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Detection of Chiral Drugs Using
HPLC with CD Detection
Recent American Food and Drug Administration Experimental
guidelines have effectively determined that mixtures of
chiral compounds can no longer be brought to the
A prescription Naproxen tablet (500mg) and an over the
pharmaceuticals market place. For new counter naproxen sodium tablet (220mg), were pharmaceuticals, each chiral form must be pure and
separately ground. The tablets were dissolved in ethanol
separately assessed for registration. The need for chiral
and sonicated for 15 minutes. These solutions were then
detection in the development of pharmaceuticals is
diluted to a final concentration of 5µg/µL and filtered
increasing due to regulatory changes and the demand for
through a 0.45µm PVDF syringe filter. A Jasco HPLC
single isomers. The key pharmaceutical industry
system with a CD, OR and fluorescence detector was
objective is now 'racemic switching' and single-isomer
used. Injections size was 1µL. Separations were
drugs. These guidelines require a means for chiral
accomplished using a ChiralPak AD column (4.6 x
250mm) with a 100% EtOH with (0.1% TFA) mobile phase and a flow rate of 1.0 mL/min. CD/UV were
monitored at 260nm for the naproxen and 310nm for the Coumadin.
Many molecules made up of the same number and type
of atoms come in two forms commonly referred to as
Prescription Nexium and Prilosec were also examined
left-handed and right-handed isomers. This is not just
by grinding the tablets and dissolving them in ethanol,
some interesting quirk of nature: left-handed and right-
and sonicating for 20 minutes. These solutions were
handed forms of the same molecules can have brought to a final concentration 0f 1µg/µL with an profoundly different properties because of their chiral
injection size of 2µL. Separations were accomplished
form. In the food industry for example, limonene (left-
using a ChiralPak AD column (4.6 x 250mm) with a
handed) smells like lemons; limonene (right-handed)
100% EtOH mobile phase and a flow rate of 0.9mL/min.
smells like oranges. One form of asparagine is used as a
sweetener in foods and beverages, whilst its chiral
Results and Discussion
Different chiral forms of molecules can have profoundly different biological effects. For example, one chiral form of the drug naproxen has 28 times the anti-inflammatory activity of the opposite chiral relative. Another example is the synthetic form of dopamine used to treat Parkinson’s disease: one isomer acts on the nerve cells to control the patient’s tremors whilst the other form is actually toxic to nerve cells. In crop protection it has been found that one chiral form of the pesticide Permethrine is much more toxic to insects than the other.
Currently there is little control over which chiral form of a chemical compound is formed during a production process. This lack of control generally results in
production of equal amounts of both chiral forms. At
the molecular level the two chiral partners have identical
Naproxen chromatograms. Top- CD detector,
physical properties and therefore are very difficult and
middle- UV detector, and bottom- OR detector.
expensive to separate. A far superior alternative to
separation would be processes in which single pure
The chromatograms of Naproxen and the naproxen
chiral compounds are formed in the first place. This
sodium are shown in Figures 1-2. Naproxen is used to
application note will describe chiral detection of several
relieve the pain, and inflammation caused by arthritis,
and other inflammatory conditions. One chiral form of
the drug naproxen (S-enantiomer) has 28 times the anti-
The chromatograms for the Nexium and the Prilosec are
inflammatory activity of the opposite chiral relative.
shown in Figures 3-4. Prilosec is a proton pump
) isomer is reported to be a liver toxin. Both the
inhibitor used to treat ulcers, heartburn, acid reflux, or
Naproxen and the sodium salt showed only one peak in
Zollinger-Ellison syndrome Nexium, (esomeprazole), is
the CD chromatogram as expected. This indicates that
the S enantiomer of omeprazole, the active ingredient in
both the prescription and the over the counter versions
Prilosec. Nexium was one of the first pharmaceuticals to
have are meeting the requirements to be be repatented and marketed as a pure enantiomer of a enantiomerically pure.
formerly mixed enantiomer drug. The Nexium has a
superior clinical efficacy due to its higher and more consistent bioavailability. As expected, the CD of the prilosec shows the inclusion of both enantiomers while in the Nexium only the esomeprazole enantiomer is detected.
. Naproxen-sodium chromatograms. Top- CD
detector, middle- UV detector, and bottom- OR detector.
. Nexium chromatograms. Top- CD detector,
middle- UV detector, and bottom- OR detector. Conclusions
HPLC with CD detection is an excellent method for the
separation and detection of chiral compounds including
pharmaceuticals. Both the fluorescence and the CD
detectors were very sensitive with respect to
concentration; however the fluorescence detector can not
give any indication as to which enantiomer is which.
The optical rotation detector is capable of discriminating
the enantiomers, but in all the materials studied was
found to be much less sensitive. In general the best
materials for use with the OR are sugars. Jasco Inc.
currently offers the world’s only CD detector for HPLC.
. Prilosec chromatograms. Top- CD detector,
middle- UV detector, and bottom- OR detector.
8649 Commerce Dr. Easton, MD 21601
Phone: 800-333-5272 Fax: 410-822-7526
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