and capsules during transfer operations, such as from the hopper to the roller compactor or tablet press. Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction.
Binders
Binders hold the ingredients in a tablet together. Hydrophilic polymers are added in either dry or liquid (solution in water) form to promote the transformation of primary powder particles into cohesive agglomerates (granules) during wet granulation or to promote cohesive compacts during direct compression. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets . A binder should be compatible with other products of formulation and add sufficient cohesion to the powders.
Binders are classified according to their application:
• Solution binders are dissolved in a solvent (for example water or alcohol can be used in wet granulation processes).
• Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula.
Lubricants
Lubricants help prevent clumping together and adherence of ingredients and tablet from sticking to the tablet punches or capsule filling machine and stainless steel processing equipment surfaces under compression forces which includes the rolls of a roller compactor. They promote flow, reduce interparticle friction, and facilitate the smooth ejection of compressed tablets from the die cavity. They also ensure that tablet formation and ejection can occur with low friction between the solid and die wall by interparticle restrictions.
There are two types of lubricant according to their water living and water hating characteristics. They are;
• Hydrophilic- Generally poor lubricants, no glidant or anti-adherent properties.
• Hydrophobic- Most widely used lubricants in use today are of the hydrophobic category. Hydrophobic lubricants are generally good lubricants and are usually effective at relatively low concentrations. Many also have both antiadherent and glidant properties. For these reasons, hydrophobic lubricants are used much more frequently than hydrophilic compounds.
Disintegrants
Disintegrants facilitate dispersion or breakup of tablets and contents of capsules into smaller particles. This leads to quick dissolution when it comes in contact with aqueous fluids in the GI tract or dissolution medium during in vitro testing. Disintegrants act by either or both (a) swelling in the presence of water and bursting tablet and granule open and/or (b) capillary action to promote rapid ingress of water into the center of the tablet or capsule.
Good disintegrants should have good hydration capacity, poor solubility, and poor gel formation capacity.
Fillers
Fillers typically also fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. It also facilitates precise metering and handling thereof in the preparation of dosage forms. May contribute to dissolution and disintegration characteristics. Used in tablets and capsules.
A good filler should typically be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compactible, and preferably tasteless or pleasant tasting.
Coating Material
Coating is a process by which an essentially dry, outer layer of coating material is applied to the surface of a dosage form. Agents which are used in this coating process are called coating agents. They provide Provide a physical barrier coating on the surface of the compressed core tablets. The barrier functions as protection, masking, elegance, ease of swallowing, identification etc. There are three types of coating agents that are used pharmaceutically. They are film coating, sugar coating, compression coating.
Colouring Agent
Coloring agents are pharmaceutical ingredients that impart the preferred color and aesthetic look to the final formulation. They add to Visual appeal of the color of the product. Dyes colouring agents are used in liquid dosage form while lakes colouring agents are used in chewable tablets. There are two types of coloring agents which are natural and synthetic.
Stabilizer
Stabilization of the drug in the dosage form from stresses such as oxidation
Sweetener (Sweetening Agents)
Sweetening agents are employed in formulations designed for oral administration specifically to increase the palatability of the therapeutic agent. Sweetening to overcome drug taste and/or improve palatability for some types of tablets (chewable, dispersible, etc) and liquid.
Flavouring Agent
Flavouring agents are added to improve taste and increase patient acceptance. The four basic taste sensations are salty, sweet, bitter and sour. It has been proposed that certain flavours should be used to mask these specific taste sensations. The same with sweetening agents in some contexts.
Sorbents
Sorbents are materials that soak up oil from the water. Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing (taking up of a liquid or a gas either by adsorption or by adsorption) in a dry state. There different types of sorbent which are natural sorbents which are anything natural that contains carbon and synthetic sorbents
Antiadherents
Antiadherent or anti-sticking agents prevent adhesion of the tablet surface to the die walls and the punches and as a consequence counter the picking or sticking of the tablet.
Preservatives
Preservatives are substances that are commonly added to various foods and pharmaceutical products in order to prolong their shelf life. They protect the product against microbial proliferation but do not compromise product performance. A good preservative must exert a wide spectrum of antimicrobial activity at low inclusion levels, maintain activity throughout product manufacture, shelf life and usage, not compromise the quality or performance of product, pack or delivery system and not adversely affect patient safety or tolerance of the product.
Antioxidant
An antioxidant is a molecule that inhibits the oxidation of other molecules. They protect the drug against oxygen and peroxide degradation. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Antioxidants must be effective at a low, nontoxic concentration, stable and effective under normal conditions of use, over a wide pH and temperature range and soluble at the required concentration
They must be compatible with a wide variety of drugs and pharmaceutical excipients, free from objectionable odor, objectionable taste, colorless in both the original and oxidized form, nontoxic both internally and externally at the required concentration, cheap and unreactive (does not adsorb, penetrate, or interact) with containers or closures.
Solvent
A solvent is a substance that can dissolve a solute (a chemically different liquid, solid or gas) resulting in solution. A solvent is usually a liquid but it can also be solid or a gas. A solvent never changes its state forming a solution. Solvents can be broadly classified into two groups. They are polar and nonpolar. Generally polar solvent dissolves polar compound best and non polar solvent dissolves non polar compound best. A good example of solvent is water. Others are water–miscible solvent such as chlordiazepoxide hydrochloride can be used to improve solubility and stability. Oils are used as emulsion, intramuscular injections and liquid fill oral preparation. Aqueous methanol is widely used in HPLC and is the standard solvent in sample extraction. Other acceptable non-aqueous solvents are glycerol, propylene glycol, ethanol and are used generally for a lipophilic drug.
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Co-solvent
Co-solvents are defined as water-miscible organic solvents that are used in liquid drug formulations to increase the solubility of poorly water soluble substances or to enhance the chemical stability of a drug. An ideal co-solvent should not cause toxicity or irritancy when administered for oral or parenteral use. It must possess values of dielectric constant between 25 and 80. The most widely used system that will cover this range is a water/ethanol blend.
Vehicles
In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Petrolatum, dimethyl sulfoxide and mineral oil are common vehicles.
Chelating Agents
They are molecules that are capable of forming complexes with the drug involving more than one bond. A complex compound contains one or more rings in its structure . For example; ethylene diamine is bidentate and ethylene diamine tetraacetic acid is hexadentate.
Example and uses of chelating agent;
* EDTA: ethylene diamine tetraacetate is used for the estimation of metals ions.
* EDTA 4: ethylenediaminetetraacetic acid is used for softening water.
* Calcium Disodium Edetate: it is used in the treatment of heavy metal poisoning mostly caused by lead.
* Disodium Edetate: it is used in hypercalcemic states. It is also useful in the treatment of cardiac arrhythmias.
Buffering Agent
These are materials which, when dissolved in solvent, will enable the solution to resist any change in pH should an acid or an alkali be added. The choice of suitable buffer depends on the pH and buffering capacity required. Features of buffering agent include low toxicity, should be buffered at the range of 7.4 as the pH of the body is 7.4 and should be non-irritant.
Viscosity Imparting Agents
These agents are used when it is desirable to increase or decrease the viscosity of a liquid either to serve as adjacent for palatability or to improve pourability. They are also called thickening agents. Viscosity imparting agents are of two types:
a) Viscosity modifier-Viscosity modifiers decrease the viscosity of a liquid to improve pour ability and make it more palatable.
b) Viscosity enhancer- Viscosity enhancers increase the viscosity of a liquid to improve pour ability and make it more palatable.
Humectant
A humectant attracts and retains the moisture in the nearby air via absorption, drawing the water vapor into and/or beneath the organism/object's surface. Humectants absorb water vapors from the atmosphere till a certain degree of dilution is attained. They are used in cream to prevent them from drying out and their package from cap locking. Aqueous solutions of humectants can reduce the rate of loss of moisture.
Ideal Properties Of Humectants
1. It must absorb moisture from the atmosphere and retain the same under the normal conditions of atmospheric humidity
2. It should be colorless or not of too intense color. 3. It should have a good odor and taste
4. It should be nontoxic and nonirritant
5. It should be non corrosive to packaging materials 6. It should not solidify under normal conditions
7. It should not be too costly. .
Classification of humectants
There are three types of humectants such as inorganic humectants, metal organic humectants and organic humectants. Inorganic humectants are limited in use in cosmetics. It has compatibility problems and is corrosive in nature. Hence it is not frequently used in cosmetics. Metal organic humectants are limited in use in cosmetics because of compatibility problems, corrosive nature and pronounced taste. Organic humectants are widely used in cosmetics.
Surfactants
Surfactants are compounds that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid and increase the solubility. They are also known as surface active agents. A surfactant must have both lipophilic and hydrophilic regions. The hydrophilic and lipophilic regions must be balanced because then both the regions will be concentrated at an interface and therefore surface tension will be lowered.
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Types Of Surfactants
There are four types of surfactants based on the charge of the hydrophilic region
1. Anionic surfactant ( here the hydrophilic region is negatively charged i.e. an anion)
2. Cationic surfactant (here the hydrophilic region is positively charged i.e. a cation)
3. Non-ionic surfactants
4. Amphoteric surfactant
Emollient
Emollients are used in the formulation of topical creams and ointments to provide smoothness and softness to the skin. They are equally used to adjust the consistency of the products. Emollients are usually used together with emulsifying agents for better results.
Emulsifying Agent
Emulsifying agent also known as emulsifiers. In the formation of emulsions micelle formation is important. Emulsion is a biphasic formulation whereby two or more immiscible liquids are forced to mix and remain together by decreasing the kinetic energy between them using emulsifying agents. This incident lowers the surface tension between three or more immiscible liquids or between liquid and solid. They are used to stabilize emotions by preventing or reducing the qualities of disperse globus by lowering the interfacial tension in their motion. This agent has surface active as it absorbs to the newly-formed oil-water interphase during emulsion preparation. This ensures the emulsion form does not coalesce or cream.
Adjuvant
Adjuvants are added to vaccines to enhance or modify the immune system response to an immunization. An adjuvant may stimulate the immune system to respond more vigorously to a vaccine, which leads to more robust immunity in the recipient.
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