The transfer of a crystallization process to a different Roche manufacturing site led to the production of an Active Pharmaceutical Ingredient (API) with a different particle size distribution than expected. For the correct identification of the root causes of process deviations, the crystallization process was monitored with Process Analytical Technology (PAT). A calibration model was developed and used to measure the concentration of API in solution. From dissolution experiments, the temperature-dependent API solubility was found and described as a polynomial function of the temperature. The difference between the measured API concentration and the temperature-dependent solubility was used to predict the absolute supersaturation. Within the first cooling crystallization experiment, a secondary nucleation event was identified as the cause of the deviation. The secondary nucleation of an undesired polymorphic form could be monitored by FBRM (increase in fines) and ATR-FTIR spectroscopy (rapid decrease in API concentration). Furthermore, we could show a correlation between the secondary nucleation and the shift of an infrared signal that is caused by the carbonyl bond of the API. The set-up was then used to support the development of a robust crystallization process.
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Chemists and Chemical Engineers interested in the optimization of a crystallization process in the Pharmaceutical, Chemical, and Consumer Products Industries as well as in Academia.
