Development of Drug Substances as Mixture of Polymorphs: Studies to Control Form 3 in Casopitant Mesylate

Polymorphism is characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice and this can impact the physical properties of a drug substance. In this paper the studies carried out on casopitant mesylate, a NK1 antagonist developed in GlaxoSmithKline (GSK), are reported. During process development studies it was discovered that what was initially considered a single crystalline phase, Form 1, was actually a mixture of two different forms, Form 1 and Form 3. A retrospective analysis of all the key drug substance batches clearly indicated that Form 3 was always present as minor component in mixture with Form 1. Furthermore any attempt to generate either pure Form 1 or pure Form 3 failed. As a result of this, the project team explored the opportunity to develop the drug substance as a mixture of polymorphs. The studies performed to assess the ability of the manufacturing process to control the amount of Form 3 in the drug substance, according to the Quality by Design principle and the assessment of the impact of this finding on the drug product performance are reported in this paper. Collectively, the data demonstrated that the level of Form 3 in the drug substance (up to a level of 27% w/w) is not a drug substance critical quality attribute (drug substance-CQA) for casopitant mesylate.