DoE-Based Optimization of Anti-solvent Crystallization for 5′-O-Dimethoxytrityl- N -benzoyl-deoxycytidine in a Couette–Taylor Crystallizer

As biotechnology advances, nucleoside-based active pharmaceutical ingredients (APIs) are emerging as a prominent therapeutic area, owing to their unique biological activities. However, the purification of intermediates such as 5′-O-dimethoxytrityl-N-benzoyl-deoxycytidine (Bz-Dmt-dC) remains challenging because conventional chromatographic methods are costly and difficult to scale. This study introduces an intensified antisolvent crystallization process utilizing Taylor vortex flow in a Couette–Taylor (CT) crystallizer. Response Surface Methodology (RSM) was employed to systematically optimize key process parameters, including the rotational speed, inner diameter of the crystallizer, and cooling rate, for achieving high crystallinity, narrow particle size distribution, and regular crystal habits. Under optimized conditions, the CT crystallizer yielded short rod-like crystals with a narrow particle size distribution (D50 ≈ 345 μm) and a crystallinity exceeding 99.87%, significantly outperforming both the mixing-tank (MT) crystallizer and static crystallization approaches. Computational fluid dynamics (CFD) simulations further revealed that the uniform shear field and enhanced mass transfer within Taylor vortices promoted the integration of sterically hindered molecules into the crystal lattice. Overall, this work demonstrates a scalable and efficient alternative for the purification of nucleoside APIs, with the potential for industrial adoption.