An investigation into the use of B-cyclodextrins as additives to effect enantiomeric separation by reversed phase HPLC.

The occurrence of chirality in organic molecules and its significance for the clinical effects of drug molecules is reviewed. A need is established for suitable methods, both analytical and preparative for the separation of enantiomers. The present range of analytical methods used for chromatographic separation and quantification of enantiomers is discussed. The ability of B-cyclodextrin (CD) as mobile phase additive in reversed phase HPLC to bring about chiral discrimination using acetonitrile/phosphate buffer and an octadecylsilica stationary phase has been investigated with methylphenobarbitone, ibuprofen, hexobarbitone and mandelic acid as model chiral drugs. CD showed negligible retention on the stationary phase, so that chiral discrimination must arise as a result of different enantiomeric complex stabilities in the mobile phase. The effect of varying either CD or solvent composition on the capacity factors shows that chiral chromatographic resolution may be optimised but is limited by the solubility of CD in the mobile phase. Reduction in this limiting effect by the addition of urea, which enhances the CD solubility in the mobile phase dose not result in any chromatographic advantages. The study also contrasts the effects on chiral resolution by 2,6-dimethyl-B-cyclodextrin. This derivative is significantly retained on the stationary phase, so that the mechanism of chiral discrimination is due to composite effects of complex formations in both mobile and stationary phases, which operate in opposition to one another. This investigation has led to the development of a mathematical model, which allows a simulation of chromatographic behaviour as a multiple model for either a CD bonded phase or CD mobile phase additive. With the model developed, the calculated result obtained by non-linear regression methods shows a good correspondence with the experimental results. The studies are linked to theoretical modelling studies of inclusion complexes formed between CD and the selected chiral drug molecules, using the molecular graphics modelling software package Chemmod. The de novo construction of models from standard atomic parameters has been refined by the use of molecular mechanics calculations to optimise molecular geometry and achieve minimal potential energy models. It is demonstrated that "mirror-image" structures for chiral drugs give rise to CD complexes of different calculated minimum energies. The stabilities of these complexes have been related to the experimental chromatographic behaviour. The complex of lowest calculated potential energy for an enantiomeric pair, which is the most stable, is shown to chromatographically elute first from a reversed phase system containing CD in the mobile phase. This offers support to the hypothetical model for the mechanism of action of CD. The method offers a theoretical approach to understanding and predicting chiral chromatographic behaviour in the system.

Grantor dc:publisher.institution

Robert Gordon University

Year dc:date.issued

1994

Author dc:creator

• Liang, Hongxi

Advisor dc:contributor.advisor

• D.G. Durham and R.B. Taylor

• B-cyclodextrins
• Enantiomeric separation
• Chirality
• Chiral discrimination
• Mobile phase additive
• Reversed phase high-performance liquid chromatography (HPLC)
• Urea
• Chemmod

Language dc:language

en

Identifier

oai:rgu-repository.worktribe.com:2807453
https://doi.org/10.48526/rgu-wt-2807453

OAI identifier oai:identifier

oai:rgu-repository.worktribe.com:2807453