Excipient

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Excipient is a substance formulated alongside the active ingredient of a medication. Excipients serve various purposes, including long-term stabilization, bulking up solid formulations containing potent active ingredients in small amounts (often referred to as "bulking agents", "fillers", or "diluents"), or enhancing the therapeutic properties of the active ingredient in the final dosage form. They can facilitate drug absorption, reduce viscosity, or enhance solubility. [1] [2] Excipients can also aid in the manufacturing process by improving the handling of active substances, facilitating powder flowability, or preventing denaturation and aggregation during the expected shelf life. The selection of excipients depends on factors such as the route of administration, dosage form, and active ingredient.

Contents

Pharmaceutical regulations and standards mandate the identification and safety assessment of all ingredients in drugs, including their chemical decomposition products. It is common for a final drug formulation to contain more excipient than active ingredient, and virtually all marketed drugs contain excipients. In some cases, novel excipients can be patented, while in others, the specific formulation involving them is kept as a trade secret to prevent reverse engineering.[ citation needed ]

Relative versus absolute inactivity

Though excipients were at one time assumed to be "inactive" ingredients, it is now understood that they can sometimes be "a key determinant of dosage form performance"; [3] in other words, their effects on pharmacodynamics and pharmacokinetics, although usually negligible, cannot be known to be negligible without empirical confirmation and sometimes are important. For that reason, in basic research and clinical trials they are sometimes included in the control substances in order to minimize confounding, reflecting that otherwise, the absence of the active ingredient would not be the only variable involved, because absence of excipient cannot always be assumed not to be a variable. [4] Such studies are called excipient-controlled or vehicle-controlled studies.

Types

Adjuvants

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.

Antiadherents

Antiadherents reduce the adhesion between the powder (granules) and the punch faces and thus prevent sticking to tablet punches by offering a non-stick surface. They are also used to help protect tablets from sticking. The most commonly used is magnesium stearate.

Binders

Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are usually:

Binders are classified according to their application:

Coatings

Tablet coatings protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. For most coated tablets, a cellulose ether hydroxypropyl methylcellulose (HPMC) film coating is used which is free of sugar and potential allergens. Occasionally, other coating materials are used, for example synthetic polymers, shellac, corn protein zein or other polysaccharides. Capsules are coated with gelatin.

Enterics control the rate of drug release and determine where the drug will be released in the digestive tract. Materials used for enteric coatings include fatty acids, waxes, shellac, plastics, and plant fibers.

Colours

Colours are added to improve the appearance of a formulation. Colour consistency is important as it allows easy identification of a medication. Furthermore, colours often improve the aesthetic look and feel of medications. Small amounts of colouring agents are easily processed by the body, although rare reactions are known, notably to tartrazine. [5] Commonly, titanium oxide is used as a colouring agent to produce the popular opaque colours along with azo dyes for other colors. By increasing these organoleptic properties a patient is more likely to adhere to their schedule and therapeutic objectives will also have a better outcome for the patient especially children.

Disintegrants

Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, or in specific segments of the digestion process, releasing the active ingredients for absorption. They ensure that when the tablet is in contact with water, it rapidly breaks down into smaller fragments, facilitating dissolution. [5]

Examples of disintegrants include:

Flavours

Flavours can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. [6] [5]

For example, to improve: [6]

Glidants

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 wall friction. Examples include silica gel, fumed silica, talc, and magnesium carbonate. However, some silica gel glidants such as Syloid(R) 244 FP and Syloid(R) XDP are multi-functional and offer several other performance benefits in addition to reducing interparticle friction including moisture resistance, taste, marketing, etc.

Lubricants

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. [5]

Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. Lubricants are agents added in small quantities to tablet and capsule formulations to improve certain processing characteristics. While lubricants are often added to improve manufacturability of the drug products, it may also negatively impact the product quality. For example, extended mixing of lubricants during blending may results in delayed dissolution and softer tablets, which is often referred to as "over-lubrication". Therefore, optimizing lubrication time is critical during pharmaceutical development. [7] [8] [9]

There are three roles identified with lubricants as follows:

To decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches and dies.
Prevent sticking to punch faces or in the case of encapsulation, lubricants.
Prevent sticking to machine dosators, tamping pins, etc.
Enhance product flow by reducing interparticulate friction.

There are two major types of lubricants:

Generally poor lubricants, no glidant or anti-adherent properties.
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 anti-adherent and glidant properties. For these reasons, hydrophobic lubricants are used much more frequently than hydrophilic compounds. Examples include magnesium stearate.

Preservatives

Some typical preservatives used in pharmaceutical formulations are

Sorbents

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 absorption) in a dry state. For example, desiccants absorb water, drying out (desiccating) the surrounding materials.

Sweeteners

Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid or liquids like cough syrup. Sugar can be used to mask unpleasant tastes or smells, but artificial sweeteners tend to be preferred, as natural ones tend to cause tooth decay. [5]

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.

See also

Related Research Articles

<span class="mw-page-title-main">Polyvinylpyrrolidone</span> Water-soluble polymer

Polyvinylpyrrolidone (PVP), also commonly called polyvidone or povidone, is a water-soluble polymer compound made from the monomer N-vinylpyrrolidone. PVP is available in a range of molecular weights and related viscosities, and can be selected according to the desired application properties.

<span class="mw-page-title-main">Tablet (pharmacy)</span> Drug delivery form in which the ingredients are solidified for later consumption

A tablet is a pharmaceutical oral dosage form or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose. The main advantages of tablets are that they ensure a consistent dose of medicine that is easy to consume.

A diluent is a diluting agent. Certain fluids are too viscous to be pumped easily or too dense to flow from one particular point to the other. This can be troublesome, because it might not be economically feasible to transport such fluids in this state. To ease this restricted movement, diluents are added. This decreases the viscosity of the fluids, thereby also decreasing the pumping/transportation costs.

An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals.

<span class="mw-page-title-main">Hydroxypropyl cellulose</span> Chemical compound

Hydroxypropyl cellulose (HPC) is a derivative of cellulose with both water solubility and organic solubility. It is used as an excipient, and topical ophthalmic protectant and lubricant.

<span class="mw-page-title-main">Capsule (pharmacy)</span> Relatively stable shell containing medicine

In the manufacture of pharmaceuticals, encapsulation refers to a range of dosage forms—techniques used to enclose medicines—in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are:

<span class="mw-page-title-main">Magnesium stearate</span> Chemical compound

Magnesium stearate is the chemical compound with the formula Mg(C
18
H
35
O
2
)
2
. It is a soap, consisting of salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate is a white, water-insoluble powder. Its applications exploit its softness, insolubility in many solvents, and low toxicity. It is used as a release agent and as a component or lubricant in the production of pharmaceuticals and cosmetics.

<span class="mw-page-title-main">Hypromellose</span> Cellulose ether used as emulsifier or thickening agent to disperse colloids in water

Hypromellose (INN), short for hydroxypropyl methylcellulose (HPMC), is a semisynthetic, inert, viscoelastic polymer used in eye drops, as well as an excipient and controlled-delivery component in oral medicaments, found in a variety of commercial products.

Dosage forms are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration, and apportioned into a particular dose. For example, two products may both be amoxicillin, but one is in 500 mg capsules and another is in 250 mg chewable tablets. The term unit dose can also sometimes encompass non-reusable packaging as well, although the FDA distinguishes that by unit-dose "packaging" or "dispensing". Depending on the context, multi(ple) unit dose can refer to distinct drug products packaged together, or to a single drug product containing multiple drugs and/or doses. The term dosage form can also sometimes refer only to the pharmaceutical formulation of a drug product's constituent drug substance(s) and any blends involved, without considering matters beyond that. Because of the somewhat vague boundaries and unclear overlap of these terms and certain variants and qualifiers within the pharmaceutical industry, caution is often advisable when conversing with someone who may be unfamiliar with another person's use of the term.

<span class="mw-page-title-main">Orally disintegrating tablet</span> Pill that dissolves on contact with saliva

An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter (OTC) and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. The ODT serves as an alternative dosage form for patients who experience dysphagia or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population and 18-22% of all patients in long-term care facilities ODTs may have a faster onset of effect than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.

Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.

<span class="mw-page-title-main">Cellulose acetate phthalate</span> Chemical compound

Cellulose acetate phthalate (CAP), also known as cellacefate (INN) and cellulosi acetas phthalas, is a commonly used polymer phthalate in the formulation of pharmaceuticals, such as the enteric coating of tablets or capsules and for controlled release formulations. It is a cellulose polymer where about half of the hydroxyls are esterified with acetyls, a quarter are esterified with one or two carboxyls of a phthalic acid, and the remainder are unchanged. It is a hygroscopic white to off-white free-flowing powder, granules, or flakes. It is tasteless and odorless, though may have a weak odor of acetic acid. Its main use in pharmaceutics is with enteric formulations. It can be used together with other coating agents, e.g. ethyl cellulose. Cellulose acetate phthalate is commonly plasticized with diethyl phthalate, a hydrophobic compound, or triethyl citrate, a hydrophilic compound; other compatible plasticizers are various phthalates, triacetin, dibutyl tartrate, glycerol, propylene glycol, tripropionin, triacetin citrate, acetylated monoglycerides, etc.

Migraleve is the brand name of a range of migraine-relief medications made by Pfizer.

Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.

A glidant is a substance that is added to a powder to improve its flowability. A glidant will only work at a certain range of concentrations. Above a certain concentration, the glidant will in fact function to inhibit flowability.

Colloidal silicas are suspensions of fine amorphous, nonporous, and typically spherical silica particles in a liquid phase. It may be produced by Stöber process from Tetraethyl orthosilicate (TEOS).

Hydrophilization is a process used for hydrophobic drugs to increase their release rate from capsules, which is dependent on the rate of dissolution, by covering the surface of the drug particles with minute droplets of a hydrophilic polymer solution.

<span class="mw-page-title-main">Tableting</span> Method of pressing medicine or candy into tablets

Tableting is a method of pressing medicine or candy into tablets. Confectionery manufacture shares many similarities with pharmaceutical production.

<span class="mw-page-title-main">Glyceryl behenate</span> Chemical compound

Glyceryl behenate is a fat used in cosmetics, foods, and oral pharmaceutical formulations. In cosmetics, it is mainly used as a viscosity-increasing agent in emulsions.

Animal products in pharmaceuticals play a role as both active and inactive ingredients, the latter including binders, carriers, stabilizers, fillers, and colorants. Animals and their products may also be used in pharmaceutical production without being included in the product itself.

References

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