Study On The Chemical Synthesis And Quality Control Of The Antitumor Drugs Bendamustine HCl

Bendamustine hydrochloride is a nitrogen mustard anticancer drug substance.It was first synthesized in Germany in the early 20’s and first marketed in Germany in October 2003.It is a unique cytotoxic drug with alkylating agent and purine analogue.It is used to treat inert B-cell non-Hodgkin’s lymphoma(stage Ⅱ-Ⅳ),leukemia(chronic lymphocytic),breast cancer,plasmacytoma and multiple myeloma.In March 2008,Cefalon developed and produced Bendamustine hydrochloride,which was approved by the US FDA for the treatment of chronic lymphocytic leukemia.At present,Bendamustine hydrochloride is still a new drug of 3.1 class in China.The product has a good market prospect.In this study,the optimization and improvement of the synthesis process of Bendamustine hydrochloride and the establishment of its quality standard were studied.It mainly includes the following research contents:Firstly,2,4-Dinitrochlorobenzene is used as a key starting material for the chemical systhesis of bendamustine hydrochloride,which reactes with methylamine,and reduction by sodium sulfide,acylation by glutaric acid,cyclization and esterification in acid condition,hydrogenation by palladium on carbon,alkylation by ethylene oxide,chlorination by phosphorus oxychloride,bendamustine hydrochloride is finally obtained with high purity.Then,the synthesis route and preparation process of bendamustine hydrochloride is optimized,scaled up and validated,and the total yield is 16.2%.Results showed that this synthesis route shows a strong processes controllability and the product obtained has a good quality with the impurities less than 0.10%.According to the guideline and requirement of ICH,EDQM and U.S.Food and Drug Administration,the quality standards for bendamustine hydrochloride were established including the product identification,related impurities,water content,residua content and residue solvents etc.The methods for the verification of related impurities by HPLC and the residue solvents by HS-GC were further verified.The validation results showed that all these methods are suitable for the determination of related impurities and residue solvents with good specification and precision,high sensitivity(0.04μg/mL),wide linearity(2μg/mL～250μg/mL)and good robustness.The forced degradation of bendamustine hydrochloride showed that it is unstable(impurities reached by 5.88%)under the treatment of light and heating.However,the expiry date of bendamustine hydrochloride is proposed for 3 years with the double PE bags package at 2～8℃.