Unravelling the Origin of Solvate Formation in the Anticancer Drug Trametinib: Insights from Crystal Structure Analysis and Computational Modeling

The discovery of new crystalline forms of large, flexible drug molecules is of significant interest to the pharmaceutical industry as a means of improving one or more physicochemical properties of the active pharmaceutical ingredient (API). Trametinib (TRMB) is an anticancer drug, for which no solid-state forms are yet reported. Here, we report the results of an extensive screen for cocrystals of TRMB in an effort to improve the poor aqueous solubility of this API. Contrary to expectations, this effort led to the discovery of only six isostructural solvates of TRMB, where the solvent molecules fill the voids of the crystal structure and are stabilized by various intermolecular interactions. Computational crystal structure prediction methods were used to rationalize the high propensity for solvent inclusion in TRMB as arising from the poor crystal packing in TRMB. All predicted polymorphs of TRMB within a relative lattice energy of 44 kJ mol–1 of the global minimum display solvent accessible voids ranging from 1.4 to 16.5% of the unit cell volume. The serendipitous discovery of solvates in experiments targeting cocrystals,strongly suggests that the well-established synthon approach for the discovery of cocrystals works relatively well for documented literature examples that use rigid coformers with minimal conformational flexibility. However, for large APIs such as TRMB, in-silico screening methods should be adopted to reduce the need for extensive experimental cocrystal screens as the ability to form a cocrystal for drug candidates relies on more than synthon complementarity.