Atorvastatin Calcium Preparation And Quality Standards

High cholesterol and hyperlipoproteinemia is a major risk factor for cardiovascular disease, lowerplasma cholesterol level is an effective method for the treatment of atherosclerotic disease, therefore, theresearch and development of the antilipemic agents has been paid more and more attention. Atorvastatincalcium is anew generation of Statins hypolipidemic drugs, it can not only lower cholesterol, but also lowertriglycerides, and its affection is more significant than simvastatin, pravastatin, fluvastatin and lovastatin.Besides Atorvastatin Calcium (Lipitor) which are imported packing sheets, the approved AtorvastatinCalciumpreparation of domestic manufacturers were few and can not meet the clinical needs. The researchaim is focused on the related impurity of Atorvastatin Calcium tablets and its quality control by the moderninstrumental analysis methods to ensure its efficacy, safety and uniformity.Firstly, the published quality standards of Atorvastatin Calcium were summarized to find theirAdvantages and disadvantages, which were set as the further research. Then, the tablet preparation processwas explored and confirmed, its preparation formula was confirmed. On this basis, the new and perfectstandards would be subsequently explored and established.Simultaneously, the impurity spectrum of Active Pharmaceutical Ingredient (API) and AtorvastatinCalcium tablets, were analyzed completely, the major related impurities, such as Lactone, methyl ester andepoxide of the tablets, which are most likely generated from API, were isolated and identified.Then, one more reasonable control method of the related substances was established by HPLC.Method: Use Phenomene Ultremex C18column（4.6mm×250mm,5μm）with the mobile phase consistingof0.05mol/L citric acid solution(adjust the pH to4.0with Ammonia)-acetonitrile-Tetrahydrofuran（53：27：20）, the flow rate was1.5mL/min; the detected wavelength was244nm; the column temperature wasroom temperature. Result: The specificity and robustness were demonstrated good; within10hours thefixed total impurity in the solution was less than1.0%; peak area RSD was0.21%, below2%, relativelystable; related substances in injection RSD was0.34%, below2%, precision well. the impurity content inthe chromatogram of the test solution was calculated compared the major peak of the control solution, theimpurity (the relative retention time, RRT0.85) is not above0.4%; the impurity (tRRT=1.3) is not above0.2%; the impurity (RRT1.5) is not above0.3%; the single unspecified impurities is not above0.2%; thetotal impurities are not above1.8%. Conclusion: All impurities was isolated perfectly and verified to meetthe requirements.The lsomer test system was established by HPLC. Method: the column was AD-H chiral column，（250×4.6mm，5ｕm）; the mobile phase is consisted of N-hexane-Anhydrous ethanol-Glacial acetic acid（920：80：3）; the detected wavelength is244nm; the column temperature is35℃;the flow rate is1.0L/min. Result: The specificity and robustness were demonstrated good; The LOD and LOQ of impurity were3.0ng(S/N=3) and7.5ng(S/N=10); the RSD of the lsomer peak area in the test solution in eight hourswas0.16%; the RSD of the injection precision is0.34%. Conclusion: the atorvastatin calcium major peakcan be well separated from the all simpurity peaks, the separated method was verified by the destructionexperiment results, the determination results show that the method is accurate and fast.The stability test shows that the atorvastatin tablest is sensitive to temperature, humidity, acid andoxygen. Suggesting that preparation packing should be packed by the dual aluminum film materials toprevent degradation; and the prepatation should be stored below room temperature; especially, the watercontent of the intermediate particles should be strictly controlled during the preparation process.Furtherly, Standard operating procedures (SOP) of the atorvastatin calcium preparation was proposed;Reference to the relevant technical requirements, the quality standard of the atorvastatin calcium tabletswas improved, especially involved the related impurity control. The above results provide adequate andreasonable support for SOP and the product quality control.