Pharmaceutical formulation
Encyclopedia
Pharmaceutical formulation, in pharmaceutics
, is the process in which different chemical substances, including the active drug
, are combined to produce a final medicinal product
.
or a capsule. It is important to appreciate that a tablet contains a variety of other substances apart from the drug itself, and studies have to be carried out to ensure that the drug is compatible with these other substances.
Preformulation involves the characterization of a drug's physical, chemical, and mechanical properties in order to choose what other ingredients should be used in the preparation. In dealing with protein pre-formulation, the important aspect is to understand the solution behavior of a given protein under a variety of stress conditions such as freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation and therefore its mitigation.
Formulation studies then consider such factors as particle size
, polymorphism
, pH
, and solubility
, as all of these can influence bioavailability
and hence the activity of a drug. The drug must be combined with inactive additives by a method which ensures that the quantity of drug present is consistent in each dosage
unit e.g. each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, or capsule disintegration.
It is unlikely that formulation studies will be complete by the time clinical trials commence. This means that simple preparations are developed initially for use in phase I clinical trials. These typically consist of hand-filled capsules containing a small amount of the drug and a diluent
. Proof the long-term stability
of these formulations is not required, as they will be used (tested) in a matter of days. Consideration has to be given to what is called the drug load - the ratio of the active drug to the total contents of the dose. A low drug load may cause homogeneity problems. A high drug load may pose flow problems or require large capsules if the compound has a low bulk density
.
By the time phase III clinical trials are reached, the formulation of the drug should have been developed to be close to the preparation that will ultimately be used in the market. A knowledge of stability is essential by this stage, and conditions must have been developed to ensure that the drug is stable in the preparation. If the drug proves unstable, it will invalidate the results from clinical trials since it would be impossible to know what the administered dose actually was. Stability studies are carried out to test whether temperature
, humidity
, oxidation, or photolysis (ultraviolet light or visible light) have any effect, and the preparation is analysed to see if any degradation
products have been formed.
It is also important to check whether there are any unwanted interactions between the preparation and the container. If a plastic container is used, tests are carried out to see whether any of the ingredients become adsorbed on to the plastic, and whether any plasticizers, lubricants, pigments, or stabilizers
leach out of the plastic into the preparation. Even the adhesives for the container label
need to be tested, to ensure they do not leach through the plastic container into the preparation.
.
Drugs are normally taken orally as tablets or capsules.
The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size
and crystal
form can significantly affect dissolution
. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma
levels. Treatment of active ingredient by special way as spherical crystallization can have some advantages for drug formulation.
The disintegration time can be modified for a rapid effect or for sustained release
.
Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum
, jejunum
and colon
as a result of enzyme
action or alkaline pH
.
Pills
can be coated with sugar
, varnish
, or wax
to disguise the taste
.
Some tablets are designed with an osmotically active core, surrounded by an impermeable membrane with a pore in it. This allows the drug to percolate out from the tablet at a constant rate as the tablet moves through the digestive tract.
in order to delay absorption. They may also contain a mixture of slow- and fast-release particles to produce rapid and sustained absorption in the same dose
.
Pharmaceutics
Pharmaceutics is the discipline of pharmacy that deals with all facets of the process of turning a new chemical entity into a medication able to be safely and effectively used by patients in the community. Pharmaceutics is the science of dosage form design...
, is the process in which different chemical substances, including the active drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
, are combined to produce a final medicinal product
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
.
Stages and timeline
Formulation studies involve developing a preparation of the drug which is both stable and acceptable to the patient. For orally taken drugs, this usually involves incorporating the drug into a tabletTablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
or a capsule. It is important to appreciate that a tablet contains a variety of other substances apart from the drug itself, and studies have to be carried out to ensure that the drug is compatible with these other substances.
Preformulation involves the characterization of a drug's physical, chemical, and mechanical properties in order to choose what other ingredients should be used in the preparation. In dealing with protein pre-formulation, the important aspect is to understand the solution behavior of a given protein under a variety of stress conditions such as freeze/thaw, temperature, shear stress among others to identify mechanisms of degradation and therefore its mitigation.
Formulation studies then consider such factors as particle size
Particle size (grain size)
Particle size, also called grain size, refers to the diameter of individual grains of sediment, or the lithified particles in clastic rocks. The term may also be applied to other granular materials. This is different from the crystallite size, which is the size of a single crystal inside the...
, polymorphism
Polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals, and is related to allotropy, which refers to chemical elements...
, pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, and solubility
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
, as all of these can influence bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
and hence the activity of a drug. The drug must be combined with inactive additives by a method which ensures that the quantity of drug present is consistent in each dosage
Effective dose
Effective dose may refer to:*Effective dose the dose of pharmacologic agent which will have a therapeutic effect in some fraction of the population receiving the drug...
unit e.g. each tablet. The dosage should have a uniform appearance, with an acceptable taste, tablet hardness, or capsule disintegration.
It is unlikely that formulation studies will be complete by the time clinical trials commence. This means that simple preparations are developed initially for use in phase I clinical trials. These typically consist of hand-filled capsules containing a small amount of the drug and a diluent
Diluent
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 problematic, because it might not be economically feasible to transport such fluids in this state.To ease this restricted movement, diluents...
. Proof the long-term stability
Economic stability
Economic stability refers to an absence of excessive fluctuations in the macroeconomy. An economy with fairly constant output growth and low and stable inflation would be considered economically stable. An economy with frequent large recessions, a pronounced business cycle, very high or variable...
of these formulations is not required, as they will be used (tested) in a matter of days. Consideration has to be given to what is called the drug load - the ratio of the active drug to the total contents of the dose. A low drug load may cause homogeneity problems. A high drug load may pose flow problems or require large capsules if the compound has a low bulk density
Bulk density
Bulk density is a property of powders, granules and other "divided" solids, especially used in reference to mineral components , chemical substances, ingredients, foodstuff or any other masses of corpuscular or particulate matter. It is defined as the mass of many particles of the material...
.
By the time phase III clinical trials are reached, the formulation of the drug should have been developed to be close to the preparation that will ultimately be used in the market. A knowledge of stability is essential by this stage, and conditions must have been developed to ensure that the drug is stable in the preparation. If the drug proves unstable, it will invalidate the results from clinical trials since it would be impossible to know what the administered dose actually was. Stability studies are carried out to test whether temperature
Temperature
Temperature is a physical property of matter that quantitatively expresses the common notions of hot and cold. Objects of low temperature are cold, while various degrees of higher temperatures are referred to as warm or hot...
, humidity
Humidity
Humidity is a term for the amount of water vapor in the air, and can refer to any one of several measurements of humidity. Formally, humid air is not "moist air" but a mixture of water vapor and other constituents of air, and humidity is defined in terms of the water content of this mixture,...
, oxidation, or photolysis (ultraviolet light or visible light) have any effect, and the preparation is analysed to see if any degradation
Chemical decomposition
Chemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
products have been formed.
It is also important to check whether there are any unwanted interactions between the preparation and the container. If a plastic container is used, tests are carried out to see whether any of the ingredients become adsorbed on to the plastic, and whether any plasticizers, lubricants, pigments, or stabilizers
Stabilizers
The Stabilizers were an American pop/rock duo founded in the early 1980s by musicians Dave Christenson and Rich Nevens. With Christenson on lead vocals and Nevens on guitars and occasional keyboards, they spent the first few years touring the Pennsylvania area and recording original compositions on...
leach out of the plastic into the preparation. Even the adhesives for the container label
Label
A label is a piece of paper, polymer, cloth, metal, or other material affixed to a container or article, on which is printed a legend, information concerning the product, addresses, etc. A label may also be printed directly on the container or article....
need to be tested, to ensure they do not leach through the plastic container into the preparation.
Oral formulations
The way a drug is formulated can avoid some of the problems associated with oral administrationRoute of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
.
Drugs are normally taken orally as tablets or capsules.
The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size
Particle size (grain size)
Particle size, also called grain size, refers to the diameter of individual grains of sediment, or the lithified particles in clastic rocks. The term may also be applied to other granular materials. This is different from the crystallite size, which is the size of a single crystal inside the...
and crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...
form can significantly affect dissolution
Solvation
Solvation, also sometimes called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute...
. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels. Treatment of active ingredient by special way as spherical crystallization can have some advantages for drug formulation.
Tablet form
A tablet is usually a compressed preparation that contains:- 5-10% of the drug (active substance);
- 80% of fillers, disintegrants, lubricants, glidants, and bindersBinder (material)-See also:*Adhesive or Glue*Cement*Paint...
; and - 10% of compounds which ensure easy disintegrationDisintegrationDisintegration is the eighth studio album by English alternative rock band The Cure, released on 1 May 1989 by Fiction Records. The record marks a return to the introspective and gloomy gothic rock style the band had established in the early 1980s...
, disaggregation, and dissolution of the tablet in the stomachStomachThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
or the intestineIntestineIn human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
.
The disintegration time can be modified for a rapid effect or for sustained release
Sustained release
Time release technology, also known as sustained-release , sustained-action , extended-release , time-release or timed-release, controlled-release , modified release , or continuous-release , is a mechanism used in pill tablets or capsules to...
.
Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
, jejunum
Jejunum
The jejunum is the middle section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms middle intestine or mid-gut may be used instead of jejunum.The jejunum lies between the duodenum...
and colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
as a result of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
action or alkaline pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
.
Pills
Pill (pharmacy)
A pill is a small, round, solid pharmaceutical oral dosage form that was in use before the advent of tablets and capsules. Pills were made by mixing the active ingredients with an excipient such as glucose syrup in a mortar and pestle to form a paste, then rolling the mass into a long cylindrical...
can be coated with sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
, varnish
Varnish
Varnish is a transparent, hard, protective finish or film primarily used in wood finishing but also for other materials. Varnish is traditionally a combination of a drying oil, a resin, and a thinner or solvent. Varnish finishes are usually glossy but may be designed to produce satin or semi-gloss...
, or wax
Wax
thumb|right|[[Cetyl palmitate]], a typical wax ester.Wax refers to a class of chemical compounds that are plastic near ambient temperatures. Characteristically, they melt above 45 °C to give a low viscosity liquid. Waxes are insoluble in water but soluble in organic, nonpolar solvents...
to disguise the taste
Taste
Taste is one of the traditional five senses. It refers to the ability to detect the flavor of substances such as food, certain minerals, and poisons, etc....
.
Some tablets are designed with an osmotically active core, surrounded by an impermeable membrane with a pore in it. This allows the drug to percolate out from the tablet at a constant rate as the tablet moves through the digestive tract.
Capsule form
A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestionIngestion
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in the substance through the mouth into the gastrointestinal tract, such as through eating or drinking...
in order to delay absorption. They may also contain a mixture of slow- and fast-release particles to produce rapid and sustained absorption in the same dose
Dosing
Dosing generally applies to feeding chemicals or medicines in small quantities into a process fluid or to a living being at intervals or to atmosphere at intervals to give sufficient time for the chemical or medicine to react or show the results....
.
Topical medication forms
(Source: )- CreamCream (pharmaceutical)A cream is a topical preparation usually for application to the skin. Creams for application to mucus membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and...
- Emulsion of oil and water in approximately equal proportions. Penetrates stratum corneumStratum corneumThe stratum corneum is the outermost layer of the epidermis, consisting of dead cells that lack nuclei and organelles. The purpose of the stratum corneum is to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress...
outer layer of skin well.
- Ointment - Combines oil (80%) and water (20%). Effective barrier against moisture loss.
- GelGelA gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
- Liquefies upon contact with the skin.
- PastePaste (rheology)In physics, a paste is a substance that behaves as a solid until a sufficiently large load or stress is applied, at which point it flows like a fluid. In rheological terms, a paste is an example of a Bingham plastic fluid....
- Combines three agents - oil, water, and powder; an ointment in which a powder is suspended.
- Powder - they were finely subdivide substances, which are used as antiseptic and prurient action.
See also
- FormulationsFormulationsFormulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula...
General aspects of formulations, its manipulation and calculations. - Formulation scienceFormulation scienceFormulation science is an interdisciplinary subject where knowledge of material science, and physical chemistry, joins with the art of formulating a formulations that can have hyper activity towards a particular action...
- Pesticide formulationPesticide formulationThe biological activity of a pesticide, be it chemical or biological in nature, is determined by its active ingredient . Pesticide products very rarely consist of pure technical material. The AI is usually formulated with other materials and this is the product as sold, but it may be further...
- Medicinal chemistryMedicinal chemistryMedicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where it is involved with design, chemical synthesis and development for market of pharmaceutical...
- Dosage formDosage form-Introduction:Dosage forms are a mixture of active drug components and nondrug components. Depending on the method of administration they come in several types. These are liquid dosage form, solid dosage form and semisolid dosage forms. A Liquid dosage form is the liquid form of a dose of a...
- Drug deliveryDrug deliveryDrug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well...
- ExcipientExcipientAn excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or...
- Excipient
- Drug designDrug designDrug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
- Drug developmentDrug developmentDrug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
- Drug discoveryDrug discoveryIn the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
- Dosage form
- Galenic formulationGalenic formulationGalenic formulation deals with the principles of preparing and compounding medicines in order to optimize their absorption. Galenic formulation is named after Claudius Galen, a 2nd Century AD Greek physician, who codified the preparation of drugs using multiple ingredients...