Screening for polymorphism in the formulation stage is important because polymorphs have different stabilities and can spontaneously convert from a metastable (or unstable) form to a stable form because of environmental factors such as temperature, a specific solvent, stirring conditions or certain impurities.
Polymorphs can also have different therapeutic activity, benefits or risks associated with them. Determining if an active ingredient has polymorphs, and if so, identifying these polymorphs is important for obtaining regulatory approval, broadening the intellectual property around an active ingredient, improving therapeutic performance and minimizing the risks associated with a polymorphic drug. Polymorphs can be identified by demonstrating different solubility, melting points, diffraction patterns or through x-ray crystallography.
Hamilton’s automation solutions can aid tremendously in determining polymorphism by preparing and subjecting low-volume samples to a large variety of solvents, temperatures, stirring conditions, impurities and precipitate generations conditions through solvent dry-down . Hamilton’s Dynamic Scheduling Software can schedule samples’ subjection to different polymorph-favorable conditions and the time points at which aliquots are taken by Hamilton’s automated liquid handler for analysis by x-ray diffraction or differential scanning calorimetry (DSC).
Hamilton’s CCD camera can also be used to capture images of liquid formulations containing polymorphs generated in situ by subjecting the samples to polarized light, which makes the non-soluble polymorph crystals visible. The images below show one formulation sample captured with standard back-lighting at two time points, and the same formulation sample captured with polarized lighting.