A Rapid HPLC Assay for the Determination of Dextro‐propoxyphene Related Substances in Combination with Aspirin, Acetaminophen, and Caffeine in Tablet and Capsule Formulations

Abstract

A 23 min gradient HPLC assay has been developed to simultaneously measure related substances of dextro‐propoxyphene salts (napsalate, hydrochloride) and other actives that are routinely found in combination in capsules or tablets: aspirin, acetaminophen, and caffeine. This method has shown the ability to resolve all known active ingredients, impurities, and degradation products from the propoxyphene and other active drug parent peaks. All the propoxyphene related substances are quantified against a 1‐point propoxyphene external standard prepared at 2% of the typical sample concentration. Propoxyphene related substance measurements occur at 210 nm. For acetaminophen combinations, wavelength switching is used starting at 280 nm to measure acetaminophen related substances, then switching to 210 nm for propoxyphene related substance measurements. Two sample solvents can be used for propoxyphene related substance quantitation, the second of which is used to provide enhanced room temperature stability‐about one month‐for aspirin containing formulations. This method provides a simple, one‐step solution for related substance analysis rather than numerous separate assay methods for each active's related substances.

Keywords:

• HPLC
• Propoxyphene
• Acetaminophen
• Aspirin
• Caffeine
• Salicyclic acid
• Validation

Acknowledgments

We thank Patrick Jansen, Mathew Clemens, and Wayne Taylor for their LC/MS and GC/MS analysis supporting identification of impurities; Don Risley for his scientific review and inputs; and Simon Mills and Alan Reeves of our United Kingdom laboratories for their assistance in early phases of this method development.