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. 2011 Apr 1;19(3):185–191. doi: 10.1016/j.jsps.2011.03.004

A validated HPTLC method for determination of terbutaline sulfate in biological samples: Application to pharmacokinetic study

Md Faiyazuddin a,b,⁎, Abdul Rauf a, Niyaz Ahmad a, Sayeed Ahmad c, Zeenat Iqbal a, Sushma Talegaonkar a, Aseem Bhatnagar d, Roop K Khar a, Farhan J Ahmad a
PMCID: PMC3745045  PMID: 23960758

Abstract

Terbutaline sulfate (TBS) was assayed in biological samples by validated HPTLC method. Densitometric analysis of TBS was carried out at 366 nm on precoated TLC aluminum plates with silica gel 60F254 as a stationary phase and chloroform–methanol (9.0:1.0, v/v) as a mobile phase. TBS was well resolved at RF 0.34 ± 0.02. In all matrices, the calibration curve appeared linear (r2 ⩾ 0.9943) in the tested range of 100–1000 ng spot−1 with a limit of quantification of 18.35 ng spot−1. Drug recovery from biological fluids averaged ⩾95.92%. In both matrices, rapid degradation of drug favored and the T0.5 of drug ranged from 9.92 to 12.41 h at 4 °C and from 6.31 to 9.13 h at 20 °C. Frozen at −20 °C, this drug was stable for at least 2 months (without losses >10%). The maximum plasma concentration (Cpmax) was found to be 5875.03 ± 114 ng mL−1, which is significantly higher than the maximum saliva concentration (Csmax, 1501.69 ± 96 ng mL−1). Therefore, the validated method could be used to carry out pharmacokinetic studies of the TBS from novel drug delivery systems.

Keywords: Terbutaline sulfate, High-performance thin-layer chromatography, Biological fluids, Ex vivo stability, Pharmacokinetic study

1. Introduction

Asthma is one of the most frequent diseases influencing the human pursuit, with ⩽10% of the adult population suffering from asthma or related conditions (Bhavna et al., 2009). Asthma has a diurnal rhythm and in most of the patients, pulmonary function gets reduced from midnight sustained up to 8 h. Thus a perfect therapeutic agent should have effective measures in preventing bronchospasm for the period of 6–8 h during which most individuals sleep. Terbutaline sulfate; β-[(tert-butylamino) methyl]-3,5-dihydroxy-benzyl alcohol (C12H19NO3) (TBS; Fig. 1) is a synthetic β2-adrenoceptor (β2AR) agonist that is widely used as a bronchodilator in acute and long-term treatment of bronchial asthma, chronic bronchitis and emphysema and other chronic obstructive pulmonary diseases (COPD) with reversible bronchial hyper-reactive conditions (Borgström et al., 1989; Daraghmeh et al., 2002). TBS is a selective β2 adrenoceptor agonist. TBS is a short-acting bronchodilator which can be administered orally, parenterally or by suitable inhalation systems (DPI or nebulization). Orally administered terbutaline is absorbed incompletely. TBS undergoes high first-pass metabolism in the gut-wall and liver and limits bioavailability up to 15% (Daraghmeh et al., 2002). Peak plasma levels are 1.2 μg mL−1 for every mg of an oral dose, reached within 2–3 h. Following inhalation, only about 10–20% of inhaled dose reaches the lungs but after nanosizing the drug candidate >50% can be targeted deeper to alveolar region (Bhavna et al., 2009). Several analytical techniques like, ultraviolet spectroscopy (Selek et al., 2003; Shahin et al., 2002), voltammetery (Beltagi et al., 2007), capillary electrophoresis (Boer and Ensing, 1998; Kim et al., 2000), chemiluminescence (Li et al., 2009), high performance liquid chromatography (Chiap et al., 2002; Herring and Johnson, 2000; Jacobson and Peterson, 1994; Reverchon and Porta, 2003; Sagar et al., 1993), LC-electrochemical detection (Edholm et al., 1984; Zhang and Zhang, 2004), LC–tandem MS (Dickson et al., 2005; Fesser et al., 2005), GC–MS (Spisso et al., 2000), and electrospray high-field asymmetric waveform ion mobility spectrometry–mass spectrometry (ESI-FAIMS–MS) (Mie et al., 2008) have been reported in the literature for quantification of TBS; but most of them either employ large sample volumes or have long extraction processes. For pharmacokinetic studies, the most useful bioanalytical method reported is GC–MS (Borgström et al., 1989; Spisso et al., 2000; Bredberg et al., 1992). Isolation of unchanged compounds and metabolites from biological samples by GC–MS necessitates elimination of matrix interferences by liquid–liquid extraction (Henze et al., 2001), solid phase extraction or both (Black and Hansson, 1999; Couper and Drummer, 1996). Owing to its potency, TBS is employed in very mere quantities and its determination in biological fluids requires the detection of nanogram or subnanogram/mL levels (Damasceno et al., 2000). Although the above methods were found promising for the determination of TBS in bio-fluids but high expertise need limits routine analysis. In order to circumvent above mentioned problems, we adopted our previously validated stability indicating high performance thin layer chromatographic method (Faiyazuddin et al., 2010), which was capable of evaluating TBS concentrations in saliva and plasma with a single step extraction with methanol. The method was validated with respect to accuracy, precision, robustness, selectivity and limit of quantification and limit of detection according to FDA guidelines (FDA, 2001).

Figure 1.

Figure 1

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Chemical structure of terbutaline sulfate.

2. Materials and methods

2.1. Materials

Terbutaline sulfate (Assigned purity >98.54%) was received as gift sample from Netco Limited, Hyderabad, India. All chemicals and reagents used were of analytical grade and were purchased from E. Merck (Mumbai, India). Plasma was received from Yash Pharma Laboratories, Mumbai, India. For validation of method, biological samples were collected from volunteers (Hamdard University, New Delhi) and processed.

2.2. Methodology

2.2.1. Chromatography

The HPTLC analysis was performed on precoated silica gel aluminum plate 60F254 (20 cm × 10 cm, 200 μm thickness, E. Merck, Germany) as a stationary phase for TBS (Faiyazuddin et al., 2010). The samples were spotted as bands of width 6 mm wide and 10 mm apart by means of CAMAG syringe using a Linomat V (CAMAG, Switzerland) sample applicator. The equipment parameters include constant application rate of 160 nL s−1, slit dimension of 5 mm × 0.45 mm and scanning speed of 20 mm s−1. The mobile phase consisted of chloroform–methanol (9.0:1.0, v/v). Densitometric scanning was performed on a CAMAG TLC scanner III in florescent mode at 366 nm and operated by win CATS software (Version 1.2.0).

2.2.2. Calibration standards (CS) and quality control (QC) samples of plasma and saliva

A stock solution was prepared by dissolving 100 mg of TBS in 10 mL of methanol. Working solutions ranging from 1 to 10 mg mL−1 were prepared by properly diluting the stock solution with methanol. Ten microliters of each working solution of TBS were used to spike plasma and saliva samples (1 mL) in order to obtain calibration standards ranging from 10 to 100 μg mL−1. QC samples were prepared at concentrations of 20, 60 and 80 μg mL−1.

2.2.3. Sample preparation

Previous to analysis, plasma and saliva samples were thawed at room temperature (RTP) for about 10 min and 1 mL of plasma and saliva calibration standards and QC samples were transferred into small eppendorf tubes and mixed with 1 mL of methanol. After vigorous vortexing for 1 min, the samples were centrifuged (5 min; >2000g). Then supernatant was transferred to glass microvials and the solvent was evaporated (<50 °C). The plasma and saliva samples were reconstituted with 100 μL of methanol. One microliter of each sample was spotted on the TLC plate to obtain the final calibration range of 100–1000 ng spot−1. QC samples at final concentration of 200, 600 and 800 ng spot−1 were obtained after spotting. Each concentration was spotted six times on the TLC plate.

2.2.4. Bioanalytical method validation

The method was validated for specificity, precision, accuracy, sensitivity, recovery and robustness according to the USFDA guidelines for validation of bioanalytical methods (FDA, 2001).

2.2.4.1. Specificity

The specificity was investigated by screening three different batches of blank plasma and saliva samples. All the samples were cleaned up as described in Section 2.2.3. The RF values of endogenous compounds in the matrices were compared with those of TBS.

2.2.4.2. Precision and accuracy

Precision and accuracy were evaluated by performing replicate analyses of QC samples at three levels (200, 600 and 800 ng spot−1) in plasma and saliva. Intra-day repeatability was determined by treating spiked samples in six replicates on the same day. Inter-day repeatability was studied by comparing the results of assays performed on different days on the same spiked samples, also in six replicates for each kind of sample. The reproducibility of the method was checked by determining precision on a different instrument. The precision was expressed in terms of percentage coefficient of variation (CV, %), whereas accuracy was expressed as percent recovery.

2.2.4.3. Robustness

Robustness studies were done in triplicate at a concentration level of 600 ng spot−1. Chloroform–methanol (9.0:1.0, v/v) (9.0 ± 0.5:1.0 ± 0.5) were tried to assess robustness of the method. The amounts of mobile phase and durations of saturation were varied at 20 ± 2 mL and 30 ± 10 min, respectively. The time from spotting to chromatography and from chromatography to scanning was varied from 0, 10 and 20 min. The effects on the results were expressed as standard deviations.

2.2.4.4. Limit of detection (LOD) and limit of quantification (LOQ)

In order to determine LOD and LOQ each of blank plasma and saliva samples were spotted six times on TLC plate and the standard deviations (σ) of the magnitude of analytical response were determined. The LOD was expressed as 3.3σ/slope, whereas LOQ was expressed as 10σ/slope of the calibration curve of the TBS.

2.2.4.5. Recovery studies

Extraction efficiency or recovery was determined for TBS in triplicate at 200, 600 and 800 ng spot−1 in all matrices. The peak areas obtained after extraction were compared with peak areas resulting from standard solutions at the same concentrations.

2.2.5. Ex vivo stability

2.2.5.1. Long term stability

For the purpose of stability concern, three different concentrations of QC samples were used. After spiking in plasma and saliva, aliquots were stored at 4 and 20 °C. The stability was assessed after 0.5, 1, 2, 4 and 8 h. The stability of the drug in frozen samples (−20 °C) was determined by periodic analysis over a period of 2 months. Previous to analysis, biological samples were brought to room temperature and extraction was performed. Degradation rate constant (Kobs), half-life (T0.5) and shelf life (T0.9) of TBS in plasma and saliva were also obtained at 4 and 20 °C.

2.2.5.2. Freeze thaw stability

In favor of freeze thaw stability studies, 9 aliquots of each QC sample (in each matrix) were stored at −20 °C for 24 h; then they were left to completely thaw at room temperature. Three aliquots of each QC sample were analyzed after extraction and rest of the aliquots were returned to −20 °C for another 24 h. The cycle was repeated three times.

2.2.5.3. Short term stability

Stability of TBS in methanol (stock solution) was assessed at 4 and 20 °C. Run time stability at room temperature of processed samples after extraction was determined for QC samples. To test the stability, samples were analyzed immediately after preparation (control) and after a stipulated time period.

2.2.6. Pharmacokinetic study

In order to authenticate the applicability of proposed method, the pharmacokinetic study with marketed TBS tablet preparation was performed in three healthy volunteers after a single oral dose (5 mg). The blood and saliva samples were collected at 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after dosing. All blood samples were collected in heparinized tubes and plasma was procured after centrifugation (1000g; 20 min). All the samples were frozen at −20 °C until analysis.

3. Results and discussion

3.1. Calibration curves

The linear regression data for the calibration curves in plasma and saliva are shown in Table 1. TBS was well resolved at RF 0.34. The peak area vs. concentration fitted well to a straight line, with the following equations: Y = (4.638 ± 0.033)X + (1255.23 ± 14.95) and Y = (3.722 ± 0.019)X + (978.65 ± 10.13) in plasma and saliva, respectively. The correlation coefficients (r2) for calibration curves were equal to or better than 0.9943. No significant difference was observed in the slopes of standard curves (ANOVA, P > 0.05).

Table 1.

Linear regression data for the calibration curves (n = 6).

Parameter Value
Plasma Saliva
Linearity range (ng spot−1) 100–1000 100–1000
Correlation coefficient (r2 ± SD) 0.9982 ± 0.0015 0.9943 ± 0.0018



Slope
Mean ± SD 4.638 ± 0.033 3.722 ± 0.019
Confidence limita 4.597–4.682 3.698–3.746
Standard error 0.013 0.008



Intercept
Mean ± SD 1255.23 ± 14.95 978.65 ± 10.13
Confidence limita 1236.25–1272.18 966.56–990.11
Standard error 6.103 4.135
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a

95% confidence limit.

3.2. Bioanalytical method validation

3.2.1. Specificity

Chromatograms of TBS (drug) free plasma and saliva samples are represented in Figs. 2(a) and 3(a) respectively. Plasma and saliva samples spiked at concentration of 600 ng spot–1 are shown in Figs. 2(b) and 3(b) respectively. As exposed in both figures (Figs. 2 and 3; RF: 0.34), TBS eluted was free of interferences in all of the drug free plasma and saliva samples.

Figure 2.

Figure 2

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Chromatograms of (a) drug-free plasma and (b) plasma spiked at a concentration of 600 ng spot−1. Chromatographic conditions: mobile phase, chloroform–methanol (9.0:1.0, v/v); UV detection at 366 nm; TBS peak RF 0.34 ± 0.02.

Figure 3.

Figure 3

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Chromatograms of (a) drug-free saliva and (b) saliva spiked at a concentration of 600 ng spot−1. Chromatographic conditions: mobile phase, chloroform–methanol (9.0:1.0, v/v); UV detection at 366 nm; TBS peak RF 0.34 ± 0.02.

3.2.2. Precision and accuracy

The intra and inter-day precision and accuracy of the assay are described in Table 2. The intra-day precision was ⩽2.86% and 4.37% in plasma and saliva, respectively. The values for inter-day precision were ⩽4.37% and 5.19% in plasma and saliva, respectively. The intra and inter-day accuracy calculated as percent recovery, ranged 96.77–99.15% for the matrices studied. The low values of CV (<5.19%), with no significant differences between values for intra and inter-day precision, indicate the method’s reproducibility.

Table 2.

Precision and accuracy of HPTLC method for TBS.

Actual concentration (ng spot−1) Intra-day reproducibility
 Inter-day reproducibility
Concentration found (ng spot−1) (mean ± SD) Precisiona (CV; %) Accuracyb (%) Concentration found (ng spot−1) (mean ± SD) Precisiona (CV; %) Accuracyb (%)
Plasmac
200 194.32 ± 5.57 2.86 97.16 193.54 ± 8.46 4.37 96.77
600 593.25 ± 8.42 1.41 98.87 591.28 ± 11.72 1.98 98.54
800 788.89 ± 14.68 1.86 98.61 790.64 ± 13.55 1.71 98.83



Salivac
200 195.16 ± 9.11 4.66 97.58 197.12 ± 10.24 5.19 97.40
600 592.27 ± 11.45 1.93 98.71 594.72 ± 12.64 2.12 99.12
800 791.35 ± 12.53 1.58 98.91 793.25 ± 13.72 1.72 99.15
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a

Precision as coefficient of variation (CV; %) = SD/mean concentration × 100.

b

Accuracy = mean concentration/nominal concentration × 100.

c

Mean of six determinations (n = 6).

3.2.3. Robustness

Table 3 summarizes the average values of SD, SE and % RSD of the peak areas for each parameter at a concentration level of 600 ng spot−1 in plasma and saliva samples. The low values of SE (⩽2.52) and % RSD (⩽1.12) obtained after introducing small deliberate changes in the developed method indicated the robustness of the HPTLC method.

Table 3.

Robustness of the HPTLC method (na = 3; 600 ng spot−1).

Parameter SDb (peak area) SEb % RSD
Mobile phase composition: chloroform–methanol (9.0 ± 0.5:1.0 ± 0.5, v/v) 3.53 2.03 1.06
Mobile phase volume (18, 20 and 22 mL) 4.38 2.52 1.12
Duration of saturation (20, 30 and 40 min) 2.76 1.59 0.96
Time from spotting to chromatography (0, 10 and 20 min) 3.62 2.09 1.11
Time from chromatography to scanning (0, 10 and 20 min) 2.57 1.48 0.84
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a

Mean of three determinations (n = 3).

b

Average of results obtained from plasma and saliva.

3.2.4. LOD and LOQ

The LOD and LOQ of TBS were found to be 7.41 and 18.35 ng spot−1, respectively. The low LOD and LOQ values indicate the adequate sensitivity of the proposed method.

3.2.5. Extraction recovery

In plasma, the mean recovery (n = 6) averaged 95.92 ± 4.41% for TBS, however in saliva (n = 6) the recovery was 98.35 ± 2.72%. The extraction efficiency is not statistically different over the range of concentration studied.

3.3. Ex vivo stability

The stability of TBS was investigated in plasma and saliva samples. Each experiment was performed in triplicate and the mean concentration of TBS was calculated. A monoexponential decline in drug (TBS) concentration was observed at both 4 and 20 °C, in all biomatrices studied. After storage at 20 °C for 8 h; the drug degradation was substantial and the percentage recovery of TBS decreases to 40.2 ± 2.58% and 58.5 ± 4.75% of the initial concentrations in plasma and saliva, respectively. In contrast, higher recovery of TBS in plasma (55.8 ± 7.12%) and saliva (68.2 ± 3.19%) was obtained after storage at 4 °C for 8 h. The degradation rate constant (Kobs) of TBS in plasma and saliva were 0.11, 0.076 h−1, respectively at 20 °C, indicating that the drug was least stable in plasma (Fig. 4). Moreover, half-life (T0.5) and shelf life (T0.9) of drug in plasma, and saliva were obtained from the slope of the straight lines at both temperatures. The corresponding half-life values ranged from 6.31 to 9.13 h at 20 °C and from 9.92 to 12.41 h at 4 °C. The long term freezer stability (−20 °C) indicated that TBS was stable in the studied matrices during 2 months. The percent recovery averaged 94.35%. The freeze thaw data indicate that, as a minimum, two freeze thaw cycles can be tolerated without losses higher than 10%. Stock solutions of TBS were stable for 2 days at 20 °C and for 6 days at 4 °C without measurable degradation. Stability at room temperature of processed samples after extraction was determined. After 12 h no significant losses occurred.

Figure 4.

Figure 4

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Concentration–time profile for TBS in the plasma and saliva samples (oral administration: 5 mg tablet).

3.4. Pharmacokinetic study

The method was used for analysis of plasma and saliva samples obtained after oral administration of single TBS (5 mg). Fig. 4 shows the mean concentration–time profiles for TBS. The maximum plasma concentration (Cpmax) was found to be 5875.03 ± 114 ng mL−1, which is significantly higher than the maximum saliva concentration (Csmax, 1501.69 ± 96 ng mL−1). The result indicates that higher plasma levels were obtained after oral administration of TBS. Experimental Cpmax values after oral administration were comparable with reported data indicating that this method is suitable for pharmacokinetic studies.

4. Conclusion

This is the foremost validated HPTLC method for determination of TBS in plasma and saliva samples. Under the described conditions, the RF 0.34; where TBS eluted, was free of interferences in all of the drug free plasma and saliva investigated. UV spectra measured on the spots showed maximal absorbance at about 366 nm; improved detection sensitivity, specificity and minimized interferences from biological fluids that may occur at lower wavelengths. The methanol used to elute the plasma samples enables rapid extraction with few impurities and no interfering substances. The present method is also used to study the stability of TBS in plasma and saliva. The results indicate that the rapid degradation of drug occurred in both matrices and that the half-life of the drug ranged from 9.92 to 12.41 h at 4 °C and from 6.31 to 9.13 h at 20 °C. However, there was no significant degradation of the compound following extraction with methanol. We observed that stock solutions of TBS in methanol were stable for 2 days at 20 °C and for 6 days at 4 °C without measurable degradation. The method described is a sensitive and specific assay for TBS in biomatrices and is suitable for pharmacokinetic studies after therapeutic doses.

Ex vivo stability and pharmacokinetic investigations were carried out for TBS in plasma and saliva samples by validated HPTLC method. As the method has low detection limits, high recovery rate and good reproducibility in biomatrices; therefore it can be employed for routine analysis. HPTLC method is user-friendly technique and our developed method is perhaps the first HPTLC method for TBS; hence in future it can be used to study the degradation mechanism of TBS in the form of its metabolites. The method could be used to carry out pharmacokinetic studies of the TBS from novel drug delivery systems.

Acknowledgements

Md. Faiyazuddin is thankful to Defense R & D Organization (DRDO), New Delhi, India for providing financial support for the work presented in this paper. The authors are thankful to Dr. G. N. Qazi, the honb’le Vice Chancellor of Hamdard University for providing the such a nice facility of HPTLC instrument. Authors acknowledge the support of Netco Ltd. (Tadbun, Hyderabad, India) and Universal Capsules (Mumbai, India) for providing gift samples of terbutaline sulphate and capsules (hard gelatin; size 3), respectively.

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