Artefact formation in the determination of residual solvents according to a method of the European Pharmacopeia.

Method 2 of the procedure for the identification and assay of residual solvents, of the European Pharmacopeia 3rd edition 1999 addendum, leads to artefactual formation of N-chlorodimethylamine when the hydrochlorides of basic compounds are examined. This is due to degradation of the dissolution solvent N,N-dimethylformamide under the prescribed conditions. N-Chlorodimethylamine has been detected during analysis of several hydrochloride salts of nitrogen bases including drug substances. Artefact formation did not occur consistently with all the compounds examined, but with diltiazem hydrochloride it was observed in the majority of experiments. The discovery that the alkylating reagent N,N-dimethylaminoethyl chloride (DMC) used in the synthesis of diltiazem gives apparently high yields of N-chlorodimethylamine was cause for concern. However, it has been confirmed that production batches of diltiazem hydrochloride contain <1 ppm of this synthetic intermediate. The formation of N-chlorodimethylamine in the presence of the drug substance is probably due to a reaction between dimethylformamide and HCl, that would be released as a result of hydrolysis by residual water of the O-acetyl function of diltiazem. In view of these findings, the compendial general method should be reviewed. It may be necessary to adopt a different approach to the drafting of methods for volatile impurities, since most of the operating conditions are in practice specific to the substance being examined.