Magnetic Sorting of Chiral Pharmaceuticals Using Fe₃O₄-Cellulose Acetate Phthalate Nanosplitters

Natural polymers have been used as stereoselective crystallization inhibitors benefiting from their intrinsic hierarchical chirality. However, the chirality of their constituent unit is intrinsically immutable due to the natural biosynthetic origin of biopolymers, fundamentally limiting their versatility, as they cannot be synthetically inverted to target the opposite enantiomer. Herein, we designed a magnetic nanosplitter by grafting cellulose acetate phthalate onto Fe₃O₄ nanoparticles to selectively interact with the crystals of one enantiomer, enabling them to form magnetized crystals that can be efficiently separated from their racemic conglomerate with an external magnetic field. This approach enabled the resolution of racemic nimodipine, simultaneously yielding considerable quantities of magnetic S-crystals and nonmagnetic R-crystals. It should be mentioned that using pristine natural polymer derivatives can only obtain crystals of one enantiomer, the less pharmacologically active R-crystals. Further structural investigation revealed that the chain length of the polymer and the size of Fe₃O₄ nanoparticles significantly influence the resolution of the nanosplitters. When containing cellulose acetate phthalate with a molecular weight above 20 kDa and Fe₃O₄ cores sized between 5 and 14 nm, the optimal performance has been achieved, producing S- and R-enantiomers with 82 ee% and 92 ee%, respectively, and a combined yield of 40%. This work pioneers a magnetically driven separation strategy that can be seamlessly integrated into automated chiral separation platforms.