Metastable Zone Width, Nucleation Kinetics, and Reactive Crystallization Optimization of D- p -Hydroxyphenylglycine Methyl Ester

In this work, in situ focused beam reflectance measurement was employed to monitor the reactive crystallization parameters of D- p -hydroxyphenylglycine methyl ester (D- p -HPGME), with the metastable zone width (MSZW) determined as a function of equilibrated pH (4.0–9.0) and temperature (from 278.15 to 293.15 K). At the same temperature, both solubility and supersolubility decreased with increasing pH over the studied pH range. The crystallization induction period ( t ind ) was also determined experimentally, and the polynuclear mechanism was employed to calculate the solid–liquid interfacial tension (γ CL ) and nucleation energy parameters with good fitting accuracy. Through multivariate optimization, D- p -HPGME products were produced at 283.15 K with an agitation speed of 300 rpm, an ammonia solution concentration of 15.0 wt %, and an equilibrated solution pH of 7.0. The final products were obtained with a 98.72% purity (HPLC), a 98.93% yield, narrow chord length distribution (D 50 = 18.23 μm), good crystal habit, and less agglomeration. These results will be beneficial for the design and optimization of the D- p -HPGME crystallization process in industrial production.