Enantioselective polar‐organic mode high‐performance liquid chromatographic separation of lifitegrast on immobilized polysaccharide stationary phase and its application to pH‐dependent chiral interconversion studies

Author:

Kandula Jony Susanna1,Rayala Veera Venkata Satya Prasanna Kumari1ORCID,Parmar Keyur1,Ponnapalli Veerabhadra Swamy2,Gantala Mahendar2,P. Radhakrishnanand1ORCID

Affiliation:

1. Department of Pharmaceutical Analysis National Institute of Pharmaceutical Education and Research, Guwahati Guwahati Assam India

2. Daicel Chiral Technologies (India) Private Limited Hyderabad Telangana India

Abstract

Abstract(S)‐Lifitegrast (LFT) is the novel integrin antagonist, approved by the Food and drug administration, to treat signs and symptoms of dry eye disease. Synthesis of racemic LFT, preparative and analytical enantiomer separation, and chiral interconversion studies are lacking in the literature. Hence, in our study, synthesis of LFT racemate, chiral preparative purification procedure of enantiomer, and comprehensive analytical advancements are focused on rapid enantioselective separation and pH‐dependent chiral interconversion studies. The synthesis of LFT racemate employed 2‐amino‐3‐(3‐(methylsulfonyl)phenyl)propanoic acid hydrochloride and 2‐(benzofuran‐6‐carbonyl)‐5,7‐dichloro‐1,2,3,4‐tetrahydroisoquinoline‐6‐carbonyl chloride as starting materials. (R)‐LFT was isolated from the racemate by preparative chiral HPLC and characterized using Q‐TOF, FT‐IR, NMR spectroscopy, and chiral HPLC. The purity of (R)‐LFT was determined to have an enantiomeric excess of 99.12%. A precise, accurate, rapid HPLC‐DAD enantioselective analytical method has been developed on Chiralpak IC [tris(3,5‐dichloro phenyl carbamate) immobilized on cellulose] using water and methanol as mobile phase. The chiral interconversion study reveals 0.22% and 0.21% of interconversion of (S)‐LFT into (R)‐LFT at 80°C in pH 7.4 and 9.5 buffers, respectively, on the 24th day. An alternative route to enantioselective synthesis of LFT enantiomers by chromatographic separation is proposed. The validated enantioselective HPLC method will help to test the regular quality control samples.

Publisher

Wiley

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