Crystallisation of the stable polymorph of hydroxytriendione: Seeding process and effects of purity

The drug substance hydroxytriendione has been found to exist in three modifications, which are equal in their pharmaceutical profile and are equally stable. Thus, Form II, the polymorph thermodynamically stable at room temperature, was chosen as the solid-state form for the active pharmaceutical ingredient. Spontaneous nucleation will lead to either of the two other forms. Thus, a seeding process was developed to ensure the reproducible crystallisation of the desired Form II. The solvent used for crystallisation was chosen according to the preparative HPLC method used to prepare the crude material, and the solubility was modified by using an appropriate cosolvent. The measurements and data necessary to develop this process are described. The process has been successfully transferred to production with extremely limited data on the system. Careful consideration shows that the conditions chosen are valid only for an impure system. A pronounced influence of the purity of the starting material on the window of seeding has been found. The point of addition of the seed should be determined according to solubility and experimentally via the addition of small amounts of seed to a continuously cooled solution.