Accurate Quality Control Of Multi-component Polysorbate 20 And Exploration Of Its Safety Structure

Multi-composition pharmaceutical excipients are approximately half in the number of commonly used pharmaceutical excipients.With the development of pharmaceutical industry and new drug delivery systems,more and more novel multi-composition pharmaceutical excipients,especially those with greatly improved functionality,have been under research.However,these pharmaceutical excipients are characterized by diverse structure and complex composition,thus it brings technical barriers to their structural characterization and identification,quantitative determination,in vivo analysis and biological effects evaluation etc.Consequently,the imperfections of such pharmaceutical excipients quality control and research system are likely to bring about great potential safety hazard in clinical applications.On the basis of the concept of precise quality control,polysorbate 20 was separated by improved HPLC method to obtain 17 chromatographic peaks.These peaks were identified by UPLC-Q-TOF-MS method and 29 categories of components were characterized,such as polyethylene glycol（PEG）,polyoxyethylene Sorbitan（PS）,polyoxyethylene isosorbide（PI）,polyoxyethylene sorbitan mono-octoate（PSM-octoate）,polyoxyethylene isosorbide mono-octoate（PIM-octoate）,polyoxyethylene sorbitanmono-decanoate（PSM-decanoate）,polyoxyethyleneisosorbide mono-decanoate（PIM-decanoate）,polyoxyethylenesorbitanmono-laurate（PSM-laurate）,polyoxyethyleneisosorbidemono-laurate（PIM-laurate）,polyoxyethylene sorbitan di-octoate（PSD-octoate）,polyoxyethylene mono-laurate（PM-laurate）,polyoxyethylene sorbitan mono-myristate（PSM-myristate）,polyoxyethylene isosorbide mono-myristate（PIM-myristate）,polyoxyethylene sorbitanmono-palmitate（PSM-palmitate）,polyoxyethyleneisosorbide mono-palmitate（PIM-palmitate）,polyoxyethylenedi-octoate（PD-octoate）,polyoxyethylene sorbitan di-decanoate（PSD-decanoate）,polyoxyethylene isosorbide di-decanoate（PID-decanoate）,polyoxyethylenedi-laurate（PD-laurate）,polyoxyethylenesorbitandi-laurate/myristate（PSD-laurate/myristate）,polyoxyethylene sorbitan di-myristate（PSD-myristate）,polyoxyethylene isosorbide di-myristate/palmitate（PID-myristate/palmitate）,polyoxyethylene sorbitan tri-laurate（PSTri-laurate）,polyoxyethylene di-myristate（PD-myristate）,polyoxyethylene sorbitan di-palmitate（PSD-palmitate）,polyoxyethylene isosorbide di-palmitate（PID-palmitate）,polyoxyethylene sorbitan tetra-laurate（PSTetra-laurate）.The study on the composite file and the precise structure of the components of polysorbate 20 lays a foundation for farteher evaluation as well as the precise quality control and application.Polysorbate 20 is multi-composition complex pharmaceutical excipient,and there are great differences in the types and contents of the commercially available products,so how to precisely distinguish the quality of polysorbate 20 products from different manufacturers is a challenge that needs to be solved.Precise quality control model based on UPLC-Q-TOF-MS method and Statistical analysis method was established.However,the model was not a rapid screenting mothod.Therefore,based on the precise structure analysis of polysorbate 20 components,the correlation between polysorbate 20 components and NIR spectra was intensively studied.It was found that the content of some components in polysorbate20 including water,PSD-laurate,PSD-palmitate,PID-palmitate,PSM-octoate,PIM-decanoate,PM-laurate,PSM-myristate,PIM-laurate and PSD-octoate had significant correlation with 5600⁴480cm^-11 and 7200⁵970cm^-1 of polysorbate 20 NIR spectra.For different Polysorbate 20 products,although the major differences in the near-infrared spectrum are in the same band,the differences in the polysorbate 20 components are significantly different.This provides a method and means for manufacturers and regulators to quickly and accurately control the quality of polysorbate 20 by near-infrared spectroscopy.In order to improve polysorbate 20 quality evaluation system,the safety of Polysorbate 20 and its main components were conducted through using cytotoxicity and zebrafish safety,respectively.It was found that the safety of PIM-laurate is much lower than that of PSM-laurate,which are main compounds in polysorbate 20.Therefore,it is necessary to precisely control the composition of polysorbate 20 and the content of each component in it to effectively ensure the safety of Polysorbate 20.The study lays the foundation for the establishment of a scientific and comprehensive polysorbate 20 precise quality control system.In summary,based on the concept of“precise quality control”,our study first charcaterised the structure of the components in polysorbate 20 and and established precise quality control model of polysorbate 20.Afterwards,the correlation between polysorbate 20 components and near-infrared spectroscopy was studied.At the same time,preliminary studies on the safety of polysorbate 20 and its major components were completed.All these studies provided methods and means for the construction of a comprehensive polysorbate 20 precise quality control system and the realization of accurate analysis and precise quality control of complex pharmaceutical excipients.They also lay the foundation of targeted quality control of complex multi-composition pharmaceutical excipients and promote high-level pharmaceutical preparations development.Consequently,the research is valuable in both theoretical guidance and practical application.