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Photodegradation Assessment of Ciprofloxacin, Moxifloxacin

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Photodegradation Assessment of Ciprofloxacin, Moxifloxacin Hubicka et al. Chemistry Central Journal 2013, 7:133 http://journal.chemistrycentral.com/content/7/1/133 RESEARCH ARTICLE Open Access Photodegradation assessment of ciprofloxacin, moxifloxacin, norfloxacin and ofloxacin in the presence of excipients from tablets by UPLC-MS/MS and DSC Urszula Hubicka1*, PawełŻmudzki2, Przemysław Talik1, Barbara Żuromska-Witek1 and Jan Krzek1 Abstract Background: Ciprofloxacin (CIP), moxifloxacin (MOX), norfloxacin (NOR) and ofloxacin (OFL), are the antibacterial synthetic drugs, belonging to the fluoroquinolones group. Fluoroquinolones are compounds susceptible to photodegradation process, which may lead to reduction of their antibacterial activity and to induce phototoxicity as a side effect. This paper describes a simple, sensitive UPLC-MS/MS method for the determination of CIP, MOX, NOR and OFL in the presence of photodegradation products. Results: Chromatographic separations were carried out using the Acquity UPLC BEH C18 column; (2.1 × 100 mm, 1.7 μm particle size). The column was maintained at 40°C, and the following gradient was used: 0 min, 95% of eluent A and 5% of eluent B; 10 min, 0% of eluent A and 100% of eluent B, at a flow rate of 0.3 mL min-1. Eluent A: 0.1% (v/v) formic acid in water; eluent B: 0.1% (v/v) formic acid in acetonitrile. The method was validated and all the validation parameters were in the ranges acceptable by the guidelines for analytical method validation. The photodegradation of examined fluoroquinolones in solid phase in the presence of excipients followed kinetic of the first order reaction and depended upon the type of analyzed drugs and coexisting substances. Photodegradation process of analyzed drugs was confirmed by differential scanning calorimetry. In addition, the identification of degradation products was carried out by mass spectrometry. Conclusion: The developed UPLC-MS/MS method enables the determination of CIP, MOX, NOR and OFL in the presence of photodegradation products and identification of photodegradation products. Keywords: Ciprofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Photodegradation, Kinetic evaluation, Ultra performance liquid chromatography, Tandem mass spectrometry, Differential scanning calorimetry Background bacteria of Chlamydia spp., Mycoplasma spp., and Legion- Ciprofloxacin (CIP), moxifloxacin (MOX), norfloxacin ella spp. genera, bacilli of genus Mycobacterium and an- (NOR) and ofloxacin (OFL), are the antibacterial syn- aerobe of Bacteroides and Clostridium genera [3-5]. thetic drugs, belonging to fluoroquinolones group. Fluoroquinolones are compounds susceptible to photo- Fluoroquinolones exhibit increased antibacterial activity degradation process, which may lead to reduction of their against the Enterobacteriaceae and other Gram-negative antibacterial activity and to induce phototoxicity as a side bacteria such as Pseudomonas aeruginosa, and exert some effect [6]. In the available literature many papers devoted activity against certain Gram-positive cocci [1,2]. Among to the studies of fluoroquinolone photodegradation in so- them, MOX also show notable efficacy against atypical lutions can be found [7-10], while only a few relate to photodegradation studies of a substance or of the pharma- * Correspondence: [email protected] ceutical preparation in the solid phase [10-13]. 1 Department of Inorganic and Analytical Chemistry, Jagiellonian University The photodegradation process of CIP in solid phase Medical College, Faculty of Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland was analyzed by thin layer chromatography method with Full list of author information is available at the end of the article © 2013 Hubicka et al.; licensee Chemistry Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hubicka et al. Chemistry Central Journal 2013, 7:133 Page 2 of 12 http://journal.chemistrycentral.com/content/7/1/133 densitometric detection in the presence and without se- chromatographic column (3,5 μm, 100 mm × 4.6 mm). lected metal ions. Samples were prepared on Petri dishes The mobile phase consisted of triethylamine (4.5 ml), by evaporation of the test solution to obtain a dry resi- double-distilled water (830 ml) and acetonitrile (140 ml). due. They were exposed to UV radiation within the The pH was adjusted to 2.3 with 85% H3PO4 before range from 240 nm to 280 nm for 96 h [11]. Assessed addition of acetonitrile. The flow rate was 1 ml/min. The the studies performed it was found that both ion con- structure of two main degradation products of OFL has centration and ion type have an effect on the degradation been postulated from LC-MS analysis [13]. process that leads to the generation of two photoproducts. In summary, the existing research concerning the The chemical structures of the photodegradation prod- photostability of fluoroquinolones in the solid phase are ucts were identified as follows 7-[(2-aminoethyl)amino] not a comprehensive but relate of individual substances. 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-qunoline-3- The study was performed using different irradiation con- carboxylic acid and 7-amino-1-cyclopropyl-6-fluoro-1,4- ditions and exposure time. Only two papers concern the dihydro-4-oxo-qunoline-3-carboxylic acid [11]. influence of excipients on the photodegradation process. Photostability of MOX after UVA irradiation in solu- Applied methods such as TLC, HPLC and LC-MS tions and solid phase, with and without participation of allowed the separation and identification of up to three Cu(II), Zn(II), Al(III), and Fe(III) was tested. Samples for photodegradation products. In any paper not carried out testing in solid phase were prepared in the same manner studies of fluoroquinolones irradiated in the solid phase as described in a publication on CIP [11]. They were ex- by DSC. posed to UVA radiation within the range from 320 nm In the presented paper we have developed and vali- to 400 nm for 15 h [10]. The studies were carried out by dated an ultra-performance liquid chromatography the TLC-densitometric method. In solid phase, all metal method coupled with tandem mass spectrometry ions decreased the photodegradation of MOX. Identifica- (UPLC-MS/MS) for the determination of CIP, MOX, tion of the degradation three products was performed with NOR and OFL, which was used to study the effect of LC-MS/MS and 1HNMR identified them as: 1-cyclopropyl- UVA irradiation on the photostability of studied 6-fluoro-7-amino-8-methoxy-4-oxo-1,4-dihydroquinoline- fluoroquinolones in powdered tablets. In addition, the 3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-4- kinetic evaluation of the photodegradation process was oxo-7-(2-oxo-octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-1, carried out and photodegradation products have been 4-dihydroquinoline-3-carboxylic acid, 7-[3-hydroxyamino- identified. In the presented studies next to UPLC-MS 4-(2-carboxyethyl)pyrrolidin-1-yl]-1- cyclopropyl-6-fluoro-8- /MS method, differential scanning calorimetry (DSC) methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [10]. was also used to compare changes in analyzed samples Photodegradation of NOR in solid phase in the pres- before and after irradiation. ence of different excipients used for making tablets has been studied. The NOR tablets were exposed under dir- Experimental ect sunlight, fluorescent light and UV radiation (con- Chemicals and reagents tinuous 254-nm UV lamp), at ambient temperature (25°C) Ciprofloxacin hydrochloride monohydrate Cat. No. 91033- and 65% relative humidity. The separation of NOR and its 1G Fluka, Moxifloxacin hydrochloride series Strasbourg degradation products was achieved isocratically using a Cedex; Council of Europe – EDQM CS; Cat No. T30026 μ Lichrosorb® C8 chromatographic column (10 m, 20 cm × F-6081, Norfloxacin Cat. No. 9890-1G Fluka, Ofloxacin 4.6 mm) and phosphate buffer solution adjusted to Cat. No. O8757-1G Sigma. HPLC grade methanol, aceto- – pH 3.0 acetonitrile (85:15, v/v) as the eluent, pumped nitrile and formic acid (98%) were purchased from J.T. at a flow rate of 2.0 ml/min. The authors proved that Baker. HPLC grade water was obtained from HLP 5 during photodegradation diamineethyl derivative of NOR (HYDROLAB Poland) apparatus and was filtered through occurs [12]. 0.2 μm filter before use. The photostability of OFL in the solid state has been investigated. Irradiation was conducted in a chamber SUNTEST CPS + at 30°C using xenon lamp (1.5 kW) Standard solution equipped with a 6 mm special glass filter, transmitting For method validation, solutions containing different con- light corresponding to exposure behind window-glass centrations of the examined fluoroquinolones in the range – -1 (cut-off approximately 310 nm). The change in colour of 0.04 2.00 mg mL were prepared. uncoated and film coated OFL tablets and compressed OFL was studied as a function of irradiance level and Pharmaceutical preparations total exposure energy. The degradation of OFL was Proxacin 500 – film-coated tablet containing 500 mg quantified by HPLC. The separation of OFL and its two of CIP (Polfa S.A, Poland). Excipients: pregelatinized degradation products was achieved using a Symmetry C-18 starch, microcrystalline cellulose, colloidal silica hydrated, Hubicka et al. Chemistry Central Journal 2013, 7:133 Page 3 of 12 http://journal.chemistrycentral.com/content/7/1/133 magnesium stearate, croscarmellose sodium, hypromellose, detector. Compound concentration (%i) after photo- macrogol 6000, titanium dioxide. degradation was calculated from quotient of peak area Norflox- AZU – film-coated tablet containing 400 mg (Ai) to the sum of all peak areas (∑A) on chromato- of NOR (Azupharma, Germany). Excipients: microcrys- grams according to formulation %i = (Ai/∑A)100 at λ = talline cellulose, hypromellose, magnesium stearate, poly 294 nm. Spectra were analyzed in 200–700 nm range (O-carboxymethyl) starch sodium salt, povidone, propyl- with 1.2 nm resolution and sampling rate 20 points/s.
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