Supercritical Fluid Chromatography—Mass Spectrometry (SFC-MS) and MALDI-TOF-MS of Heterocyclic Compounds with Trivalent and Pentavalent Nitrogen in Cough Relief Medical Forms Tuxi and Cosylan

Abstract

Alkaloids are natural, semisynthetic or synthetic organic compounds, normally polar with basic chemical properties and containing at least one nitrogen atom in a heterocyclic ring. Some synthetic or semisynthetic substances resemble the alkaloid architecture. Trivalent nitrogen in these substances is normal; however, some natural and semisynthetic alka-loids have pentavalent nitrogen. The drug pholcodine is a derivative of morphine. Pholcodine has very little addiction-developing effect. It is a semisynthetic alkaloid that was first synthesized in 1950 by Chabrier et al. Pholcodine possesses antitussive (cough relief) properties similar to codeine, morphine and ethylmorphine. The drug was used in liquid formulations as Tuxi and Tuxi Forte, and it is in present use in Tuxidrin as liquid mixture and in tablet form. Pholcodine is an Active Pharmacological Ingredient (API) in tablets and liquid mixtures. Leiras International and Weifa in Norway manufacture medical forms with pholcodine. Several impurities in pholcodine were described by J. Røe in 1997 and by Denk et al. in 2000 and 2002. In addition, several degradation products may be formed in liquid formulations under storage. Some of these products are related not to the original production of pholcodine but rather to its oxidation under storage. The appearance of degradation products strongly depends on the storage temperature and pH of the liquid phase. Pholcodine-N-oxide and pholcodine-N,N'-dioxide are among the degradation (oxidation) products; pholcodine can also degrade to morphine. There is little information about the toxicity of the N-oxide and no information on the N,N'-dioxide of pholcodine. In this study, the fact that morphine is generated during the storage of formulations containing pholcodine is presented. Another antitussive mixture under the name Cosylan was analyzed to examine the oxidation of ethylmorphine to ethylmorphine-N-oxide. Ethylmorphine is the API in Cosylan.