(181b) Inherently Safer Process Design: Assessing the Thermal Stability of Common Peptide Coupling Reagents

Amide couplings are one of, if not the most common chemical reactions performed in the pharmaceutical industry. Many amide bonds are generated with the help of highly active peptide coupling reagents. These reagents have garnered wide use in the pharmaceutical industry due to their ability to facilitate difficult couplings while avoiding epimerization of alpha stereocenters. However, many of these reagents contain high energy functional groups and some are derived from 1-hydroxybenzotriazole (HOBt), a known explosive material. As a result, significant time is spent assessing the thermal stability of these reagents before scale-up commences. Inherently Safer Process Design offers an opportunity to avoid known hazards instead of controlling them. This paper assesses the thermal stability of common peptide coupling reagents by Differential Scanning Calorimetry (DSC) and Accelerated Rate Calorimetry (ARC). If flagged as potentially impact sensitive or potentially explosive, drop hammer and explosivity screening tests are reported. The data is then presented in an effort to drive the development of these reactions toward one of the more favorable classes. A number of common reagents that were screened displayed significant exothermic decomposition events by DSC. These reagents were further evaluated by ARC, drop hammer testing as well as our internal explosivity screening protocol. The data gathered from these experiments has led to the removal of some reagents from the screening protocol used to identify potential processes before large-scale production commenced.