Polymorphism basics and cocrystal technology.

The adoption of cocrystals into oral pharmaceutical formulations is expected to propel this, as yet, moribund field into clinical and monetary prominence. The increase in resources and research that will inevitably follow is expected to address long standing problems in crystal engineering. Ab initio predictions of heterosynthon structure, identification of molecular descriptors to enable bioavailability enhancing coformer selection and a priori prediction of the cocrystal lattice have thus far been insoluble. Solutions to the prediction of supersaturation levels and polymorphic transition of the cocrystal formulated API in GI fluids, and solvation barrier and solubilization free energies, remain empirical. Properties such as on-demand/environment, formulation enabled, proton transfer between API and coformer and the development of neural networks or AI, trained on empirical data to predict ideal API-coformer pairs without the need to explicitly understand mechanisms, remain obscure, and hence un-researched. It is ironic that failure mechanisms that result in the delayed appearance of a less-soluble polymorph in pharmaceutical formulations (disappearing polymorphs) could (and should) be gainfully utilized to facilitate the delayed appearance in vivo of less-soluble polymorph(s) in cocrystal formulations. The bioavailability increase afforded by cocrystal formulations has the potential to enable greater patient compliance due to favorable posology, introduce more efficacious drugs into the therapeutic armamentarium, enable line-extensions and expand intellectual property portfolios, reduce the cost-of-goods; and hence of medicines, and add one more valuable tool in the repertoire of the pharmaceutical formulation scientist. [ABSTRACT FROM AUTHOR]