Excipient

An 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.

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.

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:

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.

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:

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

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]

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.[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:

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 and 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

Antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium

The amino acids cysteine and methionine
Citric acid and sodium citrate
Synthetic preservatives like the parabens: methyl paraben and propyl paraben.

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
Active ingredient
 Pharmaceutics
Pharmacology
Placebo
Placebo effect
Quality system

References
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"Investigation and Mathematical Description of the Real Driving Force of Passive Transport
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3816–3826. doi:10.1021/acs.molpharmaceut.6b00613 (https://doi.org/10.1021%2Facs.molp
harmaceut.6b00613). PMID 27611057 (https://pubmed.ncbi.nlm.nih.gov/27611057).
2. Hsu T, Mitragotri S (September 2011). "Delivery of siRNA and other macromolecules into
skin and cells using a peptide enhancer" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC31
79050). Proceedings of the National Academy of Sciences of the United States of America.
108 (38): 15816–21. Bibcode:2011PNAS..10815816H (https://ui.adsabs.harvard.edu/abs/20
11PNAS..10815816H). doi:10.1073/pnas.1016152108 (https://doi.org/10.1073%2Fpnas.101
6152108). PMC 3179050 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179050).
PMID 21903933 (https://pubmed.ncbi.nlm.nih.gov/21903933).
3. Lokesh B, Stefan S, Sheehan C, William R (2006). "Excipients: Background/Introduction". In
Katdare A, Chaubal M (eds.). Excipient Development for Pharmaceutical, Biotechnology,
and Drug Delivery Systems. CRC Press. ISBN 9781420004137. OCLC 476062541 (https://
www.worldcat.org/oclc/476062541).
4. JOSHUA POTTEL (July 24, 2020). "The activities of drug inactive ingredients on biological
targets" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960226). Science. 369 (6502):
403–413. doi:10.1126/science.aaz9906 (https://doi.org/10.1126%2Fscience.aaz9906).
PMC 7960226 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960226). PMID 32703874
(https://pubmed.ncbi.nlm.nih.gov/32703874).
5. Gavura S (February 21, 2019). "What's all that other stuff in my medicine?" (https://web.archi
ve.org/web/20190221184000/https://sciencebasedmedicine.org/whats-all-that-other-stuff-in-
my-medicine-2/). Science-Based Medicine. Archived from the original (https://sciencebased
medicine.org/whats-all-that-other-stuff-in-my-medicine-2/) on February 21, 2019. Retrieved
February 21, 2019.
6. Mills S (April 2007). Excipients (http://apps.who.int/prequal/trainingresources/pq_pres/Traini
ngZA-April07/Excipients.ppt) (Microsoft PowerPoint). Training Workshop on Pharmaceutical
Development with focus on Paediatric Formulations (http://apps.who.int/prequal/trainingreso
urces/Training_courseZA-April07.htm). World Health Organization. Archived (https://web.arc
hive.org/web/20121020184046/http://apps.who.int/prequal/trainingresources/pq_pres/Traini
ngZA-April07/Excipients.ppt) from the original on October 20, 2012.
7. 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 (http
s://doi.org/10.1016%2Fj.ejpb.2010.01.007). PMID 20096779 (https://pubmed.ncbi.nlm.nih.go
v/20096779).
8. 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" (https://
doi.org/10.1016%2Fj.powtec.2017.09.028). Powder Technology. 322: 332–339.
doi:10.1016/j.powtec.2017.09.028 (https://doi.org/10.1016%2Fj.powtec.2017.09.028).
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 9. Morin G, Briens L (September 2013). "The effect of lubricants on powder flowability for
pharmaceutical application" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755167).
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External links
FDA database for Inactive Ingredient Search for Approved Drug Products (http://www.access
data.fda.gov/scripts/cder/iig/index.Cfm)
Excipient selection for injectable / parenteral formulations (https://web.archive.org/web/2014
0809100407/http://www.ipapharma.org/epharmatimes/Mar2013/#65)
IPEC-Americas (http://ipecamericas.org/)
UCSF-CERSI Excipient Browser (http://excipients.ucsf.bkslab.org/)

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