In the field of pharmaceutical compound crystallization, a better knowledge of the nucleation process is essential to control the nucleation rate, the growth and therefore the size and the quality of crystals. This work focuses on difficulty to crystallize some drugs. It becomes clear that, an important stage is the phase diagram investigation of the considered substance. In our case, polymorphism and liquid-liquid (L-L) phase separation or demixing were observed. On the one hand, the temperature controlled by Peltier effect has allowed us to characterize and to keep the stable polymorph in suspension using optical microscopy. On the other hand, the L-L phase separation has been characterized in stagnant medium by light scattering, optical microscopy and each coexistence liquid phases were titrated by HPLC and Karl Fischer. The L-L phase separation was observed in the metastable zone of polymorphs and consequently hindered the crystallization. Finally, the demixing is characterized in stirred solution and its effect on the drug crystallization by seeding was studied by turbidity and in-line focused beam reflectance measurements (FBRM) techniques.
