Topiramate: A Review of Analytical Approaches for the Drug Substance, Its Impurities and Pharmaceutical Formulations

Journal of Chromatographic Science, 2016, Vol. 54, No. 2, 280–290 doi: 10.1093/chromsci/bmv120 Advance Access Publication Date: 13 August 2015 Review Review Topiramate: A Review of Analytical Approaches for the Drug Substance, Its Impurities and Pharmaceutical Formulations Eduardo Costa Pinto1,2,*, Maressa Danielli Dolzan2,3, Lucio Mendes Cabral1, Daniel W. Armstrong2, and Valéria Pereira de Sousa1 1 Department of Pharmaceutics, Faculty of Pharmacy, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, 373, CCS, Bss, sala 15, Rio de Janeiro 21941-902, Brazil, 2Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, USA, and 3Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil *Author to whom correspondence should be addressed. Email: Received 17 April 2015; Revised 27 June 2015 Abstract An important step during the development of high-performance liquid chromatography (HPLC) methods for quantitative analysis of drugs is choosing the appropriate detector. High sensitivity, reproducibility, stability, wide linear range, compatibility with gradient elution, non-destructive detection of the analyte and response unaffected by changes in the temperature/flow are some of the ideal characteristics of a universal HPLC detector. Topiramate is an anticonvulsant drug mainly used for the treatment of different types of seizures and prophylactic treatment of migraine. Different analytical approaches to quantify topiramate by HPLC have been described because of the lack of chromophoric moieties on its structure, such as derivatization with fluorescent moieties and UV-absorbing moieties, conductivity detection, evaporative light scattering detection, refractive index detection, chemiluminescent nitrogen detection and MS detection. Some methods for the determination of topiramate by capillary electrophoresis and gas chromatography have also been published. This systematic review provides a description of the main analytical methods presented in the literature to analyze topiramate in the drug substance and in pharmaceutical formulations. Each of these methods is briefly discussed, especially considering the detector used with HPLC. In addition, this article presents a review of the data available regarding topiramate stability, degradation products and impurities. Introduction An important step during the development of high-performance liquid chromatography (HPLC) methods for quantitative analysis of drugs is choosing the appropriate detector. The current trend in pharmaceutical analysis is the development of faster HPLC and ultra liquid chromatography methods coupled with universal detection, mainly mass spectrometry or aerosol-based HPLC detectors (1–3). High sensitivity, reproducibility, stability, wide linear range, compatibility with gradient elution, non-destructive detection of the analyte and response unaffected by changes in the temperature/flow are some of the ideal characteristics of a universal HPLC detector (1, 4). Sometimes, especially for simultaneous detection of multiple analytes, the detection choice and the HPLC method development might be quite challenging. Specific proprieties of the analyte, such as the presence of chromophore moieties, ionizable groups, polarity and the volatility of the compounds, should be evaluated (4). In addition, if the compounds of interest exhibit different properties, such as a wide range of polarity or different ionization characteristics, it may not be easy to establish a unique chromatographic/detection condition for all the analytes (4, 5). Topiramate (Table I) is an anticonvulsant drug mainly used for the treatment of different types of seizures and prophylactic treatment of migraine (6–11). It is also indicated for the treatment of bipolar © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: 280 Analytical Approaches for Topiramate Table I. Some Chemical Properties of Topiramate (6–10) Structure Scientific name Common names Molecular formula Molecular weight Pka Log P Melting range Vapor pressure Specific rotation 2,3:4,5-bis-O-(1-methylethylidene)β-D-fructopyranose sulfamic acid Topiramate, topiramic acid, topiramatum, topamax C12H21NO8S 339.362 8.6 0.573 125–126°C 7.0 × 10−8 mmHg at 25°C [α]20 D = −32.5° (0.4% in MeOH) disorder, post-traumatic stress disorder, mood instability disorder, binge-eating disorders, bulimia nervosa and obesity (11–16). Currently, this drug has been indicated in cases of alcohol, tobacco and other drugs addiction therapy (17–20). Different analytical approaches to quantify topiramate by HPLC have been described because of the lack of chromophoric moieties on its structure. These include derivatization with fluorescent moieties (21, 22) and UV-absorbing moieties (23–25), conductivity detection (26), evaporative light scattering detection (ELSD) (27), refractive index (RI) detection (28, 29), chemiluminescent nitrogen detection (CLND) (30) and MS detection (30–34). Some methods for the determination of topiramate by capillary electrophoresis (CE) (35, 36) and gas chromatography (GC) (37–39) have also been published. Our research group extensively researched the analytical methods available in the literature to analyze this drug, and we have recently reviewed the main analytical methods to evaluate topiramate in biological matrices (40). It is useful to evaluate and compare these available methods before selecting the most suitable method/detector to analyze topiramate. This systematic review provides a description of the main analytical methods presented in the literature to analyze topiramate in the drug substance and in pharmaceutical formulations. Each of these methods is briefly discussed, especially considering the detector used with HPLC. Analytical methods using CE and GC are also presented. The official US Pharmacopeia methods (7) for determination of the drug substance and its impurities content are discussed. In addition, this article presents, for the first time, a review of the data available regarding topiramate stability, including its degradation products and impurities. Drug stability, degradation products and impurities Relatively few papers discuss topiramate stability and its degradation products/impurities (23, 26, 29, 30, 35, 41). Here we review these for 281 the first time. The drug in the solid state is very stable at ambient temperature, and it degrades to organic and inorganic products at high temperatures and humidity (23, 26, 29). Considering the drug in solution, it was reported that a standard solution of topiramate in acetonitrile–water kept at room temperature of 26°C on an open bench might be stable up to 6 days (26). Li and Rossi (23) were the first to report a degradation pathway for the drug, which was further improved by Micheel et al. (26) and Klockow-Beck et al. (35). Later, Styslo-Zalasik and Li (30) cited an (...truncated)