Anticancer Product Melphalan HCl Process And Quality Study

Melphalan HCl is a nitrogen mustard anticancer drug substance.It has been used to treat breast cancer,ovarian cancer,chronic lymphocytic and granulocytic leukemia,malignant lymphoma and multiple myeloma.In this paper,Melphalan HCl synthesis and quality are studied.The main contents are described as follows:4-nitro-L-phenylalanine is used' as a key starting material for Melphalan HCI synthesis,which is protected by phthalic anhydride with tolune-triethylamine system and then its carboxyl group is also protected.In the following steps,aromatic nitro group is reduced into aromatic amine by with the catalyst of palladium on carbon.Aromatic amine is alkylated by ethylene oxide and then chloridized by phosphorus oxychloride.Then after de-protection and purification,melphalan HCl is obtained.The process of Melphalan HCl is optimized to and three process validation batches have been produced.The scale up production results show that Melphalan HCl process parameters used in production is under control and the product obtained has a good quality with both individual impurity and enantiomer contents less than 0.10%.The total yield in production is 16%.Based on Melphalan HCl process and following the current regular guideline,the Melphalan HCl specification is established,in which,product identification,related substance,enantiomer content,residue solvents and melamine etc are covered.HPLC Method for Melphalan HCl related substances and assay testing has been established.Melphan enantiomer is quantitied by chrial HPLC by column of(S,S)-Whelk-01.Based on the solvents used in Melphalan HCl process and the control limit indicated in ICH guideline,the headspace GC method is developed too.Furthermore,melamine testing method also is developed to deternine melamine content in Melphalan HCl requested by USFDA guideline on risk assessment control of melamine in drug substance.The method validations work has been done to verify the methods of HPLC testing for related substance,chiral HPLC for enantiomer content,HS-GC for residue solvents testing and HPLC method for melamine testing.In these validation reports,the method specificity,linearity,sensitivity,accuracy,precision and robustness etc are covered.Method validation reports shows that all these methods are suitable for quantitation with good specification and precision,high sensitivity,wide linearity and good robustness.Melphalan HCl forced degradation results shows that Melphalan HCl is unstable in oxidant,neutral and alkaline solutions.Its long term and accelerate stability study shows that Melphalan HCl is stable for 3 years with the package of double PE in aluminium pouch.