At-line determination of the enantiomeric excess in multi-component chiral samples using Raman optical activity (ROA)

Area of Science:

• Analytical Chemistry
• Spectroscopy
• Chiral Analysis

Background:

• Enantiomerically pure drugs offer superior specificity and therapeutic profiles compared to racemic mixtures.
• Current methods for determining chiral purity and absolute configuration are limited, hindering pharmaceutical development.
• Regulatory bodies like the EMA and FDA require absolute configuration data for drug approval.

Purpose of the Study:

• To develop an effective tool for in-situ analysis of chiral drugs in solution.
• To enable fast, in-flow determination of enantiomeric purity and absolute configuration.
• To address the pharmaceutical industry's need for advanced chiral analysis techniques.

Main Methods:

• Design and construction of an at-line Raman optical activity (ROA) setup.
• Integration of a 3D-printed flow reactor for in-situ and in-flow measurements.
• Quantitative analysis using Partial Least Squares (PLS) regression for enantiomeric excess (EE) determination.

Main Results:

• The developed ROA setup successfully determined the enantiomeric excess (EE) of chiral samples with high accuracy and precision (RMSECV < 1.35%, R² > 99.95%).
• The system demonstrated excellent stereosensitivity and the capability for in-flow analysis of chiral compounds.
• The method effectively discriminated components within chiral mixtures, a unique capability for ROA.

Conclusions:

• This study presents the first successful in-flow and in-situ ROA evaluation of chiral purity in complex mixtures.
• The direct approach eliminates the need for extensive sample preparation, enantiomer separation, or derivatization.
• The developed solution offers a pathway towards operando (in-line) ROA for real-time monitoring of chirality in chemical reactions.