Method development strategies for the enantioseparation of drugs by capillary electrophoresis using cyclodextrins as chiral additives

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Abstract
General strategies for the development of capillary electrophoretic methods for the enantiomeric separation of basic, acidic or neutral drugs were developed. For all kinds of compounds, the use of a buffer made of 100 mM phosphoric acid adjusted to pH 3 with triethanolamine and containing anionic and/or uncharged cyclodextrin (CD) derivatives as chiral selectors was recommended. Two different optimization schemes depending on the acidic or basic character of the analytes, were elaborated. For most basic compounds present in cationic form at pH 3, enantiomeric separation could be achieved in the normal polarity mode. Different β‐cyclodextrin derivatives were first tested at a given concentration. Five derivatives were found to be particularly useful for enantioseparations in capillary electrophoresis (CE): the anionic carboxymethyl‐β‐CD (CMCD) and sulfobutyl‐β‐CD (SBCD) and the neutral dimethyl‐β‐CD (DMCD), trimethyl‐β‐CD (TMCD) and hydroxypropyl‐β‐CD (HPCD). After selection of the most suitable CD, its concentration was optimized with respect to chiral resolution. If necessary, a further improvement in resolution could often be obtained for the enantiomers of cationic solutes by increasing the buffer pH from 3 to 5 using CMCD as chiral additive. Another possible alternative for enhancement in chiral resolution was the addition of methanol or cyclohexanol to the buffer. For acidic drugs, essentially present in uncharged form at pH 3, and for neutral solutes, anionic CD derivatives such as SBCD or CMCD were first tested at a given concentration in the reversed polarity mode. Dual systems, based on the simultaneous addition of a charged CD (SBCD or CMCD) and a neutral CD (TMCD or DMCD), could then be investigated for resolution improvement. After optimization of the CD concentrations, the use of dual systems with CMCD at pH 5 could also be tested if necessary, especially for very weak acidic and neutral drugs. By applying these optimization strategies, 48 of the 50 drugs examined as model compounds could be fully enantioseparated by CE in short analysis times (usually less than 10 min).