(614a) Multistage Crystallization of Plate-like Crystals: A Modeling and Experimental Study on Adipic Acid

The particle size and shape distribution of a crystalline powder governs critical product attributes such as filterability and flowability. Powders containing needle- or plate-like particles tend to have poor downstream processability compared to more equant particles [1]. As various active pharmaceutical ingredients crystallize in elongated shapes, strategies to manipulate the crystal shape in a desired fashion are of interest for the pharmaceutical industry. Various techniques to manipulate the shape of needle-like crystals have been previously investigated [2]. Whilst plate-like crystals pose similar difficulties as needles, a lack of adequate characterization techniques has hindered investigations into designing shape manipulation techniques. However, recently an imaging technique has been developed to accurately characterize platelets using three characteristic lengths [3, 4]. This work leverages these advances to study the effectiveness of a cyclic three-stage process, incorporating growth, wet milling, and dissolution steps. Employing a combination of experimental and modeling approaches, with adipic acid in water as the system, the influence of key multistage process parameters, e.g., the number of cycles, the milling intensity, and the fraction of mass dissolved per cycle, on the product PSSD and the filtration performance is evaluated. A multidimensional population balance equation-based model is employed to study the interplay between growth, dissolution, and breakage kinetics. The findings demonstrate the efficacy of the multistage process in modifying the particle size and fines content, and thereby reducing the filter cake resistance of the product, a key indicator of powder processability. The insights gained from this study will be instrumental in designing processes for manipulating the size and shape of crystalline powders, particularly exhibiting a complex morphology like the one studied here.

References

[1] Yu, L.; Pharmaceutical quality by design: product and process development, understanding, and control. Pharm. Res. 25 4 (2008) 781-791

[2] Bötschi, S.; Rajagopalan, A. K.; Rombaut, I.; Morari, M.; Mazzotti, M. From needle-like toward equant particles: A controlled crystal shape engineering pathway. Comput. Chem. Eng. 131 (2019) 106581

[3] Jaeggi, A.; Rajagopalan, A. K.; Morari, M.; Mazzotti, M. Characterizing Ensembles of Platelike Particles via Machine Learning. Ind. Eng. Chem. Res. 60, 1 (2021) 473-483

[4] Binel, P.; Jain, A.; Jaeggi, A.; Biri, D.; Rajagopalan, A. K.; deMello, A. J.; Mazzotti, M. Online 3D Characterization of Micrometer-Sized Cuboidal Particles in Suspension. Small Methods 7 (2023) 2201018