Rational Crystal Polymorph Design of Olanzapine

Abstract

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.

Crystal Morphology Prediction of Olanzapine Forms III and IV

“…Thus, we validated our method approaching the case of OZPN form I at first, which was observed in the experiment. [ 4 ] As shown in Figure , the calculated crystal morphology of form III exhibits an excellent consistence with the observed shape. [ 4 ] Hence, our rational theoretical design of morphology by considering their effect parameters (energies, supersaturation and temperature) would accelerate the identification of crystal habits of forms III and IV in process of experiments.…”

“…Thereby, the morphology prediction of OZPN by spiral growth mechanistic model is rational and acceptable. Based on this model, Luo [ 4 ] and Sun [ 22 ] have predicted the crystal morphologies of OZPN forms I and II, which match excellently with the observed crystal shapes from ethanol solvent. In this work, we used the same spiral growth model to predict the morphologies of OZPN form III and form IV from different solvents, that haven't been available by the experiment.…”

“…[ 3 ] On the other hand, the structures, spectra, and crystal shapes of forms I and II have been theoretically studied by the high‐level ab initio method. [ 4 ] The structure of form III (structure A162) was predicted via crystal structure prediction (CSP) based on calculations of conformational energy difference and molecular charge distribution, which has not been investigated experimentally. [ 2 ] The predicted structure provides a best visual and statistical fit to the form III powder data through a two‐phase refinement.…”

Crystal forms in pharmaceutical applications: olanzapine, a gift to crystal chemistry that keeps on giving

“…In fact, energy reranking of the 0 K structures of OZPN using a higher accuracy energy model, specifically B86bPBE-XDM (PAW), produced a crystal energy landscape with the four lowest energy candidate structures corresponding to the four known polymorphs, see Fig. 4(b) (LeBlanc & Johnson, 2019;Luo et al, 2019). Forms I and IV remain, within the margin of error, comparable in lattice energy and more stable than forms II and III*.…”

Phase Transition of Ice at High Pressures and Low Temperatures

“…Due to the limitation of computation time, the high-level quantum chemistry methods, such as the MP2 theory, cannot be directly applied for calculations of macromolecules. The EE-GMF is a fragment-based quantum mechanical (QM) method [24,[34][35][36][37], which divides the internal energy per unit cell of the crystal into a proper combination of the energies of monomers and overlapping dimers, and therefore can treat the molecular crystals at the QM level efficiently. The fragmented monomers and dimers are embedded in the electrostatic field of the rest of the crystalline environment [22][23][24]35,36,38].…”