The European Pharmacopoeia describes a general procedure for Identification and Control of Residual Solvents in a drug substances [1]. Implementation of this general method is a subject of major concern in the pharmaceutical industry. Some problems have been overcome, for instance quantitative determination of hight-boiling solvents such as 2-(2-chloroetoxy)ethanol (CEE) and N-methyl-2-pyrrolidinone (NMP).

A gas chromatographic method with direct-injection for quantitative determination of residual CEE and NMP in pharmaceutical active substance has been developed. The separation was obtained on a DB-624 column (60 m x 0.32 mm i.d. x 1.0 μm coating thickness). A dimethylformamide is proposed as sample solvent to obtain good selectivity and sensitivity.

Validation was performed within the requirement of ICH validation guidelines Q2A and Q2B [2, 3]. Precision, intermediate precision, linearity, accuracy, limits of detection and quantitation and robustness were determined, and excellent results were obtained.

References:

1. Residual solvents (5.4), European Pharmacopoeia, Supplement 4.6.

2. Harmonised Tripartite Guideline on Validation of Analytical Procedures (Q2A), ICH, Geneva, 1994.

3. Harmonised Tripartite Guideline on Validation of Analytical Procedures: Methodology (Q2B), ICH, Geneva, 1996.

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