New perspectives for the on-line monitoring of pharmaceutical crystallization processes using in situ infrared spectroscopy.

Chemists and engineers involved in the industrial production of solid drugs have to deal with difficult new challenges, including the on-line mastery of the crystal habits and size distribution, the control of polymorphic transitions or the improvement of the chemical purity. A major limitation to improving the control of industrial crystallizers lies in the lack of versatile, accurate and reliable on-line sensors. It is shown that supersaturation measurements can be performed using in situ ATR mid-infrared spectroscopy thus providing valuable real-time information about the crystallization process. Several case studies are presented to illustrate new potential applications of the technique. The reported experimental results outline recent advances in the acquisition of key data characterizing the solute/solvent system in question (i.e. solubility, metastability, phase transformations...), the design of on-line control strategies capable of improving both the crystal size distribution (CSD) and the reproducibility of the quality of the final product, the assessment of improved operating strategies (e.g. seeding batch crystallizers), and the monitoring of polymorphic transitions during cooling crystallization operations. The possibility of evaluating on-line the process impurities, which could allow the reduction of batch-to-batch variations of the quality of the solid product, is also briefly envisaged.