Design of pyrazine cocrystals of enzalutamide: a lead from 1,4-dioxane solvates†

Enzalutamide (Enz), sold under the brand name “XTANDI”, belongs to a group of drugs known as androgen receptor inhibitors and functions by suppressing androgen's actions, which in turn helps in treating castrate-resistant prostate cancer. The current study focuses on the solvates and cocrystals of enzalutamide. Firstly, we obtained single crystals of 1,4-dioxane (Dox) solvate in two different stoichiometric ratios, Enz–Dox 1 : 0.5 and Enz–Dox 2 : 0.5. Based on this, we chose the coformer pyrazine (Pyrz), which is structurally similar to the Dox solvate. Crystallization of Pyrz with Enz also yielded 1 : 0.5 and 2 : 0.5 stoichiometries like the Dox solvate, but these existed as cocrystals (Enz–Pyrz 1 : 0.5 and Enz–Pyrz 2 : 0.5). Despite the solvate and cocrystal of the same stoichiometry (1 : 0.5/2 : 0.5) exhibiting identical sorts of interactions, the inclusion of a coformer in the cocrystal prompted a few additional bonds to form, but the overall crystal environment is still preserved. From the packing similarity analysis, it was found that Enz–Dox 1 : 0.5 and Enz–Pyrz 1 : 0.5 have similar packing indexes; however, the former generates a 2D hydrogen bonded network and the latter leads to a 3D network. The same trend is observed in the cases of Enz–Dox 2 : 0.5 and Enz–Pyrz 2 : 0.5. Hirshfeld analysis was performed to evaluate the prominence of various intermolecular interactions. Void map analysis enabled us to understand the roles of solvent and coformer in the crystal packing. Periodic DFT computations and DSC studies were performed to correlate thermal stabilities of solvates and cocrystals. Accelerated stability experiments revealed the better stability of cocrystals over solvates. This study provides valuable insights into solvate formation, which can be used as an effective strategy for attaining cocrystals with desired entities.