Process Optimization Of Valaciclovir Hydrochloride

Valaciclovir Hydrochloride (VCV) L-valine erster of acyclovir and prodrug of acyclovir (ACV).It was marketed in UK and Ireland in Jan.1995firstly,and approved by FDA in June for curing herpes zoster.In Nov.1995,It was approved in UK for curing herpes progenitalis,and then for curing HSV infection of skin mucous membrane.As its bioavailability is3-5times greater than ACV,patient only can take it2-3times per day comparing with5times per day for ACV.VCV also can improve patient’s compliance,and its efficacy is equal to ACV.Process optimization in this article has solved the problem, which isomer impurity D-Valaciclovir is over the specification to cause product unqualified. In order to control the isomer, we conern on raw material, process parameter and in-process control. Results show that the isomer impurity is maily produced in the process of condensation reaction of carboxyl activation and its main influencing factors are activated temperature and activated time.Racemization is inevitable, but lower temperature can cause little possibility of racemization. However, even at low temperature, react for long time, such as24h, racemization will occur obviously. At the early stages of activation reaction, control of the temperature can effectively reduce the content of isomer to meet the requirements of pharmacopoeia.In addition,Pd/C used in the process is very expensive and is a large proportion of costs.Experiment has been designed for finding the reason of the catalyst deactivation.It has been found that hydrochloric acid can deactivate the Pd/C catalyst.To improve the use life of Pd/C and reduce the cost,the sltation sequence is adjused and the operation of washing used catalyst with odium formate and methanol for re-use is added in optimized process.The pharmaceutical crystal form is Form I containing half water molecular.The targeted crystal form, crystallization process has been developed by researching on sterring, temperature, solvent quantity and charging method.After development and research stage has been finished and scale-up production of kilo level has been succeeded.And then equipment selection has been done according to workshop condition.Pilot scale production has been finished and final product has been tested according to specification.The structure of final product has been confirmed.The control for process parameter of three batchs of product meet the requirement.the yield and quality also meet the requirement and crystal form is stable.It can be demonstrated that pilot process is stable and reliable.