Excipient

An excipient is a substance formulated alongside the active ingredient of a medication,[1] included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred to as "bulking agents", "fillers", or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption,[2][3] reducing viscosity,[4] or enhancing solubility.[5] Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerns such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The selection of appropriate excipients also depends upon the route of administration and the dosage form, as well as the active ingredient and other factors. A comprehensive classification system based on structure-property-application relationships has been proposed for excipients used in parenteral medications.[6][7]

Pharmaceutical regulations and standards require that all ingredients in drugs, as well as their chemical decomposition products, be identified and shown to be safe. Often, more excipient is found in a final drug formulation than active ingredient, and practically all marketed drugs contain excipients.[1]:1 As with new drug substances and dosage forms thereof, novel excipients themselves can be patented; sometimes, however, a particular formulation involving them is kept as a trade secret instead (if not easily reverse-engineered).

The Federation of International Pharmaceutical Excipients Council (IPEC),[8] a pharmaceutical regulatory non-profit, develops, implements, and promotes global use of appropriate quality, safety, and functionality standards for pharmaceutical excipients and excipient delivery systems. IPEC-Americas, along with its counterparts in Europe, China, and Japan serves as a primary international resource on excipients for its members, governments, and public audiences. IPEC works in collaboration with ExcipientFest to present topics ranging from regulatory affairs to research and development, often featuring speakers from FDA and other pharmaceutical organizations.[9]

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";[1] 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. Such studies are called excipient-controlled or vehicle-controlled studies.

Types

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:

  • Saccharides and their derivatives:
    • Disaccharides: sucrose, lactose;
    • Polysaccharides and their derivatives: starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC);
    • Sugar alcohols such as xylitol, sorbitol or mannitol;
  • Protein: gelatin;
  • Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)...

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). Examples include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose and polyethylene glycol.
  • Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.

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.

Colors

Colors are added to improve the appearance of a formulation. Color consistency is important as it allows easy identification of a medication. Furthermore, colors often improve the aesthetic look and feel of medications. Small amounts of coloring agents are easily processed by the body, although rare reactions are known, notably to tartrazine.[7] Commonly, titanium oxide is used as a coloring agent to produce the popular opaque colors 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.[7]

Examples of disintegrants include:

  • Crosslinked polymers: crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium).
  • The modified starch sodium starch glycolate.

Flavors

Flavors can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavorings may be natural (e.g. fruit extract) or artificial.[10][7]

For example, to improve:[10]

  • a bitter product - mint, cherry or anise may be used
  • a salty product - peach, apricot or liquorice may be used
  • a sour product - raspberry or liquorice may be used
  • an excessively sweet product - vanilla may be used

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.[7]

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.[11][12][13]

There are three roles identified with lubricants as follows:

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

There are two major types of lubricants:

  • 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 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 articificial sweeteners tend to be preferred, as natural ones tend to cause tooth decay.[7]

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

References
  1. Lokesh B, Stefan S, Sheehan C, William R (2006). "Excipients: Background/Introduction". In Katdare A, Chaubal, Mahesh (eds.). Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. CRC Press. ISBN 9781420004137. OCLC 476062541.
  2. Borbás E, Sinkó B, Tsinman O, Tsinman K, Kiserdei É, Démuth B, et al. (November 2016). "Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions". Molecular Pharmaceutics. 13 (11): 3816–3826. doi:10.1021/acs.molpharmaceut.6b00613. PMID 27611057.
  3. Hsu T, Mitragotri S (September 2011). "Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer". Proceedings of the National Academy of Sciences of the United States of America. 108 (38): 15816–21. doi:10.1073/pnas.1016152108. PMC 3179050. PMID 21903933.
  4. "Protein formulations containing amino acids".
  5. Lesney, Mark S. (January 2001). "More than just the sugar in the pill". Today's Chemist at Work. 10 (1): 30–6. ISSN 1532-4494. Retrieved August 13, 2013.
  6. Apte SP, Ugwu SO (2003). "A review and classification of emerging excipients in parenteral medications". Pharmaceutical Technology. 27 (3): 46.
  7. Gavura S (February 21, 2019). "What's all that other stuff in my medicine?". Science-Based Medicine. Archived from the original on February 21, 2019. Retrieved February 21, 2019.
  8. IPEC
  9. ExcipientFest
  10. Mills S (April 2007). Excipients (Microsoft PowerPoint). Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations. World Health Organization. Archived from the original on October 20, 2012.
  11. Wang J, Wen H, Desai D (May 2010). "Lubrication in tablet formulations". European Journal of Pharmaceutics and Biopharmaceutics. 75 (1): 1–15. doi:10.1016/j.ejpb.2010.01.007. PMID 20096779.
  12. Wang Y, Osorio JG, Li T, Muzzio FJ (2017-12-01). "Controlled shear system and resonant acoustic mixing: Effects on lubrication and flow properties of pharmaceutical blends". Powder Technology. 322: 332–339. doi:10.1016/j.powtec.2017.09.028. ISSN 0032-5910.
  13. Morin G, Briens L (September 2013). "The effect of lubricants on powder flowability for pharmaceutical application". AAPS PharmSciTech. 14 (3): 1158–68. doi:10.1208/s12249-013-0007-5. PMC 3755167. PMID 23897035.
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