Research On Polymorphism Of Clopidogrel Hydrogen Sulfate

Pharmaceutical polymorphism not only affects the preparation process, pharmaceuticalquality and stability of the priduct, but also related to the bioavailability and efficacy of thedrug. So the research of solid-state drug has drawn more and more people’s attention.In this work, we carried on a study on crystallization process of Clopidogrel HydrogenSulfate polymorphism systematically, mainly by employing PLM, SEM, FT-IR, PXRD, TGA,and DSC to characterize Clopidogrel Hydrogen Sulfate polymorphism, and then calculatedthe quantitative standard curves of amorphous vs. form I and the form I vs. form II by IR.The solubilities of three forms in different solvents were measured experimentally bygravimetric method and then regression by using Van’t-Hoff equation and Grant equationrespectively. Combined solubility datas with other thermodynamic records, the stabilityrelationship between the polymorphism, as well as the thermodynamic relationship betweencrystal transition was obtainedbased on crystal stability and system attributes judgment rules.By performing the reaction in ethyl acetate system crystallized in methanol with rapidformation of an amorphous experiment to explore the crystallization of the drug each stage ofthe reaction sequence and turn crystal generation region. Crystal transformation rates weremeasured in different crystallization conditions, then matched them with some suitabletransition crystal kinetic equations. So the transition reaction rate k, crystallization activationenergy EAand the constant A were calculated by the Arrhenius equation.Referring to the datas of thermodynamics and transition crystallization kinetics, theinfluences of means solvent removed by, temperature and solvents on the preparation of theamorphous; the effects of adding sulfate, seed, additives and solvents when form I wasprepared, and comparation of the methods for the preparation of form II. Thus, the preparationprocess of each polymorph of Clopidogrel Hydrogen Sulfate were optimized respectively. Allthese works will provide the basic data for the industrial production of the polymorph ofClopidogrel Hydrogen Sulfate.