An excipient is a substance formulated alongside the
active ingredient of a
medication
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
. They may be used to enhance the active ingredient’s therapeutic properties; to facilitate
drug
A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...
absorption; to reduce
viscosity
Viscosity is a measure of a fluid's rate-dependent drag (physics), resistance to a change in shape or to movement of its neighboring portions relative to one another. For liquids, it corresponds to the informal concept of ''thickness''; for e ...
; to enhance
solubility
In chemistry, solubility is the ability of a chemical substance, substance, the solute, to form a solution (chemistry), solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form su ...
; to improve long-term stabilization (preventing
denaturation and aggregation during the expected
shelf life); or to add bulk to solid formulations that have small amounts of potent active ingredients (in that context, they are often referred to as "bulking agents", "fillers", or "diluents"). During the manufacturing process, excipients can improve the handling of active substances and facilitate powder flow. The choice of excipients depends on factors such as the intended
route of administration
In pharmacology and toxicology, a route of administration is the way by which a medication, drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance ...
, the
dosage form, and compatibility with the active ingredient.
Virtually all marketed drugs contain excipients, and final drug formulations commonly contain more excipient than active ingredient. Pharmaceutical regulations and standards mandate the identification and safety assessment of all ingredients in drugs, including their chemical decomposition products. Novel excipients can sometimes be patented, or the specific formulation can be kept as a
trade secret
A trade secret is a form of intellectual property (IP) comprising confidential information that is not generally known or readily ascertainable, derives economic value from its secrecy, and is protected by reasonable efforts to maintain its conf ...
to prevent competitors from duplicating it through
reverse engineering
Reverse engineering (also known as backwards engineering or back engineering) is a process or method through which one attempts to understand through deductive reasoning how a previously made device, process, system, or piece of software accompl ...
.
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";
in other words, their effects on
pharmacodynamics
Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
and
pharmacokinetics, although usually negligible, cannot be ''known'' to be negligible without
empirical confirmation and sometimes are important. For that reason, in
basic research
Basic research, also called pure research, fundamental research, basic science, or pure science, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenome ...
and
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s they are sometimes included in the
control substances in order to minimize
confounding
In causal inference, a confounder is a variable that influences both the dependent variable and independent variable, causing a spurious association. Confounding is a causal concept, and as such, cannot be described in terms of correlatio ...
, 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
A vehicle () is a machine designed for self-propulsion, usually to transport people, cargo, or both. The term "vehicle" typically refers to land vehicles such as human-powered land vehicle, human-powered vehicles (e.g. bicycles, tricycles, velo ...
-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
Adhesion is the tendency of dissimilar particles or interface (matter), surfaces to cling to one another. (Cohesion (chemistry), Cohesion refers to the tendency of similar or identical particles and surfaces to cling to one another.)
The ...
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:
*
Saccharide
A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' m ...
s and their derivatives:
**
Disaccharide
A disaccharide (also called a double sugar or ''biose'') is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, ...
s:
sucrose
Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula .
For human consumption, sucrose is extracted and refined ...
,
lactose
Lactose is a disaccharide composed of galactose and glucose and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from (Genitive case, gen. ), the Latin word for milk, plus the suffix ''-o ...
;
**
Polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
s and their derivatives:
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diet ...
es,
cellulose
Cellulose is an organic compound with the chemical formula, formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of glycosidic bond, β(1→4) linked glucose, D-glucose units. Cellulose is an important s ...
or modified cellulose such as
microcrystalline cellulose
Microcrystalline cellulose (MCC) is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production. The most common form is used in vitamin supple ...
and
cellulose ethers such as
hydroxypropyl cellulose (HPC);
**
Sugar alcohol
Sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are organic compounds, typically derived from sugars, containing one hydroxyl group attached to each carbon atom. They are white, water-soluble solids that c ...
s such as
xylitol,
sorbitol
Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alco ...
or
mannitol;
* Protein:
gelatin
Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...
;
* Synthetic
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
s:
polyvinylpyrrolidone (PVP),
polyethylene glycol
Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular wei ...
(PEG)...
Binders are classified according to their application:
*Solution binders are dissolved in a solvent (for example
water
Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...
or
alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
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
allergen
An allergen is an otherwise harmless substance that triggers an allergic reaction in sensitive individuals by stimulating an immune response.
In technical terms, an allergen is an antigen that is capable of stimulating a type-I hypersensitivi ...
s. Occasionally, other coating materials are used, for example synthetic polymers,
shellac
Shellac () is a resin secreted by the female Kerria lacca, lac bug on trees in the forests of India and Thailand. Chemically, it is mainly composed of aleuritic acid, jalaric acid, shellolic acid, and other natural waxes. It is processed and s ...
, 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.
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
Organoleptic properties are the aspects of food, water or other substances as apprehended via the senses—including taste, sight, smell, and touch.
In traditional U.S. Department of Agriculture meat and poultry inspections, inspectors p ...
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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
, 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
Water is an inorganic compound with the chemical formula . It is a transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance. It is the main constituent of Earth's hydrosphere and the fluids of all known liv ...
, it rapidly breaks down into smaller fragments, facilitating
dissolution.
[
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.[
For example, to improve:]
* a bitter product– mint, cherry
A cherry is the fruit of many plants of the genus ''Prunus'', and is a fleshy drupe (stone fruit).
Commercial cherries are obtained from cultivars of several species, such as the sweet '' Prunus avium'' and the sour '' Prunus cerasus''. The na ...
or anise may be used
* a salty product–peach
The peach (''Prunus persica'') is a deciduous tree first domesticated and Agriculture, cultivated in China. It bears edible juicy fruits with various characteristics, most called peaches and the glossy-skinned, non-fuzzy varieties called necta ...
, apricot or liquorice
Liquorice ( Commonwealth English) or licorice (American English; see spelling differences; ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring is ...
may be used
* a sour product–raspberry
The raspberry is the edible fruit of several plant species in the genus ''Rubus'' of the Rosaceae, rose family, most of which are in the subgenus ''Rubus#Modern classification, Idaeobatus''. The name also applies to these plants themselves. Ras ...
or liquorice may be used
* an excessively sweet product–vanilla
Vanilla is a spice derived from orchids of the genus ''Vanilla (genus), Vanilla'', primarily obtained from pods of the flat-leaved vanilla (''Vanilla planifolia, V. planifolia'').
''Vanilla'' is not Autogamy, autogamous, so pollination ...
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
Silica gel is an amorphous and porosity, porous form of silicon dioxide (silica), consisting of an irregular three-dimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain wate ...
, fumed silica
Fumed silica (CAS_Registry_Number, CAS number 7631-86-9, also 112945-52-5), also known as pyrogenic silica because it is produced in a flame, consists of microscopic droplets of amorphous silica fused into branched, chainlike, three-dimensional ...
, talc
Talc, or talcum, is a clay mineral composed of hydrated magnesium silicate, with the chemical formula . Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent and lubricant ...
, 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
Lubricant
A lubricant (sometimes shortened to lube) is a substance that helps to reduce friction between surfaces in mutual contact, which ultimately reduces the heat generated when the surfaces move. It may also have the function of transmitting forces, ...
s 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
Friction is the force resisting the relative motion of solid surfaces, fluid layers, and material elements sliding against each other. Types of friction include dry, fluid, lubricated, skin, and internal -- an incomplete list. The study of t ...
between the solid and die wall.[
Common minerals like ]talc
Talc, or talcum, is a clay mineral composed of hydrated magnesium silicate, with the chemical formula . Talc in powdered form, often combined with corn starch, is used as baby powder. This mineral is used as a thickening agent and lubricant ...
or silica
Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , commonly found in nature as quartz. In many parts of the world, silica is the major constituent of sand. Silica is one of the most complex and abundant f ...
, and fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers specif ...
s, e.g. vegetable stearin
Stearin , or tristearin, or glyceryl tristearate is an odourless, white powder. It is a triglyceride derived from three units of stearic acid. Most triglycerides are derived from at least two and more commonly three different fatty acids. Like ...
, magnesium stearate or stearic acid
Stearic acid ( , ) is a saturated fatty acid with an 18-carbon chain. The IUPAC name is octadecanoic acid. It is a soft waxy solid with the formula . The triglyceride derived from three molecules of stearic acid is called stearin. 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.
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 A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...
, vitamin E
Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...
, vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
, retinyl palmitate, and selenium
Selenium is a chemical element; it has symbol (chemistry), symbol Se and atomic number 34. It has various physical appearances, including a brick-red powder, a vitreous black solid, and a grey metallic-looking form. It seldom occurs in this elem ...
* The amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s cysteine
Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
and methionine
Methionine (symbol Met or M) () is an essential amino acid in humans.
As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
* Citric acid
Citric acid is an organic compound with the formula . It is a Transparency and translucency, colorless Weak acid, weak organic acid. It occurs naturally in Citrus, citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, ...
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
Desiccation is the state of extreme dryness, or the process of extreme drying. A desiccant is a hygroscopic (attracts and holds water) substance that induces or sustains such a state in its local vicinity in a moderately sealed container. The ...
) the surrounding materials.
Sweeteners
Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid
An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...
or liquids like cough syrup. Sugar
Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...
can be used to mask unpleasant tastes or smells, but artificial sweeteners tend to be preferred, as natural ones tend to cause tooth decay.[
]
Vehicles
In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the active ingredient is usually called the vehicle
A vehicle () is a machine designed for self-propulsion, usually to transport people, cargo, or both. The term "vehicle" typically refers to land vehicles such as human-powered land vehicle, human-powered vehicles (e.g. bicycles, tricycles, velo ...
. Petrolatum
Petroleum jelly, petrolatum (), white petrolatum, soft paraffin, or multi-hydrocarbon, CAS number 8009-03-8, is a semi-solid mixture of hydrocarbons (with carbon numbers mainly higher than 25), originally promoted as a Topical medication, topica ...
, dimethyl sulfoxide
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
and mineral oil
Mineral oil is any of various colorless, odorless, light mixtures of higher alkanes from a mineral source, particularly a distillate of petroleum, as distinct from usually edible vegetable oils.
The name 'mineral oil' by itself is imprecise, ...
are common vehicles.
See also
* Active ingredient
* Pharmaceutics
*Pharmacology
Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...
*Placebo
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
*Placebo effect
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
* Quality system
References
External links
{{Commonscat, Excipients
FDA database for Inactive Ingredient Search for Approved Drug Products
Excipient selection for injectable / parenteral formulations
IPEC-Americas
UCSF-CERSI Excipient Browser
Drug manufacturing
Pharmacy