Rational Crystal Polymorph Design of Olanzapine

Polymorphism refers to the phenomenon that crystals of the same chemical composition can crystallize into several different forms with different physicochemical conditions. Studying the polymorphism of drugs has become an indispensable and important part of daily predesign work for drug production and formulation. Here, we use ab initio computational calculations in combination with rational crystal structure design and morphology prediction to study the polymorphism of the pharmaceutical compound olanzapine, an effective drug to treat schizophrenia, using density functional theory and second-order Møller-Plesset perturbation methods. Different crystal polymorphs are found at the calculated energy landscape, and the analysis of Gibbs free energy and Raman spectra confirms that the long-accepted form I of olanzapine is identified as the most thermodynamically stable structure. With the increase of temperature, form I of olanzapine exhibits greater stability than that of form II. Rather than the traditional lattice energy calculations, we use the Gibbs free energy to evaluate the stability of crystal structure, which includes the effects of entropy and temperature and is more accurate when predicting the crystal structures. We also provide an effective method to identify different forms of polycrystalline structures based on the vibrational spectra and offer an advanced tool to predict the crystal morphologies. The present paper offers a platform for rational design of pharmaceutical molecules, which not only reestablishes the crystal structures of existing drugs but also provides motivation for the possibility of the exploration of new drugs with special efficacy.