Study Of Atorvastation Calcium Form

In recent years,with the continuous improvement of the level of China's economic conditions and the intensification of the aging population,the number of people suffering from cardiovascular and cerebrovascular diseases has increased year by year.The demand for drugs for cardiovascular diseases has increased year by year.Atorvastatin Calcium as a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor has been listed for hypercholesterolemia,mixed hyperlipidemia and homozygotes since it was introduced in the United States in 1996 familial hypercholesterolemia has a good therapeutic effect.The annual sales volume exceeds 10 billion US dollars and has become the drug of choice for patients with cardiovascular disease.In 2013,the State Food and Drug Administration conducted a conformity assessment of generic drugs,requiring the quality of generic drugs to be consistent with that of the original research.Although the purity of domestically produced atorvastatin calcium reached the requirements of foreign countries,it was found a large difference in clinical therapeutic effects comparison with the Atorvastatin produced in foreign countries.The study found that the reason for this result is the different crystal form of the drug.This article first briefly introduced the mechanism and development of cardio-cerebrovascular diseases,hypolipidemic agents and statins.It focused on the preparation and detection methods of crystalline drugs,and briefly discussed the research status and significance of crystalline drugs.Secondly,on the basis of reference to domestic and foreign patents,an in-depth study of atorvastatin calcium crystallization process was conducted to design a crystallization process of atorvastatin calcium that is stable and easy to operate.By systematically studying the effects of crystallization solvent and its proportion,crystallization temperature,dropping rate and mode,stirring speed,and cooling mode on the crystallization of atorvastatin calcium,the optimal process parameters were obtained: the crude atorvastatin calcium was used 7 volumes of methanol and 3.5 volumes of acetonitrile were dissolved and clarified.The solution was added dropwise to distilled water at 65 °C.The rate of acceleration was 1.2 ml/min and the stirring speed was 30 r/min.The cooling procedure method for the mixture is cooling and then cool down quickly.The product obtained was a white powder solid with a yield of 88.0 % or more.Analyzed by HPLC,XRD,SEM,etc.,it was identified as type I atorvastatin calcium with a long strip shape and a purity of 99.6% or more.Again,the crystallization process of atorvastatin calcium is progressively amplified from 10 g-100 g-500 g,which leads to product failure due to the amplification effect in the actual industrial production.Therefore,the atorvastatin calcium is applied to 100 g of atorvastatin calcium.The optimum conditions for the crystallization process of 100 g of atorvastatin calcium were determined by adding 1500 ml of distilled water to a 5000 ml reaction flask at a stirring rate of 30 r/min.After incubating to 65 °C,the crude atorvastatin calcium was dissolved in 7 volumes of methanol and 3.5 volumes of acetonitrile.After clarification,the solution was rapidly added dropwise to a white solid and precipitated in large quantities.The rate of slow dropwise addition was added to 5000 ml.In the reaction flask,the addition was completed within 120 min.The heating was turned off,and the stirring was continued for 30 min.The crystal was allowed to stand and slowly cooled down to room temperature.The resulting product was a white powdery solid with a yield of 87.0 % or more.Analyzed by HPLC,XRD,SEM,etc.,it was identified as type I atorvastatin calcium with a long strip shape and a purity of 99.6% or more.Finally,the 100 g process was scaled up to 500 g to verify the three batches of parallel experiments.The average yield of the product was 84.8 %.The average purity was determined by HPLC,XRD,SEM,IR and other analytical methods to be 99.8 %,and the infrared spectra were consistent with the literature.The morphology of the test was long and the XRD peak position was consistent with the original research patent.The process is simple,stable,and reproducible.It provides reliable experimental data for crystallization of atorvastatin calcium and is suitable for industrial production.