To improve drug product quality, the size and shape of active pharmaceutical ingredient (API) crystals need to meet tight specifications, in part determined by downstream manufacturing requirements. Improved critical quality attributes may also lead to better solubilisation and bioavailability during drug product delivery. Milling-aided and sonication crystallisation are practical means to reduce the mean particle size and aspect ratio to meet these requirements and to improve downstream manufacturability. Other methods to control crystal shape employ temperature cycling during solution state crystallisation, e.g. Direct Nucleation Control (DNC) may be used to alter the particle morphology and size distribution through successive heating-cooling cycles for dissolution and recrystallisation.

In this work, the objective is to produce uniformly sized, equant shaped crystals with enhanced quality using DNC combined with in-situ wet-milling and sonication. The experiments were conducted using mefenamic acid in 2-butanol, starting with a standard linear cooling profile to help identify suitable settings for the DNC which is essentially a model-free closed-loop feedback control strategy. The wet-milling and sonicating approaches were compared in terms of cycle time and final crystal size and shape, by varying the inputs of wet-milling speed, sonication cycle and amplitude. It was shown that the in-situ sonicated DNC based crystallisations reaches the targeted quality bounds within a reduced number of cycles and delivers enhanced crystal morphology compared to the wet-mill aided DNC approach.