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Nanocrystals have the potential to address the challenges of delivering drugs with low aqueous solubility. In this study, the use of low energy anti-solvent precipitation for producing nanocrystals has been investigated. Stable nanocrystals with uniform particle size were prepared for the three model compounds, glyburide, ibuprofen, and artemisinin, which are all practically insoluble in water and have diverse molecular structures and crystal packings. The choice of crystal growth inhibitors/ stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the antisolvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. The dissolution of the nanocrystals in aqueous media under physiological conditions was shown in all cases to occur almost instantaneously, being markedly more rapid than that observed for micronized suspensions of the model drugs and their marketed tablet formulations. Rationalization of the choice of optimum stabilizers in terms of molecular interaction with the exposed crystal surfaces proved to be difficult. The study demonstrates that standard crystallization technology is effective in producing nanocrystals with the primary challenge being physicochemical (rather than mechanical), involving the identification of moleculespecific crystal growth inhibitors and/or stabilizers.

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Secondary nucleation, wherein crystal seeds are used to induce crystallization, is widely employed in industrial crystallizations. Despite its significance, our understanding of the process, particularly at the molecular level, remains rudimentary. An outstanding question is why do a few seeds give rise to a many-fold increase in new crystals? Using molecular simulation coupled with experiments we have uncovered the molecular processes that give rise to this autocatalytic behavior. The simulations reveal formation of molecular aggregates in solution, which on coming in contact with the surface of the seed undergo nucleation to form new crystallites. These crystallites are weakly bound to the crystal surface and can be readily sheared by fluid, making the seed surfaces available again to repeat the process. Further, the new crystallites on development can in turn serve as seeds. This mechanistic insight will enable better control in engineering crystalline products to design.

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