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Written by Sonja Kamptmann of Novartis Pharma AG, this paper outlines how researchers at Novartis gained a better mechanistic understanding of the factors affecting hydrogenation by-products and pressure reactions.
Hydrogenation is influenced by several factors including type of catalyst, catalyst loading, solvent, substrate purity, temperature, and pressure. Researchers at Novartis applied techniques that allow scientists to perform data-rich experiments to investigate the root cause of a critical by-product, which lead to a genotoxic impurity in the final drug substance. Knowing the exact point in time when hydrogenation by-product formation starts is critical to stop the reaction and isolate the highest product yield with the lowest by-product concentration.
Although integrating PAT tools can provide comprehensive and continuous analysis of the reaction in real time, critical information concerning low level impurity profiles is limited with these techniques. Offline techniques including HPLC, UPLC, and GC are considered to be standard for impurity analysis, but sampling hydrogenations under pressure is challenging due to cumbersome manual sampling protocols. Manual sampling of hydrogenations is tedious and error prone since it includes releasing the pressure, purging the reactor with protecting gas, opening the reactor, taking the sample, closing the reactor, performing a leak test, purging with the reactor with protecting gas again, and pressuring the reactor with H2.
By capturing streams of analytical data at regular intervals, scientists at Novartis were able to establish a path to understanding the mechanism and conditions which caused the critical hydrogenation by-product formation. By adding quantitative HPLC measurements throughout the course of the hydrogenation reaction, where sampling had previously been impossible, assumptions were quickly corrected and a realistic mechanistic model had been drawn. Based on that, better decisions were made which have improved productivity and shortened timelines to reach the next milestone in process development of a high-quality drug Active Pharmaceutical Ingredient (API).
In this example, reproducible sampling to allow quantitative determination of yields, reaction kinetics, and impurity profiles required following conditions to be maintained:
- Pressure up to 5 bar
- Elevated temperatures up to 80 °C
- Highly reproducible, failure-free sampling over 24 hours
- Sampling from a thick slurry
More experiments would be required to clarify the synthetic pathway, but the stop criterion was defined. The stop criterion can successfully be used on a production scale to stop the hydrogenation at the right point in time, where the reaction is finished but only small and acceptable amounts of by-products have formed - assuring high purity and quality.
