Use of a First Principles Model during QbD Studies to Assess Impurity Formation for a Coupling Reaction

The overall strategy that was used in QbD studies for the evaluation of reactions in the synthesis of an API will be assessed by reviewing the specific case for the coupling reaction of an amine with an acid chloride to form the corresponding amide. For each reaction in the experimental design set, a model was developed based on kinetic data that was acquired. Kinetic parameters were then obtained for each reaction and were assessed as a set to determine if the studied variables impacted impurity formation over their desired manufacturing range. In the reaction presented, two main impurities are tracked: 1) an imide impurity is formed from the product and excess acid chloride and 2) a carboxylic acid impurity is formed by hydrolysis of the acid chloride. The formation of impurities was investigated varying the amount of acid chloride, reagent level, catalyst loading, solvent amount and temperature. The resulting model was used to calculate impurity levels at reaction completion for a variety of conditions. The development and use of the kinetic model during QbD studies allowed for a deeper understanding of the reaction over its entire time course and enhanced confidence in how to control the formation of impurities.