306 Research article Drug Testing and Analysis Received: 24 September 2010 Revised: 13 December 2010 Accepted: 14 December 2010 Published online in Wiley Online Library: 16 March 2011 (www.drugtestinganalysis.com) DOI 10.1002/dta.258 Validated stability-indicating derivative and derivative ratio methods for the determination of some drugs used to alleviate respiratory tract disorders and their degradation products Sonia T. Hassib, Asmaa A. El-Zaher * and Marwa A. Fouad Derivative and derivative ratio methods are presented for the determination of butamirate citrate, formoterol fumarate, montelukast sodium, and sodium cromoglycate. Using the second derivative ultraviolet (UV) spectrophotometry, butamirate citrate and formoterol fumarate were determined by measuring the peak amplitude at 260.4 and 261.8 nm, respectively, without any interference of their degradation products. Butamirate citrate degradation product, 2-phenyl butyric acid, was determined by the measurement of its second derivative amplitude at 246.7 nm where butamirate citrate displays zero crossing. Formoterol fumarate degradation product, desformyl derivative, could be evaluated through the use of the first derivative at peak amplitude of 264.8 nm where interference of formoterol fumarate is negligible. In the first mode, the zero-crossing technique was applied at 305 nm for the determination of montelukast sodium in the presence of its photodegradation product, cis-isomer. The derivative of ratio spectra of montelukast sodium and its cis- isomer were used to determine both isomers using the first derivative of the ratio spectra by measuring the amplitudes of the trough at 305 nm and the peak at 308 nm, respectively. The later technique was also used for the determination of a ternary mixture of sodium cromoglycate and its two degradation products using zero-crossing method. In the derivative ratio spectra of the ternary mixture, trough depths were measured at 271.6, 302.8 and 302.2 nm, using the second, the first, and the second mode to evaluate sodium cromoglycate, degradation product (1) and degradation product (2), respectively. All the methods were applied successfully to the pharmaceutical preparation and were validated according to ICH guidelines. Copyright c  2011 John Wiley & Sons, Ltd. Keywords: respiratory tract drugs; degradation products; derivative spectrophotometry; derivative ratio spectrophotometry; stability indicating methods. Introduction Respiratory tract drugs include antitussive, anti-asthmatic and anti-allergic agents. [1] These drugs can alleviate illness of var- ied etiology, ranging from common cold to chronic obstructive pulmonary disease. [2] Butamirate citrate (BC) as a cough sup- pressant, formoterol fumarate (FF) as a β 2 -adrenoceptor agonist, montelukast sodium (Mont. Na) as a selective leukotriene D 2 re- ceptor antagonist, and sodium cromoglycate (NaCr) as a mast cell stabilizer, are various examples of such class used in this work. [3,4] In the literature, derivative spectroscopy was used to deter- mine BC, [5,6] as well as high performance liquid chromatogprahy (HPLC) [6] and capillary zone electrophoresis. [7] Neither of these methods considered the degradation product; 2-phenylbutyric acid (PBA). Various methods were used for the determination of FF including non-aqueous titration, [8] UV spectroscopy, [9] gas chromatography, [10] HPLC methods with UV detection, [11,12] tan- dem mass detection, [13] or electrochemical detection. [14] Capillary zone electrophoresis, [15] and quantitative nuclear magnetic reso- nance (NMR) [16] methods were also described. Only one stability- indicating method for the determination of FF and its related substance, the desformyl derivative (Des), using HPLC with UV de- tection, was described. [17] Several methods for evaluation of NaCr were described including spectroscopy, [18] thin layer chromatog- raphy (TLC), [19] HPLC using UV detection [20] and electrochemical methods [21] where other methods were used for drug determina- tion in the presence of two or three impurities. [22 – 25] Mont. Na was determined via different techniques viz., spectrophotometry, [26] fluorimetry, [27] HPLC with chiral stationary phase, [28] stability- indicating HPLC method using UV detection, [29] and HPLC using fluorescence detection. [30,31] Obviously, all the reported methods did not include stability- indicating methods for the selected drugs, using derivative spec- trophotometry or derivative of the ratio spectra methods, which are considered low cost methods and less complicated procedures. The present work utilized, derivative and derivative of the ratio spectra spectrophotometry were used to determine the targeted drugs and/in the presence of their degradation products. The proposed methods were compared with spectroscopic [6] (for BC), official [8] (for FF and NaCr) and HPLC methods [29] (for Mont. Na). ∗ Correspondence to: Asmaa A. El-Zaher, Department of Pharmaceutical Chem- istry, Faculty of Pharmacy, Cairo University, Kasr El- Aini 11562, Cairo, Egypt. E-mail: elzaher a@yahoo.com Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El- Aini 11562, Cairo, Egypt. Drug Test. Analysis 2011, 3, 306–318 Copyright c  2011 John Wiley & Sons, Ltd.