The Biopharmaceutical Classification System (BCS) Dr Mohammad Issa

Biopharmaceutical Classification System (BCS) Biopharmaceutics Classification System (BCS) is a predictive approach to relate certain physicochemical characteristics of a drug substance and drug product to in-vivo bioavailability BCS categorized drugs according to two key physico-chemical parameters: Solubility Permeability

Biopharmaceutical Classification System (BCS) These two factors were selected because most orally administered drugs are absorbed via a passive diffusion process through the small intestine, where the extent of oral absorption is largely influenced by a drug’s membrane permeability and solubility

BCS Classes Class I Highly permeable Highly soluble Class II Poorly soluble Class III Poorly permeable Class IV

Biopharmaceutical Classification System (BCS) According to the FDA guidelines, a high solubility drug is defined as one that, in the largest dose strength, fully dissolves in 250 mL of aqueous medium with the pH ranging from 1 to 7.5 at 37 ° C. Otherwise, drugs are considered poorly soluble. In other words, the highest therapeutic dose must dissolve in 250 mL of water at any physiological pH In the same guidance as mentioned above, a drug is considered highly permeable if the extent of oral absorption is greater than 90%

Biopharmaceutical Classification System (BCS) objectives to guide decisions with respect to in vivo and in vitro correlations and the need for bioequivalence studies to provide a useful framework to identify appropriate dosage form designs that are aimed at overcoming absorption barriers posed by solubility and permeability related challenges

BCS Class I: High Solubility and High Permeability Compounds belonging to this class are normally expected to dissolve quickly in gastric and intestinal fluids, and readily cross the intestinal wall through passive diffusion BCS Class I are unlikely to show bioavailability or bioequivalence issues Therefore, for BCS class I drugs, in vitro dissolution studies are thought to provide sufficient information to assure in vivo product performance making full in vivo bioavailability / bioequivalence studies unnecessary

BCS Class I: High Solubility and High Permeability Although class I compounds are expected to have excellent oral absorption, given their high solubility and high permeability, additional absorption barriers may exist beyond the scope of the BCS For example, luminal complexation and degradation can significantly limit the amount of drug available for absorption. Even after the drug crosses the intestinal membrane, it may be metabolized within the enterocytes/hepatocytes and/or pumped out of the cells due to efflux mechanisms.

BCS Class II: Poor Solubility and High Permeability By definition, poor solubility and/or slow dissolution are the rate-limiting steps for oral absorption of BCS class II compounds For compounds with a very large dose-to-solubility ratio, poor solubility is likely to be the rate-limiting step for absorption. In other words, the compounds may dissolve quickly enough to reach their equilibrium solubility, but the solubility is too low to establish a wide enough concentration gradient to drive passive diffusion

BCS Class II: Poor Solubility and High Permeability Formulations designed to overcome solubility or dissolution rate problems: Salt formation Particle size reduction Metastable forms Solid dispersion Complexation Lipid based formulations Precipitation inhibitors

BCS Class III: High Solubility and Low Permeability Since passive diffusion is the rate-limiting step for oral absorption of BCS class III compounds, the most effective way to improve absorption and bioavailability of this class of compounds is to increase the membrane permeability Approaches to improve permeability: Prodrugs Permeation enhancers

BCS Class IV: Low Solubility and Low Permeability Class IV compounds exhibit both poor solubility and poor permeability, and they pose tremendous challenges to formulation development As a result, a substantial investment in dosage form development with no guarantee of success should be expected A combination of class II and class III technologies could be used to formulate class IV compounds, although the success rate is not expected to be high