A new view on the metastable zone width during cooling crystallization

The Metastable Zone Width (MSZW) is the difference between the saturation temperature and the temperature at which crystals are detected under constant cooling rate. The MSZW is conventionally treated as a reproducible, deterministic, volume independent property and is commonly used to characterize crystal nucleation and to determine the crystallization process operation window. In this paper we investigate the volume dependency of the MSZW both experimentally and theoretically. MSZW measurements were performed for paracetamol–water and isonicotinamide–ethanol model systems at four different volumes between 500 mL and 1 L. A stochastic model developed based on the Single Nucleus Mechanism and a deterministic population balance were used to theoretically study the effect of volume on MSZW. It was experimentally observed that the MSZW is not a reproducible point at small volumes but a spread which increases roughly inversely proportional to the volume. The dependency on volume of the MSZW cannot be explained by the deterministic population balance model but can be explained by the stochastic model based on the single nucleus mechanism. The knowledge of the MSZW behaviour at a certain volume and nucleation rate would help in identifying a process operating window limited by the saturation temperature on one side and the smallest MSZ limit on the other for a particular concentration. The knowledge of the process window at given conditions of volume and concentration would lead to better crystalline product quality as controlled seeding can be performed without the influence of crystals appearing as a result of a primary nucleation event.

► At 1 mL scale MSZW is not a sharply defined reproducible point.
► The Single Nucleus Mechanism (SNM) is responsible for the fluctuations in the MSZW.
► A stochastic model based on SNM developed to describe MSZW as function of volume.
► Stochastic model suggests that MSZW gets reproducible above a certain volume.
► MSZW measurements at different volumes confirm such a transition volume.