Tazofelone

To continue the realization of new therapeutics, a more diverse range of solid forms is being considered.Synthetic modalities are broadening beyond simple organic mols. to more complicated structures, including organic salts, cocrystals, and solvates.As in all crystalline applications, engineering the morphol. of such systems remains an important consideration, but traditional in silico approaches require further development to become capable of accurately describing these systems.A necessary, but not sufficient, condition to enact mechanistic crystal growth models is to calculate and organize solid-state interactions between growth units.The typical software framework for acquiring this information is to apply crystallog. symmetry operations to generate a unit cell from the asym. unit.While this approach is feasible for systems where the asym. unit corresponds to the growth unit itself, many systems do not satisfy this criterion, particularly the emerging therapeutic solid forms.By redesigning the input preparation software framework, we can build a description of the solid-state interactions that is independent of the asym. unit and applicable to any crystallog. complexity.We demonstrate the application of this method to three organic mol. crystals with crystallog. of varying degrees of complexity.The studied systems are naphthalene (Z' = 0.5), benzoic acid (Z' = 1), and tazofelone (Z' = 2), resp. (where Z' is the number of mols. in the asym. unit).This new software framework lays the groundwork for rapid in silico habit predictions of organic salts, cocrystals, and solvates.The traditional method of obtaining solid-state interactions to predict crystal morphol. relies on applying crystallog. operations to generate a unit cell from the asym. unit using a.cif file, which is difficult for complex solid forms (Z' ≠ 1).We built a description of the solid-state interactions using a.mol2 file that is independent of the asym. unit and applicable to any crystallog. complexity.

Almost 20 years after the crystal polymorphism of tazofelone was 1st studied at Lilly, the compound was revisited by calculating the crystal energy landscape and complementing the calculations with exptl. work for calibration purposes.The crystal structure prediction study confirmed the stability of racemic form II (RCII) and showed that the racemic compound had greater potential for polymorphism than the single enantiomer.The seeding experiment that has previously been shown to produce a racemic solid solution (SS) correlates with the isostructurality between some low energy racemic structures and the enantiopure form.Other low energy structures have the same layer structure as both racemic polymorphs and the newly-discovered, but closely related, polymorph RCIII, which accounts for the difficulty in obtaining phase pure samples of the metastable RCI and RCIII and the problems of structural purity evidenced by streaked diffraction spots for RCI-III in the single crystal diffraction.This mol. picture of the problems in ensuring structural purity in the layer structure polymorphs of tazofelone not only explains the crystal dependent thermochem. measurements of tazofelone, but also shows the value of combining a range of exptl. and computational techniques to investigate the organic solid state.