Abstract:

A simple HPLC method was developed and validated according to the ICH guidelines to detect and quantify the related substances of codeine phosphate in the raw material and in its combination formulation with ibuprofen before and after forced degradation. These products were further identified by using HPLC-TOF/MS and MS/MS techniques. Good separations were obtained on a C₁₈ (250 mm×4.6 mm, 5 µm) column maintained at 50 °C with linear gradient elution by a mixture of mobile phase A (ammonium acetate (pH 6.0 regulated with acetic acid, 0.04 M)–acetonitrile (92:8, v/v)) and mobile phase B (acetonitrile) at a flowrate of 1 mL/min. UV detection was set at 245 nm. Codeine was found to be instable under oxidation with the production of mainly two stereoisomers of codeine N-oxide. A new degradation product, not reported previously, was detected under alkaline hydrolysis, which was identified as 6-hydroxy-3-methoxy-17-methyl-7,8-didehydromorphinan-5-ol and shortly named as deshydrolevomethorphandiol. The esterification of codeine by ibuprofen occurred in very small amount and only under acidic stress. These results contribute to the understanding of the degradation behavior of codeine and its interaction with ibuprofen. The developed method is sensitive and precise and could be applied for the quality control of codeine bulk drug, preparations of codeine phosphate, and its combination with ibuprofen.

Key words: Codeine phosphate, Degradation product, Codeine-ibuprofen ester, Interaction impurity, LC-MS