Effect Of Light And Heat On The Stability Of Montelukast In

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Journal of Pharmaceutical and Biomedical Analysis 45 (2007) 465–471

Effect of light and heat on the stability of montelukast in solution and in its solid state
Mahmoud M. Al Omari ∗ , Rufaida M. Zoubi, Enas I. Hasan, Tariq Z. Khader, Adnan A. Badwan
The Jordanian Pharmaceutical Manufacturing Company, Naor, Jordan Received 13 March 2007; receivedin revised form 10 July 2007; accepted 14 July 2007 Available online 20 July 2007

Abstract The chemical stability of montelukast (Monte) in solution and in its solid state was studied. A simultaneous measurement of Monte and its degradation products was determined using a selective HPLC method. The HPLC system comprised a reversed phase column (C18) as the stationary phase and a mixture ofammonium acetate buffer of pH 3.5 and methanol (15:85 v/v) as the mobile phase. The UV detection was conducted at 254 nm. Monte in solution showed instability when exposed to light leading to the formation of its cis-isomer as the major photoproduct. The rate of photodegradation of Monte in solution exposed to various light sources increases in the order of; sodium < neon < tungsten < daylight < UV(254 nm). The extent of photodegradation was influenced by solvent type, where Monte was found to be most stable in 70% methanol. In solid state, Monte showed more than 20% decrease in its potency after exposure to daylight for 1 week. Also unpacked Monte chewable tablets, exposed to daylight for 2 weeks, showed a decrease of about 10% with the formation of Monte S-oxide as a major photoproduct. Onthe other hand, Monte film-coated tablets either unpacked or in its immediate pack showed excellent stability under the same condition. The thermal stress testing study of Monte in solutions at 65 ◦ C showed that it is highly stable in NaOH solution, while it degrades rapidly in both acidic and H2 O2 solutions. The major degradation product in the latter solvent was Monte S-oxide and it was alsodetected as a major degradation product in Monte tablet dosage form during the incubation at 40◦ C/75% RH for 6 months. Findings of this study have helped to understand the stability behavior of Monte and to establish the critical parameters, which may affect its analysis and manufacturing activities. © 2007 Elsevier B.V. All rights reserved.
Keywords: Montelukast; Photodegradation; Chemicalstability; Oxidation; HPLC

1. Inroduction Montelukast (Monte) is an oral selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene cysLT1 and has been shown to be effective in the treatment of chronic asthma [1]. Chemically, it is 2[1-[(R)-[3-[2(E)-(7-chloroquinolin-2-yl) vinyl]phenyl]-3-[2-(1hydroxy-1-methylethyl)phenyl]propyl-sulfanylmethyl] cyclopropyl] acetic acid sodiumsalt (Fig. 1). Monte is a light sensitive compound and this necessitates special handling precautions to protect it from light, in solution and in its solid state [2–9]. Several workers reported such precaution. For example, in the determination of Monte and its S-enantiomer

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Corresponding author. E-mail address: momari@jpm.com.jo (M.M. Al Omari).

in human plasma by HPLC, it was mentionedthat all samples should be protected from light during preparation and injection [2]. The use of amber glass vials was required for storage the samples prior the HPLC analysis in Monte pharmacokinetics and bioavaliability study [3] and in using a pressurized liquid extraction (PLE) technology to extract Monte from chewable tablets [4]. In simultaneous analysis of Monte and loratadine by HPLC, allvolumetric flasks were wrapped with black paper and stored in the dark prior to analysis [5]. During the investigation of self-association properties for Monte, samples were wrapped with aluminum foil and protected from light [6]. During the synthesis of Monte [7] and its metabolic oxidation products [8], it was also reported that the reaction mixture and the isolated product were protected from...