Fentanyl

Abstract

Fentanyl is a potent synthetic lipophilic opiate agonist used to control pain as a single agent or in combination with local anesthetics. The chemical stability of the undiluted commercial solution (50 µg/mL) in polypropylene syringes or polyvinylchloride bags has never been reported. Undiluted fentanyl solution, 50 µg/mL, was aseptically transferred to polypropylene syringes or polyvinylchloride bags. Samples were then stored, either at 5°C and protected from light, or at 22°C and exposed to light, for 28 days. A stability-indicating high-performance liquid chromatographic method was used to monitor the fentanyl concentration of the samples. Color, clarity, and pH also were monitored. After storage for 28 days, there were no signs of chemical degradation of fentanyl packaged in either polypropylene syringes or polyvinylchloride bags at either 5°C or 22°C. All solutions remained colorless and clear over the course of the study. The pH did not change significantly after storage for 28 days. Fentanyl solutions, when packaged undiluted in polypropylene syringes or polyvinylchloride bags, are chemically stable for 28 days when stored either at 5°C and protected from light or at 22°C and exposed to light.

Introduction

Fentanyl may be used as a single agent or in combination with local anesthetics to control pain. The stability of fentanyl, when diluted with isotonic saline solution, has been studied over the range of concentrations from 12.5 µg/mL to 33.3 µg/mL for up to 30 days in polypropylene (PP) syringes and polyvinylchloride (PVC) bags.1-4 A pH of greater than 5.5 seems to cause sorption of the drug on PVC surfaces; refrigeration decreases this effect.5

The objective of this study was to determine the chemical stability of undiluted fentanyl when packaged in PP syringes or PVC bags and stored either at 5°C and protected from light, or at 22°C and exposed to light, for 28 days.

Materials and Methods

All chemicals and reagents used were United States Pharmacopeia-National Formulary (USP-NF) or high-performance liquid chromatographic (HPLC) grade. There was no further purification of the chemicals. Undiluted fentanyl solution (Lot 15058NJ, Abbott Laboratories Ltd., Montreal, Canada) was used for the study.

Equipment

An HPLC system was used to monitor the fentanyl concentration of the samples. A C^sub 18^ reverse phase column was used (Partisil, 4.6 × 250 mm, 10 pm; Phenomenex, Torrance, California). The HPLC system consisted of an isocratic solvent pump (Model LC-10AT[VP]; Shimadzu Corporation, Kyoto, Japan), an autoinjector (Model SIL-10A^sub XL^; Shimadzu Corporation), and a photodiode array detector (Model SPD M6A; Shimadzu Corporation). The pH measurements were determined with a calibrated pH meter (Model Accumet 25; Fisher Scientific Ltd., Nepean, Canada).

Chromatographic Conditions

The mobile phase was prepared by mixing methanol, acetonitrile, and ammonium acetate buffer in the ratio of 20:20:60. The ammonium acetate buffer was prepared by dissolving 6 g of ammonium acetate in 600 mL of HPLC-grade water and then adding 0.6 mL of glacial acetic acid. The pH of the mobile phase was adjusted to 6.6 ±0.1 using ammonium hydroxide 6 N.

Sample Preparation

Undiluted fentanyl (50 µg/mL) was aseptically transferred to PP syringes (which were then capped) or to PVC bags and stored either at 5°C and protected from light or at 22°C and exposed to light. Three samples were collected from each type of container on days 0, 7, 14, 23, and 28. Color and clarity changes were determined by visual inspection. The pH of each sample was determined with a calibrated pH meter. Samples were then frozen at -70°C and analyzed at a later date. On the day of analysis, samples were warmed to room temperature, 100 µL of internal standard was added to 1000 µL of sample, and the samples were assayed in duplicate.

Assay Validation

The stability-indicating nature of the HPLC method was confirmed by monitoring forcibly degraded fentanyl samples. For one sample, undiluted fentanyl solution was adjusted to a pH of approximately 1.5 with concentrated hydrochloric acid. A second solution was adjusted to a pH of approximately 12.0 with 5 N sodium hydroxide, while a third solution had 1 mL of 30% hydrogen peroxide added to it. The acidic and alkaline solutions were incubated in a 70°C water bath. All solutions were then subjected to chromatography at 0, 2, 21, 48, 96, 192, and 216 hours after preparation. Monitoring for interfering peaks was done at 230 nm. Peak purity was determined using multiple wavelength (220 and 230 nm) and ultraviolet (UV) spectral analyses (200 to 350 nm).

Intraday variation was measured by analysis of five replicate injections at 0, 16, and 25 hours. Interday variation was determined by comparing slopes, correlation coefficients (r^sup 2^), and peak ratios from a standard solution on five separate days. Method accuracy was determined from analysis of a recovery solution of known concentration on five separate days. Least squares linear regression was used to calculate the linearity of a concentration versus response curve.

Results and Discussion

In experiments validating the stability-indicating ability of the HPLC assay, the acidic conditions produced a faster eluting degradation peak, while the alkaline conditions produced a slower eluting peak. Oxidation of the fentanyl produced multiple faster eluting peaks. None of the degradation peaks interfered with the parent or internal standard peaks. All parent peaks were confirmed to remain pure by multiple wavelength and UV spectral analyses. Overlay of the UV spectra from parent peaks in the degradation samples on the fentanyl peak from a reference sample gave a correlation coefficient of 0.9928 or greater.

The correlation coefficient for the intraday analysis was 1.7%. Interday variations of the slopes, r^sup 2^, and peak ratios were 1.10, 0.01, and 0.97%, respectively. The average recovery result was 101.4 ± 1.9%. The concentration versus response curve was linear over the range of 5 to 50 µg/mL (r^sup 2^ = 0.9913).

All solutions remained clear and colorless over the course of the study. There was no significant change in pH in any of the solutions and no pH greater than 5.43 was measured during the study.

The results of the chemical analyses of the fentanyl samples are summarized in Tables 1 and 2. Concentrations of all solutions remained greater than 90% of the original concentration for 28 days, whether stored at 5°C and protected from light or at 22°C and exposed to light.

Conclusion

The chemical stability of undiluted fentanyl solution (50 µg/mL) packaged in PP syringes or PVC bags was determined to be at least 28 days when stored either at 5°C and protected from light or at 22°C and exposed to light.

References

1. Stewart JT, Warren FW, King DT et al. Stability of ondansetron hydrochloride and 12 medications in plastic syringes. Am J Health Syst Pharm 1998; 55(24): 2630-2634.

2. Wilson KM, Schneider JJ, Ravenscroft PJ. Stability of midazolam and fentanyl in infusion solutions. J Pain Symptom Manage 1998; 16(1): 52-58.

3. Allen LV Jr, Stiles ML, Tu YH. Stability of fentanyl citrate in 0.9% sodium chloride solution in portable infusion pumps. Am J Hosp Pharm 1990; 47(7): 1572-1574.

4. Bing CM. Extended Stability for Parenteral Drugs. Bethesda, MD: American Society of Health-System Pharmacists; 2001.

5. Sattler A, Jage J, Kramer I. Physico-chemical stability of infusion solutions for epidural administration containing fentanyl and bupivacaine or lidocaine. Pharmazie 1998; 53(6): 386-391.

Ronald F. Donnelly, MSc (Chem), BSc (Pharm)

The Ottawa Hospital (Civic Campus)

Ottawa, Canada

Address correspondence to Ronald F. Donnelly, MSc (Chem), BSc (Pharm), Department of Pharmaceutical Services, The Ottawa Hospital (Civic Campus), Ottawa, Canada K1Y 4E9. E-mail: rdonnelly@ottawahospital. on.ca

Copyright International Journal of Pharmaceutical Compounding Nov/Dec 2005
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