Crystallization is a key purification technology adopted in more than 80% of all pharmaceutical products. However, the control of crystal shape and size can be very challenging particularly in the case of needle-like and plate-like crystals. The control of crystal shape and size distribution is critical to improve processability and physical properties of active pharmaceutical ingredients, such as dissolution, downstream processability and flowability. In recent years, spherical agglomeration (SA) received growing interest in the pharmaceutical industry as a shape modification technique, as an alternative to temperature cycling, shape modifiers, or wet milling. SA is commonly achieved in batch systems by adding a suitable bridging liquid (BL) to a system containing fully formed (after equilibrium) or growing (spherical crystallization) crystals. One of the major challenges in spherical agglomeration is to fine-tune particle size distribution, as most of the SA processes suffer from poor scalability and poor control of the droplet size of the BL.

In this study, two novel SA processes based on membrane systems were successfully implemented to produce spherical agglomerates of benzoic acid in a solvent: antisolvent crystallization process. Two membrane configurations were implemented; a flat disc mounted in a dispersion cell equipped with a mixing impeller, and a second one which was a cylindrical membrane equipped with a vibrating module which created shear with upward-downward vibration. To optimize the performance of the SA process, the impact of the BL flowrate, membrane pore size and pore arrangement, as well as agitation rate were investigated. Both systems were successfully used to generate spherical agglomerates with enhanced quality and size distribution. Smaller agglomerates were obtained with smaller pore size. In near future, the membrane systems will be scaled-up to investigate the scalability of the proposed SA system under the optimized operating conditions identified from the current study.