Mechanochemical Cocrystallisation in a Simplified Mechanical Model: Decoupling Kinetics and Mechanisms Using THz-TDS

This study employs Terahertz Time-Domain Spectroscopy (THz-TDS) to investigate the influence of mechanical forces on the kinetics and mechanisms of spontaneous cocrystallisation of theophylline and malonic acid, providing insights into mechanochemical reactions through a simplified model. A single-punch compaction method was used to simulate discrete collision events. Three types of spontaneous cocrystallisation were examined: one in powder form and two in compacted pellet forms. Two compaction techniques were compared: a traditional hydraulic press and an advanced compaction simulator that provides controlled force profiles. Polyethylene (PE) was incorporated as an 80% diluent to modulate and decelerate the compaction-assisted cocrystallisation process, with particle size and storage conditions carefully controlled to ensure consistency. Kinetic analysis was performed by fitting the cocrystal formation data over time to the Avrami-Eroféev model, yielding rate constants, k, between 0.11 and 0.30 h-1 across samples 1 to 8. In addition, a dual fitting strategy was used, comparing freely fitted and fixed models (n = 1) to separate the effects of compaction on the crystallisation rate and mechanism. The results revealed that increasing the compaction force induced a mechanistic transition from nucleation-limited to growth-controlled crystallisation, with higher forces eventually restricting molecular mobility and slowing kinetics. These findings provide valuable perspectives on the role of mechanical compaction as both a kinetic modulator and a mechanistic influencer in solid-state transformations, offering new strategies for optimising pharmaceutical cocrystallisation processes and supporting the development of scalable, sustainable manufacturing technologies.