In situ monitoring of the impact of liquid-liquid phase separation on drug crystallization by seeding

In a previous paper (Veesler, S.; Lafferrere, L.; Garcia, E.; Hoff, C. Org. Proc. Res. Dev. 2003, 7, 983), the impact of a liquid-liquid-phase separation (LLPS) or demixing on solution crystallization in quiescent medium of a pharmaceutical compound, C35H41C12N3O2, in an ethanol/water mixture was presented. In this contribution, drug crystallization experiments by seeding are monitored by in situ turbidity, focused beam reflectance measurement, and video microscopy. Two cases are studied: in the first case for seeding experiments in the metastable zone for nucleation and outside the demixion zone we observe the classical secondary nucleation and growth mechanism. In the second case for seeding experiments in the demixion zone, the first stage is the growth of crystals as well as the growth and coalescence of droplets; in the second stage crystals and droplets are still growing and droplet heterogeneous nucleation occurs; and in the last stage, droplets disappear and the secondary nucleation starts. LLPS changes the medium and the conditions of crystallization, prevents the drug nucleation, both primary and secondary, and consequently affects the process. Depending on the point of seeding in the phase diagram, inside or outside the LLPS region, the crystallization mechanisms and kinetics are different.