Quality And Safety Study And Risk Evaluation Of Cinedipine Preparation Based On Modern Analytical Techniques

Aiming at problems in quality standard,raw material,preparation and production process,packaging material of cinidipine preparation,this paper explored quality study of cinidipine preparation based on national evaluation project issued by National Medical Products Administration by using modern analytical techniques to ensure the safety and effectiveness of clinical medication.1.Study on impurity profile and impurity formation mechanism in cinidipine and its preparationLC-Q-Orbitrapmass spectrometry is a new high-resolution mass spectrometry developed in recent years,this new technology was applied to separate and identify structures of photodegradation impurities in cilnidipine and impurity profile in its normal samples,photodegradation pathway and formation mechanism of impurities were revealed.Five photodegradation impurities in cinnidipine and five impurities in cinidipine tablets and capsules were separated and their structures were identified,two photodegradation pathways were found in cinnidipine: Z-isomers was mainly produced in solid powder of cinnidipine after illumination,and pyridine ring impurities were mainly produced in ethanol solution and not completely shielded from light of cinnidipine.Z-isomers and pyridine ring impurities were synthesized and their structures were confirmed by NMR.Cytotoxicity of Z-isomers and pyridine ring impurities was determined.The results showed that the cytotoxicity of Z-isomers and pyridine ring impurities was 10 and 4 times higher than that of cilnidipine,respectively.A control method for impurities in cilnidipine preparations was established,more impurities with low polarity after main peak were detected by gradient elution method of HPLC instead of equivalence method.Further research found that there was significant defect in packaging material of cinidipine preparation,and the reason was explained.4 enterprises samples were removed from carton packaging and placed indoors for 4 days.It was found that there are two tablets produced 5-7% photodegradation products,the result showed that different shading properties of packaging materials resulting in different content of photodegradable impurities in the four enterprises cinidipine samples,it provided scientific basis for enterprises to improve their packaging materials.2.Study on material state of cinidipine in preparation and its relationship with dissolution behaviorLaser confocal micro-Raman spectroscopy,a new technique was applied to crystal analysis of cilnidipine in preparation,and relationship between cilnidipine raw materials and its crystal form with solubility and dissolution was also discussed.Two crystal forms of cilnidipine were prepared,the results showed that the solubility of ?-crystal was lower than that of ?-crystal,and the dissolution of amorphous was higher than that of crystalline.Similarity of dissolution curves between tablets of three domestic enterprises and original tablets was evaluated with four dissolution media and factor in prescription technology influenced the dissolution curve was analyzed.A new dissolution test method was established to distinguish different preparation technology.It was found that the formulation process of cilnidipine tablets could be distinguished by using pH 6.8 phosphate buffer as dissolution medium,which could distinguish between advanced and common processes.3.Factors affecting quality of cilnidipine preparations and existence of quality risk points were revealed.Correlation among excipients,preparation,production processes and packaging materials with impurities was studied based on the study of impurity structure identification and dissolution behavior.Factors affecting the quality of cinidipine preparations were analyzed and the causes of impurities were found out,these research results could guide enterprises to improve their process to reduce impurity content and improve their dissolution,so as to improve the quality and competitiveness of medicines.Quality risk of the product was assessed: impurity of pyridine ring in preparation process,defect in shading effect of packaging material,difference in dissolution curve from original sample,existing dissolution determination methods had no distinction between different prescription and processe products.According to the results of exploratory research,a new quality standard for cinidipine tablets and capsules was formulated,which comprehensively improved the standard quality control level.Some important discoveries and achievements have been made through the above exploratory research,which provided a scientific basis for drug supervision and the Chinese Pharmacopoeia to revise the national drug standards of cinidipine preparations.