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Identification and characterization of a photolytic degradation product of telmisartan using LC–MS/TOF, LC–MSn, LC–NMR and on-line H/D exchange mass studies

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Abstract

Telmisartan, an anti-hypertensive drug, was subjected to stress studies under ICH prescribed conditions of hydrolysis (acidic, neutral and basic), photolysis, oxidation and thermal stress. The drug showed labiality under only photo-acidic condition by forming a single degradation product. HPLC separation of the drug and the degradation product was achieved on C-8 column using gradient method. To characterize the product, a complete mass fragmentation pathway of the drug was initially established. Subsequently, the degradation product peak was subjected to LC–MS/TOF and on-line H/D exchange mass studies. Based on these studies, a tentative structure was assigned to the product as 3-((1,7′-dimethyl-2′-propyl-1H,3′H-2,5′-bibenzo[d]imidazol-3′-yl)methyl)-6H-benzo[c]chromen-6-one, which was verified through 1H LC–NMR experiments.

Introduction

Telmisartan is an angiotensin II receptor antagonist used in the treatment of hypertension. Although, it was approved by US FDA in 2000 [1], no information exists in literature on identification and characterization of its degradation products. Only, a few analytical methods for the determination of drug in biological samples and in the presence of other drugs have been reported [2], [3], [4], [5]. Hence, the purpose of the present study was to investigate the stress degradation behaviour of the drug, which was carried out by employing the following steps: (i) the drug was subjected to ICH prescribed hydrolysis, oxidative, photolytic and thermal stress [6], [7], (ii) the stressed samples were analysed by HPLC, (iii) the mass fragmentation pattern of the drug was established using MS/TOF, MSn and H/D exchange studies, (iv) the degradation product was characterized through LC–MS/TOF, on-line H/D exchange and LC–NMR data and comparison of the same with that of the drug, and (v) the elucidated structure of the degradation product was justified through mechanistic explanation.

Section snippets

Drug and reagents

Pure telmisartan was obtained as gratis sample from Ranbaxy Research Laboratories (Gurgaon, India). Analytical reagent (AR) grade sodium hydroxide was purchased from Ranbaxy Laboratories (S.A.S. Nagar, India), hydrochloric acid from LOBA Chemie Pvt. Ltd. (Mumbai, India) and hydrogen peroxide from s.d. fine-chem Ltd. (Boisar, India). Buffer salts and all other chemicals of AR grade were bought from local suppliers. HPLC grade acetonitrile (ACN) was procured from J.T. Baker (Phillipsburg, NJ,

Degradation behaviour

The drug showed degradation only in photo-acidic condition, while it was stable to all other studied conditions. The chromatogram of the photo-degraded sample is shown in Fig. 1a.

Mass fragmentation behaviour of the drug

Fig. 1b shows the mass spectrum of the drug obtained from MS/TOF studies. In total, 10 fragments were formed from the drug. The most probable molecular formula for each fragment, calculated with the help of Elemental Composition Calculator, along with errors in mmu, is shown in Table 1. The reason for high error in the

Conclusions

Stress degradation studies on telmisartan, carried out according to ICH guidelines, provided information regarding degradation behaviour of the drug. The drug was only susceptible to photo-acidic degradation, whereas it was stable in all other conditions. The degradation product formed in stressed sample was characterized using LC–MS, on-line H/D exchange mass and LC–NMR studies. It was elucidated as tricyclic lactone of the drug, viz.,

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