The stereoselectivity of the in vitro dissolution of two commercially available sustained release formulations of rac-verapamil (rac-VER) has been investigated. The studies were carried out using a single-tablet continuous-flow apparatus and the concentrations of R-and S-VER released from the formulations were measured using enantioselective chromatography on a high performance liquid chromatography (HPLC) chiral stationary phase containing immobilized a,-acid glycoprotein (Chiral AGP-column). The data from this study demonstrates that the two formulations have different dissolution profiles and that the amount of drug dissolved was highly dependent on pH. In addition, between pH 3 and 8, the total cumulative amount of R-VER released was greater than the amount of S-VER and a statistically sigmficant difference (P < 0.01) was detected at pH 6. The results of this study indicate that bioavailability and bioequivalency studies should consider the possibility of enantioselective dissolution when racemic compounds are present in the formulations.
KEY WORDS: in vitro dissolution, enantioselective, enantiomers, bioequivalencyThe stereoisomeric composition of chiral drug substances, especially enantiomeric drugs, has become a key issue in the development of new pharmaceutical products. Most of the regulatory concern and research efforts have centered on the enantiomeric composition of the bulk drug and the stereoselectivity of in vivo processes, i.e., pharmacokinetics, pharmacodynamics, metabolism, etc. One area which has been essentially overlooked is the effect of the pharmaceutical formulation on the stability and bioavailability of the individual enantiomorphs of a chiral substance, particularly when the drug is administered as a racemic mixture.The design of dosage forms is an essential part of the development of drug products. The dosage form must: 1) be able to deliver the active ingredient to the site of action at the necessary rate and in sufficient concentration to evoke the desired pharmacological response; 2) be of reproducible quality; 3) be appropriate for the route of administration. ' v 3 One of the key aspects in the formulation of a drug product is the nature and quality of the excipients. The choice of excipient can impact on the bioavailability of the drug substance, control the site of release, and affect the rate of r e l e a~e .~ Thus, excipients are not inert additions to a pharmaceutical formulation. They often interact with the drug substance forming complexes which can alter the physicochemical properties of the target compound. When enantiomeric compounds and chiral excipients are combined in a formulation, interactions between the individual enantiomers and the chiral excipient can produce diastereomeric complexes which may differ in stability, solubility, and rate of release. Consequently, 0 1993 Wiley-Liss, Inc. the use of a chiral excipient can result in an enantioselective difference in bioavailability.A number of excipients are, in fact, chiral. For example, chiral biopolymers ...