Autonomous Control of the Crystal Size and Shape in Dense Suspensions via Imaging

This article presents a novel approach to controlling the particle size and shape distribution (PSSD) during cooling crystallization at solid loadings representative of industrial processes. The methodology combines stereoscopic imaging with an automated dilution system for high-quality size and shape characterization of the particles. This data is fed into a process control scheme that cools, heats, and performs wet milling to reach a specified particle size at a target temperature, thereby ensuring the specified yield. The effectiveness and adaptability of the control strategy were demonstrated using cooling crystallization of γ d-mannitol in water as a case study. Key process parameters were systematically varied to assess the robustness and reproducibility. The results demonstrate that the control method consistently reaches the desired particle size and yield. A significant achievement of this work is the successful operation of the automated dilution and imaging system under supersaturated conditions at suspension densities typical of pharmaceutical manufacturing (5–10 wt %) for extended durations without human intervention. This work advances the state of crystallization control by providing a versatile, compound-agnostic methodology capable of real-time particle characterization and process control under conditions relevant to industrial crystallization.