Synthesis and Characterization of Tolvaptan Impurities

Twenty-six possible as well as observed impurities during the preparation of Tolvaptan have been identified, prepared, and characterized by HPLC (high performance liquid chromatography), NMR (nuclear magnetic resonance), and mass spectra. Control of these impurities, formed during various stages of Tolvaptan preparation, has been mentioned in this paper. 1. Introduction Impurity profiling is a major step in the drug development process followed by drug making companies world over [1, 2]. Impurities even if present in fairly small quantity could affect the overall safety and efficacy of the drug. Hence it is of tremendous importance to prepare an impurity profiling of the drug and to set their limits within the range set by ICH [3]. Drug related impurities could be classified into categories such as starting material, intermediate, degradation products, by-products derived from impurities in starting material and by-product stability, and shelf life derived from side reaction. There are several reports wherein impurities related to drug are first identified and then prepared and characterized by different methods such as MASS, NMR, and HPLC [4]. Tolvaptan (N-[ -4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-3-methylphenyl]-2-methyl-benzamide) is a drug used to treat hyponatremia associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone [5, 6]. It is available under the brand name Samsca produced by Otsuka Pharmaceutical Co Ltd. Tolvaptan is metabolized by the CYP3A4 in the liver. Various methods for synthesis of Tolvaptan have been reported in the literature [7–11]. During the preparation of Tolvaptan, impurities were detected in HPLC. Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan pharma (Scheme 1). Scheme 1: Synthetic route used for preparation of Tolvaptan. A comprehensive study was undertaken to synthesize and characterize these impurities by spectroscopic techniques. Present studies describe the synthesis and characterization of possible as well as observed impurities in the process for preparation of Tolvaptan. As per the guidelines recommended by ICH (the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), the acceptable level for a