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A direct enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method was developed for determining the content, enantiomeric purity, and related substances of the chiral antidepressant drug sertraline HCl in a single chromatographic run. The separation was achieved on a chiral stationary phase based on amylose tris(3-chloro-5-methylphenylcarbamate) under reversed-phase conditions. The method was optimized by evaluating the influence of the temperature and mobile phase composition on the retention and selectivity. The application of the single-run approach allowed to baseline resolve all investigated species in less than 15 min, without using buffers or tandem-coupled columns. The chromatographic method was validated according to the guidelines of the Official Medicines Control Laboratory and applied to control the content of sertraline HCl and related chiral substances in a generic antidepressant formulation., Graphical abstract Image 1, Highlights • Sertraline displays two stereogenic centers but only the (1S,4S) form is clinically useful. • A direct method was developed for evaluating assay and impurities in a single HPLC run. • The single-run RP method allowed resolving all species within 15 min, without using buffers. • Amylose tris(3-chloro-5-methylphenylcarbamate)-based CSP was used as a chiral support. • The method is selective, precise and accurate and it meets the requirements of the EP guidelines.

Chromatography on chiral stationary phases has been recently used as an additional tool for the study of internal molecular dynamics of a range of stereochemically labile organic compounds and for the determination of kinetic parameters of the reversible isomerization of one enantiomer into the other occurring during chromatography [enantio- and diastereoselective dynamic chromatography (DC)]. Within this context, the implementation of highly efficient chromatographic techniques pushed to their extreme limits represents a very effective method to extract thermodynamic and kinetic data, otherwise difficult or impossible to obtain by classical alternative approaches, such as dynamic nuclear magnetic resonance spectroscopy or batchwise thermal equilibration studies. This chapter provides a basic overview of the concepts behind the determination of stereoisomerization rate constants and activation barriers by DC. Several examples of the application of such technique in the study of model stereochemically labile compounds have been provided, with a focus on the extreme conditions of temperature and speed of analysis that can be achieved using state-of-the-art materials, columns, and instrumentation.