Automated Reaction Monitoring Using LC-MS

Alton, Dominick J., Braydon L. Dymm, Melanie M. Smalley, and Kendra R. Evans

We have developed a liquid chromatography-mass spectrometry (LC-MS)-based method for automated on-line monitoring of reactions.  The system allows automated on-line sampling, injection, and detection of reaction components.  A 10-port switching valve is used for computer-controlled injections, and the system can be coupled to reaction vessels for continuous monitoring of starting materials, intermediates, and products.  Our system was used to monitor the forced degradation of pharmaceutical compounds.  This is an important application since the process by which a drug breaks down and the rate at which it does so must be thoroughly understood in order to assure its safety and efficacy before it is released for use by human patients.  Reliable, automated methods for reaction monitoring are advantageous for monitoring forced degradation reactions of pharmaceutical compounds because some degradation reactions proceed for many hours and would otherwise require laborious manual sampling or complex robotic systems.  The automated, multi-analyte capabilities of the LC-MS system have been demonstrated using carbamazepine and caffeine as model compounds.  The automated method was applied to monitor the pH- and temperature-dependent degradation of a germicidal compound, chlorhexidine, for 24 h.  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 method allows continuous reaction monitoring for 24 h or longer with 12-min temporal resolution.