Simultaneous monitoring of crystal and mother liquor phases during batch crystallization using in-line Raman spectroscopy
Systematic methods and tools for managing the complexity
Process Analytical Technology - PAT (T4-6)
Keywords: API, Raman spectroscopy, crystallization, in-line monitoring, anhydrate/hydrate
The crystallization of active pharmaceutical ingredient (API) that is capable of forming hydrate from aqueous solutions is very complex due to the fact that various fundamental mechanisms, such as the nucleation and crystal growth of the anhydrate and hydrate, and the phase transformation between them, are involved during the process. Minor changes in the operation condition can have strong impact on the crystallization kinetics of the anhydrate/hydrate phase and therefore influence the purity of the crystalline product. The in-line monitoring of both solute concentration in the liquid phase and the anhydrate/hydrate composition of the crystals is required.
In the present work, the in-line probe of a Raman spectrometer was applied to the monitoring of batch cooling crystallization of carbamazepine (CBZ) from ethanol-water solution. The information about the solution phase and the solid was interpreted from the collected in-line spectra. The simultaneous monitoring of both the anhydrate/hydrate phase of the crystals and the concentration of the mother liquor was implemented. Two different cooling strategies and the effect of one surfactant were studied. With the stepwise cooling mode, the solution saturated at 48.6°C was cooled down from 55°C and the anhydrate carbamazepine (CBZA) was crystallized out at 37°C. The CBZA was subsequently transformed into dihydrate form (CBZH) when the solution was further cooled to 17°C. A cooling-heating mode was utilized to investigate the dehydration of CBZH. The solution saturated at 35°C was first cooled from 40°C to 15°C and then it was heated to 35°C. The crystallization of CBZH was encountered at 20.5°C and then the CBZH transformed to CBZA at 34°C. The effect of the surfactant on the crystallization of both CBZA and CBZH was not significant in the present study. The in-line measured evolution trend of the supersaturation level was in good agreement with the off-line measurement. The onset of the primary nucleation of CBZA or CBZH from solution can be clearly identified from the in-line measured supersaturation profile. The initiating of the phase transformation can be easily observed from the solid phase monitoring. The kinetics of the crystallization of CBZA and CBZH, and the phase transformation can be followed. The Raman spectroscopy was proved to be a powerful tool for the in-line monitoring of anhydrate/hydrate crystallization process. The information obtained from the Raman spectroscopy leads to improved understanding of the process and it also offers great potential for the optimization of the process and the control of the crystalline quality.
Reference:
[1] Qu, H., Louhi-Kultanen, M., Kallas, J. Solubility and stability of anhydrate/hydrate in solvent mixtures, International Journal of Pharmaceutics, 321, 2006, pp. 101-107.
[2]Qu, H., Louhi-Kultanen, M., Rantanen, J., Kallas, J. Solvent-mediated phase transformation kinetics of an anhydrate/hydrate system, Crystal Growth & Design, 6, 2006, pp. 2053-2060.
[3]Qu, H., Louhi-Kultanen, M., Kallas, J.Additives effects on the solvent-mediated anhydrate/hydrate phase transformation in a mixed solvent, Crystal Growth & Design, submitted, 2006.
Presented Wednesday 19, 11:20 to 11:40, in session Process Analytical Technology - PAT (T4-6).
