Cold Plasma-Induced Nucleation of Paracetamol in a Batch Stirred Tank Reactor

Abstract Cold plasma generates multiple physical and chemical phenomena that can promote crystal nucleation. However, its use for crystallization under process-relevant conditions remains unexplored. In this work, cold plasma was evaluated as a novel strategy to initiate the crystallization of paracetamol, a model pharmaceutical active ingredient (API), in acetonitrile within a stirred tank reactor. An in-house probe was designed to generate nanosecond repetitively pulsed (NRP) discharges inside nitrogen bubbles injected into the solution. Above a supersaturation threshold within the metastable zone, cold plasma treatment significantly decreased the induction time and improved its reproducibility. Enhancing the number of plasma-treated bubbles further reduced the induction time and increased the desupersaturation rate. Surprisingly, no significant effect on the final particle size distribution was observed, probably due to agglomeration. This work demonstrates, for the first time, that cold plasma is an effective tool to trigger the crystallization of API on-demand, automatically, and without seed preparation. It offers a promising nonintrusive alternative to conventional seeding.