Application Note: The Development of Solubility and Metastability Design Spaces - Sponsored Whitepaper

The Development of Solubility and Metastability Design Spaces UCD Crystallization Research Group, Schoolof Chemical and Bioprocess Engineering, University College Dublin, Ireland and the Solid State Pharamaceutical Cluster (SSPC) Ireland Email: mark.barrett@ucd.ie

Background: The HEL polyblock system was used, in conjunction with the polythermal method, to

create solubility and metastability design space information for two API compounds. By creating a solubility design space a fundamental understanding can be defined between the limitations for both cooling and anti-solvent crystallization processes. The resulting knowledge allowed crystallization process selection to be based on process benefits such as favorable yields and conditions which would be beneficial for crystal growth.

Methods: Known concentrations of API and solvent mixtures were prepared within the polyblock system and heated to dissolution. Variable cooling rates (between 0.1 °C/min to 0.6 °C/min) were used to quantify the shift in the metastable zone. Solubility information was assessed by heating the obtained slurries at a rate of 0.1 °C/min. Heating rates from 0.1°C/min to 0.5 °C/min were examined, however the low heating rate of 0.1 °C/min was deemed adequate to prevent any over estimation of the saturation temperature.

Up to 8 different concentrations of API in solution were assessed for solubility. Differing solvent / anti-solvent composition were obtained automatically by the attached dosing unit to the polyblock. The outputted information was coupled with the Van't Hoff expression for solubility so the saturation temperatures, for different concentration, could be predicted over the entire design space. This information, in addition to the nucleation temperatures, were then inputted to a Matlab program which facilitated the production of the desired solubility and metastability design spaces.