Research On The Crystallization Process For Purification Of Atorvastatin Calcium

Atorvastatin calcium is the active ingredient in lipid-lowering drug Lipitor,and it has a significant effect in reducing blood lipid levels.The drug is produced by synthesis,separation,purification,and formulation.The research focuses on the purification of atorvastatin calcium using crystallization.The goal of atorvastatin calcium purification is that the product purity should be higher than 99.2%,the content of five main impurities is reduced to less than 0.1%,the solid form is crystal form I,the mass yield is not less than 90%,and the water content is between 4～5 wt%.Since the research is oriented towards actual production,purity,crystal form,yield and water content are the focuses of this work.In the research development of atorvastatin calcium crystallization,nucleation,polymorphic transformation,and the relationship between crystal structure and property were investigated.Based on experimental results,a concurrent flow solvent-out crystallization was developed.There are two solutions are simultaneously added into a third solution,and solvent composition of the third solution remains unchanged.Compared with the conventional solvent-out crystallization,the method has reduced the micromixing effect on the local supersolubility and avoided preparing the irregular crystal products.In order to make the method easy to operate in industrial production,this paper further simplifies the method in combination with the production conditions.After simplification,methanol mass fraction of mixed solvent maintains in 15～30% in concurrent flow solvent-out process,and form I atorvastatin calcium crystals can be obtained in the end.Through the research,the purity of crystalline atorvastatin calcium powder is not less than 99.6%.Each impurity has a content of no more than0.1%.It also has a crystal form of complete form I,crystals have a mean size of no more than 30 μm and a water mass content of 4～5%,and the mass yield is more than90%.There are four distinct endothermic peaks in DSC pattern of the crystalline powder,which is consistent with DSC pattern of the original drug.Namely,the product stability is significantly improved,and all quality indicators meet enterprise standards.