These salts (most often sodium) from bile acids are mainly present in the small intestine and are excreted by the gall bladder. Bile acids are biological surfactants which solubilize fatty components, such as fat soluble vitamins and dietary fat. They can also solubilize poorly soluble drugs.
This describes how much of an orally administered drug is absorbed through the gut wall and appears intact in the bloodstream. Bioavailability depends on the solubility, stability, permeability and first-pass metabolism of a drug.
Bioequivalence studies are carried out to demonstrate that a drug product has the same pharmacokinetic properties as the original product in order to be able to limit the amount of clinical trials. It particularly refers to generic drug products but can also be used for innovator products in late stage clinical testing and after approval when substantial formulation or manufacturing changes have been made.
A generic formulation can be bioequivalent to the original product when the product has the same active ingredient, dosage form, strength, route of administration and conditions of use as the original.
Biopharmaceutical Classification System (BCS)
The Biopharmaceutical Classification System or 'BCS' is a way to classify drugs into 4 categories according to their aqueous solubility and permeability. The BCS was developed by Gordon L. Amidon in 1995 (GL Amidon et al., Pharm Res Vol 12(3): 413-420, 1995).
Class I: High Solubility – High Permeability
Class II: Low Solubility – High Permeability
Class III: High Solubility – Low Permeability
Class IV: Low Solubility – Low Permeability
These parameters can be used to justify whether or not an oral drug product with immediate release may be eligible for a Biowaiver.
A term coined by Professor Jennifer Dressman to describe in vitro fluids that simulate in vivo fluids closely.
If a drug product meets certain specifications detailed in the FDA guidance (there is also guidance from the EMA and WHO), it is possible that it can be approved without having to show bioequivalence in a human pharmacokinetic study. Highly water soluble drugs that are also highly permeable are the best candidates for the biowaiver and the product must be a solid oral drug product with immediate release characteristics. To determine whether the biowaiver approval procedure can be applied, you must compare the dissolution from the test and reference formulations at pH 1.2, 4.5 and 6.8. The procedure is most useful for approval of generic drug products and after scale up or post approval changes to existing products.
An aqueous solution which resists changes in pH when small quantities of an acid or alkali are added to it. Buffer solutions are therefore used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications.
'Buffer capacity' is a measure of the resistance of a buffer solution to pH change on addition of hydroxide ions.
Critical Micelle Concentration (CMC)
In physical chemistry, 'CMC' stands for the Critical Micelle Concentration of a surfactant. Below the CMC, the amphiphilic molecules are concentrated at the interface between the two phases (e.g. water and air) and decrease the free energy (surface tension). Once the CMC is reached, the amphiphilic molecules start forming micelles because the interface is completely saturated. The micelles can act as solubilizers for poorly soluble drugs.
Developability Classification System (DCS)
In 2010 Butler et al. proposed the 'DCS' or Developability Classification System. The DCS has a greater focus on the developability of a compound based on solubility and dissolution rate limiting absorption than its counterpart, the BCS. It also takes into account the solubility in Biorelevant Media such as FaSSIF or FeSSIF and the compound’s estimated clinical dose.
A dissolution test determines the amount of compound dissolved over a certain period of time. Dissolution testing is most often carried out with standardized dissolution equipment such as the USP 2.
Jennifer Dressman is the Professor of Pharmaceutical Technology at J.W. Goethe University in Frankfurt, Germany. She conceived of the original Biorelevant Media in the late 1990's.
'FaSSCoF' stands for Fasted State Simulated Colonic Fluid. You can learn more about it here.
'FaSSIF' stands for Fasted State Simulated Gastric Fluid. You can learn more about it here.
'FaSSIF' stands for Fasted State Simulated Intestinal Fluid. You can learn more about it here.
The 'Fasted State' refers to the physiological conditions of the fluid in the gastro-intestinal tract before a meal. The concentration of natural surfactants such as bile salts and phospholipids are typically lower in the fasted than fed state.
The 'Fed State' refers to the physiological conditions in the gastro-intestinal tract after a meal. Typically, the body responds to the intake of food by increasing the secretion of the natural surfactants, bile salts and phospholipids. These enable the lipid components in the meal to be digested.
'FeSSCoF' stands for Fed State Simulated Colonic Fluid. You can learn more about it here.
'FeSSGF' stands for Fed State Simulated Gastric Fluid. You can learn more about it here.
'FeSSIF' stands for Fed State Simulated Intestinal Fluid. You can learn more about it here.
The GI tract, short for gastro-intestinal tract, comprises the stomach and the intestines. It can be separated into the upper, middle and lower regions.
in vitro is Latin for 'within glass'. The term is often used in biopharmaceutics to describe laboratory tests which are performed to simulate the dissolution, disintegration or permeability behaviour of a compound or formulation in vivo.
in vivo is Latin for 'within the living'. The term is often used in biopharmaceutics for pre-clinical animal or clinical human trials to understand the behaviour of a drug product.
'IVISIVC' stands for in vivo/in silico/in vitro correlation. In addition to the data needed for an IVIVC, it uses physiologically based pharmacokinetic (PBPK) modelling software to generate plasma profiles from the in vitro dissolution data. The in silico programmes use physiological parameters together with available/predicted in vitro data for the drug (solubility, dissolution, permeability, metabolism and disposition of the drug) to simulate the plasma profiles.
'IVIVC' stands for in vivo/in vitro correlation. Achieving an IVIVC can allow you to link the in vitro performance of a compound to its in vivo bioavailability. A correlation allows you to predict how changes in formulation parameters will affect the in vivo performance of the drug product. This can reduce the amount of expensive in vivo testing needed significantly because it enables good formulations to be distinguished from poor ones. Typical data needed to establish an IVIVC are dissolution and pharmacokinetic profiles for three or more formulations of the same drug and pharmacokinetic profiles for either an oral solution or after intravenous administration of the drug.
A general term for any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic (so they attract both water and fatty substances). Lecithins are usually phospholipids and act as surfactants in Biorelevant Media.
'NCE' stands for New Chemical Entity. The FDA (Food and Drug Administration) define an NCE as a potential drug candidate which contains any functional group not yet known or approved by the FDA.
'Osmolarity' is the concentration of a solution expressed as the total number of solute particles per litre. It is expressed as mmol/L.
The permeability of a compound describes the ability of a compound to permeate through a membrane. Permeability depends on the chemical and physical properties of the compound and the membrane and is an important factor in the bioavailability of drugs.
Phospholipids are a group of lipids which comprise a mono- or di-glyceride with a phosphate group and an organic head group. Phospholipids are the major components of cell membrane and can form lipid bilayers. They are secreted along with bile salts from the gall bladder.
The states relating to a meal: fasted is before a meal and fed is after a meal.
'SIF Powder' was the original name for the product which produces Biorelevant Media in an instant. It is now known as 'FaSSIF/FeSSIF/FaSSGF' which describes the media it makes.
Simulated Gastric Fluid (SGF)
Simulated Gastric Fluid (or 'SGF') is a buffer solution intended to represent stomach acid. It should not be confused with FaSSGF which simulates gastric juice much more accurately. SGF does not contain any biological surfactants whilst FaSSGF does. These enable FaSSGF to mimic the reflux (backwards flow) of the small amount of small intestinal fluid (containing bile salts and lecithin) into the human stomach. The presence of these surfactants lowers surface tension and can influence the wetting of dosage forms and hydrophobic drugs. This can give an insight into how dosage forms interact with the media.
Simulated Intestinal Fluid (SIF)
Simulated Intestinal Fluid (or 'SIF') is a buffer solution with pH 6.8 that was introduced more than 50 years ago and should not be confused with FaSSIF. It does not contain the biological surfactants (bile salts, lecithin) present in Biorelevant Media. Unlike FaSSIF, it does not accurately reflect the prandial state (fasted or fed), pH and osmolarity of small intestinal fluid.
In a solubility test, you aim to determine how many molecules of a compound can be dissolved in a certain volume of liquid.
Supersaturation occurs if the concentration of a drug in solution exceeds its equilibrium solubility. It is important to understand because it gives an insight into how a compound can be delivered orally and can highlight potential technical risks during the development of a poorly soluble compound.
A surfactant is a compound which lowers the surface tension of a liquid, the interfacial tension of two different liquids or between a solid and a liquid. Surfactants are amphiphilic compounds. This means they have a hydrophilic group and a hydrophobic group which enables surfactants above their CMC to form micelles.
'Taurocholate' refers to Taurocholic Acid and its corresponding salt Sodium Taurocholate which is a bile acid/salt found in the GI tract of human beings and several animals. It is a natural surfactant which, together with lecithin, forms mixed micelles in the gut which can then solubilize fatty dietary components and poorly soluble drugs.
The USP (United States Pharmacopeia) Apparatus 2 is a standardized dissolution apparatus. The USP 2 refers to the paddle apparatus and comprises 8 vessels, which have a defined volume and shape, into which the compound or formulation is put together with the dissolution medium. A paddle stirs the dissolution medium at a defined speed (most often between 50 and 100 rpm).
The USP (United States Pharmacopeia) Apparatus 4 is a standardized dissolution apparatus. The USP 4 is a flow-through apparatus where the compound or formulation is placed in a cell which is continuously rinsed with the dissolution medium. A filter at the top of the cell prevents undissolved material from being lost.