A molecular picture of the problems in ensuring structural purity of tazofelone

Almost twenty years after the crystal polymorphism of tazofelone was first studied at Lilly, the compound was revisited by calculating the crystal energy landscape and complementing the calculations with experimental 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 molecular picture of the problems in ensuring structural purity in the layer structure polymorphs of tazofelone not only explains the crystal dependent thermochemistry measurements of tazofelone, but also shows the value of combining a range of experimental and computational techniques to investigate the organic solid state