Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on experimental co-crystal screening or computational prediction, but hardly any work has been done toward fast, efficient, and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallize from the solution phase. With this work, we investigate whether there is a link between prenucleation aggregation in solution and co-crystal formation and how to harness this for crystallization prediction. 1H and 13C NMR spectroscopy is used to study the prenucleation interaction between caffeine and benzoic acid in methanol, acetone, and acetonitrile as examples of common solvents. In this system, crystallization from methanol leads to no co-crystallization, from acetone to concomitant crystallization of co-crystal and caffeine, and from acetonitrile to pure co-crystal formation from solution. Strong heteromeric dimers were found to exist in all three solvents. Ternary phase diagrams were defined and a solution-accessible co-crystal region was found for all solvents. For this system, the prenucleation clusters found in solution could be linked to the crystallization of the co-crystal. Crystallization from DMSO did not yield the co-crystal and there were no detectable prenucleation aggregates. NMR spectroscopy to probe dimers in solution can thus be used as a fast, reliable, and promising tool to predict co-crystallization from specific solvents and to screen for suitable solvents for manufacturing and scale-up

Thylakoid-Inspired Multishell g‑C₃N₄ Nanocapsules with Enhanced Visible-Light Harvesting and Electron Transfer Properties for High-Efficiency Photocatalysis

Inspired by the orderly stacked nanostructure and highly integrated function of thylakoids in a natural photosynthesis system, multishell g-C₃N₄ (MSCN) nanocapsule photocatalysts have been prepared by SiO₂ hard template with different shell layers. The resultant triple-shell g-C₃N₄ (TSCN) nanocapsules display superior photocatalysis performance to single-shell and double-shell counterparts owing to excellent visible-light harvesting and electron transfer properties. Specially, with the increase of the shell layer number, light harvesting is greatly enhanced. There is an increase of the entire visible range absorption arising from the multiple scattering and reflection of the incident light within multishell nanoarchitectures as well as the light transmission within the porous thin shells, and an increase of absorption edge arising from the decreased quantum size effect. The electron transfer is greatly accelerated by the mesopores in the thin shells as nanoconduits and the high specific surface area of TSCN (310.7 m² g^–1). With the tailored hierarchical nanostructure features, TSCN exhibits a superior visible-light H₂-generation activity of 630 μmol h^–1 g^–1 (λ > 420 nm), which is among one of the most efficient metal-free g-C₃N₄ photocatalysts. This study demonstrates a bioinspired approach to the rational design of high-performance nanostructured visible-light photocatalysts