Track: Manufacturing and Analytical Characterization - Chemical - Drug Substance Manufacturing and Development - Control of Impurity Formation
Category: Poster Abstract
Determination of Trace Amounts of N-Bromosuccinimide in N-Chlorosuccinimide
Purpose: N-Chlorosuccinimide (NCS) is a very important pharmaceutical intermediate and organic synthetic chlorination agent. The existence of trace amount of N-bromosuccinimide (NBS) in NCS may result in some impurities when NCS is used as chlorination agent in the synthesis. It is crucial to monitor and control the quality of NBS in NCS. Methods: Due to the high polarity and the thermal instability of NBS, ion chromatogram method was developed to overcome the limitation of using HPLC or GC method to track the trace amount of NBS in NCS. Method was carried on using Dionex IonPac AS18 column with Dionex IonPac AG18 guard column; Column, column temperature was controlled at 30℃；Detection Mode was conductivity detection; Flow Rate was 0.9 ml/min; AERS-4mm Suppressor was 40mA; Program of RFC KOH eluent generator is 20mM. Samples was prepared with a diluent of DMSO/H2O (4/96). Results: To quantify NBS, Ion Chromatography was selected since NBS quantitatively release free bromide ion in alkaline solution. In the method, sample was prepared by dissolving the sample in sodium hydroxide. The trace amount of NBS in the NCS solution released Br ion quantitatively in alkaline solution and the Br ion was analyzed by IC. The Br ion peak shape in IC chromatogram was improved by selecting a proper diluent and optimizing the method.
Method validation was performed and the results were as follows: the resolution between the peak of interest and its adjacent interference peaks was more than 1.5. NBS at the 0.015% (0.5ug/mL) level in NCS can be quantified. The linear range for NBS was from 0.015% to 0.6% of NCS (ie. 0.5 ug/mL to 20 ug/mL) with R2 of 0.997. Average recovery was 92.4%. Method precision and method ruggedness were all in the acceptable range. Conclusion: A method to detect trace amount of NBS in NCS was developed and validated to demonstrate that the method is selective, accurate, precise, robust, rugged with acceptable sensitivity.