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 alkaloids 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. Roe 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’-di- oxide 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.

Highlights

  • Since September 2011, Leiras has been a part of Takeda, a global, research-based pharmaceutical company

  • 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

  • In Tuxi, it was possible to detect the presence of major Active Pharmacological Ingredient (API) the pholcodine, and the degradation products as morphine, pholcodine-N-oxide

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Summary

Introduction

Since September 2011, Leiras has been a part of Takeda, a global, research-based pharmaceutical company. Takeda is the 12th largest company in the world. Weifa is a Norwegian private company, and one of the largest private pharmaceutical companies in Norway. Both companies manufacture antitussive (cough relief) medical forms. Pholcodine was accepted as a low-addiction substance, and Tuxi (a pholcodine-containing liquid mixture) did not need a prescription. Use of pholcodine came under scrutiny in the past 10 years, and Weifa recalled the Tuxi liquid mixture from the market,

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