Identification And Source Investigation Of The Impurities In The Quality Control Of Fluticasone Propionate

Fluticasone propionate,a very important and highly selective glucocorticoid,is mainly used in the treatment of inflammatory diseases such as asthma and allergic rhinitis.The Chinese Phaemacopoeia adopted a 0.1%threshold for impurity identification in drug substance.In this paper,the chemical structures of unknown impurities above 0.1%in fluticasone propionate active pharmaceutical ingredient(API)were elucidated.The impurity source was also investigated.Firstly,LC-MS was used to study the chemical structure of the impurities.An efficient and fast UPLC method suitable for LC-MS analysis was established by optimizing the chromatographic conditions.Six major impurities were detected in the API,five of which were above0.1%and named target impurities(the one that was less than 0.1%was named as impurity 4).The LC-MS method for target compounds analysis was developed with optimized MS parameters.The chemical structures of these impurities were inferred based on UPLC-QTOF-MS and ESI-IT-MS~n analysis data.Moreover,the most possible mass fragmentation pattern of fluticasone propionate and the impurities were summarized.Secondly,the chemical structures were elucidated by using NMR technique.Five of these six impurities were isolated and purified from the crude product of the synthesized API by semi-preparative HPLC.The LC purity of each purified component was about 95%.Impurity 1,2 and 6were analyzed by 1D,2D NMR.These NMR data,combined with MS analysis results revealed the chemical structure of impurity 1,2 and 6.The chemical structure of impurity 3 was predicted from MS analysis.Finally,forced degradation studies were carried out according to the related ICH guidelines.And the source of the target impurities was analyzed.Impuritiy 1 and 2 are the residual intermediates,while impurity3,4,5 and 6 are probably some by-products of the synthesis.UPLC analysis of these degradation products indicated that impurity 1 increases after base degradation.No target impurities were found from the other degradations.