Designing a Green Chiral High‐Performance Liquid Chromatography Method: Proof‐of‐Concept with Crizotinib

With the growing emphasis on environmentally friendly analytical practices, green approaches to chiral separation have become vital for assessing the enantiomeric purity of chiral pharmaceutical agents. This study aimed to develop a green HPLC method for the enantioseparation of crizotinib, a tyrosine kinase inhibitor targeting anaplastic lymphoma kinase. The enantioselective performance of seven polysaccharide‐based chiral stationary phases was systematically evaluated under polar organic conditions. Two chiral stationary phases—Lux Cellulose‐3 and Lux Amylose‐1—were identified as providing excellent enantiorecognition. Using experimental design‐based approaches, we optimized three methods and retained them as final: (i) Lux Cellulose‐3 with a methanolic mobile phase, (ii) Lux Cellulose‐3 with an ethanol–water mobile phase, and (iii) Lux Amylose‐1 with an ethanolic mobile phase. All three methods met ICH criteria: linearity ( r 2 ≥ 0.9996), precision (RSD ≤ 2%), and accuracy (~98%–101%), allowing quantification of the 0.02% distomer relative to the active enantiomer. Environmental performance was benchmarked using AGREE, Complex MoGAPI, Eco‐Scale/Modified Eco‐Scale, AMGS, and RGB‐fast. All the developed methods showed superior environmental performance compared to the one method previously reported in the literature. However, it is also evident that applying green solvents does not inherently guarantee a cost‐effective or sustainable approach. Overall, the developed methods provide an analytically robust and environmentally sustainable framework for the enantioseparation of crizotinib.