| Montelukast sodium is a leukotriene receptor antagonist developed by Merck and is mainly used for the treatment and prevention of asthma.In 1998 and 2002,the US Food and Drug Administration(FDA)approved its tablets(10mg,5mg specifications)and granules(4mg specifications),and the brand names are all Singulair.The tablets are suitable for people above aged 15 years(10mg)and 6 years(5mg),and granules are suitable for people over 1 year old.Currently,only domestic original granules are available in the market,and imitation of its granules has good social and economic benefits.The key to the imitation of oral solid preparations is consistency evaluation and quality control of related substances.The multi-pH dissolution curve method used for in vitro consistency evaluation requires good discrimination.Currently,the dissolution curve method of montelukast sodium particles cannot meet the requirements.Regarding related substances,after 2018,Montelukast sodium granules were included in the United States Pharmacopoeia(USP)and British Pharmacopoeia(BP),but all the literature did not explain the types and sources of the related(including the unknown)substances of the original granules.It is not clear why Montelukast ketone,a related substance to Montelukast sodium's degradation in USP,has not been included by BP.In this paper,the original research montelukast sodium granules are taken as the research object.According to the national guidelines for the determination and comparison of the dissolution curve of ordinary oral solid products,the automatic dissolution instrument technology was used to carry out the screening and optimization of the dissolution curve,and the multi-pH dissolution curve method with good discrimination was established as well.HPLC rapid determination method for multi-pH dissolution curve samples was established based on core-shell chromatography column technology.High performance liquid chromatography-mass spectrometry(HPLC-MS)and tandem mass spectrometry(MS/MS)were used to analyze the types and sources of related substances of the original research montelukast sodium granules.The unknown related substances produced in preparation processhave been deduced.The present work could provide a valuable reference and basis for imitation of montelukast sodium granules.The research content of this paper mainly includes the following aspects:1.High-throughput HPLC method for rapid quantification of dissolution samplesUsing montelukast dicyclohexylamine as an external standard,a rapid HPLC quantitative method was established for dissolution curve samples based on core-shell phenyl bonded silica technology,and method validation was also carried out.The chromatographic column used in this method had the characteristics of low column pressure and fast peak out,which could realize fast and high-throughput determination with HPLC.This method has good quantification capacity for dissolution samples at different pHs,especially for the dissolution samples of acidic(pH1.2)medium with poor stability,its rapid determination capability can ensure the accuracy of the measurement results.2.Establishment of dissolution curve method for montelukast sodium granulesAccording to the guidelines for the determination and comparison of the dissolution curves of ordinary oral solid products in China and the PMDA literature in Japan,pH 1.2-0.4%sodium dodecylsulfate(SDS),pH 4.5-0.5%SDS,and pH 6.8-0.1%Tween 80were establishedto evaluate the consistency of imitation montelukast sodium granules.The discriminating power of the dissolution curve method was investigated by the samples preparedby changing the amount of the key excipient hydroxypropyl cellulose(HPC),the adding way and different bedequipments.The results showed that the established method has good discriminating power and could be used in the consistency evaluation of imitation drugs of Montelukast sodium granules,and improve bioequivalence experiment passing rate of Imitation drugs.At the same time,according to the experimental results,we also discussed how to establish the dissolution curve method of oral solid products,which was of a good reference.3.Qualitative analysis of related substances of montelukast sodium granulesUsing two kinds of liquid chromatography conditions,a total of 8 related substances were separated from the original research montelukast sodium granules.According to the related literature,8 related substances were identified with HPLC-MS/MS.There were 7 known components among the related substances,and the unknown component was deduced.The related substances of the original research montelukast sodium granules were initially clarified.4.Study on the sources of related substances of montelukast sodium granulesThe sources of related substances in the original research granules were studied through multi-angle analysis including synthesis route,forced degradation,and preparation process detection.The results show that the related substances such as Michael adducts(2 species,spatial isomers)and Methyl styrene compounds were produced from the raw material synthesis process;sulfoxide compounds(2 species,spatial isomers)were produced from oxidative degradation pathways;isomers were produced from light degradation pathways;the unknown component was produced from the drying process after granulation with HPC.The low content(0.02%)of montelukast ketone(USP degradation impurities)in the original research granules may be due to its slow degradation.The research in this chapter preliminarily clarified the source routes of the related substances in the original research montelukast sodium granules and the stability of the preparation,and had an important reference for the design of the imitation preparation process. |
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