Inducing the stable polymorph using heterogeneous primary nucleation

Polymorphism plays an important role in crystallization of active pharmaceutical ingredients (APIs). At the earlier stage of development of a new API, a polymorph screening is performed to find out its different polymorphic forms. In particular, it is interesting to obtain the stable form. However, the form which nucleates spontaneously from solution is often a metastable form. This phenomenon corresponds to the so-called Ostwald rule of stages which is explained by the difference existing between the nucleation kinetics of the metastable and stable forms. The paper shows how a control of the heterogeneous primary nucleation can favour the nucleation of a more stable form. Several heterogeneous supports were tested with an API. The efficient supports did not act as templates but reduced the metastable zone widths and facilitated the primary nucleation of the different polymorphs. Optimising the operating conditions, i.e. mainly support concentration and supersaturation with respect to each polymorph modification, has allowed the preferential nucleation of the stable form. In the absence of heterogeneous support, a metastable form was systematically obtained. Since the interactions with the heterogeneous support do not need to be polymorph specific, the approach can a priori be used to perform the polymorph screening of any API, in addition to the usual in house screening methods.