Kinetic Pathways in a Phase Diagram

The previous section highlighted the importance of the kinetic aspects since the development of co-crystals may be in competition with the crystallization of single component crystals. Knowledge of the start and end points in the phase diagram of a co-crystallization process is not sufficient in order to operate and optimize a co-crystallization pathway. Information about the kinetic pathway followed in the phase diagram during the operation remains essential. 

In situ probes are often used in order to provide information about solid phases and to measure the solute concentration during batch solution crystallization experiments. For instance, Gagniere et al have qualitatively used an in situ video probe to monitor the evolution of single CBZ crystals and CBZ/NCT co-crystals in the slurry since the crystal habits of these two solid phases are largely different in ethanol. Measurement of the concentrations in solution of the two components of the co-crystal phase is very instructive about the competition between the metastable and stable phases. This monitoring is carried out most of the time using mid-infrared spectroscopy in ATR mode which provides estimates with time of the solute concentrations of the chemical components involved in the co-crystallization process. Three case studies taken from the literature are discussed hereinafter in order to present different situations. 

1 First Case Study Isothermal Co-crystallization in CBZj NCTjEthanol System (from Gagniere et 

Experiments were performed in a restricted part of the CBZ/NCT phase diagram, more particularly in domains always undersaturated with respect to NCT. Batch runs were carried out in a thermostatted stirred vessel. 

The second kinetic pathway considered (run 36) was started in domain 2b. It followed a vertical direction until equilibrium was reached. Only CBZ crystals have nucleated and grow. No significant deviation from the vertical line, which could indicate the temporary presence of co-crystals could be detected. Under similar conditions, the nucleation of CBZ/NCT co-crystals was reported but the kinetic pathway was not monitored. The occurrence of a metastable CBZ/NCT crystal population by primary nucleation would have 

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