3-Bromo-2-chloropyridine is a halogenated heterocyclic building block used in many pyridine-based synthetic applications such as catalysis, drug design, and natural product synthesis. It is used as an early starting material in the synthetic route of an immunology drug candidate at BMS. It is also a possible mutagenic impurity that has the potential to directly cause DNA damage when present at low levels, leading to mutations and therefore possibly causing cancer. Based on the threshold of toxicological concern and the estimated maximum tolerated dose, a strategy was established to conservatively control 3-bromo-2-chloropyridine to ≤ 7.5 ppm in the penultimate of the active pharmaceutical ingredient. The low ppm control limit restricted the use of LC-UV for a sensitive determination. Limited solubility of the penultimate in common organic solvents posed additional challenges for sample preparation and analysis.<br/> <br/>In this presentation, we will discuss the development and optimization of a sensitive and reliable LC-MS method with simple, nominal mass detection for use in testing for 3-bromo-2-chloropyridine in the penultimate with a control limit of 7.5 ppm. Systematic method development was performed, including column screening, sample preparation evaluation, and LC and MS condition optimization, to ensure method specificity, sensitivity, accuracy, precision, and stability. The established LC-MS method was successfully implemented for scale-up penultimate batches, demonstrating excellent control of 3-bromo-2-chloropyridine prior to the final drug substance step.

Analytical control of potential mutagenic impurity 3-bromo-2-chloropyridine in pharmaceutical process development

ACS Fall 2021

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