Biopharmaceutical classification compounds

Fig. 15.5. The biopharmaceutics classification system (BCS). Drug-like molecules are grouped into four BCS classes based on their solubility and permeability. A drug is regarded as a highly soluble compound if the maximum dose given orally is soluble in 250 mL fluid in the...

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

The publication of the U.S. FDA Guidelines allowing the waiver of bioequivalence study for compounds classified as Class I based on the Biopharmaceutics Classification System... 

Following oral administration, dissolution of the drug molecule in the intestinal milieu is a prerequisite for the absorption process. According to the Biopharmaceutical Classification System (BCS) [2], poor water-soluble compounds (i.e., aqueous solubility less than 100 pg/ mL) are class 2 or class 4 compounds. For class 2 compounds, the absorption level is dictated by the dissolution properties of the molecule in the gastrointestinal (GI) fluids. BCS class 4 compounds, which are characterized by both low solubility and poor intestinal wall permeability, are generally poor drug candidates (unless the dose is very low). 

M. G. Choc and W. T. Robinson, Gastrointestinal variables and water insoluble compounds in normal and disease states, Presentation to the AAPS/CRS/FDA workshop on scientific foundation and applications for the biopharmaceutics classification and in vitro-in vivo correlations, April 14-16, 1997, Arlington VA. 

The Biopharmaceutics Classification System (BCS)3 defines four classes of compounds based upon solubility and permeability. Particle size and size distribution... 

This serves as an example of the extremes one can go if one tmly wants to better understand the process and the form of the compound in the product. This approach is less important for detecting polymorphic form conversion in the solid state, since polymorphic solubility typically varies by less than a factor of two and tablets at very low strength would generally be classified as a type one by the biopharmaceutical classification system. In addition, polymorphs rarely have pronounced differences in chemical stability. On the other hand, if a compound is somewhat unstable and significant amount of amorphous material is potentially present, this approach can be used to determine if it is responsible for drug instability in the tablet formulation. In any event, this reference serves as a very good example of the strength of a powerful approach that has not been widely applied in our industry. 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

Improved bioavailability. More than 40% of the NCEs (new chemical entity) discovered have good membrane permeability but poor aqueous solubility (i.e.. Biopharmaceutics Classification System II). By formulating the NCE in solution inside a Softgel (e.g., lipid based) or in micro/nano emulsion, the solubility and hence the bioavailability of the compound may be improved. ... 

Attempting to measure a thermodynamic solubility of compounds which will then be used under these screening conditions, will not necessarily give a useful picture of the compounds performance. They will not reflect the more transient nature of the compound that is present in nonequilibrium systems. The presence of organic solvents changes the dielectric constant of an aqueous solution and thus helps to solvate lipophilic compounds in particular, and will give an increased solubility for some series of compounds across the Biopharmaceutics Classification System (BCS) [4]. This is an important consideration in the ultimate use of the solubility data, and a lack of full solubility of the analyte at the test concentration will lead to an underestimation of the compound s true activity. Measuring the solubility of the compounds in close approximation to the assay conditions to which they will be exposed will be more relevant. Indeed, if sensitivity is not an issue, then the quantities, concentrations, and incubation conditions used should reflect those available in the discovery assays. 

Figure 1. Biopharmaceutical Classification System and Development Classification System. Class I compounds are defined as soluble and permeable through the gastrointestinal tract, Class II as poorly soluble but permeable through the GI tract, Class III as soluble but poorly permeable and Class IV as both poorly soluble and permeable. The further classification of Class II and III (simple and complex) is intended to provide additional data on the develop-ability of the drug candidate.

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