Identification, Isolation, and Characterization of Five Potential Degradation Impurities in Candesartan Cilexetil Tablets Arivozhi Mohan 1,& , S. Shanmugavel 1 , Ajay Goyal 1 , B. R. Venkataraman 2 , D. Saravanan 3 1 Torrent Pharmaceuticals Ltd., Analytical Development, Torrent Research Center, Gandhi Nagar 382428 Gujarat, India; E-Mail: arivozhimohan@hotmail.com 2 Post Graduate Department of Chemistry, Periyar E.V.R. College (Autonomous), Tiruchirappalli 620 023, Tamilnadu, India 3 Department of Chemistry, National College, Tiruchirappalli 620001, Tamilnadu, India Received: 12 October 2008 / Revised: 16 December 2008 / Accepted: 17 February 2009 Abstract Five impurities were observed when candesartan cilexetil tablets were subjected to stability and forced degradation studies. These impurities were successfully isolated and character- ized as desethyl candesartan cilexetil, 1N-ethyl candesartan cilexetil, 2N-ethyl candesartan cilexetil, 1N-ethyl oxo candesartan cilexetil, and 2N-ethyl oxo candesartan cilexetil. A gradient reverse phase liquid chromatography (LC) and an isocratic preparative LC method were used to detect and isolate all five degradation products impurities simultaneously. Mass spectrometry, 1 H/ 13 C, DEPT and 2D NMR experiments were extensively utilized to char- acterize these impurities. Even though desethyl candesartan cilexetil, 1N-ethyl candesartan cilexetil were 2N-ethyl candesartan cilexetil were documented in the literature as known impurities, the regioisomers 1N-ethyl oxo candesartan cilexetil and 2N-ethyl oxo cande- sartan cilexetil were never noticed. Single-crystal diffraction data has been used to confirm their structure unambiguously and synthetic preparations of all known and unknown impu- rities were also presented. Keywords Column liquid chromatography-mass spectrometry NMR spectroscopy Candesartan cilexetil degradation products Introduction Candesartan cilexetil, (±)-1-(cyclohexyl- oxycarbonyloxy) ethyl-2-ethoxy-1-[[2 0 - (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate (Fig. 1), is a nonpeptide antihypertensive drug and used either single or in combination with other drugs, to treat high blood pressure. In the gastrointestinal tract candesartan cilexetil is converted to candesartan, an angiotensin II receptor antagonist (ARA II) which blocks the ability of angioten- sin II to raise blood pressure by con- stricting or squeezing arteries and veins and ultimately leads to a reduction in blood pressure. It also reduced the work of heart by reducing the pressure against which the heart must pump blood, and is useful in patients with heart failure [1–3]. It is marketed under the brand name of Atacand and in combination with a thi- azide diuretic drug hydrochlorothiazide (HCTZ) as Atacand HCT by Astra Zeneca. Several impurities of candesartan cilexetil have been identified and docu- mented in the literature [4–6]. Identifi- cation of the impurities and analytical method for quantitation in drug sub- stances, drug products and plasma sam- ples has been described. Stenhoff et al. have reported the identification of hydroxy candesartan or desethyl cande- sartan (metabolite) and candesartan in plasma samples [4]. Ferreiro´s et al. have reported the base hydrolytic impurities of candesartan cilexetil, i.e.; candesartan and its transesterification product of methyl ester [5]. Recently Rao et al. [6] established candesartan, candesartan methyl ester, candesartan ethyl ester, hydroxy candesartan cilexetil or desethyl DOI: 10.1365/s10337-009-1066-3 Ó 2009 Vieweg+Teubner | GWV Fachverlage GmbH Original