Physical Compatibility and Chemical Stability of Fentanyl and Naloxone Hydrochloride in 0.9% Sodium Chloride Injection Solution for Patient-Controlled Analgesia Administration

Figures & data

Figure 1 Structures of (A) fentanyl citrate and (B) naloxone hydrochloride.

Table 1 Validation of HPLC Method for Determination of Fentanyl Citrate and Naloxone Hydrochloride

Drug	Measured Concentrations, μg/mL	Accuracy, %	Precision RSD, %
			Intraday	Interday
Fentanyl citrate	10.0	101.2	0.7	1.3
	30.0	99.8	0.4	0.8
	60.0	99.7	0.9	1.7
Naloxone hydrochloride	2.0	100.1	1.0	1.9
	4.0	99.6	0.6	0.5
	8.0	99.8	0.8	1.4

Abbreviations: HPLC, high-pressure liquid chromatography; RSD, relative standard deviation.

Figure 2 Chromatograms of 20μg/mL fentanyl citrate that was freshly prepared (A), exposed to 0.1 mol/L hydrochloric acid (HCl) at 60°C for 5 hours (B), exposed to 0.1 mol/L sodium hydroxide (NaOH) at 60°Cfor 5 hours (C), and exposed to 3% hydrogen peroxide (H₂O₂) at 60°C for 5 hours (D). Fentanyl citrate elutes at 6.21 min.

Figure 3 Chromatograms of 4μg/mL naloxone hydrochloride admixtures that were freshly prepared (A), exposed to 0.1 mol/L hydrochloric acid (HCl) at 60°C for 5 hours (B), exposed to 0.1 mol/L sodium hydroxide (NaOH) at 60°Cfor 5 hours (C), and exposed to 3% hydrogen peroxide (H₂O₂) at 60 for 5 hours (D). Naloxone hydrochloride at 11.97 min.

Figure 4 Chromatograms of 20μg/mL fentanyl citrate and 4μg/mL naloxone hydrochloride admixtures that were freshly prepared (A), exposed to 0.1 mol/L hydrochloric acid (HCl) at 60°Cfor 5 hours (B), exposed to 0.1 mol/L sodium hydroxide (NaOH) at 60°Cfor 5 hours (C), and exposed to 3% hydrogen peroxide (H₂O₂) at 60°C for 5 hours (D). Fentanyl citrate elutes at 6.21 min (peak 1) and naloxone hydrochloride at 11.97 min (peak 2).

Table 2 Amount of Initial Concentration of Fentanyl Citrate (20μg/mL) and Naloxone Hydrochloride (4μg/mL) Remaining After 72-h Storage at 25°C in Polyolefin Bags or Glass Containers (%; Mean ± Sd; n=3)

Program	Glass Containers		Polyolefin Bags
	Fentanyl Citrate	Naloxone Hydrochloride	Fentanyl Citrate	Naloxone Hydrochloride
Initial concentration (mg/L)	20.0±0.12	4.0±0.45	20.1±1.02	4.2±0.72
0h	99.62±1.04	99.72±0.93	100.42±0.26	99.89±0.26
4h	98.51±0.72	99.97±0.54	100.54±0.43	99.99±0.14
8h	100.36±0.81	100.43±0.26	100.45±0.92	99.97±0.37
12h	98.95±0.14	101.14±0.48	100.68±0.33	100.24±0.25
24h	100.42±0.27	100.74±0.22	100.41±0.86	99.97±0.44
48h	100.45±0.52	100.81±1.05	99.96±0.51	99.41±0.23
72h	100.58±0.23	100.52±0.39	100.03±0.27	99.64±0.40

Table 3 Amount of Initial Concentration of Fentanyl Citrate (20μg/mL) and Naloxone Hydrochloride (4μg/mL) Remaining After 72-h Storage at 4°C in Polyolefin Bags or Glass Containers (%; Mean ± Sd; n=3)

Program	Glass Containers		Polyolefin Bags
	Fentanyl Citrate	Naloxone Hydrochloride	Fentanyl Citrate	Naloxone Hydrochloride
Initial concentration (mg/L)	20.1±0.32	3.9±0.84	20.4±0.15	4.0±0.36
0h	99.62±1.24	99.87±0.94	100.56±0.24	99.79±0.74
4h	98.77±0.46	99.95±0.32	100.52±0.31	99.87±0.47
8h	100.04±0.51	100.41±0.13	100.34±0.57	100.48±1.01
12h	99.98±0.64	100.58±0.66	99.89±0.34	99.96±0.22
24h	100.42±0.68	100.72±0.41	100.24±0.61	99.76±0.37
48h	101.34±0.19	101.02±0.76	100.71±0.34	99.74±0.25
72h	100.52±0.38	100.79±0.54	100.60±0.25	99.98±0.82

Figure 5 Typical chromatograms of fentanyl citrate and naloxone hydrochloride admixtures on study 72th hour. Mixtures stored at 25°C in glass containers (A) and polyolefin bags (B); Mixtures stored at 4°C in glass containers (C) and polyolefin bags (D). Fentanyl citrate elutes at 6.21 min (peak 1) and naloxone hydrochloride at 11.97 min (peak 2).