Isoreticular Contraction of kgd‐Topology Covalent Organic Framework Membranes for Precise Pharmaceutical Separation

ABSTRACT Covalent organic frameworks (COFs) provide a structurally programmable platform for membrane‐based separation of small‐molecule active pharmaceutical ingredients (APIs). Nevertheless, constructing membrane pores with subnanometer precision and resolving structurally similar molecular mixtures remain major challenges. Herein, we report an isoreticular contraction strategy to construct a series of kgd‐topology COF membranes with progressively narrowed apertures in situ on polyacrylonitrile (PAN) substrates through contra‐diffusion interfacial polymerization between hexa(4‐formylphenyl)benzene (HFPB) and three triamine monomers of decreasing size. Systematic framework contraction decreased the aperture from 12.1 to 10.2 Å and then to 6.5 Å, giving molecular weight cut‐offs of 500, 380, and 290 Da, respectively. Notably, membranes with different contraction degrees were further integrated into a cascade separation system with well‐separated molecular‐weight rejection thresholds, enabling the purification of a four‐component mixture of camptothecin‐related compounds with equal mass concentrations, achieving a maximum fraction purity of 96.6%. This work establishes isoreticular contraction as an effective strategy for programming transport‐relevant pores in COF membranes and highlights the potential of kgd‐topology COF membranes for cascade pharmaceutical purification.