Supersaturation and Direct Nucleation Control of an Industrial Pharmaceutical Crystallisation Process Using a Crystallisation Process Informatics System

Crystallization is the key unit operations in the pharmaceutical industries representing the link between the synthesis and downstream process units. The operating conditions of the crystallization process determine the physical properties of the products such as purity, size and shape distribution or polymorphic form. These properties will strongly influence the efficiency of the subsequent downstream process units as well as the final product effectiveness, such as bioavailability and shelf-life. Crystallization is especially important in the production of pharmaceuticals, where the cost of a single batch can exceed £1 million. Despite the long history and widespread application of crystallization, there remains a disproportionate number of problems associated with its control, mainly related to the lack of understanding of the underlying mechanisms, variations in kinetics, the complex nonlinear dynamics and various disturbances characteristic to these systems. With the recent change of the regulatory climate from Quality-by-Testing to Quality-by-Design and the advent of process analytical technology (PAT) initiative of the US Food and Drug Administration, it is timely to develop novel quality-based product engineering approaches and systems in the pharmaceutical sector.