Quality by Design Strategy for Simultaneous HPLC Determination of Bromhexine HCl and Its Metabolite Ambroxol HCl in Dosa
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ORIGINAL
Quality by Design Strategy for Simultaneous HPLC Determination of Bromhexine HCl and Its Metabolite Ambroxol HCl in Dosage Forms and Plasma Heba M. El‑Sayed1 · Hisham Hashem1,2 Received: 16 March 2020 / Revised: 9 May 2020 / Accepted: 16 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The quality by design strategy was applied for the simultaneous chromatographic quantification of a binary mixture of bromhexine HCl and its pharmacologically active metabolite ambroxol HCl in dosage forms as well as in human plasma. In this study, five independent parameters were screened by fractional factorial design to specify the critical ones. The optimal conditions were determined by a response surface methodology using a central composite design. Response surface methodology enabled the best separation in minimal run time, as well as, prediction of separation and retention parameters with minimum error. Separation and quantitation were carried out on BDS Hypersil C 8 (250 × 4.6 mm, 5 μm) RP-column at 1.1 mL min−1 flow rate, 25 mM of KH2PO4 (pH 3.5) in aqueous mobile phase, 65% MeOH, 210 nm wavelength of detection and 10 µL injection volume. After optimization of the chromatographic parameters, validation of the method was achieved according to ICH guidelines. Linearity ranged from 0.195 to 100 µg mL−1 ambroxol HCl, and 0.391–100 µg mL−1 bromhexine HCl, with R2 values of 0.9998 and 0.9999 and limits of detection of 0.098 and 0.195 µg mL−1, respectively. Recovery results ranged from 98.06 to 100.18 and 97.88 to 100.68 for bromhexine HCl and ambroxol HCl, respectively, with RSD less than 1.80. Keywords Ambroxol HCl · Bromhexine HCl · Dosage forms · RP-HPLC · Quality by design · Plasma
Introduction Bromhexine hydrochloride, which chemically is 3,5-dibromo-N (alpha) cyclohexyl-N (alpha)-methyl toluene-alpha-2-diamine hydrochloride (Fig. 1), acts as mucolytic agent and expectorant through affecting the mucous at the formative stage within the mucus-secreting cells in the glands. It leads to production of less viscous mucus via disruption of the structure of acid muco-polysaccharide fibers. Bromhexine has low toxicity level [1]. It is official in British Pharmacopeia (BP) [2]. After its oral administration and Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10337-020-03924-w) contains supplementary material, which is available to authorized users. * Heba M. El‑Sayed [email protected] 1
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
Chemistry Department, Faculty of Science, Jazan University, Jazan, Saudi Arabia
2
absorption, it undergoes first-pass metabolism. The plasma half lifetime of bromhexine is about 6 h. Its metabolism includes conjugation with sulphate or glucuronic acid. One of its major metabolites is ambroxol which has the same pharmacological actions as bromhexine [3]. Ambroxol hydrochloride, which is chemically defined as trans-4-((2amino-3,5-dibromobenzyl
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