Study On The Determination Method Of Zoledronic Acid Content And Related Substances

Research Background:Zoledronic acid is the third generation of diphosphonates,which can be used for malignant tumor-induced bone metastasis,osteoporosis,high calcium Blood and so on,the treatment has a small dose,convenient administration,good compliance and so on.The treatment with small dosage,convenient administration,has the advantages of good compliance etc.Based on the preliminary work of the laboratory,Imidazole was used as raw material to produce imidazole acetic acid(intermediate).Then by two-step phosphorylation,the zoledronic acid was producted.The early stage of the pilot process,the imidazole acetate(intermediate)pilot scale-up to870.40 g,the amplification of the zoledronic acid the technology of to 1kg,and optimize the reaction conditions,which provides the basis for industrialized production.The results and the purity were satisfactory.According to the preliminary work of this experiment,the pilot technology of zoledronic acid was further studied in this paper.(1)For the intermediate imidazole acetic acid,we developed the pilot process of imidazole dosage of 2kg,5kg,8kg,10 kg,The yield is higher,the purity is better.(2)The target product zoledronic acid monohydrate,we developed the intermediate imidazole acetic acid feeding volume in 2kg,5kg,8kg,and its important parameters were systematically optimized,which obtained a good results.Through the references and our synthesis experience,the preparation of important impurities A and B,and the structure identification provided the conditions for the next step.On the basis of preliminary work,by HPLC the methodology for zoledronic acid was studied systematacially.Condition: 4.6*250mm 5?m(Han Bang)phenyl column;mobile phase: 2m L of triethylamine was added to 800 m L deionized water,and the p H of the mixture adjusted to 3.0,and add water to volume 1L,and methanol(95:5,v/v)as the mobile phase.Detection wavelength: 220 nm,flow rate: 0.7 m L/min,column temperature: 40 degrees,sample size: 10?L.And we tested the three of homemade batch of samples,results: 99.91%,100.2%,99.78%.The contention of zoledronic acid is stable in the process,the results is good.In addition,for imidazole acetic acid we researched the residual imidazole and impurities.For zoledronic acid we researched the residual imidazole and imidazole acetic acid.Impurity and imidazole have not been found in imidazole acetic acid.Imidazole and imidazole acetic acid have not been found in zoledronic acid.This study laid the foundation for the quality standard of zoledronic acid and imidazole acetic acid.