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  • 1 Hubei University of Medicine, Shiyan, Hubei, 442008, P.R. China
  • | 2 Hubei University of Medicine, Shiyan, Hubei, 442000, P.R. China
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A simple and rapid high-performance liquid chromatographic (HPLC) method was established for simultaneous determination of butorphanol tartrate and ondansetron hydrochloride in analgesic mixture samples used for patient-controlled analgesia (PCA). The separation of butorphanol tartrate and ondansetron hydrochloride in PCA solution was carried out on phenomenex C18 column (4.6 mm × 150 mm, 5 μm) using 50 mM sodium acetate (pH 4.0) buffer and acetonitrile (72:28, v/v). Flow rate was 1.0 mL min−1 with a column temperature of 30 °C, and detection wavelength was carried out at 280 nm and 306 nm. Validation of the method was made in terms of specificity, linearity, accuracy, and intra- and inter-day precision, as well as quantification and detection limits. The developed method was successfully used to evaluate the chemical stability of butorphanol tartrate and ondansetron hydrochloride in analgesic mixtures at the usual concentration used for PCA.

Abstract

A simple and rapid high-performance liquid chromatographic (HPLC) method was established for simultaneous determination of butorphanol tartrate and ondansetron hydrochloride in analgesic mixture samples used for patient-controlled analgesia (PCA). The separation of butorphanol tartrate and ondansetron hydrochloride in PCA solution was carried out on phenomenex C18 column (4.6 mm × 150 mm, 5 μm) using 50 mM sodium acetate (pH 4.0) buffer and acetonitrile (72:28, v/v). Flow rate was 1.0 mL min−1 with a column temperature of 30 °C, and detection wavelength was carried out at 280 nm and 306 nm. Validation of the method was made in terms of specificity, linearity, accuracy, and intra- and inter-day precision, as well as quantification and detection limits. The developed method was successfully used to evaluate the chemical stability of butorphanol tartrate and ondansetron hydrochloride in analgesic mixtures at the usual concentration used for PCA.

Introduction

Butorphanol tartrate (Figure 1a) is a mixed agonist–antagonist opioid with strong κ-receptor agonist and weak μ-receptor antagonist activity. Chemically, it is morphinan-3,14-diol,17-(cyclobutylmethyl)-, (–)-, [S-(R*,R*)]-2,3-dihydroxy butanedioate (1:1) (salt). Butorphanol tartrate is commonly used for the management of cancer, postoperative, gynecologic, and obstetric pain. As with other opioid analgesics, patient-controlled analgesia (PCA) butorphanol tartrate is associated with troublesome side effects such as nausea and/or vomiting, somnolence, and dizziness [1, 2].

Figure 1.
Figure 1.

Chemical structure of butorphanol tartrate (a) and ondansetron hydrochloride (b)

Citation: Acta Chromatographica Acta Chromatographica 30, 1; 10.1556/1326.2016.00142

Ondansetron hydrochloride (Figure 1b) is a selective type 3 serotonin (5-HT3) receptor antagonist. Chemically, it is 4H-carbazol-4-one,1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1H-imidazol-1-yl) methyl-, monohydrochloride, (±)-, dihydrate. Ondansetron hydrochloride is an effective and potent antiemetic drug which is used in the treatment of vomiting and nausea induced by cancer chemotherapy and anesthetics [3, 4]. Literature survey has revealed that coadministration of butorphanol tartrate with ondansetron hydrochloride via PCA for postoperative pain produces favorable analgesic effect and is efficacious decrease the incidence of postoperative nausea and vomiting [5]. However, there are no commercially available drug mixtures, and they must be prepared in the hospital pharmacy departments for clinical use. To our knowledge, no method was reported for the estimation of butorphanol tartrate and ondansetron hydrochloride in PCA solution by using high-performance liquid chromatographic (HPLC), and stability of this mixture in infusion solutions has not been reported in the literature. Hence, the objective of the current study was to develop and validate an HPLC method to determine the stability of mixtures of butorphanol tartrate and ondansetron hydrochloride in PCA solutions.

Experimental

Chemicals and Reagents

The working standards of butorphanol tartrate and ondansetron hydrochloride were purchased from the National Institutes for Food and Drug Control (Beijing, China) and stored at 4 °C. The pharmaceutical formulations used in this study were butorphanol tartrate injection 1 mg/1 mL (Hengrui Medicine Co., Ltd., Jiangsu, China) and ondansetron hydrochloride injection 8 mg/4 mL (Qilu Pharmaceutical Co., Ltd., Shangdong, China). Sodium acetate and acetic acid of AR grade were obtained from Jinlu Chemical Ltd. (Shanghai, China). HPLC grade acetonitrile was purchased from Fisher Scientific International (St. Louis, MO, USA). Ultrapure water was purified using a Milli-Q system (Millipore, Bedford, MA, USA).

HPLC Instrumentation and Chromatographic Conditions

A UltiMate® 3000 Standard LC systems (Dionex, Germany) composed of an UltiMate 3000 quaternary gradient pump, an ASI- 100 auto sampler, a TCC-100 thermostat column oven, an ultraviolet (UV) detector (diode array detector [DAD]) equipped with Chromeleon® software was used. HPLC separations were performed on a phenomenex C18 column (4.6 mm × 150 mm, 5 μm). The mobile phase contained a mixture of 50 mM sodium acetate buffer (pH 4.0) and acetonitrile in the ratio 72:28 (v/v). The pH was adjusted to 4.0 using diluted acetic acid, and the mobile phase was filtered through a 0.22-μm filter. The flow rate of the mobile phase was kept at 1.0 mL min−1. The selected detection wavelengths for butorphanol and ondansetron were 280 nm and 306 nm, respectively. The assay was performed at 30 °C, and injection volume was 20 μL.

Preparation of Stock and Working Solutions

One hundred milligrams of butorphanol tartrate and 80 mg of ondansetron hydrochloride working standards were accurately weighed and transferred into 100 mL volumetric flask; then, about 60 mL of deionized water was added, sonicated to dissolve it completely, and the volume was made up to the mark with the same solvent to obtain the final concentration of 1.0 mg mL−1 of butorphanol tartrate and 0.8 mg mL−1 of ondansetron hydrochloride, respectively. The solutions were kept at −20 °C until use. Fresh working standard solutions were prepared by diluting the stock solution with deionized water to the required concentrations before use.

Preparation of Butorphanol-Ondansetron Solutions

In order to mimic the concentration relevant to clinical practice, 10 mg butorphanol tartrate injection (10 mL) and 8 mg ondansetron hydrochloride injection (4 mL) were transferred to a 100-mL polyolefin bags (Kelun Pharmaceutical Co., Sichuang, China) and filled with 0.9% sodium chloride solution. The combinations were prepared under aseptic conditions in laminar flow hoods and kept in the dark at 4 °C and 25 °C.

Validation of the Method

The developed analytical method was subjected to validation with respect to various parameters such as linearity, intra- and inter-day precision, accuracy, limit of quantification (LOQ), limit of detection (LOD), and reproducibility for each analyte.

Stability Study of the PCA Solutions

In the stability study, a 5-mL sample was collected from the polyolefin bags after storage for 0, 1, 2, 3, 5, and 7 days. At each time point, the changes in appearance and pH value of the mixture were evaluated. Moreover, the concentrations of the drugs were determined at each analysis by the above described HPLC–DAD method. In the concentration analysis, samples were diluted 1:1 in deionized water before injection into HPLC system and analyzed in triplicate (total n = 3).

Results and Discussion

Optimization of Chromatographic Conditions

The present study is aimed at developing a chromatographic system capable of eluting the individual drugs, permitting their separation and simultaneous determination in PCA solutions. On the basis of the literature consulted [615], an acidic aqueous medium and acetonitrile were selected to start the optimization of mobile phase composition. Trials showed that an acidic mobile phase with reverse phase C18 column gives symmetric and sharp peaks. The best resolution and analysis time was obtained through isocratic elution using a mobile phase consisting of 50 mM sodium acetate buffer (pH 4.0)–acetonitrile 72:28 (v/v) at a flow rate of 1.0 mL min−1. Buffer pH was evaluated in the range from 2.0 to 6.0, and good resolution and peak shapes were achieved at pH 4.0. Figure 2 displays representative HPLC profiles of mixtures detected at 280 nm for the two components. Under these chromatographic conditions, the average retention time for ondansetron hydrochloride and butorphanol tartrate was found to be 7.98 and 9.30 min, respectively. DAD was used because it has advantages over conventional UV detection. It enables peak purity to be checked and simultaneous recording at the wavelength of maximum absorbance. The absorption maximum of butorphanol and ondansetron at 280 nm and 306 nm was selected for detection (Figure 3).

Figure 2.
Figure 2.

Typical chromatogram of ondansetron hydrochloride (1) and butorphanol tartrate (2)

Citation: Acta Chromatographica Acta Chromatographica 30, 1; 10.1556/1326.2016.00142

Figure 3.
Figure 3.

Overlaid UV spectrum of butorphanol tartrate (1) and ondansetron hydrochloride (2)

Citation: Acta Chromatographica Acta Chromatographica 30, 1; 10.1556/1326.2016.00142

Linearity, Limit of Detection (LOD), and Limit of Quantitation (LOQ)

Linearity was performed by preparing mixed standard solutions of butorphanol tartrate and ondansetron hydrochloride and at six concentration levels. The linearity of detector response for butorphanol tartrate and ondansetron hydrochloride was demonstrated by prepared solutions of over the concentration range of 5.0–150.0 μg mL−1 and 4.0–160.0 μg mL−1, respectively. The peak area ratio of each sample against respective concentration of butorphanol tartrate and ondansetron hydrochloride was found to be linear. The correlation coefficient for both drugs was greater than 0.998. Linearity results were presented in Table 1. The LOD and LOQ for butorphanol tartrate and ondansetron hydrochloride were determined based on the standards/baseline signal-to-noise (S/N) ratio. Two standard stock solutions were initially prepared. Dilutions and injections of two standards were then made until an HPLC chromatograph showed that the three peaks' height reached an S/N of approximately 10:1 and 3:1 for LOQ and LOD solutions, respectively. The LOD and LOQ for both drugs were determined as shown in Table 1.

Table 1.

System suitability parameters for butorphanol tartrate and ondansetron hydrochloride

Analytical parameterButorphanolOndansetron
Detection wavelength (nm)280306
Retention time (min)9.307.98
Theoretical plate (mean ± SD)16,468 ± 121914,441 ± 887
Linear range (mg L−1)5–1504–160
Linear equationY = 128.7X − 0.832Y = 1438.1X − 12.67
Coefficient of correlation (r)0.99990.9997
Quantification limit (mg L−1)1.00.2
Detection limit (mg L−1)0.40.06

Precision

The precision (relative standard deviation [RSD]) of the method was determined as intra-day precision and intermediate precision. Intra-day precision was estimated by assaying quality control samples at three concentration levels (25, 50, and 100 μg mL−1 for butorphanol tartrate; 20, 40, and 80 μg mL−1 for ondansetron hydrochloride) with six determinations per concentration at the same day. Inter-day precision (6 days) was also estimated as the RSD calculated from three quality control samples in the same way. The calculated RSD values from repeated measurements were summarized in Table 2.

Table 2.

Precision of the method

CompoundConcentration tested (mg L−1)Precision RSD (%)
Intra-dayInter-day
Butorphanol200.851.88
500.631.43
1000.201.22
Ondansetron200.141.48
400.921.52
800.160.97

Accuracy

The accuracy of the method was demonstrated at three different concentration levels (80–120%) by spiking a known quantity of standard drugs into PCA solutions sample in triplicate. The results for accuracy of the method are given in Table 3. Recoveries of butorphanol tartrate and ondansetron hydrochloride in PCA solutions were between 98.0% and 102.0%, indicating the good accuracy of the developed method.

Table 3.

Accuracy of the method

CompoundAmount added (mg L−1)Amount recovered (mean ± SD, mg L−1)% Recovery (mean ± SD, n = 3)
Butorphanol4039.879 ± 0.28499.70 ± 0.71
5050.106 ± 0.516100.21 ± 1.03
6060.552 ± 0.743100.87 ± 1.24
Ondansetron3231.937 ± 0.23099.80 ± 0.72
4039.903 ± 0.26299.76 ± 0.66
4847.632 ± 0.53199.23 ± 1.11

Chemical Stability of PCA Solutions

The chemical stability results of butorphanol tartrate-ondansetron hydrochloride PCA solutions stored under different conditions are presented in Figures 4 and 5. There was no loss in butorphanol tartrate and ondansetron hydrochloride concentrations in PCA infusions stored at 4 °C or 25 °C for 7 days. The average pH of the analgesic mixtures stored under different conditions measurements is given in Table 4. The results show that the pH of the drug mixture in both storage temperatures was similar. All PCA infusions remained clear and colorless for the duration of the study at both storage temperatures.

Figure 4.
Figure 4.

Drug concentrations (mean ± SD [%]; n = 3) of butorphanol tartrate and ondansetron hydrochloride in PCA solution over 7 days at 4 °C

Citation: Acta Chromatographica Acta Chromatographica 30, 1; 10.1556/1326.2016.00142

Figure 5.
Figure 5.

Drug concentrations (mean ± SD [%]; n = 3) of butorphanol tartrate and ondansetron hydrochloride in PCA solution over 7 days at 25 °C

Citation: Acta Chromatographica Acta Chromatographica 30, 1; 10.1556/1326.2016.00142

Table 4.

pH values (mean ± SD; n = 3) of butorphanol tartrate and ondansetron hydrochloride in PCA solution over 7 days at different storage conditions

Time (days)pH value
4 °C25 °C
04.78 ± 0.014.78 ± 0.02
14.78 ± 0.024.77 ± 0.03
24.79 ± 0.034.78 ± 0.06
34.77 ± 0.044.79 ± 0.04
54.77 ± 0.064.78 ± 0.04
74.78 ± 0.034.81 ± 0.03

Conclusion

The developed HPLC–DAD method is simple, sensitive, specific, and adequate to the simultaneous quantification of butorphanol tartrate and ondansetron hydrochloride in PCA solutions. The method was successfully applied to a study of the chemical stability of this analgesic mixture under different storage conditions for 7 days. The method might also be suitable for application to other analytical problems, for example, quality control of pharmaceutical formulations or evaluation of the chemical stability of referred drugs in mixtures for clinical use. The results of the stability study showed that mixtures of butorphanol tartrate 0.1 mg mL−1 and ondansetron hydrochloride 0.08 mg mL−1 in 0.9% sodium chloride injection and stored in polyolefin bags were chemically stable for 7 days at 4 °C or 25 °C.

Acknowledgments

The authors gratefully acknowledge the financial supports for the research: Hubei Province Health and Family Planning Scientific Research Project, China (nos. WJ2015MB215 and WJ2015MB290) and Technology Key Program of Shiyan, China (no. 14Y45).

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  • 1.

    Wang, F. Z.; Shen, X. F.; Liu, Y. S.; et al. Eur. J. Anaesthesiol. 2009 , 26 , 28 34.

  • 2.

    Thakore, B.; D'Mello, J.; Saksena, S.; et al. Acute Pain 2009 , 11 , 93 99.

  • 3.

    Wu, S. J.; Xiong, X. Z.; Lin, Y. X.; et al. Surg. Laparosc. Endosc. Percutan. Tech. 2013 , 23 , 79 87.

  • 4.

    Schwartzberg, L.; Barbour, S. Y.; Morrow, G. R.; et al. Support Care Cancer 2014 , 22 , 469 477.

  • 5.

    Zeng, X. Y.; Liu, J. Z.; Li, G. Q. Med J Liaoning 2010 , 24 , 119 122.

  • 6.

    Chen, F. C.; Fang, B. X.; Li, P.; et al. Am. J. Health Syst. Pharm. 2013 , 70 , 515 519.

  • 7.

    Chen, F. C.; Xiong, H.; Liu, H. M.; et al. Am. J. Health Syst. Pharm. 2015 , 72 , 1374 1378.

  • 8.

    Shirish, R. P.; Patel, L. J.; Yogeshvar, P. T.; Nimesh, D. P. Int. J. Chemtech. Res. 2010 , 2 , 1531 1536.

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    Dedania, Z.; Dedania, R.; Karkhanis, V.; et al. Asian J. Res. Chem. 2009 , 2 , 108 111.

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    Suneetha A. ; Chandana, P. T. J. Pharm. Res. 2014 , 13 , 106 110.

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    Chen, F. C.; Shi, X. Y.; Li, P.; et al. Medicine 2015 , 94 , e432.

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    Meyyanathan, S. N.; Venkatesh, D. N.; Krishnaveni, N.; et al. Int. J. Health Allied Sci. 2012 , 1 , 129.

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    Venkateshwaran, T. G.; King, D. T.; Stewart, J. T. J. Liq. Chromatogr. Relat. Technol. 1995 , 18 , 117 126.

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    King, D. T.; Stewart, J. T. J. Liq. Chromatogr. Relat. Technol. 1993 , 16 , 2309 2323.

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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s) Danica Agbaba (University of Belgrade, Belgrade, Serbia);
Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland),
Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

R. Bhushan (The Indian Institute of Technology, Roorkee, India)
J. Bojarski (Jagiellonian University, Kraków, Poland)
B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
M. Daszykowski (University of Silesia, Katowice, Poland)
T.H. Dzido (Medical University of Lublin, Lublin, Poland)
A. Felinger (University of Pécs, Pécs, Hungary)
K. Glowniak (Medical University of Lublin, Lublin, Poland)
B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
H. Kalász (Semmelweis University, Budapest, Hungary)
I. Klebovich (Semmelweis University, Budapest, Hungary)
A. Koch (Private Pharmacy, Hamburg, Germany)
Ł. Komsta (Medical University of Lublin, Lublin, Poland)
P. Kus (Univerity of Silesia, Katowice, Poland)
D. Mangelings (Free University of Brussels, Brussels, Belgium)
E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
G. Morlock (Giessen University, Giessen, Germany)
J. Sherma (Lafayette College, Easton, PA, USA)
R. Skibiński (Medical University of Lublin, Lublin, Poland)
B. Spangenberg (Offenburg University of Applied Sciences, Germany)
T. Tuzimski (Medical University of Lublin, Lublin, Poland)
Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
A. Voelkel (Poznań University of Technology, Poznań, Poland)
B. Walczak (University of Silesia, Katowice, Poland)
W. Wasiak (Adam Mickiewicz University, Poznań, Poland)

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

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