Analysis of the probability distribution of induction times for acetaminophen and glycine supersaturated solutions showed that reduction in sample volume results in an exponential increase in induction times. It approximately increased by a factor of 55 when the volume was reduced from 1000 to 25 μL. To elucidate the use of confinement as an approach to nanocrystal development and polymorph access, we demonstrated the effect of volume reduction on the nucleation of two model compounds, acetaminophen and glycine. Using supersaturated solutions of both compounds at volumes ranging from 1000 to 25 μL, induction time statistics were obtained experimentally. Image analysis revealed that form I acetaminophen and β-glycine formed as the initial primary nucleation event, with β-glycine sometimes followed by a polymorph transformation to γ-glycine shortly after. Image analysis showed no variation in polymorphism occurring for acetaminophen systems across all volumes. However, it was revealed that at volume sizes below 100 μL, primary nucleation in glycine systems shifts toward γ-glycine nucleation. These results demonstrate the effects of volume reduction on nucleation induction times, its implications on polymorphism, and the extent of lessening the probability of a nucleation event.

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