Study On The Analysis Methods Of The Critical Quality Attributes Of Antimalarial APIs Piperaquine Phosphate

In this paper,the physical,chemical and microbiological characteristics which directly or indirectly affect the quality and efficacy of Piperaquine Phosphate,are investigated based on the general rules and requirements of drug quality research and quality control.The critical quality attributes?CQAs?which affect the safety and efficacy of piperazine phosphate are also measured,including crystal form,related substances,heavy metals,inorganic impurities,residual solvents and assay of the drug.The method development and validation of Piperaquine Phosphate was carried out in accordance with the current principles of drug research guidelines and pharmacopoeia specification,to establish the quality standard with sufficient theoretical and technical supports and ensure the quality,efficacy and safety of the drug.Referring to "Chinese Pharmacopoeia" 2010 and 2015 edition[1],ICH-related guidelines,the United States Pharmacopoeia?USP?and European Pharmacopoeia?EP?8.0,we determine the analytical methods and quality standards according to the analysis of crystal form,related substances?including degradation impurities?,heavy metals,inorganic impurities,residual solvents and assay employing X powder diffraction method?XRPD?[1]^[14],high performance liquid chromatography?HPLC?and gas chromatography?GC?etc.The detail contents of this paper are:1.HPLC method was used in the determination of the related substances.After intensive study of the chromatography columns,the p H,the gradient and time of elution,the method for HPLC was determined as: Phase A : 0.01mol/L Na₂HPO₄ +0.12%Triethylamine?adjusted to p H 7.1 with phosphoric acid?;Phase B: acetonitrile?HPLC grade?;the detection UV wavelength:320 nm;temperature of the column:40?.According to the relevant technical requirements of Chinese Pharmacopoeia,USP,EP-related Pharmacopoeia and ICH registration,six impurities obtained from the beginning of the starting materials to the whole process of the finished product,were successfully analyzed qualitatively and quantitatively.The studies confirmed that our methods can effieciently separate and detect the trace impurities in the sample with good specificity.The analysis method of forced degradation of Piperaquine Phosphate was consistent with that of the related substances.The forced degradation conditions contained acid,base,oxidation,reduction,high-temperature and low-humidity,high-temperature and high-humidity,and light exposure etc.The results showed that:piperaquine phosphate was easily degradable under alkaline conditions and was stable under other conditions of forced degradation.Under the conditions of the forced degradation,the peak purity of the main peak of the piperaquine phosphate in the test solution was above 980,which was the pure peak,and the resolution of the adjacent peaks was ? 1.5.The results indicated that the analytical method adopted was capable of detecting piperaquine phosphate accurately.The mass balance indicated that the analytical method adopted had good validity and applicability,and was suitable for the detection and control of piperaquine phosphate.2.Analysis methods of inorganic impurities and residual solvents referred to the Chinese Pharmacopoeia,the United States Pharmacopoeia,the European Pharmacopoeia and ICH related guidance,and also considered the solubility of Piperaquine Phosphate.The heavy metal residue was measured by colorimetric method with lead standard solution.The residual chloride ion was studied by turbidimetric method.Residual solvents and reagents in Piperaquine Phosphate,such as piperazine,1-bromo-3-chloropropane and ethanol,were analyzed by GC and the corresponding quality standard was established.3.The patent?CN201110435860 [5]?reported that the Piperaquine Phosphate was a polymorphic compound.XRPD patterns of the API?Piperaquine Phosphate?,reference formulation?Piperaquine dihydroartemisinin tablets?and the excipients were analyzed.The crystal form was confirmed as Type A referring to the reported patent.The XRPD characteristic peaks were used to determine the quality standard and analyze the crystal form.According to the Chinese Pharmacopoeia?2015 edition?method,the assay of Piperaquine Phosphate was measured using the same chromatographic conditions with the aforementioned related substances.Following the method of Chinese Pharmacopoeia,the assay of Piperaquine phosphate was determined by high performance liquid chromatography [1],[13] [14],and we optimized the HPLC method which achieved better resolution of impurities.The analysis results were accurate,and could be reliable reference for the quality control of product.In summary,in this paper,the method established for analyzing the CQAs ofpiperazine phosphate was proved to satisfy the requirements,and able to effectively control the quality of piperazine phosphate.It provided scientific support for establishing the quality standard of piperazine phosphate,so as to achieve the purpose of quality control.