Strategic feedback control of pharmaceutical crystallization systems

Crystallization is a widely used purification and separation technique in the pharmaceutical industry. More than 90 % of the active pharmaceutical ingredients are produced in the crystalline form. The quality of the crystalline product greatly affects the downstream processing and bioavailability of the drug. The Food and Drug Administration (FDA) initiated in 2004 the use and implementation of process analytical technology (PAT) in the pharmaceutical development and production and encourages the pharmaceutical industry to adopt quality by design (QBD) approaches. The prime objective of this initiative has been to optimize the drug development and manufacturing process by reducing cost, improving product quality and reducing the number of failed batches. The work presented in this thesis focuses on expanding the use of two PAT tools, namely attenuated total reflection ultra violet/visible spectroscopy (ATR-UV/Vis spectroscopy) and focused beam reflectance measurement (FBRM). ATR-UV/Vis spectroscopy and FRBM are mostly used for process monitoring. The aim here was to develop sophisticated control approaches using these in situ tools for enhancing the product quality. Chemometrics is an integral part of PAT, and can provide valuable information about the system. This tool has also been used in this study for calibration model development and monitoring the cooling and antisolvent crystallization processes for single and muticomponent crystallisations. The development of an accurate and robust calibration model is necessary for qualitative and quantitative analysis of a system using spectroscopy. A systematic methodology was therefore presented for the selection of a suitable calibration model for ATR-UV/Vis spectroscopy. The developed model was then used as part of supersaturation control approach (SSC). SSC uses information from ATR-UV/Vis spectroscopy in a feedback control loop to keep the system at desired supersaturation. The developed approach resulted in the production of crystals of uniform size and can represent the bases for a model-free direct design approach for crystallization systems. (Continues...)