Physicochemical Profiling (Solubility, Permeability and Charge State) (2001)

About 30% of drug candidate molecules are rejected due to pharmacokinetic-related failures. When poor pharmaceutical properties are discovered in development, the costs of bringing a potent but poorly absorbable molecule to a product stage by "formulation" can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stages of discovery. This review will consider recent developments in physicochemical profiling used to identify candidate molecules with physical properties related to good oral absorption. Poor solubility and poor permeability account for many PK failures. FDA's Biopharmaceutics Classification System (BCS) is an attempt to rationalize the critical components related to oral absorption. The core idea in the BCS is an in vitro transport model, centrally embracing permeability and solubility, with qualifications related to pH and dissolution. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In principle, the framework of the BCS could serve the interests of the earliest stages of discovery research. The BCS can be rationalized by considering Fick's first law, applied to membranes. When molecules are introduced on one side of a lipid membrane barrier (e.g., epithelial cell wall) and no such molecules are on the other side, passive diffusion will drive the molecules across the membrane. When certain simplifying assumptions are made, the flux equation in Fick's law reduces simply to a product of permeability and solubility. Many other measurable properties are closely related to permeability and solubility. Permeability (Pe) is a kinetic parameter related to lipophilicity (as indicated by the partition and distribution coefficients, log P and log D). Retention (R) of lipophilic molecules by the membrane (which is related to lipophilicity and may predict PK volumes of distribution) influences the characterization of permeability. Furthermore, strong drug interactions with serum proteins can influence permeability. The unstirred water layer on both sides of the membrane barrier can impose limits on permeability. Solubility (S) is a thermodynamic parameter, and is closely related to dissolution, a kinetic parameter. The unstirred water layer on the surfaces of suspended solids imposes limits on dissolution. Bile acids effect both solubility and dissolution, by a micellization effect. For ionizable molecules, pH plays a crucial role. The charge state that a molecule exhibits at a particular pH is characterized by the ionization constant (pKa) of the molecule. Buffers effect pH gradients in the unstirred water layers, which can dramatically affect both permeability and dissolution of ionizable molecules. In this review, we will focus on the emerging instrumental methods for the measurement of the physicochemical parameters Pe, S, pKa, R, log P, and log D (and their pH-profiles). These physicochemical profiles can be valuable tools for the medicinal chemists, aiding in the prediction of in vivo oral absorption.