In this contribution we present two cases of phase transitions, in which the ability to control the reproducible formation of the desired physical form requires a control of crystallization parameters and a deep understanding of the phase diagram.

Here we review the polymorphism of organic molecules, obtained through batch crystallization in solution carried out in a stirred vessel. Preferential formation of a polymorph, crystal habit, and size depend strongly on the kinetics of the mechanisms involved. First, we recall the concepts of crystallization from solution. Second, phase transitions are introduced, discussed, and illustrated. Third, we focus on the development of batch-crystallization processes to obtain a given polymorph. Prerequisites are recalled, and experimental techniques used for the screening of polymorphs are presented. Recent developments in the determination of the kinetics of solution-mediated phase transition are reviewed, and the advantages and drawbacks of using process analytical technologies to monitor such transitions are discussed. Lastly, we present control strategies.

This paper presents and compares crystallization experiments of an active pharmaceutical ingredient and a biological molecule in the presence of a liquid−liquid phase separation monitored by in situ video. The advantage of this setup is that it requires a small quantity of these products to study the influence of the physicochemical parameters on crystallization. Crystallization mechanisms and kinetics are different depending on the starting position in the phase diagram and on the temperature reduction, when crystallization is temperature-induced. Liquid−liquid phase separation changes the medium and the conditions of crystallization, hinders both primary and secondary nucleation for several hours, and consequently affects the process. For great temperature reduction and, inside the spinodal zone, namely high supersaturation (> 15), crystals nucleate inside the droplets. Therefore, we take advantage of the formation of droplets to propose a new approach to spherical crystallization. The final products are quasi-spherical monodisperse agglomerated particles of about 500 μm made up of small crystals of a few micrometers.

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Despite a century of active research on first-order phase transitions, discrepancies between predictions based on nucleation theory and experiments on nucleation rates are still of several orders of magnitude. This is partly due to the way the work needed to create a critical cluster is modeled. Here, using slightly modified classical nucleation theory, we reconsider confinement effect leading to one single and stable critical cluster. We relate the new cluster equilibrium size arising from confinement to the usual critical cluster size in infinite systems. The single and stable critical cluster opens new experimental horizons: it can be studied in detail. We stress the model-free nature of these results.

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Phase diagrams of cocrystals often show a highly unsymmetrical nature. The solvent has an important impact on the overall aspect of these diagrams. In this paper, we show how the solvent affects the composition of the stoichiometric solid phase nucleated. Suitable conditions for nucleation and growth of a single 2:1 caffeine/maleic acid cocrystal are obtained in ethyl acetate, showing comparable solubility toward both caffeine and maleic acid. Through a full kinetic screen, we were able to identify, for the first time, reproducible conditions for the spontaneous crystallization of the 2:1 phase in solution. Furthermore, during the screening experiments, a hithertho unknown form of the 1:1 cocrystal phase was encountered. Structural X-ray diffraction analyses of both the 2:1, as well as the 1:1 polymorphic phases, show an out of plane maleic acid compound. The carboxylic acid groups are oriented in such a manner to promote intermolecular formation of hydrogen bonded synthons

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