The structural evolvement of a solute determines the crystallization outcome. The self-association mechanism leading to nucleation, however, remains poorly understood. Our current study explored the solution chemistry of a model compound, tolfenamic acid (TFA), in three different solvents mainly by solution NMR. It was found that hydrogen-bonded pairs of solute-solute or solute-solvent stack with each through forming a much weaker π-π interaction as the concentration increases. Depending on the solvent, configurations of the solution species may be retained in the resultant crystal structure or undergo rearrangement. Yet, the π-π stacking is always retained in the crystal regardless of the solvent used for the crystallization. The finding suggests that nucleation not only involves the primary intermolecular interaction (hydrogen bonding) but also engages the secondary forces in the self-assembly process.
Spherical crystallization of water-insoluble
drugs was investigated
based on thermal-induced liquid–liquid phase separation (TILLPS)
without the use of organic solvent. The phase diagram of the drug
in water was constructed first, consisting of solid–liquid
and liquid–liquid equilibrium regions. Within the liquid–liquid
phase region, droplets of the solute-rich phase were formed and dispersed
under appropriate agitation in the solvent-rich phase. After being
stabilized by a surfactant, the solute-rich droplets can be converted
to monodisperse spherical particles by performing quench cooling crystallization
where the drug is crystallized within the confinement of the droplets.
Furthermore, the influences of the oil droplets on the size of the
resulting crystals were investigated, demonstrating that a decrease
of the oil droplet size, controlled by agitation speed, would result
in the decline of the product size. l-Menthol and ibuprofen
products with a spherical shape and a yield of more than 95% were
prepared successfully using the above method, revealing the application
prospect of TILLPS in the drug spherical crystallization and it gives
important guidance for the preparation of spherical particles of water-insoluble
drugs.
The precipitation of calcium oxalate can be either grown into structural support in plants or precipitated as stones in human kidneys. Previously, citrate, an effective inhibitor for oxalate stone formation, was suggested to alter the crystallization pathway of calcium oxalate and enhance the formation of less stable calcium oxalate trihydrate; however, the underlying mechanism is unknown. Herein we investigated the role of citric acid on crystallization pathways of calcium oxalate hydrates and the effect of supersaturation. It was found that the presence of citric acid can modulate the water content of amorphous nucleated precipitates by TEM and XRD and hence promote the formation of different calcium oxalate hydrates. The remaining water content in amorphous precipitates depends upon the amount of citric acid employed. FTIR and XRD analyses further reveal the extreme structural similarities between amorphous precipitates and the resultant hydrates. Additionally, the role of citric acid on crystallization pathways could be completely changed by supersaturation of calcium oxalate. High supersaturation dominated by homogeneous nucleation can diminish or even invalidate citric acid roles. The findings highlight the interplay of roles between additives and supersaturations, and could improve current understandings on the formation mechanism of oxalate stone.
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