Assessment of Experimental Solubility Determination Methods for Cooling Crystallization Process Design of Carbamazepine in Ethanol

The determination of an accurate solubility curve is critical for efficient design of the crystallization process. Inaccurate determination can lead to use of a higher or lower supersaturation level that would result in undesired extra nucleation or crystal growth. Here several solubility measurement techniques are evaluated for determining solubility data for crystallization process design. In this study, carbamazepine (CBZ) was chosen as the model drug due to its various polymorphic forms. The goals were to evaluate the effect of (a) dissolving methods, (b) sampling separation methods, and (c) quantification techniques on the accuracy and precision of thermodynamic solubility data of CBZ form III. The mechanic stirring dissolving method demonstrated similar mean values but with less variance compared to the shake-flask dissolving method. Through analysis of means, there was no significant difference between using centrifugation or filtration as the sampling separation method. But it is noted that a minimum of 30 minutes is required for settling time to ensure the measurement accuracy of the equilibrium concentration. Between the two off-line concentration quantification methods (gravimetric and HPLC), the HPLC method always showed lower mean values, but its difference from the gravimetric values are < 4.6%. Also, the solubility curve developed from on-line measurement was compared to off-line concentration quantification methods, and the difference for the mean values is below 5%. In addition, the dissolution profile of the metastable form (form II) was analyzed, and the results suggest that this is a mono-tropic system between 5 °C and 50 °C for form II and form III. This work presents a comprehensive study on the solubility data of CBZ and the solubility determination methods that are important during the process development and design of crystallization processes.