Chemical reaction impurity control is an essential component of quality risk management in pharmaceutical drug substance manufacturing. Transformations involving reactive/unstable intermediates or multi-phase reaction media often present a challenge for conventional analytical techniques (e.g. HPLC, GC, NMR). During process development and plant execution of such processes, utilization of in-situ spectroscopic techniques offers a significant advantage from both sensitivity and time-of-analysis perspectives. In this work, two industrial case studies implementing spectroscopy will be discussed in the context of small molecule pharmaceutical intermediate laboratory process design and pilot plant execution.
In the first case study, process development for preparation of a triazole-based intermediate was performed utilizing Raman and Near IR spectroscopy. Such in-situ measurements were necessary as the reagents were both non-chromophoric and unstable using conventional off-line analytical methods. The data allowed for rapid analysis of kinetic information as well as mechanism elucidation. The approach was ultimately leveraged to define robust processing parameters (e.g. temperature, concentration, order of addition) for optimal impurity control. In the second case study, Near IR spectroscopy was utilized to monitor ammonia concentration in a telescope reductive amination process. Control of residual ammonia proved critical to limit formation of a des-halogenation impurity during the hydrogenation step. Application of Near IR to trigger additional vessel purges was successfully demonstrated in both the laboratory and pilot plant scale.
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