Zidovudine

Abstract

The stability of a 2-mg/mL zidovudine and 1-mg/mL dobutamine hydrochloride admixture stored in 0.9% sodium chloride and 5% dextrose injections in 50-mL polyvinyl chloride bags at ambient temperature (23 ± 2°C) and 4°C for up to 24 hours was studied. The samples were analyzed at 0, 4, 8 and 24 hours after preparation of the controls and known mixtures by means of a reverse-phase stability indicating high-performance liquid Chromatographic method. The drug mixtures were stable for up to 24 hours, as shown by the greater than 90% of initial concentrations at the time of preparation. The pH of the drug solutions remained constant in the pH 6 to 7 range. These data support the stability of the zidovudine and dobutamine admixture under the storage conditions studied.

Introduction

Zidovudine (3'- azido-3'-deoxythymidine), popularly known as AZT (Figure 1), is a nucleoside analogue approved by the US Food and Drug Administration in 1987 for the treatment of AIDS.1 Dobutamine hydrochloride (Figure 2) is a synthetic catecholamine indicated for short-term inotropic support in adults with cardiac decompensation or myocardial infarction or after cardiac surgery. Dobutamine hydrochloride acts by stimulating primarily [beta]^sub 1^ receptors and lesser [alpha] and [beta]^sub 2^ receptors.2,3 Hospital pharmacists are sometimes asked to make admixtures containing these drugs for immediate use or for storage for different time periods prior to use. Before this can be done, the stability of the mixture over time must be known.4-6 The stability of zidovudine and dobutamine admixtures in sodium chloride and dextrose injections has not been reported. The purpose of this study was to investigate the stability of 2-mg/mL zidovudine and 1-mg/mL dobutamine as an admixture prepared in polyvinyl chloride (PVC) bags stored at either ambient temperature or 4°C for up to 24 hours. Each bag was assayed for drug concentration, and the pH was measured at 0, 4, 8 and 24 hours after the bags had been prepared.

Methods

Chemicals and Reagents

All chemicals (J. T. Baker, Phillipsburg, New Jersey) were high-performance liquid Chromatographic (HPLC) grade. Zidovudine and Dobutamine Hydrochloride reference standards were obtained from the United States Pharmacopeial Convention, Tnc. (Rockville, Maryland). Zidovudine infusion 1 0-mg/mL vials (Lot 1Hi585) were obtained from GlaxoSmithKline (Research Triangle, North Carolina), and dobutamine hydrochloride injection 12.5-mg/mL vials (Lot 891753) were obtained from Abbott Laboratories (Chicago, Illinois). The 0.9% sodium chloride injection and 5% dextrose injection in 50-mL PVC bags were obtained from Cardinal Health (McDonough, Georgia). Sodium dihydrogen phosphate was obtained from Chemical Research Stores, the University of Georgia campus. HPLC-grade acetonitrile was obtained from Fischer Scientific (Pittsburgh, Pennsylvania). Deionized water was obtained by use of cartridges from Continental Water System (Roswell, Georgia).

Equipment

The HPLC system consisted of a Beckman Model 110 solvent delivery pump (Fullerton, California), a manual Rhcodyne injector (Model 7125, Rheodyne, Cotati, California) equipped with a 20-µL loop and a lambda max ultraviolet (UV) detector Model 481 (Waters Corporation, Milford, Massachusetts) set at 280 nm. The peak heights were monitored with a Shimadzu Model CR3A electronic integrator (Columbia, Maryland). A locally built microprocessor-controlled pH meter with autocalibration and accuracy to 0.01 pH units, a C^sub 16^ column that contained an amide hexadecylsilane packing material (4.6 mm × 250 mm, 5-µm particle size, Supelco, Bellefonte, Pennsylvania), Nylon-66 membrane niters (0.2 µm × 47 mm, Supelco) and a 60-cc syringe (Lot 133709, Tyco Health Systems, Mansfield, Massachusetts) were used.

Chromatographie Conditions

The isocratic elutions were performed at 1 mL/minute with a mobile phase consisting of 16:84 v/v acetonitrile-phosphate buffer (25 mM) adjusted to pH 3.0 by using 0.1 M phosphoric acid. The mobile phase was Altered through a 0.2-µm Nylon-66 filter.

Preparation of PVC Bags for Stability Studies

A pooled sample of 200 mL containing 2-mg/mL zidovudine and 1-mg/mL dobutamine hydrochloride admixture was prepared by adding 40 mL (10mg/mL) of zidovudine, 16 mL (12.5 mg/mL) of dobutamine and 144 mL of 0.9% sodium chloride injection to a suitably sized beaker. After thorough mixing, 5 mL of the solution was removed for zero-hour assay, and the remaining 195 m L was evenly divided into six empty 50-mL PVC bags.

A second pooled sample of 200 mL containing 2 mg/mL zidovudinc and 1 mg/mL dobutamine hydrochloridc was prepared by adding 40 mL (10 mg/mL) of zidovudine, 16 mL (12.5 mg/mL) of dobutamine and 144 mL of 5% dextrose injection to a suitably sized beaker. After thorough mixing, 5 mL of the solution was removed for time-zero assay and the remaining 195 mL was evenly divided into six empty 50-mL PVC bags. Appropriate controls of zidovudine and dobutamine in 0.9% sodium chloride and 5% dextrose injections were also prepared.

Three bags from each pool were stored at 23 ± 2°C under continuous fluorescent light, and the remaining three bags from each pool were stored at 4°C. The drug content in each hag was determined by a stability-indicating HPLC assay at 0, 4, 8 and 24 hours; and the pH values were also recorded at those times. The controls of zidovudine and dobutamine stored at ambient temperature and 4°C were also assayed, and pH values were recorded at the specified times.

Preparation of Standard Solutions

Two 2-mg weighed quantities of Zidovudine USP reference standard were added to 5-mL test tubes. To one tube was added 1 mL of 0.9% sodium chloride injection, and to the second tube was added 1 mL of 5% dextrose injection, to give two solutions, each containing 2 mg/mL. The solutions were diluted 1:80 to give final concentrations of 25 µg/mL zidovudine. Diluted standards of 100 µL were injected in triplicate into the HPLC system.

Two 2-mg weighed quantities of Dobutamine Hydrochloride USP reference standard were added to 5-mL tubes. To one tube was added 2 mL of 0.9% sodium chloride injection and to the second tube was added 2 mL of 5% dextrose injection, to give solutions each containing 1 mg/mL. The solutions were diluted 1:80 to give final concentrations of 12.5 µg/mL of dobutamine. Of the diluted standard, 100 µL was injected in triplicate into the HPLC system. All standard solutions were prepared fresh daily.

Degradation of Zidovudine and Dobutamine

To ensure that the HPLC assay was stability indicating, zidovudine and dobutamine were previously forced to degrade under acidic, basic, oxidative and UV irradiation conditions. The method was developed and validated prior to this study.7

Preparation of Assay Solutions

A 5-mL aliquot was removed from each PVC bag stored at ambient temperature and 4°C at 0, 4, 8 and 24 hours. A 1:80 dilution was made using the mobile phase as a diluent.

Calculation of Medication Content

Triplicate injections of both the analytical samples prepared from PVC bags and standard solutions were injected into the HPLC system. Peak heights from the chromatogram were used to calculate the mean response factors for each drug standard. The appropriate mean response factor and the peak height of the analyte in the PVC bag and standard samples were then used to calculate the drug concentration in each analytical sample.

Results

A typical HPLC chromatogram of the zidovudine and dobutamine mixture is shown in Figure 3. The zidovudine and dobutamine injections prepared in 0.9% sodium chloride injection or 5% dextrose injection stored in 50-mL PVC bags were judged to be stable if the drug levels remained greater than 90% of the initial drug concentration at the time of preparation.8 The concentrations, ie, the percentage of the initial concentration remaining of zidovudine and dobutamine, are shown in Tables 1 through 4. The pH of the PVC mixtures did not change appreciably during the study period. Typically, the pH of the samples ranged from 6.01 to 6.70.

Conclusion

Zidovudine (2-mg/mL) and dobutamine (1-mg/mL) injections stored as admixtures in 50-mL PVC bags were stable for 24 hours at 23 ± 2°C and 4°C in both 0.9% sodium chloride injection and 5% dextrose injection.

References

1. Lam NP, Kennedy EP, Jarosinski PF. Stability of zidovudine in 5% dextrose injection and 0.9% sodium chloride injection. Am J Hosp Pharm 1991;48:281-282.

2. Dobutamine injection [package insert]. North Chicago, IL:Abbott Laboratories; 1997.

3. Husseini H, Mitrovic V, Schlepper M. Rapid and sensitive assay of dobutamine in plasma by high-performance liquid chromatography and electrochemical detection. J Chromatogr 1993;620:164-168.

4. Stewart JT, Warren FW, King AD. Stability of ranitidine hydrochloride and seven medications. Am J Hosp Pharm 1994;51:1802-1807.

5. Mehta AC. Analytical issues in the chemical stability testing of drugs in solution. Anal Proc 1995;32:67-70.

6. Lampasona V, Mullins RE, Parks RB. Stability of ranitidine admixture frozen and refrigerated in minibags. Am J Hosp Pharm 1986;43:921-925.

7. Caufield WV, Stewart JT. HPLC separations of zidovudine and selected pharmaceuticals using a hexadecylsilane amide column. Chromatographia 2001;54:561-568.

8. Trissel LA. Avoiding common flaws in stability and compatibility studies of injectable drugs. Am J Hosp Pharm 1983;40:1159-1160.

Patrick Musami, MS

James T. Stewart, PhD

E. Wil lTaylor, PhD

Department of Pharmaceutical and Biomedical Sciences

College of Pharmacy

University of Georgia

Athens, Georgia

Address correspondence to: James T. Stewart, PhD, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30606. E-mail: jstewart@mail.rx.uga.edu

Copyright International Journal of Pharmaceutical Compounding Jan/Feb 2004
Provided by ProQuest Information and Learning Company. All rights Reserved