Study On The Quality Consistency Evaluation Of The Statin Generic Drugs

Statins are the most classic and effective lipid-lowering drugs widely used in treating hyperlipidemia.Now,generic together with original statins are clinically used.Generic drugs have exactly the same active ingredient?API?as the original drugs.In addition,it is expected to be same in dosage form,route of administration,therapeutic effect,safety,strength and quality as the original drug.Generic drugs have important economic and social advantages such as reducing medical expenditure,improving medical service level,improving drug accessibility and affordability,since it provides a new way to solve the difficult situation of patients who can,t access to drugs because of financial burden.Due to some historic reasons,there is still a big gap for generics compared with original drugs in quality and efficacy etc.Currently,the consistency evaluation of generic drugs has attracted much attention and has become a focused spotlight in the domestic drug research.And it will play an important role in improving the drug safety and effectiveness,and upgrading the research and manufacturing in Chinese pharmaceutical industry as well.Our interest in this research is focused on consistency evaluations of simvastatin tablets and fluvastatin sodium capsules.The consistency tests are conducted including crystal forms,dissolution effects,related substances,so as to illustrate the differences between original and generic drugs,and how it is formed as well.The main content of this paper are as follows:1.Simvastatin tablet?1?Powder X-ray diffraction?PXRD?technique was employed to identify the characteristic peaks first,then established the quantitative analysis method of the crystal content in simvastatin tablets which laid a foundation for the control of crystal content.The results showed that the crystal content of original and generic drugs is quite different,and the average content is 64.6%and 99.4%respectively.?2?The correlation between crystal content and dissolution behavior was studied,which indicated slower dissolution in drugs with lower content of the major crystal form.In addition,a differentiating dissolving curve was established based on series of experiments.The results showed that the dissolution factor was f₂<50,and the dissolution curve was not similar.The research results have the extensive applicability and practical significance for the consistency evaluation of other statins.?3?LC-QTOF-MS was used and four new degradation products were found.It also found that the impurity profiles of the generic and the original drugs were different to some extent with established HPLC method.The amount of simvastatin ring-opening impurity and total impurities in the generics were 0.62%and 2.03%which were higher than the originals'0.17%and 1.11%.It was found that antioxidant can provent simvastatin from opening the ring to generate hydroxyl acid.In summay,the quality control of simvastatin should be concentrated on the related substances and dissolution activities,since the analysis of related substances is of guiding significance for the formulation process.2.Fluvastatin sodium capsule:?1?Original and generic API has defferent cristal forms.However,it was revealed that fluvastatin sodium was amorphism in the original capsules and cristal in the generic capsules.Experiments were carefully designed on effect of conditions such as high temperature,high humidity and illumination on crystal form transformation of APIs and capsules.?2?The phenomenon of capsular cross linking in the dissolution of Fluvastatin Sodium Capsules was found.To dissolve this problem,a new dissolution test method for fluvastatin sodium capsules was established?papain solution was used as medium?,which will definitely supplement the dissolution method for gelatin capsule cross-linking phenomenon,providing a basis for revising the dissolution standard of fluvastatin sodium capsules.The dissolution curve of the original and generic products were compared and found to be not similar with the dissolution factor f₂<50.?3?The analytical method of related substances was revised based on USP40 which improved the national standard.The proportion of mobile phase in chromatographic conditions was carefully optimized,which provided accurate ralative retention time and relative response factor of the main components and related substances.The results showed that related substances in original and generic products were the same.The impurity profile and stability of fluvastatin sodium API and its capsule were investigated by LC-QTOF-MS.Totally seven new impurities are found,which can be supplement to the impurity profile.It can be concluded that the key quality control of fluvastatin sodium capsule lies in the control of degradation impurities.And consequently,manufacturing and storage conditions should be focused on.