Bottom-up production of pharmaceutical crystal suspensions offers advantages in surface property control as compared to top-down production but face downstream challenges. In this study, addressing the downstream challenge of high solvent concentration in the naproxen crystal suspension, a membrane diafiltration process using nano-filtration membranes was developed for solvent (ethanol in this case) removal from the naproxen crystal suspension. The process reduced the ethanol concentration from 9.6 wt% to below 0.5 wt% as per European Medicine Agency (EMA) guidelines, keeping the crystals' stability intact. For well controlled particle formation, the excipient requirement (PVP (Polyvinylpyrrolidone) K30), during naproxen crystallization, was high and can raise issues during downstream processing. Consequently, the diafiltration process was adapted by replacing nanofiltration membranes with ultrafiltration membranes to better adjust PVP K30 concentration in the naproxen suspension post crystallization. A seven-stage diafiltration process removed 98% of the PVP K30 from the suspension thereby reducing the PVP-to-naproxen ratio from 1:2 to 1:39 while keeping the stability of naproxen crystals. Similarly, the diafiltration process was applied to itraconazole crystal suspension removing excess TPGS (D-Tocopherol polyethylene glycol succinate). The diafiltration process was later combined with a concentration step for itraconazole crystal suspension. During this process, N-methyl-2-pyrrolidone (solvent) concentration decreased from 9 wt% to below 0.05 wt%, the TPGS-to-itraconazole ratio reduced from 1:2 to below 1:50 and the itraconazole loading increased from 1 wt% to 35.6 wt%, without affecting the crystals' stability in suspension. These findings contribute to optimizing pharmaceutical processes and hold promise for advancing the development of pharmaceutical crystal suspensions via bottom-up production techniques at a commercial scale.weiterlesen