Terbutaline

Abstract

The stability of terbutaline sulfate (0.1 mg/mL) in 0.9% sodium cloride injection was studied at 25°C when stored in polyvinylchloride bags, using a stability-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and percent relative standard deviation based on five injections was 1.0. The drug decomposed when boiled after adding sodium hydroxide, and the products of decomposition did not interfere with the assay procedure. The injection did not lose any potency after 23 days of storage at 25°C, and the pH value of 4.3 did not change. The physical appearance of the injection remained clear throughout the study period.

Introduction

Terbutaline sulfate (Figure 1) is a beta-adrenergic receptor agonist. The injection is extensively used for the relief of bronchospasm in acute and chronic obstructive pulmonary dis ease since it increases the pulmonary flow rate.1 The commercially available injection (1-mg/mL ampules) is usually diluted with normal saline to a concentration of 0.1 mg/mL and stored in the polyvinylchloride (PVC) bags for infusion. Terbutaline sulfate is a catecholamine and very susceptible to oxidation, especially on the alkaline side.2 The stability of the diluted injection (0.03 mg/mL) has been reported in the literature.3 The diluted injection was stored at room temperature in PVC bags. The authors reported that the concentration of the drug remaining in 0.9% sodium cloride injection after 1 day of storage was 110.2% of the label claim and after 7 days it was 113.9%. These results indicate that there may be something interfering with the assay method. The stability guidelines usually require a change in potency of less than 10% of the label claim. Furthermore, the high-performance liquid chromatographic (HPLC) method used by these authors required ion-pairing, which shortened the lives of the columns.

The purpose of this investigation was to develop a stability-indicating assay method for the quantitation of terbutaline sulfate in the admixture and to study the stability of the diluted injection after storage in PVC bags at 25°C.

Materials and Methods

Chemicals and Reagents

All the chemicals and reagents were United States Pharmacopeia-National Formulary (USP-NF) or American Chemical Society (ACS) grade and were used without further purification.

Terbutaline sulfate powder (Lot 82209) was generously supplied by Professional Compounding Centers of America, Houston, Texas, and the injection (1-mg/mL ampules) was from commercial Lot 075 D7300 by Novartis Pharmaceutical Corporation, East Hanover, New Jersey.

Equipment

An HPLC system (M-45 pump and model 484 multiple wavelength detector by Waters Corporation, Milford, Massachusetts) equipped with an injector (Model 7125, Rheodyne, Cotati, California) and a recorder (Omniscribe 5213-12, Houston Instruments, Austin, Texas) were used. The column used (Beckman Coulter's Ultrasphere, 15 cm, 4.6 mm ID, 5 µm) is available from Phenomenex Inc., Torranee, California. The pH values were measured using a Beckman Coulter Zeromatic SS-3 pH meter (Beckman Instruments, Fullerton, California).

Chromatographic Conditions

The mobile phase contained 7% (v/v) acetonitrile in water containing 0.02 M ammonium acetate and 1% glacial acetic acid buffer. The pH of the mobile phase was approximately 4.0. The flow rate was 1.2 mL/min., the sensitivity was 0.05 AUFS at 278 nm, the chart speed was 30.5 cm/hr and the temperature was ambient.

Preparation of Injection for Stability Studies

Terbutaline sulfate injection (1 mg/mL) was diluted with 0.9% sodium chloride injection without preservative (Lot PS 112722, Baxter Healthcare, Deerfield, Illinois) to a concentration of 0.1 mg/mL. The injection was immediately filled into 50-mL PVC bags (from which 0.9% sodium chloride injection was withdrawn) and stored at 25°C (± 1°C). On day zero, the injection was assayed and the pH value recorded. The contents of the bags were assayed again at appropriate intervals. The pH values were also recorded.

Preparation of Standard Solutions

A 50.0-mg quantity of the powder was accurately weighed and dissolved in enough water to make 250 mL of the solution. This stock solution was used to prepare solutions of lower concentrations as needed. The most commonly used standard solution of the drug (20 µg/mL) was prepared by diluting 2.5 mL of the stock solution to 25 mL with water. Before diluting to volume, a 4.5-mL quantity of the 0.9% sodium cloride injection was added (same concentration as in the assay solution).

Preparation of Assay Solutions

A 5.0-mL quantity of the assay solution was diluted to 25 mL with water.

Decomposition of Terbutaline Sulfate

To a 25-mL quantity of the standard solution (0.02 mg/mL), 3 drops of 0.5 N NaOH solution were added, and the mixture was transferred to a 150-mL beaker and heated to boiling using a hotplate. More water was added if needed. After 15 minutes it was allowed to cool, the mixture was neutralized, and volume was brought back to 25 mL with water and assayed using the method described in the assay procedure and the calculations.

Assay Procedure and the Calculations

An 80-µL quantity of assay solution was injected into the chromatograph using the conditions described. For comparison, a similar volume of the standard solution containing the same concentration of the drug (based on the label claim) was injected. Since peak heights of the drug were directly related to the concentrations (14-22 µg/mL), the results were calculated using a simple equation:

(Ph)^sub a^/(Ph)^sub s^ × 100 = percentage of the label claim found where (Ph)^sub a^ is the peak height of drug of the assay solution and (Ph)^sub s^ is that of the standard solution. The results are presented in Table 1.

Results and Discussion

Assay Method

The assay method developed is precise and accurate, with a percent relative standard deviation of 1.0 based on five readings. Apparently the large injection volume (80 µL) gave accurate and precise results without the use of an internal standard. The concentrations of the drug were directly related to the peak heights (range tested, 14-22 µg/mL). The R value was 0.992. The volume of injection (80 µL) should be kept the same for a linear relationship between the concentrations and the peak heights. The standard solution, which was decomposed using heat and sodium hydroxide, lost potency by approximately 40% (Figure 2B). There were many new peaks in the chromatogram from the products of decomposition (Figure 2B). The products of decomposition have been reported.2 The catechol ring in the drug is sensitive to oxidation and the light acts as a catalyst.

The potency or pH value of the terbutaline sulfate admixture (0.1 mg/mL), which was stored at 25°C for 23 days in PVC bags, did not change (Table 1). Obviously terbutaline sulfate is a very stable compound. Its stability was expected because the pH value of the admixture remained 4.3 during the study period and the physical appearance was clear. When terbutaline decomposes (oxidation) it becomes discolored.

Conclusion

When terbutaline sulfate injection is diluted 1 in 10 with 0.9% sodium cloride injection and stored in PVC bags at room temperature, it is stable for at least 23 days.

References

1. Terbutaline sulfate (Brethine) injection [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corporation; April, 2000: 1.

2. Ajuja S, Ashman J. Terbutaline sulfate. In: Florey K, ed. Analytical Profiles of Drug Substances. 19th ed. New York, NY: Academic Press; 1990: 615.

3. Mehta J, Searcy CJ, Jung DT. Stability of terbutaline sulfate admixtures stored in polyvinyl chloride bags. Am J Hosp Pharm 1986; 43(7): 1760-1762.

Vishnu D. Gupta, PhD

Pharmaceutics Division

University of Houston

Houston, Texas

Address correspondence to: Vishnu D. Gupta, PhD, Pharmaceutics Division, University of Houston, 1441 Moursund Street, Houston, TX 77030. E-mail: vgupt.a@uh.edu

Copyright International Journal of Pharmaceutical Compounding Sep/Oct 2004
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