Major differences in pharmacokinetic behaviour and pharmacological activity have been reported between enantiomers of chiral pharmaceuticals. As a result, each of the enantiomers of a chiral pharmaceutical should be considered as a single active compound according to guidelines published by the FDA and EMA. Therefore, proper separation and chiral recognition of molecules used as active pharmaceutical ingredients and their metabolites play an important role in comprehension of the way they work. Chiral pharmaceutical separations require high resolving power to achieve satisfactory separation of analytes in complex (biological or synthetic) samples. This can be, in theory, achieved by comprehensive two-dimensional liquid chromatography (LC x LC) as this would allow to significantly increase peak capacity per unit of time. In practice, However, finding compatible solvents for the second dimension, can be challenging. On the other hand, the relatively slow speed of chiral separations has limited the use of chiral stationary phases as the second dimension in 2D-LC, especially in the comprehensive model. In this study, the combination of temperature-responsive and reversed-phase chiral liquid chromatography is assessed in terms of enantioselective separation of a broad range of pharmaceutical compounds (log p: 0.9-4.1). Applying temperature-responsive liquid chromatography (TRLC) in the first dimension allows for analysis to be performed under purely aqueous conditions, and therefore allows for complete and more generic refocusing of organic solutes prior to the second-dimension separation. Combination thereof with small particle (sub-2 micron) based chiral stationary phases as second dimension in TRLCxChiral-RPLC allows for the construction of a chiral screening platform which in principle offers much promise for solving chiral screening issues.