Process Research and Development of a MTP Inhibitor: Another Case of Disappearing Polymorphs upon Scale-up

Abstract

LAB687 is an inhibitor of microsomal triglyceride transfer protein (MTP) designed to lower triglycerides and LDL cholesterol. The discovery of its polymorphic forms closely intertwines with the synthesis development of the molecule. At the early development stage, LAB687 was known to crystallize in two modifications, Forms A and B. Knowledge of the molecule’s polymorphic nature prompted extensive polymorphic screening using drug substance produced by the earlier synthesis routes. These studies revealed the existence of a third polymorph, Form C. Subsequently, Form C was selected for further development based on data from the additional formulation and polymorphic studies. Surprisingly, a new modification, Form D, appeared when the crystallization process known to routinely produce Form C was scaled up in the pilot plant. Once Form D was introduced to the laboratory, Forms A and C could no longer be made. We hypothesize that a change in drug substance impurity profile due to the changes in synthesis, led to the emergence of the most stable Form D.