More than 70% of the liquid chromatography methods developed in the industry (pharmaceutical, biological, and food) are based on reversed-phase liquid chromatography separation methods. Oddly enough, most practitioners have been complaining about the lack of a true and sound retention mechanism in RPLC for more than fifty years. This ongoing situation has led method development to be mostly supported by empirical and statistical models. It still remains expensive, time consuming, and risky for the separation scientists.    <br/> <br/>The general problem related to the determination of the true retention mechanism in RPLC has been the source of many theories, scientific debates, and controversies in the last five decades. In the first part of this presentation, we will then review past and successive research achievements that aimed at delivering a complete and sound theory of retention in RPLC. Their debunk (from accurate experimental retention data) or their intrinsic flaws (as recognized from the fundamentals of liquid-to-solid adsorption thermodynamics) will also be described in detail. Up to date, in the early 2020s, there is still no clear and obvious retention models capable to accurately predict retention in RPLC and speed up safely method development. Therefore, in the second part of this presentation, we will then open a discussion and propose some alternative tools (physical chemistry, molecular dynamics simulation, etc.) to possibly unravel the long hidden secrets of retention in RPLC since the very first silica-C<sub>18</sub> material has been synthetized in the early 1970s.

Retention Mechanism in Reversed Phase Liquid Chromatography: 50 years of scientific debates and still counting

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ACS Fall 2022

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