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
