Process Development and Optimization of Linagliptin Aided by the Design of Experiments (DoE)
Hailong Wang, Kai Chen, Biyue Lin, Jingping Kou, Lijun Li, Shuming Wu, Shouzhu Liao, Guodong Sun, Junwen Pu, Hua Yang, Zhongqing Wang
Abstract
A design of experiments (DoE) approach was applied to the development and optimization of the manufacturing process to prepare linagliptin. DoE techniques such as a central composite face-centered design and a fractional factorial design were applied to obtain the critical process parameters and establish the optimal reaction conditions. With process-related impurities determined and successfully removed, a robust high-yielding and high-purity procedure was identified, which has been successfully demonstrated at a 100 g scale level to prepare the desired product in a 68% overall isolated yield and high-performance liquid chromatography (HPLC) purity of around 99.9%.