The integration of rotor-stator wet mill and continuous mixed suspension mixed product removal crystallizer (MSMPRC) is studied in this work. The wet mill is applied in two different configurations: (1) downstream in a recycle loop to continuously reduce particle size via controlled secondary nucleation and breakage; and (2) upstream as a high shear nucleator to continuously generate seed crystals in situ. These two novel approaches are compared to continuous MSMPRC without wet mill. In addition, the influences of wet mill operating conditions (i.e., tip speed, number of turnover per residence time) on five important product and process qualities, including average particle size, particle number, width of size distribution, yield, and startup duration are identified for both configurations. The paper demonstrates that desired average crystal size, narrow size distribution, high yield, and very short startup duration can be achieved at the same time by applying the rotor-stator wet mill upstream as a continuous in situ high shear seed generator followed by continuous MSMPRC.

Automated direct nucleation control (ADNC) is a focused beam reflectance measurement-based feedback control approach that is used to produce large and uniform crystals in batch cooling crystallization. In this work, this feedback control approach is modified to work for continuous cooling crystallization processes, including single-stage and multistage mixed suspension mixed product removal crystallizers. The proposed continuous ADNC approach is observed to provide quick startup, high quality control of crystal size distribution, as well as automated and effective disturbance suppression.

The solubility equilibrium of clopidogrel hydrogen sulfate (Form I) was set up without the nucleation of Form II, as the nucleation rate of Form II is very slow under the low supersaturation. Using the laser monitoring technique, solubilities of clopidogrel hydrogen sulfate (Form I) in ethanol, 1-propanol, 1-butanol, 1-pentanol, and 2-propanol were measured at temperatures ranging from (273.15 to 318.15) K. The experimental data were correlated by the modified Apelblat equation, and the dissolution enthalpy and entropy of Form I were determined with van't Hoff plots. Compared with those of Form II, Form I exhibits a higher solubility and a lower enthalpy of dissolution. Therefore, we can draw the conclusion that Form I was the metastable form under the conditions in this work.