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Original article
12 (
8
); 2077-2083
doi:
10.1016/j.arabjc.2014.12.038

Determination of flurbiprofen in pharmaceutical preparations by GC–MS

,
 Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey

⁎Corresponding author. Tel.: +90 442 2315213; fax: +90 442 2360962. yilmazb@atauni.edu.tr (Bilal Yilmaz)

Received: , Accepted: ,
© The Author(s) 2015
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

This article describes a gas chromatography–mass spectrometry (GC–MS) method for the determination of flurbiprofen in pharmaceutical preparations. The method is based on the derivatization of flurbiprofen with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA). For GC–MS, electron ionization mode (EI = 70 eV) and selected ion monitoring (SIM) mode were used for quantitative analysis (m/z 180 for flurbiprofen). Calibration curve was linear between the concentration range of 0.25–5.0 μg/mL. Intra- and inter-day precision values for flurbiprofen were less than 3.64, and accuracy (relative error) was better than 2.67%. The mean recovery of flurbiprofen was 99.4% for pharmaceutical preparations. The limits of detection and quantification of flurbiprofen were 0.05 and 0.15 μg/mL, respectively. No interference was found from tablet excipients at the selected assay conditions. Also, the method was applied for the quality control of five commercial flurbiprofen dosage forms to quantify the drug and to check the formulation content uniformity.

Keywords

Flurbiprofen
Derivatization
Gas chromatography–mass spectrometry
Validation
Pharmaceutical tablet
1

1 Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed agents worldwide to treat a variety of pain-related conditions, including arthritis and other rheumatic diseases. In addition, epidemiological studies have shown that long-term use of NSAIDs reduces the risk of developing Alzheimer’s disease and delays its onset (Townsend and Pratico, 2005; McGeer et al., 1996; Cudaback et al., 2014).

Flurbiprofen is a non-steroidal anti-inflammatory agent, one of the propionic acid group, which has significant anti-inflammatory, analgesic and antipyretic properties. Clinically, it is used for the treatment of rheumatoid arthritis, degenerative joint disease, osteoarthritis, ankylosing spondylitis, acute musculoskeletal disorders, low back pain and allied conditions (Murali Mohan Babu et al., 2002; Rousseau et al., 2008; Muraoka et al., 2004; Uchino et al., 2014). It contains a fluorine atom in its molecular structure, producing better effects at a lower therapeutic dose and with less adverse effects compared with similar drugs.

Several methods have been reported for the determination of flurbiprofen including high performance liquid chromatography (HPLC) (Rajani and Mukkanti, 2014; Albert et al., 1984; Han et al., 2008; Chi et al., 1994; Johnson and Wilson, 1986; Adams et al., 1987; Hutzler et al., 2000; Berry and Jamali, 1988; Pe’hourcq et al., 2001; Geisslinger et al., 1992; Knadler and Hall, 1989) and liquid chromatography–mass spectrometry (LC–MS) (Mano et al., 2002). Over the last 20 years, several HPLC methods using UV or fluorescence detection have been reported for the estimation of flurbiprofen either alone or together with their metabolites in plasma/serum (Albert et al., 1984; Askholt and Nielsen-Kudsk, 1986; Chi et al., 1994; Johnson and Wilson, 1986; Adams et al., 1987; Hutzler et al., 2000), in urine (Berry and Jamali, 1988; Pe’hourcq et al., 2001; Geisslinger et al., 1992; Knadler and Hall, 1989; Hirai et al., 1997) and in ocular fluids (Riegel and Ellis, 1994). USP 2000 (USP, 2000) and BP 1993 (BP, 1993) both have recommended HPLC method for analysis of pure flurbiprofen and in dosage form (tablet and ophthalmic drops). Both the methods recommended use of a mobile phase of acetonitrile–water–glacial acetic acid (60:35:5) at a flow rate of 1 mL/min. IP 1996 (IP, 1996) has suggested titrimetric method for flurbiprofen estimation.

There is no literature, which performed the determination of flurbiprofen in pharmaceutical preparations using MSTFA as derivatization agent by GC–MS. Therefore, the present work describes the O-silylation of the hydroxyl group of flurbiprofen using N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) as a silylating reagent. The method is validated with respect to precision of peak response, linearity range, specificity, accuracy, limit of detection (LOD) and limit of quantification (LOQ). Also, the proposed method is applied to the analysis of five flurbiprofen pharmaceutical preparations, and the results are compared with USP 2000, BP 1993 and IP 1996.

2

2 Experimental

2.1

2.1 Chemicals and reagents

Flurbiprofen (99.6% purity) was obtained from Sigma (St. Louis, MO, USA). N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and acetonitrile (99.8% purity) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Majezik, Frolix, Maximus, Zero-P and Fortine tablets (100 mg flurbiprofen) were obtained from the pharmacy (Erzurum, Turkey).

2.2

2.2 Apparatus and analytical conditions

Chromatographic analysis was carried out on an Agilent 6890 N gas chromatography system equipped with 5973 series mass selective detector, 7673 series autosampler and chemstation (Agilent Technologies, Palo Alto, CA). HP-5 MS column with 0.25 μm film thickness (30 m × 0.25 mm I.D., USA) was used for separation. Splitless injection was used and the carrier gas was helium at a flow rate of 1 mL/min. The injector and detector temperatures were 250 °C. The MS detector parameters were transfer line temperature 280 °C, solvent delay 3 min and electron energy 70 eV.

2.3

2.3 Preparation of stock solutions

Stock solution (1 mg/mL) of flurbiprofen was prepared in acetonitrile. The initial stock solution was further diluted in acetonitrile to produce solutions of flurbiprofen (10 μg/mL). Calibration standards of flurbiprofen at concentrations of 0.25–5 μg/mL (0.25, 0.5, 1, 2, 3, 4 and 5 μg/mL) were prepared by spiking appropriate amount of the stock solution. Standard solutions were stored at +4 °C.

2.4

2.4 Preparation of quality control samples

The concentrations of flurbiprofen were 0.75, 2.5 and 4.5 μg/mL in acetonitrile to represent low, middle and high quality controls, respectively. Appropriate volumes from stock solution of flurbiprofen were added to normal acetonitrile to get low, middle and high quality control samples, respectively, and stored at +4 °C. The quality control samples were taken out from storage for analysis to determine intra- and inter-day precision and accuracy.

2.5

2.5 Procedure for pharmaceutical preparations

The average capsule mass was calculated from the mass of tablets of Majezik, Frolix, Maximus, Zero-P and Fortine (100 mg flurbiprofen tablet, which was composed of flurbiprofen and some excipients). They were then finely ground, homogenized and portion of the powder was weighed accurately, transferred into a 100 mL brown measuring flask and diluted to scale with acetonitrile. The mixture was sonicated for at least 10 min to aid dissolution and then filtered through a Whatman 42 paper. An appropriate volume of filtrate was diluted further with acetonitrile so that the concentration of flurbiprofen in the final solution was within the working range and then analyzed by GC–MS.

2.6

2.6 Data analysis

All statistical calculations were performed with the Statistical Product and Service Solutions (SPSS) for Windows, version 10.0. Correlations were considered statistically significant if calculated P values were 0.05 or less.

3

3 Results

3.1

3.1 Method development and optimization

The method development for the assay of flurbiprofen was based on its chemical properties. The column and acquisition parameters were chosen to be a starting point for the method development. Flurbiprofen is a polar molecule. Therefore, the capillary column coated with 5% phenyl and 95% dimethylpolysiloxane is a good choice for separation of flurbiprofen.

The GC/MS parameters used in the method development were based on the boiling point. The injection port and detector temperature was set to 250 °C for GC–MS. Different temperature programs were investigated for method. At the end of this investigation, the temperature program of the GC–MS was as follows: initial temperature was 150 °C, held for 1 min, increased to 250 °C at a rate of 30 °C/min held for 1 min, and finally to 300 °C at a rate of 10 °C/min and held for 1 min. The effects of time and temperature on the reaction were investigated. To confirm the complete derivatization of flurbiprofen, since only one peak appears on the chromatogram, flurbiprofen compound was derivatized and analyzed. After establishing the optimum reaction conditions, the compound was derivatized for analysis. To 100 μL of 1000 ng/mL flurbiprofen and 100 μL of MSTFA solution was added and reacted at room temperature, 50, 70 and 80 °C for 15, 30, 45 and 60 min. The resulting samples were quantitated by GC–MS system. The effects of the time and temperature were shown in Fig. 1.

The effect of reaction time and temperature on derivatization reaction.
Figure 1
The effect of reaction time and temperature on derivatization reaction.

3.2

3.2 Validation of the methods

To evaluate the validation of the present method, parameters such as specificity, linearity, precision, accuracy, limit of detection (LOD), limit of quantification (LOQ), recovery and stability were investigated according to ICH validation guidelines (ICH, 1996).

3.2.1

3.2.1 Specificity

The specificity of the method was investigated by observing interferences between flurbiprofen and the excipients. For GC–MS, electron impact mode with selected ion monitoring (SIM) was used for quantitative analysis (m/z 180 for flurbiprofen). The mass spectra of the flurbiprofen are shown in Fig. 2.

MS spectra after derivatization of flurbiprofen with MSTFA.
Figure 2
MS spectra after derivatization of flurbiprofen with MSTFA.

The retention time of flurbiprofen for GC–MS was approximately 5.5 min with good peak shape in scan and SIM mode (Figs. 3 and 4).

GC–MS chromatograms of flurbiprofen (a) and derivatized flurbiprofen (b) (scan ion monitoring mode).
Figure 3
GC–MS chromatograms of flurbiprofen (a) and derivatized flurbiprofen (b) (scan ion monitoring mode).
GC–MS chromatograms of flurbiprofen (0.25, 0.5, 1, 2, 3, 4 and 5.0 μg/mL) [selected ion monitoring (SIM) mode, m/z 180 for flurbiprofen].
Figure 4
GC–MS chromatograms of flurbiprofen (0.25, 0.5, 1, 2, 3, 4 and 5.0 μg/mL) [selected ion monitoring (SIM) mode, m/z 180 for flurbiprofen].

3.2.2

3.2.2 Linearity

The linearity of peak area response versus concentration for flurbiprofen was studied between concentration range of 0.25–5.0 μg/mL. The calibration curve constructed was evaluated by its correlation coefficient. The calibration equation from six replicate experiments, y = 2532.3x + 186.52 (r = 0.996), demonstrated the linearity of the method. Standard deviations of the slope and intercept for the calibration curves were 1.5275 and 4.5832, respectively (Table 1).

Table 1 Linearity of flurbiprofen.
Method Range (μg/mL) LRa Sa Sb R LOD (μg/mL) LOQ (μg/mL)
GC–MS 0.25–5.0 y = 2532.3x + 186.52 1.5275 4.5832 0.996 0.05 0.15

Sb: standard deviation of slope of regression line, R: coefficient of correlation, y: peak area, x: flurbiprofen.

LOD: limit of detection, LOQ: limit of quantification.

a Based on six calibration curves, LR: linear regression, Sa: standard deviation of intercept of regression line.

A one-way analysis of variance (ANOVA) test (Duncan et al., 1983; Bolton, 1997) was performed based on the values observed for each pure drug concentration during the replicate measurement of the standard solutions. The calculated F-value (Fcalc) was found to be less than the critical F-value (Fcrit) at 5% significance levels (Table 2).

Table 2 One-way ANOVA test for linearity of pure flurbiprofen solution by the proposed method.
Method Source of variation Degree of freedom Sum of squares Mean sum of squares F-value
Fcalc Fcrit
GC–MS Between groups 4 6.1264 × 103 3.1243 × 103
Within group 30 6.2109 × 108 1.3254 × 107 0.9999 2.6896a
Total 34 6.2112 × 108
a Theoretical value of F (4, 30) based on one-way ANOVA test at P = 0.05 level of significance.

3.2.3

3.2.3 Precision and accuracy

The precision of the analytic method was determined by repeatability (within-day) and intermediate precision (between-day). Three different concentrations which were quality control samples (0.75, 2.5, 4.5 μg/mL) were analyzed six times in one day for within-day precision and once daily for three days for between-day precision. The RSD value for within-day precision was ⩽1.21% and for between-day precision was ⩽3.64%. The bias value for within-day accuracy was ⩽0.40% and for between-day accuracy was ⩽2.67%. These values are summarized in Table 3.

Table 3 Precision and accuracy of flurbiprofen.
Method Added (μg/mL) Intra-day Inter-day
Found ± SD Accuracy Precision RSD %a Found ± SD Accuracy Precision RSD %a
GC–MS 0.75 0.74 ± 0.017 −1.33 2.30 0.77 ± 0.028 2.67 3.64
2.50 2.49 ± 0.066 −0.40 2.65 2.48 ± 0.086 −0.80 3.47
4.50 4.48 ± 0.054 −0.44 1.21 4.47 ± 0.072 −0.67 1.61

SD: standard deviation of six replicate determinations, RSD: relative standard deviation

a Average of six replicate determinations, accuracy: (% relative error) (found-added)/addedx100.

3.2.4

3.2.4 Recovery

To determine the accuracy of the proposed method and to study the interference of formulation additives, the recovery was checked as three different concentration levels (0.5, 1.5, 3.5 μg/mL) and analytical recovery experiments were performed by adding known amount of pure drugs to pre-analyzed samples of commercial dosage forms. The percent analytical recovery values were calculated by comparing concentration obtained from the spiked samples with actual added concentrations. These values are also listed in Table 4.

Table 4 Recovery of flurbiprofen in pharmaceutical preparations.
Method Pharmaceutical preparation Added (μg/mL) Intra-day Inter-day
Found ± SD Recovery (%) RSDa (%) Found ± SD Recovery (%) RSDa (%)
GC–MS Majezik (0.50 μg/mL) 0.50 0.49 ± 0.016 98.0 3.27 0.49 ± 0.019 98.0 3.88
1.50 1.48 ± 0.041 98.7 2.77 1.49 ± 0.071 99.3 4.77
3.50 3.51 ± 0.145 100.3 4.13 3.47 ± 0.178 99.1 5.13
Frolix (0.50 μg/mL) 0.50 0.49 ± 0.010 98.0 3.27 0.49 ± 0.021 98.0 4.29
1.50 1.49 ± 0.041 99.3 2.75 1.49 ± 0.079 99.3 5.30
3.50 3.52 ± 0.144 100.6 4.13 3.47 ± 0.175 99.1 5.04
Maximus (0.50 μg/mL) 0.50 0.51 ± 0.025 98.0 4.09 0.49 ± 0.018 98.0 3.67
1.50 1.49 ± 0.039 99.3 2.60 1.49 ± 0.073 99.3 4.89
3.50 3.52 ± 0.158 100.6 4.51 3.47 ± 0.184 99.1 5.13
Zero-P (0.50 μg/mL) 0.50 0.49 ± 0.012 98.0 2.40 0.49 ± 0.012 98.0 3.30
1.50 1.47 ± 0.046 98.0 3.13 1.49 ± 0.049 99.3 3.29
3.50 3.53 ± 0.157 100.9 4.44 3.52 ± 0.145 100.6 4.12
Fortine (0.50 μg/mL) 0.50 0.51 ± 0.015 102.0 2.94 0.49 ± 0.017 98.0 3.47
1.50 1.48 ± 0.056 98.7 3.78 1.48 ± 0.046 98.7 3.11
3.50 3.49 ± 0.152 100.3 4.36 3.51 ± 0.149 100.3 4.24

SD: standard deviation of six replicate determinations, RSD: relative standard deviation.

a Average of six replicate determinations.

3.2.5

3.2.5 Limit of detection and quantification

The limit of detection (LOD) and limit of quantification (LOQ) were evaluated by serial dilutions of flurbiprofen stock solutions in order to obtain signal to noise ratios of 3:1 for LOD and 10:1 for LOQ. The LOD and LOQ values for analyte were found to be 0.05 and 0.15 μg/mL, respectively (Table 1).

3.2.6

3.2.6 Stability

Stability studies indicated that the samples were stable when kept at room temperature, +4 °C and −20 °C refrigeration temperature for 24 h (short-term) and refrigerated at +4 and −20 °C for 72 h (long-term). The results of these stability studies are given in Table 5, where the percent ratios are within the acceptance range of 90–110%.

Table 5 Stability of flurbiprofen in solution.
Stability (%) Room temperature stability Refrigeratory stability +4 °C Frozen stability −20 °C
Method Added (μg/mL) (Recovery % ± RSD) (Recovery % ± RSD) Recovery % ± RSD
8 h 24 h 24 h 72 h 24 h 72 h
GC–MS 0.5 101.2 ± 3.84 101.8 ± 5.34 98.3 ± 3.12 99.2 ± 4.13 102.2 ± 5.38 98.4 ± 4.09
2.5 102.1 ± 6.43 99.1 ± 2.58 98.2 ± 3.25 98.6 ± 3.42 102.3 ± 3.84 991.2 ± 2.94
5.0 101.3 ± 3.87 98.2 ± 4.46 101.4 ± 4.42 98.4 ± 5.24 99.2 ± 5.46 102.4 ± 5.62

RSD: relative standard deviation of six replicate determinations.

3.2.7

3.2.7 Ruggedness

In this study, GC–MS determination of flurbiprofen was carried out by a different analyst in same instrument with the same standard (Table 6). The results showed no statistical differences between different operators suggesting that the developed method was rugged.

Table 6 The results of analyses of standard flurbiprofen by different analyst.a
Method Added (μg/mL) Intra-day Inter-day
Found ± SD Recovery (%) RSDa (%) Found ± SD Recovery (%) RSDa (%)
GC–MS 0.50 0.49 ± 0.012 98.0 2.45 0.49 ± 0.016 98.0 3.27
1.50 1.49 ± 0.039 99.3 2.62 1.49 ± 0.058 99.3 3.89
3.50 3.53 ± 0.136 100.9 3.85 3.52 ± 0.142 100.6 4.03
a Average of six replicate determinations.

4

4 Discussion

Today, GC–MS and HPLC methods are important and widely used as analytical techniques of qualitative and quantitative analysis. As compared to HPLC, high-resolution capillary GC–MS has inherently high resolving power and high sensitivity with excellent precision and accuracy (Yilmaz et al., 2009).

GC–MS method sensitivity is not enough for the determination of flurbiprofen in solution medium. For this reason, MSTFA was chosen as a chromagenic derivatization reagent. In this study, the purpose of the derivatization reaction is the raise of sensitivity thus the possibility of working in low concentrations has been occurred.

A study of some potential interfering substances in the GC determination of flurbiprofen was performed by selecting them as the excipients often used in pharmaceutical preparation formulations. Samples containing a fixed amount of the flurbiprofen (1.0 μg/mL) and variable concentrations of excipients (lactose, starch, avicel, povidone, sodium dodecylsulfate, aerosil and magnesium stearate) were measured. All the results obtained by using the method described above were compared with each other and no significant difference was observed between the amount of drugs found as theoretical values for t at P = 0.05 level for commercial formulations.

Pharmacopoeias (USP, 2000; BP, 1993 and IP, 1996) have reported titrimetric and liquid chromatographic methods for the analysis of flurbiprofen in pure form and in pharmaceutical formulations. Titrimetric method involves dissolving about 0.5 g of accurately weighed flurbiprofen in 100 mL of alcohol (previously neutralized with 0.1 M sodiumhydroxide versus to the phenolphthalein end point) and then, titrating the same (after adding phenolphthalein) with 0.1 M sodium hydroxide versus till the first appearance of faint pink color that persists for not less than 30 s. Each ml of 0.1 M sodium hydroxide is equivalent to 24.43 mg of flurbiprofen. Other method has recommended liquid chromatographic (HPLC) method for analysis of related substances in pure flurbiprofen and assay of flurbiprofen in pharmaceutical dosage form (tablet and ophthalmic drop). The methods recommended use a mobile phase of water–acetonitrile–glacial acetic acid (60:35:5, v/v) at a flow rate of 1 mL/min, using UV detection (254 nm) on a stainless steel column (4 μm, 3.9 × 15 cm i.d.).

Although HPLC has been utilized in these studies, there have been several problems. For example, retention times of 16 min (Hutzler et al., 2000) and 7.1 min (Han et al., 2008) for the compound of interest may be considered excessive when it is necessary to analyze multiple samples. The method uses the rapid run time of 6 min. Hence, this method can be used for the analysis of large number of samples.

A survey of literature reveals that no GC–MS method for determination of flurbiprofen in pharmaceutical preparations. The present work describes the validation parameters stated either by USP 26 (USP, 2000) or by the ICH guideline (ICH, 1996) and BP 1993 (BP, 1993) to achieve GC–MS method for determination of flurbiprofen.

The main objective of the validation of the developed GC–MS method is to obtain the consistent, reliable and accurate data. Validation of the developed the method plays its foremost role to achieve these goals. The results obtained from the validation of developed method may be used to verify the quality, quantity, accuracy and consistency of the active pharmaceutical ingredient in pharmaceutical preparations.

We validated the developed method by performing linearity, accuracy, precision, LOD and LOQ analysis. Linearity is used to determine the response of different concentrations of flurbiprofen. We evaluated the developed method by detecting the linearity using coefficient of correlation (Table 1). From the analysis of validation parameters, we found that the developed method showed highest linearity (r > 0.996) in the range of 0.25–5.0 μg/mL. The calibration curve of flurbiprofen was linear over the concentration range of 0.25–5.0 μg/mL which is as good as or superior to that reported in other papers (Hutzler et al., 2000; Han et al., 2008; Rajani and Mukkanti, 2014).

The proposed method is very effective for the assay of flurbiprofen in five different tablets. The validity of the proposed method was presented by recovery studies using the standard addition method. For this purpose, a known amount of reference drug was spiked to formulated tablets and the nominal value of drug was estimated by the proposed method. Each level was repeated six times. The results were reproducible with low SD and RSD. No interference from the common excipients was observed. The RSD for intra- and inter-day variation was less than 3.64% for GC–MS method, which falls well below the acceptance criteria described by Shah et al., (1992); Hutzler et al., (2000); Han et al., (2008). No internal standard was used as no extraction step was involved in estimation of flurbiprofen in pharmaceutical preparations. Also, the accuracy of the results established no need for internal standard for the suggested method.

LOD and LOQ are the most important parameters for the validation of the developed method. LOD is the lowest amount of active ingredient present in the dosage form that can be detected and it cannot be quantified as an exact value. LOD is a point at which measured value is greater than the uncertainty associated with it (Hutzler et al., 2000; Rajani and Mukkanti, 2014). LOQ is the lowest amount of active ingredient that can be quantitatively determined with accuracy. It is used to determine the quantity of the ingredient with known concentrations by establishing the minimal level at which the active ingredient can be quantified with suitable accuracy and precision. In the present study, the value of LOD was 0.05 μg/mL whereas for LOQ, it was 0.15 μg/mL. The lowest values of LOD and LOQ made the developed method more suitable for the analysis of flurbiprofen in different brands of flurbiprofen tablets. The precision results of the validated method were within the acceptable range (Table 3). In comparison with earlier reported and official methods for estimation of flurbiprofen in pharmaceutical formulations the proposed GC–MS method gave a lower LOD and LOQ at 50 and 150 ng/mL when compared to 100 ng/mL and 1 mg/mL of two methods proposed earlier (Beaulieu et al., 1991; Mathew et al., 1993). The proposed method also gave a comparable or in most cases lower range of the calibration plot. Unlike reported methods, the proposed method does not utilize a special extraction step for recovering the drug from the formulation excipients matrices thereby decreasing the degree of error and time in estimation. The proposed method of estimation of flurbiprofen is, therefore, more accurate and precise, rugged, reproducible and easier compared to other reported methods. Also, the sample recoveries in all formulations were in good agreement with their respective label claims and thus suggested the validity of the methods and non-interference of formulation excipients (Table 7).

Table 7 Application of the method for the determination of flurbiprofen in pharmaceutical preparations.
Method Pharmaceutical preparation n Found ± SD (mg) % RSD % Recovery F-test
GC–MS Majezik 10 99.1 ± 2.861 2.89 99.1
Frolix 10 99.6 ± 3.065 3.08 99.6
Maximus 10 100.1 ± 2.432 2.43 100.1 5.1a
Zero-P 10 98.6 ± 2.362 2.39 98.6
Fortine 10 99.4 ± 3.153 3.17 99.4

n: Number of determination, SD: standard deviation, RSD: relative standard deviation.

Ho hypothesis: no statistically significant difference exists between five pharmaceutical preparations.

Ho hypothesis is accepted (P > 0.05).

a Theoretical values at P = 0.05.

4

4 Conclusion

In the present report, a simple, rapid, sensitive, reliable, specific, accurate and precise GC–MS method for the determination of flurbiprofen in pharmaceutical preparations was developed and validated. The method described in the present report has been effectively and efficiently used to analyze flurbiprofen pharmaceutical dosage forms without any interference from the pharmaceutical excipients. Therefore, GC–MS method can be used for the routine quality control analysis of flurbiprofen in pharmaceutical preparations. Also, the method with its low detection level (50 ng/mL) can also be used as an analytical tool for the cleaning validation studies after batch change over in the industrial manufacturing area.

Acknowledgments

This study was supported by a Grant from Ataturk University Research Foundation (Project No: 2011/296). Also, we are thankful to Vedat Akba (Criminal Police Laboratory, 25060, Erzurum, Turkey) for their help in GC–MS analyses.

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