Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Gent, Belgium.
Int J Pharm. 2024 Apr 10;654:123977. doi: 10.1016/j.ijpharm.2024.123977. Epub 2024 Mar 6.
Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.
反溶剂结晶法制备活性药物成分（API）晶体悬浮液的自下而上生产方法在控制表面性质和操作简便性方面优于自上而下的方法。然而，下游分离和浓缩仍然存在挑战。本概念验证研究探讨了膜透析作为一种全面的解决方案，用于反溶剂结晶法制备的 API 晶体悬浮液的下游处理。该方法涉及用纯水置换残留溶剂（N-甲基-2-吡咯烷酮，NMP），调整赋形剂（d-α-生育酚聚乙二醇 1000 琥珀酸酯，TPGS）的用量，并提高伊曲康唑晶体悬浮液中的 API 载量（固体浓度）。NMP 浓度从 9wt%降低到 0.05wt%以下（符合欧洲药品管理局指南），而 TPGS 浓度从 0.475wt%降低到 0.07wt%。这将 TPGS 与伊曲康唑的比例从 1:2 降低到小于 1:50，并将伊曲康唑的载量从 1wt%提高到 35.6wt%。重要的是，这些变化并没有对悬浮液中伊曲康唑晶体的稳定性产生不利影响。本研究表明，膜透析是一种一步解决自下而上的 API 晶体悬浮液生产中下游挑战的方法。这些发现有助于优化制药生产工艺，并有望通过自下而上的生产技术在商业规模上推进长效 API 晶体悬浮液的发展。
