Post-Breakage Regeneration and Growth Kinetics of Paracetamol Crystals in Ethanol Solutions

Abstract

This work explores post-breakage crystal growth and regeneration phenomena observed in paracetamol crystallisation in ethanol, focusing on studying regenerative growth kinetics and the impact of regeneration on mass-based growth rates. Previous studies reported rapid growth for the regenerating facet (010) for this system, attributed to this exposed facet’s lower attachment energy. In this work, post-breakage regenerative growth was experimentally studied with single crystal experiments automatically operated by a robotic arm (Dobot) and quantified by a MATLAB code. The study reveals that crystals cleaved along the (010) facet exhibit faster mass growth rates compared to unbroken crystals during the regeneration period, demonstrated by 22%, 104%, and 139% faster rates for 3 different sizes. Kinetics of the regenerating facet (010) was studied via batch cooling crystallisation with varying supersaturation, temperature, and agitation. Prior knowledge on metastable zone was obtained to operate within a supersaturation ratio (S) range of 1.05-1.30 to avoid nucleation. Results indicate that crystal growth transitions from a mass transfer-limited regime to a surface integration-limited regime for agitation rates beyond 200 rpm. In this regime, the linear growth rate of the (010) facet was formulated with a power-law relationship indicating a dependence on the absolute supersaturation (S-1) by an exponent of 1.59 and an activation energy of 17.0 kJ/mol. These findings provide critical insights for estimating and improving crystallisation processes in pharmaceutical manufacturing, suggesting that controlled crystal fracture could enhance growth rates and improve production efficiency.