(84b) Quality-by-Design of the Crystal Size Distribution of An Anti-Arrhythmic Drug Using a Crystallisation Process Informatics System (CryPRINS)

A crystallization control strategy is proposed, which combines the supersaturation control and direct nucleation control to obtain in situ consistent seed production and minimize undesired secondary nucleation, to achieve enhanced robustness in the product quality. Focused beam reflectance measurement (FBRM) is used for direct nucleation control where the number of nuclei is maintained at a desired level, during the beginning of the operation by correcting the number of counts by heating the system to produce controlled fine dissolution. After the number of counts is stabilized, and consistent seed is generated, the approach switches to a closed loop supersaturation control using concentration measurement based on ATR-UV/Vis probe. The supersaturation control prevents multiple nucleation events and at the same time maintains enough supersaturation for crystal growth. Supersaturation is maintained at the desired level by variation of temperature or of solvent/anti-solvent ratio. The benefits of this approach include suppression of secondary nucleation, better final crystal size distribution and production of desired polymorphs as well as significant decrease in the variability of crystalline product properties. The approach is evaluated using several pharmaceutical compounds (small organic molecules such as paracetamol, sufathiazole and a large molecule anti-arrhythmic drug). The quality of the crystals obtained both from lab scale and pilot plant are compared in order to check the robustness of the approach. The approach is implemented in an object oriented software environment, the Crystallisation Process Informatics System (CryPRINS), which enables the application of various process analytical tools (PAT) in different feedback control strategies, providing industry standard OPC communication interface to any distributed control system. The CryPRINS allows straightforward application of the proposed feedback control approaches at both laboratory as well as industrial scale from the same software environment providing an automated scale-up system through adaptation of the operating profiles via feedback control.