Study On Olanzapine Polymorph Based On Computer Simulation Technology

Polymorph forms of drug molecules will lead to differences in the physical and chemical properties,affecting the usage and safety of drugs.The study of molecular polymorph of drugs has become an essential part of drug development and production.With the development of computer simulation technology and basic theories theoretical calculations are used to simulate molecular structures and study the polymorphic properties of drug molecules,which can provide guidance for experiments and greatly shorten the development cycle.This paper selects the anti-schizophrenia drug olanzapine molecule as the research object.Olanzapine is a typical polymorphic drug with more than 60 crystal structures.Based on computer simulation technology,this paper focuses on the polymorphic structure of two anhydrous forms of olanzapine,and explores its energy,spectrum,morphology and other properties.The details are as follows:Using first-principles calculations,this paper combined with quantum mechanical(QM)fragmentation methods,molecular simulation and Raman spectrum studies of two forms were carried out.The results show that the simulation calculation method used in this paper can accurately construct the steady state structure of the olanzapine polymorph.The simulated Raman spectrum is consistent with the experimental Raman spectrum.The Raman spectrum can effectively reflect the similarities and differences of the two forms.In addition,unlike traditional lattice energy calculations,this paper used Gibbs free energy to evaluate the stability of crystal structures,including the effects of entropy and temperature.The results show that the Gibbs free energy of Form I is smaller than that of Form II,and thus Form I is the most thermodynamically stable structure.The Gibbs free energy difference between Form I and Form II widens as temperature rises,and there is no possibility of polymorphic transformation between the two forms.Furthermore,when predicting crystal structure,using Gibbs free energy to perform secondary screening on the predicted structure can make the result more accurate.This paper also carried out research on the prediction of crystal morphology of two forms,by using different models.The results show that the two forms can form flaky crystals in ethanol solvents,and that the actual morphology of the crystals can be accurately predicted by the spiral growth model considering the environmental factors such as solvents.This paper provides the possibility to use theoretical calculations to complete the rational design of drug molecules.It not only studies crystal forms of existing drugs,but also motivates the exploration of new crystal forms with special effects.