Designing a Green Chiral High-Performance LiquidChromatography Method: Proof-of-Concept with Crizotinib

Mhammad, Ali and Dombi, Gergely and Dobó, Máté and Tóth, Eliza and Molnár, Gergely and Mirzahosseini, Arash and Szabó, Zoltán-István and Tóth, Gergő (2026) Designing a Green Chiral High-Performance LiquidChromatography Method: Proof-of-Concept with Crizotinib. CHEMISTRY-METHODS, 6 (2). No. e202500131.

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Abstract

With the growing emphasis on environmentally friendly analytical practices, green approaches to chiral separation have becomevital for assessing the enantiomeric purity of chiral pharmaceutical agents. This study aimed to develop a green HPLC method forthe enantioseparation of crizotinib, a tyrosine kinase inhibitor targeting anaplastic lymphoma kinase. The enantioselective per-formance 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 amethanolic mobile phase, (ii) Lux Cellulose-3 with an ethanol–water mobile phase, and (iii) Lux Amylose-1 with an ethanolicmobile phase. All three methods met ICH criteria: linearity (r2 ≥ 0.9996), precision (RSD ≤ 2%), and accuracy (~98%–101%),allowing quantification of the 0.02% distomer relative to the active enantiomer. Environmental performance was benchmarkedusing AGREE, Complex MoGAPI, Eco-Scale/Modified Eco-Scale, AMGS, and RGB-fast. All the developed methods showed supe-rior environmental performance compared to the one method previously reported in the literature. However, it is also evident thatapplying green solvents does not inherently guarantee a cost-effective or sustainable approach. Overall, the developed methodsprovide an analytically robust and environmentally sustainable framework for the enantioseparation of crizotinib.

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