Enabling Rapid Process Development for the Endgame Steps of an API

Azzeddine Lekhal, Russell Hensley, David Lamberto, Ivan Lee, Shane Grosser, Alexei Kalinin, Jingjun Yin, Tetsuji Itoh, Bangping Xiang, Margaret Figus, Yu He, Liam Corcoran, Eamonn Joyce, Thorsten Konekamp, Mick Lucey, Nick Rogus, Ruth Rosenthal, Khateeta Emerson, Glenn Spencer, Laura Artino, and Rich Varsolona, Merck & Co.

The 2 endgame steps of an API synthesis involves a double Suzuki coupling reaction, the product of which is isolated by a mandelate salt formation, followed by a salt break and precipitation of the neutral API.  The Suzuki reaction of the penultimate step is particularly challenging both to execute and to understand due to the oxygen sensitivity of the catalyst and starting material, and to the sheer amount of impurities which can be formed during the reaction, respectively. The high number of impurities formed during the reaction makes the mandelate salt formation used to isolate the Suzuki product equally challenging, since impurity rejection is critical.  In parallel with the process development for the Suzuki, the Pure step has faced several fluctuations over the last 2 years.  The changing landscape of the product market has significantly impacted the Pure step specifically in the last ~6 months due to variations in both API demand and drug product formulation.  The potential shift from spray drying to conventional formulation has significantly impacted the process development and desired physical attributes of the API.  This poster will detail the comprehensive and hefty process development work which was executed to support the endgame steps, and their respective impacts on the broader program.