ISSN 10619348, Journal of Analytical Chemistry, 2015, Vol. 70, No. 7, pp. 860–868. © Pleiades Publishing, Ltd., 2015. Original Russian Text © I.S. Yaroshenko, A.Ya. Khaimenov, A.V. Grigor’ev, A.A. Sidorova, 2015, published in Zhurnal Analiticheskoi Khimii, 2015, Vol. 70, No. 7, pp. 745–753.

ARTICLES

A Chromatographic–Mass Spectrometric Method for the Determination of Moxifloxacin in Blood Plasma for Pharmacokinetic Studies I. S. Yaroshenkoa, A. Ya. Khaimenovb, A. V. Grigor’evc, and A. A. Sidorovac a

St. Petersburg State University, Universitetskii pr. 26, Petrodvorets, St. Petersburg, 198504 Russia Dr. Reddy’s Laboratories Ltd, Representative Office, Ovchinnikovskaya nab. 20, Moscow, 115035 Russia c Analytical Spectrometry Center, St. Petersburg State Polytechnic University, Gzhatskaya ul. 27, St. Petersburg, 195220 Russia email: [email protected] b

Received February 5, 2014; in final form, April 28, 2014

Abstract—A method for the determination of moxifloxacin in human blood plasma has been developed and validated by reversedphase HPLC on a YMCTriart C18 (150 × 2.0 mm, 3 µm) column with mass spectro metric detection. Sample preparation has been performed by solidphase extraction on Waters SepPak car tridges. The recovery of moxifloxacin was 90 ± 3%. A quadrupole mass analyzer with electrospray ionization has been used for detection at m/z 402.2 and 362.2 for moxifloxacin and ofloxacin (internal standard), respec tively. The lower limit of the analytical range was 1 ng/mL. The developed method has been used for the phar macokinetic study of moxifloxacin. Keywords: moxifloxacin, fluoroquinolones, HPLC with mass spectrometric detection, solidphase extrac tion, bioequivalence DOI: 10.1134/S1061934815050160

Moxifloxacin belongs to fluoroquinolones (FQ), representing an important class of broadspectrum synthetic antibiotics [1]. This is a large and constantly expanding group of compounds with similar structures because of the presence of a fluorine atom and con densed rings bearing a nitrogen atom:

O

O

R F

HO N R

R

N R

R

(1)

The fluoroquinolone series became accessible for use with the appearance of ciprofloxacin in the end of the 1980s [2]. Four generations of FQ are known. Lomefloxacin, ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, and moxifloxacin are included into the Essential Drugs List (Table 1). Moxifloxacin (see below) belongs to the fourth generation of FQ; it demonstrates activity to a wide spectrum of grampositive and gramnegative micro organisms, anaerobic, acidresistant, and atypical bacteria.

O

O F

HO N

N OMe

H N

(2)

Drugs containing moxifloxacin are used to treat infections of the upper and lower respiratory tract (acute sinusitis, acute chronic bronchitis, and com munityacquired pneumonia), as well as skin and soft tissue infections [3]. There are data that moxifloxacin has high bioavailability: the concentration of the drug in blood after oral administration is comparable to its concentration after intravenous injection. Moxifloxa cin is characterized as a drug with rather prolonged halflife and good penetration into the tissues of the organisms [1]. According to the data of the Elsevier publishing house, interest in the study of moxifloxacin keeps steadily growing in the last 15 years (Fig. 1). Various biological objects, such as urine [4–6], blood serum [2, 7] and plasma [1, 4, 6, 8–18], saliva [4, 19], and even lacrimal fluid [20] were studied. Monitoring of moxifloxacin concentration in blood plasma for attaining the optimum dosage conditions and the pre

860

A CHROMATOGRAPHIC–MASS SPECTROMETRIC METHOD

861

Table 1. Fluoroquinolines and the spectrum of their activity Generation

Drugs

I

Nonfluorinated quinolones: nalidixic acid, oxolinic acid, pipemidic acid “Gramnegative” fluoroquinolones: norfloxacin, ciprofloxacin, pefloxacin, ofloxacin, lomefloxacin “Respiratory” fluoroquinolones: levofloxacin, spar floxacin “Respiratory” and “antianaerobic” fluoroquino lines: moxifloxacin, gemifloxacin, gatifloxacin, sita floxacin, trovafloxacin

II III IV

Activity spectrum

vention of bacterial resistance is of special importance. This requires simple and valid analytical methods that can be easily implemented into clinical practice. Squarewave pulse voltammetry [5], capillary elec trophoresis [8], atomic adsorption spectrometry, con ductometry, and photometry [21] are among the described methods of moxifloxacin determination. However, the majority of studies were performed using chromatographic methods, i.e., thinlayer chroma tography with densitometric detection [22, 23] and HPLC with ultraviolet [12, 13, 17, 24], fluorescence [1, 2, 4, 6, 7, 9–11, 13–15, 18–20, 25], and mass spectrometric detection (HPLC/MS) [16, 26, 27]. There are few works on the chromatographic–mass spectrometric determination of moxifloxacin; in reported works, the tandem version utilizing the most complex equipment and being most expensive was used. In the pharmacological control of moxifloxacin in blood plasma various methods of sample preparation were used, such as liquid–liquid extraction (LLE)

Active mainly in relation to gramnegative flora Wide activity spectrum arises: gramnegative flora, certain grampositive flora Activity against coccal and atypical flora Activity against gramnegative, grampositive, and atypical flora, and anaerobic infections

with dichloromethane from an alkaline plasma solu tion [17], solidphase extraction (SPE) on Oasis HLP cartridges [12, 16]; in most of works proteins are pre cipitated with acetonitrile from an acidic plasma solu tion [1, 4, 6, 9, 10, 14]. A method of sample prepara tion combining protein precipitation with methanol, derivatization with 4chloro7nitrobenzodioxazole, and triple extraction with ethyl acetate were also described [15]. Depending on the sample preparation and detection methods, rather wide analytical ranges for moxifloxacin in blood plasma were obtained: 1–1000 ng/mL for SPE and tandem mass spectrometry [16], and 50– 10000 ng/mL for LLE and UVdetection [17] for the moxifloxacin doses 200 or 400 mg. Almost the whole range of fluoroquinolones with similar structures and correspondingly close retention parameters in chro matographic columns were used as internal standards in determining moxifloxacin. Sarafloxacin [14, 20], enrofloxacin [12], norfloxacin [1, 15], lomefloxacin [16], gatifloxacin [6, 7, 17], and ofloxacin [4, 10, 11, 19] were among them. A comparison of the methods of

700

Number of publications

600 500 400 300 200 100 0 1998

2000

2002

2004 2006 2008 Year of publication

2010

2012

Fig. 1. Growth of the number of publications dealing with moxifloxacin over the last 15 years. JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

No. 7

2015

862

YAROSHENKO et al.

Table 2. Comparison of methods for determining moxifloxacin in blood plasma by HPLC Detector

Sample preparation

FL

Protein precipitation with ace tonitrile Protein precipitation with a mixture of H3PO4 and acetoni trile Protein precipitation with ace tonitrile The same Protein precipitation with HClO4 Protein filtration, SPE SPE Protein precipitation with a mixture of acetonitrile and phosphate buffer Protein precipitation with a mixture of H3PO4 and acetoni trile Protein precipitation with methanol SPE LLE with dichloromethane Protein precipitation with methanol

FL

FL FL FL FL UV UV FL FL

FL MS UV MS

Linearity range, ng/mL

LOQ, ng/mL

Pharmacokinetics study

Dose, mg

References

40–5000

20

+

400

[1]

5–1500

3

+

200

[4]

20–4000

10

+

400

[6]

300–7000 125–10000

100 75

+ +

400 400

[9] [10]

3–1300 25–3200 100–10000

1 6 50

+ – ⎯

400 – ⎯

[11] [12] [13]

20–5000 20–7500

10 5

+

400

[14]

15–2700

6

+

400

[15]

1–1000 50–5000 50–6000

0.5 15 30

– + +

– 400 400

[16] [17] [27]

FL is fluorescent, UV is ultraviolet, MS is mass spectrometric.

moxifloxacin determination in blood plasma is pre sented in Table 2. The aim of this work was the development of a rapid, reliable, and available method for determining moxifloxacin in blood plasma by HPLC/MS using ofloxacin as an internal standard (see below) and the selective isolation of the analytes by solidphase extraction on a Waters SepPak adsorbent. O

O F

HO N H3C

O H

(3)

N N

CH3

The developed method was validated in accordance with the presentday international criteria [28–30] and ensures the determination of moxifloxacin in a wide concentration range (1–2500 ng/mL). The method was successfully applied to the study of com parative pharmacokinetics and bioequivalence of two drug formulations containing moxifloxacin.

EXPERIMENTAL Reagents and materials. Reference standards of moxifloxacin hydrochloride and ofloxacin (EDQM, France) were used. For the preparation of the mobile phase and sample preparation we used ethyl acetate (SigmaAldrich, United States), methyltertbutyl ether (SigmaAldrich, United States), acetonitrile (Biosolve, France), methanol (Merck, Netherlands), formic acid (Fluka, Germany), ammonium formate (Fluka, United States), diethylamine (Vekton, Rus sia), sodium hydroxide (Merck, Germany), hydro chloric acid (BioReagent, Germany), deionized water purified on a Milli Q Advantage A10 system, and Sep Pac®Vac tC18 (100 mg, 1 mL) SPE cartridges (Waters, Ireland). Equipment. The work was performed on an Agilent 1100 liquid chromatograph equipped with a gradient pump, a thermostatted autosampler, an electrospray ionization mass spectrometric detector, and a quadru pole mass analyzer. Separation was performed on a YMCTriart C18 (150 × 2.0 mm ID, 3 µm, 12 nm) col umn with a YMCTriart C18 guard column (10 × 2.1 mm ID, 5 µm, 12 nm). Liquid–liquid extraction and pro

JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

No. 7

2015

A CHROMATOGRAPHIC–MASS SPECTROMETRIC METHOD

tein precipitation were performed using a Heidolph Multi Reax shaker. To perform SPE, a Gast vacuum pump and a Waters system for SPE were used. Biohit adjustable volume micropipettes, an Ohaus Discovery electronic balance, an Eppendorf Centrifuge 5415R, a Biosan CH100 thermostat with heating and cooling function, and a TurboVap LV evaporator (Calliper) were used. Sanyo biomedical freezers (from –18 to –40°C and from –60 to –80°C) were used for the stability study. Preparation of standard solutions. Standard solu tions of moxifloxacin and ofloxacin with the concen tration 1 mg/mL were prepared in 25mL volumetric flasks by dissolving precisely weighed portions of refer ence standards in methanol. The solutions obtained were stable for a month at –25 ± 3°С. Solutions with concentrations from 1 to 2500 ng/mL were prepared from the standard solution of moxifloxacin by succes sive dilutions with blood plasma. Sample preparation. An internal standard solution (25 µL) of the concentration 10 µg/mL and 500 µL of a 1.5 % HCl solution were added to 500 µL of blood plasma (or solution for the construction of calibration curve, or a quality control solution) and stirred in a shaker for 3 min at 2000 rpm. After centrifugation for 1 min at 13000 rpm, the analytes were extracted on Waters SepPak cartridges. The cartridges were suc cessively conditioned with 1 mL of methanol and 1 mL of a 0.05% HCl solution. Then the cartridge was loaded with 1 mL of a sample, washed first with 1 mL of a (95 : 5 : 0.5) water–methanol–HCl solution and thereafter with water (2 × 1 mL). The analytes were eluted into autosampler vials with 1 mL of methanol and evaporated at 30°С in a nitrogen flow. The dry res idue was dissolved in 250 µL of a 0.25% formic acid solution. Conditions of moxifloxacin determination by HPLC/MS. Based on the results of preliminary experiments, the optimum composition of the mobile phase acetonitrile–water–formic acid (65 : 35 : 0.1) with an addition of 1 mM of ammonium formate was found. The mobile phase was prepared daily. The mobile phase flow rate was 0.2 mL/min, sample injec tion volume was 5 µL, autosampler thermostat tem perature was 4°С, and column temperature was 25°С. Chromatograms were recorded at positive polarity in the selected ion monitoring mode for m/z 402.2 and 362.2, corresponding to protonated molecular ions of moxifloxacin and ofloxacin. Method validation. The selectivity, sensitivity, recovery, stability of analytes, and performance charac teristics of the method were evaluated in accordance with international requirements [28–30]. According to the values of these analytical characteristics, the bioan alytical method can be used for clinical studies [31]. Selectivity was determined in the analysis of blood plasma samples from 10 different donors. The lower limit of the analytical range (LOQ) for moxifloxacin was determined as the minimum concentration that can be detected with a relative standard deviation JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

863

(RSD) of not higher than 20% and accuracy 80– 120%. The precision and accuracy were determined for three levels of concentration of quality control samples and for LOQ. Five measurements for each concentration level were performed in three days. The precision and accuracy of moxifloxacin determination were calculated for one analytical batch and for differ ent batches. The recovery of moxifloxacin from blood plasma was calculated by the equation: S1 (4) × 100%, S2 where S1 is peak area in the chromatogram of solution after sample preparation and S2 is peak area in the chromatogram of the extracted matrix with an addi tion of an analyte. Bioequivalence study. Samples of blood were taken from 24 healthy volunteers after the oral administra tion of two drug formulations, each containing 400 mg of moxifloxacin in 0, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 32, and 48 h time intervals into heparinized tubes. Plasma was separated by centrifugation (3000 rpm, 15 min, 4°C) and stored at –25 ± 3°C before analysis. R=

RESULTS AND DISCUSSION Sample preparation of blood plasma for analysis. In the development of a sample preparation procedure, protein precipitation with methanol and acetonitrile was studied. The maximum recovery (72% for moxi floxacin and 93% for the internal standard) were attained using methanol as the precipitant with the sample : precipitant ratio 2 : 5. However, tests of blood plasma samples with no analytes added demonstrated that the components of the matrix interfering with the detection of moxifloxacin and ofloxacin were also extracted in great amounts. Liquid–liquid extraction with chloroform, ethyl acetate, methyltertbutyl ether, and their mixtures in various ratios were studied. The highest recovery was obtained with ethyl acetate. Based on the pKa values of moxifloxacin (5.69 and 9.42) and ofloxacin (5.45 and 6.21), the effect of the pH of the plasma in the pH ranges >10 and <5 was studied (at these pH values, the analytes converted into the uncharged forms with a higher affinity to the organic solvent). Acidic medium was created with a formic acid solution, and alkaline medium was created with a diethylamine and a NaOH solution. However, the recoveries appeared to be low (Table 3). In development of an SPE procedure for moxiflox acin extraction from blood plasma, Oasis HLB and Waters SepPak adsorbents were studied: the condi tions of adsorbent washing and analyte elution were varied. The recoveries of moxifloxacin and ofloxacin on the Oasis HLB cartridges were 52 and 68% and on Waters SepPak cartridges, 92 and 77%, respectively. No. 7

2015

864

YAROSHENKO et al. (a)

R, % 100

2 1

80 60 40 20

0

10

20

30

40 50 c(CH3OH), vol %

(b)

R, % 100

2

80 1 60 40 20

0

5

10

15 20 c(ACN), vol %

Fig. 2. Dependence of (1) moxifloxacin and (2) ofloxacin recovery on the concentration of (a) methanol and (b) acetonitrile in the solution for washing SPE adsorbent.

Based on the results of the study, Waters SepPak car tridges were selected. To keep analytes in the uncharged form and, con sequently, attain their better retention on the car tridge, the adsorbent was conditioned with a 0.05% Table 3. Recoveries (%) of analytes with ethyl acetate at dif ferent pH of plasma (n = 3) Additive

pH

Moxifloxacin

Ofloxacin

14% HCOOH

1.7

23

25

4% HCOOH

2.7

25

22

1.5% HCOOH

3.7

21

19

0.1 M NaOH

11.2

12

13

(C2H5)2NH

11.3

10

15

HCl solution (pH 2.6), while sample was acidified by adding 500 µL of 1.5% HCl to 500 µL of plasma. Gra dient elution with methanol and acetonitrile in 0.05% HCl ensures the selection of 5 vol % of methanol in 0.05% HCl as the optimum solution for adsorbent washing without a loss of analytes (Fig. 2). Approxi mately similar recoveries were obtained for methanol and acetonitrile in the selection of an eluting system; however, the methanol eluate was much cleaner; therefore, methanol was selected as an eluent. The recoveries were on the average 93.5% at the lower limit of analytical range (1 ng/mL) and 87.0% at its upper limit (2500 ng/mL). Chromatographic–mass spectrometric determina tion of moxifloxacin. For the optimization of separa tion conditions, the composition of the mobile phase based on methanol or acetonitrile with pH 3–4 was varied. When a mobile phase containing methanol was used, peaks of analytes were small and had poor shapes; therefore, the further experiments were per formed with water–acetonitrile mobile phases acidi

JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

No. 7

2015

A CHROMATOGRAPHIC–MASS SPECTROMETRIC METHOD S, arb. units 2500000 2000000 2

1500000 1000000

1 500000

0

5

10

15

20 cbuffer, mM

Fig. 3. Dependence of peak area of (1) moxifloxacin and (2) ofloxacin on the concentration of the ammonium for mate buffer solution in the composition of the mobile phase.

fied with formic acid. An addition of an ammonium formate buffer solution (pH 3.2) resulted in an increase in signal intensity; the lower was the concen tration of the buffer solution, the larger were the peak areas of analytes (Fig. 3). The optimum mobile phase was a an acetonitrile– water–formic acid (65 : 35 : 0.1) mixture with an addi tion of 1 mM of ammonium formate (retention times for moxifloxacin and the internal standard were 3.2 and 1.7 min, respectively). In the optimization of the mass spectrometric detection, we varied ionization conditions. The opti mum conditions were as follows: temperature of dry ing gas 350°C, flow rate of drying gas 13 L/min, capil lary voltage 2000 V, and fragmentor voltage 100 V. Analytical characteristics of the method. The lower limit of analytical range for moxifloxacin was 1 ng/mL. Ten samples of blood plasma from different donors were analyzed. It was proved that no compounds inter

865

fered with the detection of moxifloxacin (Fig. 4a) and the internal standard (Fig. 4b). To build a calibration curve, we used the internal standard. In the selected concentrations range (1– 2500 ng/mL) each of 7 levels was analyzed in triplicate and the ratio of peak areas of moxifloxacin and oflox acin was calculated. The weighting factor (1/х) was selected so that the sum of relative errors in the calcu lations of concentrations of calibration levels was the minimal. The curve was described by the equation у = 0.7918х + 0.0015. The correlation coefficient (R) was 0.9989. For the evaluation of the precision and accuracy of the developed method, three series of quality control samples and samples of LOQ concentration (n = 5) were analyzed. It was found that the accuracy of the intrabatch determination of moxifloxacin varies from 97.7 to 101.4% with RSD 0.019–0.046, and the inter batch accuracy was from 92.0 to 105.9% with RSD 0.050–0.098. The stability of moxifloxacin in a biological matrix was evaluated under various samples storage condi tions: for three weeks at –25 ± 3°С (longterm stabil ity), 18 h at room temperature (shortterm stability), and at three cycles of freezethaw. Moreover, the sta bility of the analyte was evaluated in the samples pre pared for analysis under the conditions of storage in an autosampler for 18 h at +4°С. Each type of moxiflox acin stability was studied for two concentration levels (3 and 800 ng/mL) at n = 5. It was demonstrated that the change of the analyte concentration in a sample during storage relative to the concentration in freshly prepared samples did not exceed the acceptance limit of 15% (Table 4). Evaluation of bioequivalence. The developed method was applied to the study of the pharmacoki netics of moxifloxacin in the tested formulation and reference sample at the oral administration of a single dose (moxifloxacin dose 400 mg). A typical chromato gram of moxifloxacin extracted from a volunteer plasma is presented in Fig. 4c. The major pharmaco

Table 4. Stability of moxifloxacin under different storage conditions (n = 5) Deviation from concentration of the freshly prepared sample, % Conditions 3 ng/mL

800 ng/mL

Three freezethaw cycles of blood plasma samples

5.8

7.9

Storage of blood plasma samples for 1 month at –25°C

5.6

4.7

Storage of blood plasma samples for 18 h at 22°C

3.2

4.2

Storage of prepared for analysis samples in autosampler for 18 h at 4°C

7.8

0.8

JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

No. 7

2015

866

YAROSHENKO et al. (a) 280 260 240 220 200 180 160 0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5 min

(b)

Intensity, arb. units

10000 8000 6000 4000 2000

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5 min

(c) 50000 40000 30000 20000 10000

0

1

2

3

4

5 min

Fig. 4. Chromatograms of (a) blood plasma samples without additives of analytes and a sample with an addition of 1 ng/mL of moxifloxacin; (b) samples of blood plasma without an addition of analytes and sample with additions of 500 ng/mL of ofloxacin; and (c) sample of volunteer’s blood plasma after the administration of a formulation containing moxifloxacin. Conditions: YMC Triart C18 column (150 × 2 mm ID, 3 µm, 12 nm); mobile phase: acetonitrile–water–formic acid (65 : 35 : 0.1) with addition of 1 mM of ammonium formate, flow rate 0.2 mL/min; sample injection volume 5 µL; positive polarity, m/z 402.2 for moxifloxacin and m/z 362.2 for ofloxacin. JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

No. 7

2015

A CHROMATOGRAPHIC–MASS SPECTROMETRIC METHOD Table 5. Pharmacokinetic parameters of moxifloxacin in the tested formulation (T) and reference formulation (R) Parameter

T

AUCt, ng h/mL

30415 ± 6430

1864 ± 358

1849 ± 296

tmax, h

1.8 ± 0.6

2.0 ± 0.6

t1/2, h

11.9 ± 2.2

13.2 ± 3.1

cmax, ng/mL

kinetic parameters are presented in Table 5. The area under the curve concentration of the active ingredient vs. time) for the time range from 0 to the moment t of the last sampling of biomaterial (AUCt), the maxi mum concentration (cmax) and time of attainment of the maximum concentration (tmax) appeared to be equivalent in the studied formulation and the refer ence formulation (Fig. 5). The method for the determination of moxifloxacin in blood plasma we developed has several advantages over the method [16]. The tandem mass analyzer used in [16] is much more expensive, while the LOQs (1 ng/mL) were similar. Solidphase extraction was performed using a hydrophilic–lipophilic HLB sor bent. Because of the use of a SepPak adsorbent, the method we developed does not require10fold precon centration as in [16]. The linearity range was 1– 1000 ng/mL [16], while in this work it was 1– 2500 ng/mL which, corresponds to the possible con centrations of moxifloxacin in the samples of volun teer blood plasma. In contrast to [16], the method for с, ng/mL 2000 1800 1600 1400 1200 1000 800 600 400 200 0 0 4

1 2

8

determining moxifloxacin we developed was used for the analysis of real samples of blood plasma.

R

29412 ± 6310

12 16 20 24 28 32 36 40 44 48 t, h

Fig. 5. Kinetic curves of moxifloxacin (therapeutic dose 400 mg) in blood of volunteers at administration of (1) ref erence formulation and (2) tested formulation. JOURNAL OF ANALYTICAL CHEMISTRY

Vol. 70

867

REFERENCES 1. Sousa, J., Alves, G., Campos, G., and Fortuna, A., J. Chromatogr. B: Biomed. Sci. Appl., 2013, vol. 930, p. 104. 2. Nguyen, H., Grellet, J., Ba, B., Quentin, C., and Saux, M., J. Chromatogr. B: Biomed. Sci. Appl., 2004, vol. 810, p. 77. 3. Schekina, E.G., Provisor, 2007, no. 21. www.provisor. com.ua/archive/2007/N21/shekina.php. Accessed January 16, 2014. 4. Stass, H. and Dalhoff, A., J. Chromatogr. B: Biomed. Sci. Appl., 1997, vol. 702, p. 163. 5. Trindade, M., Silva, G., and Ferreira, V., Microchem. J., 2005, vol. 81, p. 209. 6. Wagenlehner, F., Kees, F., Weidner, W., Wagenlehner, C., and Naber, K., Int. J. Antimicrob. Agents, 2008, vol. 31, p. 21. 7. Justinger, C., Schilling, M., Kees, M., Kauffels, A., Hirschmann, K., Kopp, B., Kees, F., and Kollmar, O., Int. J. Antimicrob. Agents, 2012, vol. 39, p. 505. 8. Moller, J., Stass, H., Heinig, R., and Blaschke, G., J. Chromatogr. B: Biomed. Sci. Appl., 1998, vol. 716, p. 325. 9. Kontou, P., Manika, K., Chatzika, K., Papaioannou, M., Sionidou, M., Pitsiou, G., and Kioumis, I., Int. J. Anti microb. Agents, 2013, vol. 42, p. 262. 10. Kumar, A. and Ramachandran, G., J. Chromatogr. B: Biomed. Sci. Appl., 2009, vol. 877, p. 1205. 11. LabanDjurdjevic, A., JelikicStankov, M., and Djurd jevic, P., J. Chromatogr. B: Biomed. Sci. Appl., 2006, vol. 844, p. 104. 12. Lemoine, T., Breilh, D., Ducint, D., Dubrez, J., Jougon, J., Velly, J., and Saux, M., J. Chromatogr. B: Biomed. Sci. Appl., 2000, vol. 742, p. 247. 13. Liang, H., Kays, M., and Sowinski, K., J. Chromatogr. B: Biomed. Sci. Appl., 2002, vol. 772, p. 53. 14. Smet, J., Boussery, K., Colpaert, K., Sutter, P., Paepe, P., Decruyenaere, J., and Bocxlaer, J., J. Chromatogr. B: Biomed. Sci. Appl., 2009, vol. 877, p. 961. 15. Ulu, S., J. Pharm. Biomed. Anal., 2007, vol. 43, p. 320. 16. Vishwanathan, K., Bartlett, M., and Stewart, J., J. Pharm. Biomed. Anal., 2002, vol. 30, p. 961. 17. Xu, Y., Li, D., Liu, X., Li, Y., and Lu, J., J. Chromatogr. B: Biomed. Sci. Appl., 2010, vol. 878, p. 3437. 18. Zhang, L., Li, L., Shi, W., Liu, S., Liang, X., Ye, Z., Wang, W., Zhang, B., Li, R., Chen, Y., Yu, C., Zhuo, L., and Wang, X., Int. J. Antimicrob. Agents, 2013, vol. 42, p. 244. 19. Kumar, A., Sudha, V., Srinivasan, R., and Ramachan dran, G., J. Chromatogr. B: Biomed. Sci. Appl., 2011, vol. 879, p. 3663. 20. Chan, K., Chu, K., Lai, W., Choy, K., Wang, C., Lam, D., and Pang, C., Anal. Biochem., 2006, vol. 353, p. 30. 21. AlGhannam, S., Spectrochim. Acta, Part A, 2008, vol. 69, p. 1188. No. 7

2015

868

YAROSHENKO et al.

22. Dhillon, V. and Chaudhary, A., Pharm. Meth., 2010, vol. 2, p. 54. 23. Motwani, S., Khar, R., Ahmad, F., Chopra, S., Kohli, K., and Talegaonkar, S., Anal. Chim. Acta, 2007, vol. 582, p. 75. 24. Djurdjevic, P., Ciric, A., Djurdjevic, A., and Stankov, M., J. Pharm. Biomed. Anal., 2009, vol. 50, p. 117. 25. Ba, B., Etienne, R., Ducint, D., Quentin, C., and Saux, M., J. Chromatogr. B: Biomed. Sci. Appl., 2001, vol. 754, p. 107. 26. Szultka, M., Krzeminski, R., Jackowski, M., and Buszewski, B., J. Chromatogr. B: Biomed. Sci. Appl., 2013, vol. 940, p. 66. 27. Vu, D., Koster, R., Alffenaar, J., Brouwers, J., and Uges, D., J. Chromatogr. B: Biomed. Sci. Appl., 2011, vol. 879, p. 1063.

28. Guidance for Industry Bioanalytical Method Validation, U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM), 2001. 29. Guideline on Bioanalytical Method Validation, European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP), 2011. 30. Rukovodstvo po ekspertize lekarstvennykh sredstv (Guid ance for Examination of Pharmaceutical Prepara tions), Moscow: Grif i K, 2013, vol. 1. 31. Yaroshenko, D.V., Grigor’ev, A.V., Sidorova, A.A., and Kartsova, L.A., J. Anal. Khim., 2013, vol. 68, no. 9, p. 801.

JOURNAL OF ANALYTICAL CHEMISTRY

Translated by I. Duchovni

Vol. 70

No. 7

2015