Quality Studies For Starting Materials,Genotoxic Impurities,Residual Solvents Of Saxag Liptin Raw Materials

Saxagliptin,a dipeptidyl peptidase Ⅳ inhibitor,represents a new generation of oral drugs to treat diabetes.Because of its significant treatment effect,this drug becomes important for patients,families and society.The quality of saxagliptin active pharmaceutical ingredient(API)was studied in this thesis from the aspects of starting materials,genotoxic impurities and residual solvents.The quality standard draft was also formulated in order to ensure the safety and effectiveness.By reference to the production technology of saxagliptin,the properties,related substances,isomers,residue on ignition,residual of organic solvent and content of starting materials were studied in this thesis.Related CQAs were determined and reasonable internal control quality standards were established.Quality control was implemented throughout the production process.The analysis methods were studied and validated according to the ICH guidance.The methods were proved to be accurate and reliable with high selectivity,sensitivity and were suitable for the quality control of starting materials.Isopropyl methanesulfonate(IPMS)is a genotoxic impurity produced in the first step of saxagliptin synthesis.In this thesis,GC methods were developed for the quality control of IPMS in intermediates and saxagliptin.Methodology validation was performed which indicates that these methods are accurate and reliable.The acceptable level of IPMS in intermediates and saxagliptin has been determined.The IPMS monitoring was carried out throughout the whole production process which ensures the safety of saxagliptin.The content of residual solvent is an important control index for the synthesis of API.If the content of residual solvents in pharmaceuticals exceeds the safety value,they will be harmful to the human body and the environment.Ten organic solvents inlcuding methanol,acetone,dichloromethane,ethyl acetate,isopropyl alcohol,isopropyl ether,tertiary butanol,pyridine,acetonitrile and N,N-Diisopropylethylamine were used in the synthesis process of saxagliptin.Among these solvents,dichloromethane,pyridine and acetonitrile are classified as the second class of solvents in the Pharmacopoeia.In order to provide the experimental basis for the quality control of saxagliptin API,headspace gas chromatography methods were established to detect these organic solvents.The methods were proved to be accurate and reliable with high selectivity,sensitivity and were suitable for the quality control of Saxagliptin’s residual solvents.