Diffusion and Flux Improvement of Drugs through Complexation

Improving the solubility and permeability of drugs via cocrystallization is an important theme in crystal engineering with practical applications for the discovery and development of high bioavailability medicines. The past decade has witnessed a surge of publications on pharmaceutical cocrystals/salts to improve the permeability of Biopharmaceutics Classification System (BCS) class IV drugs. In this review article, the reader is introduced to the fundamentals of drug permeability mechanisms and then examples of pharmaceutical cocrystals and salts designed to enhance drug diffusion and permeability are presented, in order to understand the different structural factors that modulate drug flux and transport across a semipermeable membrane. Broadly, two main phenomena can be summarized from the 50 or so examples: (1) The heterosynthons in hydrogen-bonded drug-coformer aggregates survive long enough in the experimental media such that the drug, which is present in high concentration due to supersaturation, exhibits higher flux across the semipermeable membrane. (2) The coformer or cocrystal is able to reduce the transepithelial electrical resistance (TEER) values of lipid monolayers, which impairs their tight junctions, and facilitates drug passage to improve its diffusion/permeability. The medicinal chemistry literature on high permeability drugs is recapitulated with the idea that these principles may be utilized in the de novo design of high permeability coformers for the synthesis of improved-performance pharmaceutical cocrystals. Enhancing drug solubility and permeability without changing its molecular structure in supramolecular complexes of pharmaceutical cocrystals and salts will address the poor bioavailability challenge for a majority of BCS class II and IV drugs.