Research On Polymorphism And Spherical Crystallization Of Atorvastatin Calcium

Lipitor, the trade name of atorvastatin calcium, has achieved a sales record inworld for its good therapeutic effect. According to the applied patent of atorvastatincalcium, it has more than30polymorphs. The patents of the most importantpolymorphs I and II are about to expire in2016, then, its generic drugs will belaunched by the competitive manufactures. The research object of this paper ispolymorph I and II of atorvastatin calcium.Atorvastatin calcium Form I was prepared from atorvastatin lactone. Form II wasobtained through the slurring experiment of Form I. Form I and II were furthercharacterized by scanning electron microscopy, powder X-ray diffractometry, KFwater content analysis, thermal analysis and isothermal moisture absorption analysis.The results indicate that Form I and II are both trihydrate; Form I contains twochannel water and one isolated site water in its crystal lattice; Form II is channelhydrate.The solubility and stable form of atorvastatin calcium in mixed solvent ofmethanol and water at25℃were determined through slurring experiments. And sowas the stable form in ethanol and water. The water activities of these mixed solventwere calculated. The conclusion is as follows: the stable form of atorvastatin calciumin mixed solvent at25℃is determined by the water activity in solvent, when thewater activity is0.696, form I and II coexist; when water activity is above0.696, formI is stable; form II is more stable when water activity is lower than0.696. Thecomposition change of solid and liquid phase in the process of polymorphtransformation from I to II in mixed solvents of methanol and water was measured byoffline sampling. It indicated that solvent mediated polymorph transformation of fromI was nucleation-growth control. The effects of temperature, solvent composition andstirring speed on the induction time of polymorph transformation were measured byFBRM.Size-controllable spherical particles of atorvastatin calcium with good flow ability,improved water solubility and acceptable CH2Cl2residual content were successfullyprepared by spherical agglomeration with CH2Cl2, CH3OH and H2O as bridging agent,good solvent and bad solvent. The process of spherical agglomeration was characterized by FBRM. The results suggested an immediate agglomeration occurredwhen CH2Cl2was added together with drug solution and this may restrict polymorphtransformation. The effects of stirring speed and the amount of CH2Cl2on the size ofspherical particles were also determined which indicated that higher stirring speed andmore CH2Cl2,the smaller size.Up to date, the research in this work is still rare in literatures.