Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing

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, but many contain high-energy functional groups. As a result, significant time is spent assessing the thermal stability of these reagents before scale-up commences. This paper assesses the thermal stability of 45 common peptide coupling reagents by differential scanning calorimetry and accelerating rate calorimetry. Those compounds which flagged as potentially impact-sensitive or potentially explosive were tested by drop hammer and explosivity screening techniques. The data are presented in an effort to drive the development of these reactions toward the use of one of the more thermally stable reagents.