Direct nucleation control of crystal size distribution in pharmaceutical crystallization

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events will result in the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the onset of nucleation. The approach uses information on nucleation, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating policy, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve; the system automatically and adaptively detects the boundary of the operating curve. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations.