Influence of Impurities on the Solution-Mediated Phase Transformation of an Active Pharmaceutical Ingredient

The solution-mediated phase transformation of the metastable A form of an active pharmaceutical ingredient ( 1 ) to the stable B form is investigated in 2-propanol. The transformation behavior (or rate) is quantified using powder X-ray diffraction. The studies show that the rate of transformation is sensitive to the tailor-made impurities and that the presence of certain inhibitors reduces the rate of transformation. Concurrently molecular modeling studies are undertaken to investigate the incorporation of these structurally related impurities into the crystal lattice, and it is observed that the build-in approach used in morphology predictions for additive−host systems can be applied to evaluate the extent of impurity incorporation. The build-in approach employs the attachment energy method in which the host molecules are substituted by impurity molecules, and the relative incorporation energies are calculated for various crystal faces. The order of the relative incorporation energies of the structurally similar impurities is identical to the order of the percentages of the amount of impurities incorporated into the crystal lattice as determined by high performance liquid chromatography (HPLC).