Module 5 : Pharmaceutical Preformulation : Basics and Industrial Applications

Biopharmaceutics Classification System

Permeability along with solubility forms the scientific basis of Biopharmaceutics Classification System (BCS). Oral absorption involves permeability across intestinal membrane. USFDA document defines permeability as ‘effective human jejunal wall permeability of drug and includes apparent resistance to mass transfer to intestinal membrane’. Drugs after dissolution have to cross this barrier, for reaching into systemic circulation. According to the BCS, drug substances are classified as follows:

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Class 1: High Solubility – High Permeability
Class 2: Low Solubility – High Permeability
Class 3: High Solubility – Low Permeability
Class 4: Low solubility – Low permeability

How much solubility and permeability are good enough?

A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1-7.5. A drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. In terms of apparent permeability coefficient (Papp) across Caco-2 cell line, a value greater than 2×10-5 cm/s indicates good permeability.

Structural requirements for solubility and permeability

Interestingly contrasting physico-chemical properties are required for achieving optimal aqueous solubility and permeability. A biological membrane like the intestinal membrane consists of a lipid bilayer that regulates absorption of solutes like drug molecules. The lipid bilayer does not allow passage of water soluble polar molecules. Similarly ionized molecules though have higher water solubility, but their permeability is poor. A successful drug molecule should possess a balance between hydrophilicity and lipophilicity, to achieve optimal solubility and permeability. A log P value of about 2 is considered optimal for good permeability. Apart from this physiological phenomenon like cytochrome P450 mediated metabolism and Pgp efflux play a crucial role in permeability across biological membranes.

Modulation of permeability for formulation development

Permeability can be determined using in vitro tools like PAMPA, Caco-2 cell lines, everted rat intestine; in situ experiments like single pass intestinal perfusion in rats and in vivo data like human absorption data. Apart from its role in candidate selection in drug discovery, permeability dictates selection of route of administration and drug delivery system. Drugs belonging to BCS class 3 and 4 have poor permeability and are hence administered using parenteral route. Modulation of permeability finds limited applications in drug delivery. Permeability can be modulated to a limited extent by use of permeability enhancers. Some of the commonly used excipients like polysorbate 80, poloxamer and cremophor RH 40, can inhibit Pgp efflux transporters, thus enhancing permeability. Even from a drug designing perspective, it is preferred to enhance solubility rather than permeability. Permeability can vary only over a narrow range of about 50 folds, as compared to solubility, which can be varied over a million folds. Hence a greater enhancement in oral bioavailability can be achieved by modifying solubility.

Dr. Arvind Bansal

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