What is the stability data for compounded nitroprusside syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

What is the stability data for compounded nitroprusside syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

Comment by InpharmD Researcher

Most studies evaluating stability of sodium nitroprusside are dated, originating from 1970-1980. These studies have observed acceptable stability of compounded nitroprusside syringes for durations ranging from 1-9 days. The most important factor to preserve stability is widely regarded to be light protection. Diluent solutions have included D5W, D10W, distilled water, normal saline, and lactated Ringers. Most recently, a 2016 study observed physical and chemical stability for a full duration of 9 days with nitroprusside solutions compounded in D5W, stored at 4°C, and protected from light in polypropylene syringes. A 1984 study determined nitroprusside to be stable in three diluents (D5W, lactated Ringers, and normal saline) for 48 hours when protected from light. A 1988 study found cyanide concentrations to be highest in D5W after 72 hours of light exposure when compared with other electrolyte solutions, including normal saline.

Background

A commentary of a 1995 review article mentions conflicting recommendations regarding sodium nitroprusside preparation. While the Physicians Desk Reference states sodium nitroprusside should be mixed only in 5% dextrose in water, no explanation was provided as to why. The reason could be assumed to be due to concerns regarding the concentration of cyanide in the solution, however, a 1988 study found cyanide concentration was highest in D5W compared with five other solutions (including both normal saline and lactated Ringer's solution) after 72 hours [Table 2]. The authors of that study concluded that solutions containing electrolytes are preferable to 5% dextrose for the dilution of sodium nitroprusside. The author of this commentary suggests that normal saline or lactated Ringer's solution should be considered for sodium nitroprusside dilution. [1]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the stability data for compounded nitroprusside syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

Please see Tables 1-5 for your response.

In Vitro Stability of Sodium Nitroprusside Solutions for Intravenous Administration
Design	Experimental in vitro study
Objective	To investigate the stability of sodium nitroprusside in various intravenous solutions and during simulated infusions
Study Groups	Lactated Ringer's solution, Normal Saline, 5% Dextrose
Methods	Sodium nitroprusside (50 mg) was dissolved in 5 mL of water and then added to a test solution of 500 or 1000 mL to create a 100 and 50 μg/mL concentration. The stability of the sodium nitroprusside was tested in 5% dextrose, 0.9% NaCl (normal saline), and Lactated Ringer's solutions in plastic and glass containers. Once mixed, samples of the test solutions were taken and wrapped in aluminum foil while being exposed to laboratory light for 48 hours. Standards of the solutions were protected from light and stored in 4°C.
Duration	48 hours
Outcome Measures	Stability of sodium nitroprusside in Lactated Ringer's solution, normal saline, and 5% dextrose over 48 hours in glass and plastic containers
Results		Lactated Ringer's		Normal Saline		5% Dextrose
		Glass (50 μg/mL)	Plastic (100 μg/mL)	Glass (100 μg/mL)	Plastic (50 μg/mL)	Glass (50 μg/mL)	Plastic (100 μg/mL)
	Stability 2 hours 4 hours 8 hours 24 hours 32 hours 48 hours	104.0% 103.7% 101.7% 98.2% 102.7% 103.1%	100.7% 100.7% 99.4% 99.4% 101.9% 100.3%	100.4% 100.6% 100.2% 104% 98.2% 101.3%	100.4% 100.6% 100.9% 101% 100.4% 100.7%	101% 103.4% 98.7% 100.7% 98.8% 100.0%	100% 101% 100.9% 101.7% 101.8% 104.2%
	Values represent the mean of two experiments and are expressed as the percent of control solution remaining.
Study Author Conclusions	The results of the stability studies of sodium nitroprusside in 5% dextrose, lactated Ringer’s, and normal saline revealed that when a glass or plastic container is wrapped in aluminum foil and then left exposed to light for 48 h, there is no appreciable breakdown of sodium nitroprusside at a concentration of either 50 or 100 μg/mL.
InpharmD Researcher Critique	The authors state that the present study found similar results to past studies that showed sodium nitroprusside to be stable in 5% dextrose in glass and plastic containers when protected from light. This study extends those observations to include normal saline and lactated Ringer’s solution as test solutions as well.

References:
[1] Mahony C, Brown JE, Stargel WW, Verghese CP, Bjornsson TD. In vitro stability of sodium nitroprusside solutions for intravenous administration. J Pharm Sci. 1984;73(6):838-839. doi:10.1002/jps.2600730636

In Vitro Cyanide Release From Sodium Nitroprusside In Various Intravenous Solutions
Design	In vitro experimental comparison study
Objective	To measure the cyanide ion concentration in various intravenous solutions in which sodium nitroprusside was dissolved
Study Groups	5% dextrose in water, 10% dextrose in water, distilled water, 0.9% sodium chloride, lactated Ringer's with and without 5% dextrose
Methods	Sodium nitroprusside powder (25 mg) was dissolved in 250 mL of six various solutions in polyvinyl chloride bags. Test solutions included 5% dextrose in water (D5W), 10% dextrose in water (D10W), distilled water (DW), 0.9% sodium chloride (NS), and lactated Ringer's with (LR) and without (LR/D5W) 5% dextrose. Five bags of each solution were prepared and exposed to 300-foot candles of fluorescent lamps for 72 hours without aluminum foil wrapping at room temperature. Cyanide ion concentration was measured using electrodes with a sensitivity of 0.026 to 260 ppm and a model pH meter. Measurements were taken at 4, 8, 24, 48, and 72 hours at room temperature after the sodium nitroprusside dissolved in the test solutions. The absolute concentration and rate of change of cyanide ion concentration were examined in the six solutions.
Duration	72 hours
Results	Cyanide ion concentrations	D5W	D10W	DW	NS	LR	LR/D5W
	4 hours	0.160±0.004	1.190±0.018	0.130±0.016	0.113±0.008	0.179±0.016	0.177±0.010
	8 hours	0.287±0.095	0.304±1.125	0.337±0.033	0.313±0.016	0.429±0.100	0.225±0.067
	24 hours	3.66±1.07	2.08±0.52	2.47±0.24	2.08±0.32	1.85±0.26	1.17±0.12
	48 hours	6.06±0.41	4.09±0.19	5.35±0.18	3.56±0.48	1.49±0.05	1.06±0.61
	72 hours	*9.12±2.25	*7.36±1.08	*7.47±0.27	**4.57±0.28	**1.91±0.22	2.08±0.19
	Comparison of Cyanide Concentrations in Six Solutions across a 72-Hour Period CN concentration is expressed as mean and standard deviation. statistically significant difference when compared with the same solution at 24 h *statistically significant difference when compared with D5W at same time period
Study Author Conclusions	Solutions containing electrolytes are preferable to 5% dextrose in water for the dilution of sodium nitroprusside, especially when dextrose infusion is not medically desirable. We also emphasize that sodium nitroprusside-containing solutions should be as fresh as possible and protected from light.
InpharmD Researcher Critique	Based on results from previous studies which did not find a significant change between light exposure and darkness, the authors exposed the sodium nitroprusside-containing solutions to light without any type of protection. The authors included distilled water for comparison to the other solutions in the study.

References:
[1] Ikeda S, Frank PA, Schweiss JF, Homan SM. In vitro cyanide release from sodium nitroprusside in various intravenous solutions. Anesth Analg. 1988;67(4):360-362.

The Determination and Stability of Sodium Nitroprusside in Aqueous Solutions (Determination and Stability of SNP)
Design	Stability study
Objective	To determine the purity and concentration of sodium nitroprusside in various aqueous solutions
Study Groups	D5W, 4% dextrose/0.18% saline, normal saline
Methods	Solutions were prepared by injecting 10 mg/mL of sodium nitroprusside into 500 mL bottles of either 0.9% sodium chloride (normal saline), 5% dextrose, or 4% dextrose plus 0.18% sodium chloride. After thoroughly mixing, bottles were exposed to either daylight, tungsten light, fluorescent light, or no light (control; foil-wrapped bottles). The foil-wrapped controls were stored at 4°C or at room temperature. Each experiment involved solutions prepared and analyzed in duplicate.
Results	The dextrose and saline solutions of sodium nitroprusside (200 mg/L) in foil-wrapped bottles showed no significant change in concentration over a period of seven days at room temperature. The amount of free cyanide, which is probably a more sensitive measure of decomposition, showed only a very minute increase in both solutions. Upon exposure to light, the sodium nitroprusside concentrations decreased substantially in all solutions and the free cyanide contents rose exponentially.
Study Author Conclusions	Solutions of sodium nitroprusside in water, at a concentration of 10 g/L, are stable for at least two years both at room temperature and at 4°C if completely protected from light. More dilute solutions in dextrose or saline show little change either in concentration or free cyanide content when stored under light-free conditions at room temperature for a week. In practice, such infusion solutions would not be kept so long but the storage of aseptically prepared infusion solutions of sodium nitroprusside of guaranteed concentration is a possibility.

References:
[1] Vesey CJ, Batistoni GA. The determination and stability of sodium nitroprusside in aqueous solutions (Determination and stability of snp). J Clin Pharm Ther. 1977;2(2):105-117. doi:10.1111/j.1365-2710.1977.tb00080.x

Stability of Sodium Nitroprusside in 5% Dextrose Stored at 4°C in Polypropylene Syringes Protected from Light
Design	Stability study
Objective	To determine the stability of batch compounded nitroprusside stored in polypropylene syringes
Methods	Sodium nitroprusside was diluted in 5% dextrose to yield a final concentration of 1 mg/mL, with 6.25 mL of this dilution solution placed into each Luer-Lok polypropylene syringe (Becton-Dickinson). Syringes were wrapped in aluminum foil to protect from light and placed in a refrigerator at 4°C. A high-performance liquid chromatographic (HPLC) analysis was conducted initially and on days 2, 5, and 9. Turbidity, pH measurements, and visual observation was conducted initially and on days 2, 5, and 9 to evaluate for clarity, color changes, particulate matter, and gas evolution.
Duration	Observation: up to 9 days
Outcome Measures	Concentration, pH, appearance, turbidity
Results	Endpoint	Sodium nitroprusside in D5W (1 mg/mL)
	Initial concentration, mg/mL Day 2 (% remaining) Day 5 (% remaining) Day 9 (% remaining)	1.007 ± 0.003 100.54 ± 0.76 99.53 ± 0.28 100.00 ± 0.41
	Initial pH Day 2 Day 5 Day 9	4.84 ± 0.1 5.06 ± 0.13 5.03 ± 0.17 4.88 ± 0.14
	Initial turbidity, NTU Day 2 Day 5 Day 9	0.45 ± 0.14 0.54 ± 0.14 0.59 ± 0.24 0.52 ± 0.15
	NTU, nephelometric turbidity units
Study Author Conclusions	Sodium nitroprusside solutions compounded in 5% dextrose at a concentration of 1 mg/mL stored at 4°C protected from light in polypropylene syringes are physically and chemically stable for at least 9 days. These results are important for hospitals and practitioners who wish to store compounded sterile preparations of sodium nitroprusside according to USP Chapter <797> regulations.
InpharmD Researcher Critique	Only one preparation method, concentration, diluent, and storage condition (protected from light at 4°C) was evaluated, but results indicated stability was maintained for at least 9 days. Stability past day 9 was not assessed.

References:
[1] Anderson CR, Collins D, Laursen T, Arave T, Helm M. Stability of Sodium Nitroprusside in 5% Dextrose Stored at 4°C in Polypropylene Syringes Protected from Light. Int J Pharm Compd. 2016;20(5):435-437.

The stability of sodium nitroprusside infusion during administration by motorized syringe-pump
Design	Stability study
Objective	To determine stability of concentrated sodium nitroprusside (SNP) infusions during administration by a motorized syringe-pump system
Methods	Concentrations of SNP and free-cyanide (the most toxic degradation product) were measured. Sodium nitroprusside was used in Nipride ampules, each with 50 mg SNP lyophilized powder. Glucose injection 5% was used as diluent. A sample solution of 1.0 mL with 0.2 to 0.8 mg/mL SNP was evaluated using reagents to determine concentration. SNP infusions were drawn into polypropylene syringes, with two wrapped in aluminum foil and two unwrapped. Syringes were exposed to light.
Duration	Observation: up to 24 hours
Outcome Measures	Concentration
Results	Endpoint	Ferricyanide, mcg/mL	Ferrocyanide, mcg/mL
	SNP 0.5 mg/mL infusion
	Non-wrapped syringe 0 6 12 24	2.86 19.51 19.92 27.24	0 2.23 2.23 2.23
	Foil-wrapped syringe 0 6 12 24	2.86 3.25 3.44 4.07	0 0 0 0
	SNP 1.67 mg/mL infusion
	Non-wrapped syringe 0 6 12 24	1.00 20.33 48.78 50.59	0 1.86 2.36 3.72
	Foil-wrapped syringe 0 6 12 24	1.00 2.36 6.50 10.16	0 0 0.62 0.62
Study Author Conclusions	The importance of overwrapping the syringe and manometer line with aluminum foil and siting the motorized syringe-pump system out of direct sunlight cannot be over-emphasized. Providing these simple precautions are strictly observed, we consider concentrated SNP infusions (0.5-1.67 mcg/mL) in 5% dextrose to be sufficiently stable for administration over periods of up to 12h as required by current practice. The need to prepare fresh infusions every 4 h, as directed by the manufacturers of SNP, was considered unnecessary.
InpharmD Researcher Critique	This is a dated study which may not incorporate modern day preparation practices to adequately assess drug stability.

References:
[1] Sewell GJ, Forbes DR, Munton TJ. The stability of sodium nitroprusside infusion during administration by motorized syringe-pump. J Clin Hosp Pharm. 1985;10(4):351-360. doi:10.1111/j.1365-2710.1985.tb00933.x