Influence of Agitation and Fluid Shear on Nucleation of m -Hydroxybenzoic Acid Polymorphs

The influence of agitation and fluid shear on nucleation of m -hydroxybenzoic acid polymorphs from 1-propanol solution has been investigated through 1160 cooling crystallization experiments. The induction time has been measured at different supersaturations and temperatures in two different crystallizer setups: small vials agitated by magnetic stir bars, for which experiments were repeated 40–80 times, and a rotating cylinder apparatus, for which each experiment was repeated five times. The nucleating polymorph has in each case been identified by FTIR spectroscopy. At high thermodynamic driving force for nucleation, only the metastable polymorph (form II) was obtained, while at low driving force both polymorphs were obtained. At equal driving force, a higher temperature resulted in a larger proportion of form I nucleations. The fluid dynamic conditions influence the induction time, as well as the polymorphic outcome. Experiments in small vials show that the agitation rate has a stronger influence on the induction time of form II compared to form I. The fraction of form I nucleations is significantly lower at intermediate agitation rates, coinciding with a reduced induction time of form II. In experiments in the rotating cylinder apparatus, the induction time is found to be inversely correlated to the shear rate. The difference in polymorphic outcome at different driving force is examined in terms of the ratio of the nucleation rates of the two polymorphs, calculated by classical nucleation theory using determined values of the pre-exponential factor and interfacial energy for each polymorph. A possible mechanism explaining the difference in the influence of fluid dynamics on the nucleation of the two polymorphs is based on differences between the two crystal structures. It is hypothesized that the layered structure of form II is comparatively more sensitive to changes in shear flow conditions than the more isotropic form I structure.