Study On The Behavior And Structure Prediction Of Apremilast Polymorph

The active drug ingredients(API)have different solid forms,such as polymorph,solvate,salt,amorphous,and co-crystal.Among them,polymorphs refer to the possibility that the molecules of a given compound may be arranged in two or more ways in the unit cell.According to statistics,more than 50%of drugs have polymorphism.Different crystal forms of the same drug have significant differences in morphology,solubility,dissolution rate,and bioavailability.This will affect the stability,bioavailability,and efficacy of the drug.Apremilast is an oral small-molecule PDE4 inhibitor developed by Celgen in the United States,which is a typical polymorphic drug.In this work,Apremilast forms B and E were chosen as the research object.The method of combining experiment and computer simulation was used to study its crystal structure,thermodynamics,and nucleation kinetics.A method of polymorphic prediction is proposed to assist the screening and development of the drug crystal form of Apremilast.(1)Prepare the powders and single crystals of Apremilast forms B and E,use PXRD,FT-IR,DSC,TGA and PLM to characterize the properties of the crystal powder,and analyze the single crystal structure data by SXRD.In addition,the powder and single crystal structure data of the forms B and E are compared to determine the corresponding the forms of the single crystal and the powder.(2)Determine the solubility of Apremilast forms B and E in different molar ratios of methanol-water,acetonitrile-water,and acetonitrile-methanol binary solvents by static method.The activity coefficient models such as Wilson,NRTL and UNIQUAC were selected to fit the solubility data,and the parameters were used to explain the change trend of solubility.Under the Born-Haber cycle,molecular simulations were used to calculate the Gibbs dissolution free energy during the dissolution process,and the radial function distribution(RDF)was used to study the influence of solute-solvent and solvent-solvent interactions on solubility in the solution model.(3)Analysis the metastable zone and induction time of the forms B and E by self-consistent Nyvlt-like model and Classic Nucleation Theory.Through molecular simulation calculations,the state of the two crystal forms at the initial stage of nucleation and the mechanism of Apremilast polymorphic form were analyzed from a microscopic point of view.(4)Predict the possible crystal structures of Apremilast molecule.The probability of hydrogen bond formation,the energy change of molecular conformation and the energy-density distribution of the crystal packing effect are calculated.Discuss the influence of these three factors on the prediction process of Apremilast polymorphs.The predicted structures were compared with the experimentally measured forms B and E and the accuracy of the prediction is analyzed.