Current Edition

The Importance of Polymorph Screenings: Risk Mitigation and Manufacturing Control   

Polymorphism in pharmaceuticals may affect drug product (DP) development, clinical studies, manufacturing, quality and stability. Therefore, it is mandatory to gain knowledge of the polymorphic behaviour of active pharmaceutical ingredients (APIs) in the early development phase by performing polymorph screen programs.

The Importance of Polymorphism
in Drug Development
Crystalline APIs often exhibit the “poly- morphism” phenomenon, meaning that different crystalline arrangements of an API are possible in the solid state. The API’s polymorphic behaviour can significantly affect its physical properties.

Polymorphic transformations can be prompted in DP manufacturing by physical processes, including compression, grinding, milling, processes involving solvents and moisture, or under storage conditions. Unexpected changes in polymorphic form may affect the quality and efficacy of the final DP and dramatically impact patients.

The most notorious example of poly- morphic conversion affecting DP quality and efficacy is the Ritonavir case.1 Form I, the only solid form of Ritonavir known in 1996, was marketed as a liquid formulation in hydroalcoholic mixtures. In 1998, precipitation from the DP solutions was noticed. This precipitation affected the API bioavailability as a lower amount of drug was present in the solution. Due to this inconsistency in the DP, Abbott had to remove the oral capsule formulation from the market. Investigations revealed that the emerged solid was a more stable polymorph, hence less soluble, known now as Form II. Eventually, the issue was solved, and the product returned to the market as a gel cap formulation. The discovery and reformulation of Ritonavir cost $250 million.2