Crystallization, as a solid−liquid separation process, is employed to purify and isolate a great diversity of crystalline pharmaceutical products. In recent years, continuous crystallization has attracted increasing attention because of the product and process robustness as well as higher productivity. In this work, we review the use of novel continuous crystallizers or modified conventional continuous crystallizers for the preparation of polymorphs, chiral enantiomers, solvates/hydrates, cocrystals, and spherical crystals. In addition, the theoretical framework and verification of the model-based control approaches are demonstrated. The application of process analytical technology tools in classical feedback loop control strategies in continuous crystallization is also discussed. Despite all this, the application of continuous crystallization still remains challenging because of the existence of drawbacks such as fouling and blockages. Therefore, a systematic discussion should be done before continuous crystallization is more widely applied.

L-Valine crystallizes in a flake-like shape generally; however, compared with the flake-like products, spherulitic L-valine has better filterability, flowability, and bulk density and has potential for wider industrial applications in the future. In this study, L-valine spherulites have been successfully prepared by an evaporative crystallization method in the presence of no more than 0.5% hydroxypropyl methyl cellulose (HPMC). The spheroidization of L-valine proceeds via a layer-by-layer transformation from an initial flake-like shape to a petal-like form, and then it continues to grow into the final sphere-like shape. Molecular dynamics simulations show that HPMC interacts with hydrophilic (001) faces preferentially and promotes the continuous layer growth process. Only the substituent groups of hydroxypropyl and methyl exist simultaneously within a certain spatial distance and, in a viscosity of 40−50 mPa•s, can promote the formation of L-valine spherulites. The particle size increased with the increase in the HPMC dosage and decrease of temperature or evaporation rate. This effect of HPMC promoting the spherical formation provides a method to enrich the design of spherulites and new insights into the fabrication mechanism of spherulitic growth.

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The solvate and the solvent-free form of sulfadiazine (SD) were investigated. SD was found to exist in one solvent-free form and the N-methylpyrrolidone (NMP) solvate form. The NMP solvate was shown to be a channel-type compound. The intrinsic properties of the solvents were used to evaluate the effects of solubility on the phase transformation of SD and the NMP solvate. The SD phase could transform to the NMP solvate by NMP-mediated phase transformation, which was governed by crystallization of the NMP solvate. The crystalline NMP solvate could transform to the solvent-free solid state through solid-solid transformation upon heating or water penetration-mediated phase transformation. The rate of this water penetration-mediated phase transformation of the NMP solvate to SD was unusually fast. It can be used to obtain SD aggregates of well-defined shape and good powder properties.

The influence of the solvent content on the solution-mediated phase transformation of sulfadiazine (SD) N-methyl pyrrolidone (NMP) solvate into SD was investigated for process development. The solubility results of the NMP solvate and SD in NMP solvent/water mixtures supported by the analysis of solvent-solvent interactions between NMP solvent molecules were used to understand and optimize the transformation of the NMP solvate into SD. Needle-on-rhombic-like aggregated crystals and rod-like single crystals of SD were obtained and reported for the first time. By combining Raman spectroscopy, focused-beam reflectance measurements, and scanning electron microscopy, the phase transformation of NMP solvate into SD was tracked. Higher temperatures and stirring rates accelerate the transformation process and have a negative influence on the final SD product quality.

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Ostwald’s rule of stages is one of the most important empirical rules to understand the crystallization behavior of crystalline materials, however, it may not be always satisfied. Herein, we demonstrate...