Volume Effects on Acetaminophen Nucleation through an Induction Time Approach

Confined crystallization is an approach to develop nano-crystalline active pharmaceutical ingredients which improves dissolution and bioavailability properties of a formulated drug. To elucidate on this, the effect of volume reduction to the nucleation of acetaminophen in ethanol was explored. Using a supersaturated solution of acetaminophen in ethanol at volumes of 1000 μL to 25 μL, induction times for the primary nucleation event were obtained experimentally. The probability distribution of induction times showed that as sample volume is reduced, the induction time increases exponentially. The induction time at the volume of 25 μL is obtained to be at 4214 minutes, which is at a 5400% increase from the observed induction time of 78 minutes when the volume is set at 1000 μL.These results demonstrate the effect of volume reduction to nucleation induction times. Confinement may relate to very low probabilities of a nucleation event.