View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of Pharmaceutical Analysis 5 (2015) 213–222 HOSTED BY Contents lists available at ScienceDirect Journal of Pharmaceutical Analysis journal homepage: www.elsevier.com/locate/jpa www.sciencedirect.com Review Paper Quantitative bioanalytical and analytical method development of dibenzazepine derivative, carbamazepine: A review$ Prasanna A. Datar n Department of Pharmaceutical Chemistry, Sinhgad Institute of Pharmacy, Narhe, Pune 411041, India article info abstract Article history: Bioanalytical methods are widely used for quantitative estimation of drugs and their metabolites in Received 10 July 2014 physiological matrices. These methods could be applied to studies in areas of human clinical pharma- Received in revised form cology and toxicology. The major bioanalytical services are method development, method validation and 25 February 2015 sample analysis (method application). Various methods such as GC, LC–MS/MS, HPLC, HPTLC, micellar Accepted 26 February 2015 electrokinetic chromatography, and UFLC have been used in laboratories for the qualitative and quan- Available online 9 March 2015 titative analysis of carbamazepine in biological samples throughout all phases of clinical research and Keywords: quality control. The article incorporates various reported methods developed to help analysts in choosing Carbamazepine crucial parameters for new method development of carbamazepine and its derivatives and also enu- HPLC merates metabolites, and impurities reported so far. LC–MS/MS & 2015 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. All rights reserved. This is an HPTLC RP-UFLC open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Micellar electrokinetic chromatography Contents 1. Introduction........................................................................................................ 213 2. Mechanism of action . 214 3. GC................................................................................................................ 214 4. LC................................................................................................................ 215 5. HPLC.............................................................................................................. 217 5.1. API and metabolites. 217 5.2. Combination product. 218 5.3. Formulation . 219 6. HPTLC............................................................................................................. 219 7. UFLC..............................................................................................................220 8. MEKC.............................................................................................................220 9. Overview..........................................................................................................220 References.............................................................................................................220 1. Introduction enhance human health. Bioanalytical methods are widely used for quantitative estimation of drugs and their metabolites in physio- One of the major challenges faced by the pharmaceutical in- logical matrices, and could be applied to studies in area of human dustry today is finding new ways to increase productivity, de- clinical pharmacology and nonhuman pharmacology/toxicology crease costs whilst still ultimately developing new therapies that that involves evaluation and interpretation of bioequivalence, pharmacokinetic, and toxicokinetic studies. The major bioanaly- tical services include method development, method validation and ☆Peer review under responsibility of Xi'an Jiaotong University. n Tel.:þ91 9823161187. sample analysis (method application). E-mail addresses: [email protected], [email protected] Chromatographic methods such as gas chromatography (GC), http://dx.doi.org/10.1016/j.jpha.2015.02.005 2095-1779/& 2015 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 214 P.A. Datar / Journal of Pharmaceutical Analysis 5 (2015) 213–222 liquid chromatography–mass spectrometry (LC–MS), and high potentiation of synaptic transmission in the spinal cord [1]. performance liquid chromatography (HPLC) are commonly used in CBZ has a narrow therapeutic index and the relationship be- laboratories for the qualitative and quantitative analysis of drug tween dose and plasma concentrations of CBZ may be un- substances and biological samples throughout all the phases of predictable because of differences in genetics, age, gender, ab- method development of a drug in research and quality control. sorption, autoinduction and disease state between individuals. Further, method validation is carried out to ensure that the Also, the presence of numerous clinically significant drug inter- method developed was accurate, specific, reproducible and rugged actions supports the need of using therapeutic monitoring of CBZ over the specified range in which an analyte is analyzed. The as an essential tool in designing a safe and effective therapeutic present review covers the wide range of chromatographic tech- regimen for patients with epilepsy [2,3]. niques used in determination of carbamazepine (CBZ) and its CBZ (5H-dibenzo[b, f]azepine-5-carboxamide) is insoluble in congeners. It also incorporates records for simultaneous estima- water, soluble in alcohol, acetonitrile and acetone. CBZ is available tions performed using analytical techniques for CBZ or its con- in market with the brand names Carbamazepen, Carbatrol, Car- geners with other drug members, impurities and metabolites. bazepine, Carbelan and Epitol. Although CBZ is poorly soluble in CBZ is an anticonvulsant and mood-stabilizing drug used pri- aqueous media, it has a high oral bioavailability in humans [4]. marily in the treatment of epilepsy and bipolar disorder, as well as Metabolism occurs primarily in the liver via the cytochrome trigeminal neuralgia in old age patients. CBZ is indicated for the P-450 oxidase system, producing carbamazepine-l0, 11-epoxide treatment of partial seizures with simple or complex symptoma- (CBZ-EP) which is as active and may reach a level up to half that of tology (psychomotor, temporal lobe) and genaralized tonic-clonic CBZ. This is almost entirely converted to carbamazepine-trans-10, seizures (grand mal). CBZ is also used as a diuretic and antic- 11-dihydrodiol (CBZ–Di OH) by epoxide hydrolase before excretion holinergic. CBZ is a first-choice anticonvulsant because of its re- in the urine (Fig. 1). CBZ along with its metabolite was required to latively low psychological toxicity and the rarity of serious adverse be routinely measured, since there were patients for whom high effects. CBZ was discovered in 1953 by chemist Walter Schindler at concentrations of this metabolite could be responsible for other- J.R. Geigy AG in Basel, Switzerland. The drug was then synthesized wise unexplained toxicity. These toxicities may be due to de- in 1960 by chemist Schindler. Later, its anti-epileptic properties gradation products, metabolites present as impurities in the for- were discovered. In 1971, Drs. Takezaki and Hanaoka first used CBZ mulation, such impurities can be studied by forced degradation of to control mania in patients' refractory to antipsychotics. CBZ was CBZ under acid, base, oxidation, heat and photolytic conditions. first marketed as a drug to treat trigeminal neuralgia in 1962. It Degradation was observed in CBZ samples under stress conditions has been used as an anticonvulsant and antiepileptic in the UK like acid hydrolysis, photolysis and thermal exposure. Mild de- since 1965, and has been approved in the US since 1974. It is of- gradation was observed for alkaline hydrolysis and exposure to ficial in most of the pharmacopoeias. It is the drug of choice for oxidation by hydrogen peroxide [5,6]. many combination therapies and used in treatment of geriatric Identification and determination of unknown organic im- patients with multiple disease states. Method development for purities is the key to the production of high quality drug sub- such combination product formulations is still a challenge. stances. ICH guidelines indicate that impurities at or above 0.1% in the drug substance require identification [7]. Fig. 2 gives the list of pharmacopoeial impurities in CBZ reported in EP and BP. 2. Mechanism of action Various chromatographic methods such as GC, LC, LC–MS, HPLC, high performance thin layer chromatography (HPTLC), ultra- CBZ acts postsynaptically by limiting the ability of neurons to force liquid chromatography (UFLC) and micellar electrokinetic sustain high frequency repetitive firing of action potentials chromatography (MEKC) were used in laboratories for the quali- through enhancement of sodium channel inactivation. In addition tative and quantitative analysis of CBZ. to altering neuronal excitability, it may act presynaptically to block the release of neurotransmitter by blocking the presynaptic so- dium channels and the firing of action potentials, which in turn 3. GC decreases synaptic transmission. Pain relief is believed to be as- sociated with blockade of synaptic transmission in the trigeminal GC is a common type of chromatography used in analytical nucleus and seizure control with reduction of post-tetanic