The earliest clinical studies were carried out in postmenopausal women with advanceed breast cancer in Manchester, United Kingdom ( Cole et al., 1971). It was shown to be an anti-fertility agent in rats ( Harper & Walpole, 1967a, b), but was soon found to induce ovulation in women and to have either oestrogenic or antioestrogenic effects, depending on species specificity and tissue and receptor status ( Harper & Walpole, 1966, 1967a). Tamoxifen was first synthesized by Bedford and Richardson in the United Kingdom ( Bedford & Richardson, 1966). Tamoxifen and its metabolites can be analysed in biological fluids and tissues by thin-layer chromatography ( Furr & Jordan, 1984), gas chromatography–mass spectrometry (MS) ( Furr & Jordan, 1984) and high-performance liquid chromatography with ultraviolet, fluorimetric or electrochemical detection ( Chamart et al., 1989 Berthou & Dréano, 1993 Lim et al., 1993 Fried & Wainer, 1994). An assay for heavy metal impurities is also specified ( British Pharmacopoeial Commission, 1993 United States Pharmacopeial Convention, 1994 Council of Europe, 1995). The assays specified for tamoxifen citrate in tablets use LC and ultraviolet/visible absorption spectroscopy with standards. Several international pharmacopoeias specify Potentiometric titration with perchloric acid as the assay for purity of tamoxifen citrate, and liquid chromatography (LC) or gas chromatography with flame ionization detection for determining levels of the E-isomer and other impurities and decomposition products. Trade names and designations for tamoxifen citrate and its pharmaceutical preparations include: Apo-Tamox Citofen Dignotamoxi Duratamoxifen 5 Emblon ICI-46 474 Jenoxifen Kessar Ledertam Noltam Nolvadex Nourytam Novofen Oestrifen Oncotam Retaxim Tafoxen Tam Tamaxin Tamifen Tamofen Tamone Tamoplex Tamoxasta Tamox-Gry Tamoxigenat Tamox-Puren Taxfeno Terimon Valodex Zemide Zitazonium. The United States of America and British pharmacopoeias limit the E-isomer content to not more than 0.3% and 1%, respectively ( British Pharmacopoeial Commission, 1993 United States Pharmacopeial Convention, 1994). The impurities limited by the requirements of the European Pharmacopoeia include: ( E)-2-(1,2-diphenylbut-1-enyl)phenoxy]ethyldimethylamine (the E-isomer of tamoxifen) 2-ethyldimethylamine 2-ethyldimethylamine 2-dimethylamine 2-ethyldimethylamine ( Z)-2-ethylmethylamine and 1-(4-dimethylaminoethoxyphenyl)-2-phenylbutan-1-one ( Council of Europe, 1995). Tamoxifen citrate is available as 15.2-, 30.4- and 45.6-mg (equivalent to 10, 20 and 30 mg tamoxifen base) tablets which also may contain carboxymethylcellulose calcium, croscarmellose sodium (type A), gelatin, hydroxypropyl methylcellulose 2.910, lactose, Macrogel 300, magnesium stearate, mannitol, polyvinylpyrrolidone (povidone), sodium carboxymethylstarch, corn starch or titanium oxide ( Thomas, 1991 Farmindustria, 1993 Reynolds, 1993 British Medical Association/Royal Pharmaceutical Society of Great Britain, 1994 Medical Economics, 1996). Tamoxifen in pharmaceutical formulations is invariably present as its citrate salt.
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