Forced degradation studies are widely used in the pharmaceutical industry to investigate the degradation pathways of drugs. Forced degradation reactions are often monitored by liquid chromatography-mass spectrometry (LC-MS), which enables the quantitation of reactants, intermediates, and degradation products and aids in the identification of unknown species. Because degradation reactions may proceed for many hours, and because frequent sampling allows more precise determination of reaction time course, the investigations would benefit from automated analysis. Traditionally, aliquots of a degradation reaction are sampled into vials and are analyzed later by LC-MS. Disadvantages of this approach include the need for manual sampling from the reaction vessel and the delay in analysis of several hours or longer that necessitates reaction quenching and could result in further degradation in the autosampler vials. We have developed a simple instrument for online monitoring of forced degradation reactions which can be adapted to any commercial LC-MS equipment. The system allows automated, continuous sampling of reaction mixtures by low flow rate vacuum aspiration followed by continuous, computer-controlled injections for online LC-MS analysis. The stability of the automated sampling and injection system was excellent, with 3% relative standard deviation in peak area over a 24-h period. The system was used to examine the forced degradation of a common antiseptic, chlorhexidine, for 24 h with 15-min temporal resolution. Additionally, the effect of low pH and high temperature on a mixture of drugs found in over-the-counter cold medicine was also investigated for over 12 h. The system is versatile and can be used for any application in which continuous sampling, automated injections, and liquid chromatography-mass spectrometry analysis are desired.

Automated reaction monitoring using liquid chromatography-mass spectrometry

249th National Meeting (2015)

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