Application to Chiral Separations of Pharmaceutical Mixtures

Many pharmaceutical products are chiral molecules, either as single isomers or more commonly as racemic mixtures. In addition, many formulated products are mixtures of active compounds together with a number of additives such as excipients. For chiral molecules, the pressure to develop single isomer forms as 

In achiral media, different NMR spectra are expected for each of the four types of enantiomeric pairs and for the two meso compounds. In general, because of the synthetic approach, the ratio of cis- to /nmv-rcsiducs is about three, which, assuming that quaternisation at one tetrahydroisoquinoline residue does not affect quaternisation at the other, leads to proportions of cis-cis, cis-trans and trans-trans isomers in the approximate ratio of 11 6 1. The preference for cis-residues has been proved by using nuclear Overhauser effect NMR measurements and by X-ray crystallography on related substances [37,38]. The H NMR chemical shifts, principally of the H8 proton, can be affected not only by whether the C1-N2 configuration in the residue is cis or trans but also by the configuration of the remote tetrahydroisoquinoline unit. 

In summary, therefore, after on-line chiral HPLC separation, NMR spectroscopy has been used to characterise compounds in terms of the cis- and trans-isomers and to identify the racemic pairs on the basis of their identical NMR spectra. In addition, HPLC-circular dichroism (HPLC-CD) was used to identify 

Chiral HPLC was performed isocratically at a flow rate of 3 ml min-1 using two 250 x 4.6 mm, 5 pan Chiracel OD-H columns connected to a Chiracel OD guard column of 50 x 4.6mm id and an eluent comprising 60 40 v/v 0.5 M sodium perchlorate buffer (pH 2.0) acetonitrile. 

Peaks A and B were identified as the trans-trans isomers by NMR spectroscopy. This is because not only are they the smallest peaks in the chromatogram, 

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