Over 300 chiral drug substances lack official United States Pharmacopeia (USP) methods for the enantiomeric purity determination. Because enantiomeric analysis typically requires specialized methods for each drug compound, developing protocols for each of these 300+ substances would be an expensive and laborious endeavor. Alternatively, if a detector capable of determining the enantiomeric composition without chiral separation could be used with certain drug compounds, this could be implemented relatively rapidly into official testing monographs. Circular dichroism (CD) detection following HPLC (HPLC-CD) has been proposed for this purpose but studies performed thus far have not prioritized its compatibility with validated regulatory methods. In this study, HPLC-CD was evaluated for enantiomeric purity determinations of 13 drug substances using HPLC methods consistent with assay protocols described in United States Pharmacopeia (USP) monographs. Of these selected substances, three (sitagliptin, timolol, and levalbuterol) showed no CD activity and one other (levofloxacin) could not be analyzed due to incompatibility of the mobile phase with the CD detector. For the remaining 9 substances, method validation was performed to determine the linearity, accuracy, precision and limits of quantitation of enantiomer impurities, which was compared to limits established by USP. It was found that enantiomeric impurities for four substances (pramipexole, levocetirizine, (S)-citalopram, and tolterodine) could be quantitatively determined at levels suitable to USP specifications. This analysis demonstrated that HPLC-CD does provide an effective enantiomeric characterization strategy for compatible chiral compounds, and can be implemented quickly and economically compared to traditional column-dependent chiral separation or derivatization methods.