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

General strategies for the development of capillary electrophoretic methods for the enantiomeric separation of basic, acidic or neutral drugs were dev eloped. For all kinds of compounds, the use of a buffer made of 100 mM phos phoric acid adjusted to pH 3 with triethanolamine and containing anionic an d/or uncharged cyclodextrin (CD) derivatives as chiral selectors was recomm ended. Two different optimization schemes depending on the acidic or basic character of the analytes, were elaborated. For most basic compounds presen t in cationic form at pH 3, enantiomeric separation could be achieved in th e normal polarity mode. Different P-cyclodextrin derivatives were first tes ted at a given concentration. Five derivatives were found to be particularl y useful for enantioseparations in capillary electrophoresis (CE): the anio nic carboxymethyl-beta-CD (CMCD) and sulfobutyl-beta-CD (SBCD) and the neut ral dimethyl-beta-CD (DMCD), trimethyl-beta-CD (TMCD) and hydroxyprapyl-bet a-CD (HPCD). After selection of the most suitable CD, its concentration was optimized with respect to chiral resolution. If necessary, a further impro vement in resolution could often be obtained for the enantiomers of cationi c solutes by increasing the buffer pH from 3 to 5 using CMCD as chiral addi tive. 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, ani onic CD derivatives such as SBCD or CMCD were first tested at a given conce ntration in the reversed polarity mode. Dual systems, based on the simultan eous addition of a charged CD (SBCD or CMCD) and a neutral CD (TMCD or DMCD ), could then be investigated for resolution improvement. After optimizatio n of the CD concentrations, the use of dual systems with CMCD at BI-I 5 cou ld also be tested if necessary, especially for very weak acidic and neutral drugs. By applying these optimization strategies, 48 of the 50 drugs exami ned as model compounds could be fully enantioseparated by CE in short analy sis times (usually less than 10 min).