Can diazepam injection be repackaged into polypropylene IV syringes? What is the stability of diazepam injection in polypropylene IV syringes?

Can diazepam injection be repackaged into polypropylene IV syringes? What is the stability of diazepam injection in polypropylene IV syringes?

Comment by InpharmD Researcher

Most literature suggests diazepam liquid preparations should not be stored in plastic syringes and, as such, evidence investigating the stability of diazepam in plastic containers is limited. Two dated but relevant studies were found. A 1981 study failed to identify detectable adsorption of diazepam into plastic syringes (Table 2), but a slightly more recent 1991 study observed a rapid loss of diazepam concentration in polypropylene syringes (Table 1). Preloading diazepam into plastic syringes may not be recommended.

Background

Due to diazepam’s absorption into plastics, it may leach into plastic bags or tubing during intravenous infusion. The majority of studies only reported stability tests of diazepam stored in glass syringes instead of plastic syringes. Therefore, diazepam liquid preparations should not be kept in plastic bottles or syringes. Several factors, including temperature, concentration, flow rates, and tube length, may affect the extent of absorption. [1], [2], [3], [4]

The stability of diazepam in plastic syringes was investigated in a 1991 research article. Three different brands of polypropylene syringes (Becton-Dickinson [BD], Sherwood Monoject, and Terumo) were used to evaluate the possibility of interaction of the drug and components of the syringe. Each of the drugs examined in the study, including diazepam 5 mg/mL, were drawn into 3 mL plastic syringes, capped, and stored in the dark at temperatures ranging from -20 ℃ to 25 ℃ for 6 hours to 30 days. Each syringe contained 2.5 mL of the drug solution and was weighed to the nearest 10 mg. Syringes were examined for gross changes and concentrations of diazepam were measured using high performance liquid chromatography (HPLC). No syringes exhibited gross physical changes and no drug solutions were found to contain leachates. However, changes in drug concentrations were observed over time, with the most rapid changes occurring in samples stored at room temperature. Please refer to Table 1 for full results of diazepam injection concentration remaining at measured time points. The authors concluded that highly lipophilic drugs, such as diazepam, were less stable in polypropylene syringes and exhibited more rapid loss of drug concentration. Preloading such drugs into polypropylene syringes may not be recommended. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Can diazepam injection be repackaged into polypropylene IV syringes? What is the stability of diazepam injection in polypropylene IV syringes?

Please see Tables 1-2 for your response.

Average Percent of Original Diazepam Injection Concentration Remaining after Storage in Three Types of Syringes at Three Temperatures
	Brand of syringe
Length of storage/temperature	BD	Sherwood	Terumo
30 days at -20 ℃	86.7 ± 0.3	89.3 ± 3.4	95.8 ± 1.0
1 day at -20 ℃	102.3 ± 0.5	99.3 ± 4.3	98.6 ± 1.1
7 days at 4 ℃	95.1 ± 1.3	92.3 ± 0.9	96.9 ± 2.6
1 day at 4 ℃	97.5 ± 3.8	97.9 ± 3.2	98.3 ± 0.7
1 day at 25 ℃	94.1 ± 4.9	94.1 ± 1.8	94.1 ± 3.0
0.25 day at 25 ℃	94.7 ± 0.8	96.6 ± 1.2	97.8 ± 0.9

References:

Speaker TJ, Turco SJ, Nardone DA, Miripol JE. A study of the interaction of selected drugs and plastic syringes. J Parenter Sci Technol. 1991;45(5):212-217.

Diazepam Adsorption to Infusion Sets and Plastic Syringes

Design

Observational kinetics study

Objective

To study the adsorption of diazepam, through multiple mediums, to infusion sets, and plastic syringes

Methods

Part 1

Diazepam formulations were prepared by adding either 4 mL of diazepam injection (Valium 5mg/mL) or diazepam emulsion (Diazemuls 5mg/mL) to 500 mL of glucose 5.5% or Intralipid 10%. This was done with diazepam concentrations of 0.04 mg/mL and 0.01 mg/mL.

Part 2

Diazepam emulsion concentrations of 0.1 mg/mL, 0.2 mg/mL, and 0.4 mg/mL were added to glucose 5.5%, glucose 10%, and sodium chloride 0.9%; and were observed visually at four, eight, and 24 hours to evaluate degree of creaming.

Part 3

Ten sterile syringes were filled with 2 mL diazepam emulsion, and ten sterile syringes were filled with diazepam injection (Valium 5 mg/mL). The diazepam concentrations were determined by UV-spectrophotometry.

Outcome Measures

Part 1- diazepam adsorption for infusion sets

i) Diazepam adsorption at concentration (0.04 mg/mL) infused over 4mL/hr

ii) Diazepam adsorption at concentration (0.01 mg/mL)

Part 2- miscibility of diazepam emulsion/degree of creaming

i) Diazepam in glucose 5.5%

ii) Diazepam in glucose 10%

iii) Diazepam in sodium chloride 0.9%

Part 3- effect of storing diazepam in plastic syringes

i) Diazepam concentration in syringe after being filled with emulsion

ii) Diazepam concentration in syringe after being filled with an injection solution

Results

Part 1

i) Diazepam adsorption at concentration (0.04 mg/mL) infused over 4mL/hr

Diazepam diluted in glucose 5.5%:

A greater amount of diazepam was lost when glucose 5.5% was used to dilute the injection and the emulsion.

The concentration after two hours was less than 20% of the initial concentration (value not defined by researchers).

Diazepam diluted in intralipid 10%:

The infusion mixer passed the infusion set with a potency loss of 20-40%.

ii) Diazepam adsorption at concentration (0.01 mg/mL) infused over 20mL/hr

Diazepam diluted in glucose 5.5%:

After 30 minutes of infusion, 30% of diazepam injection solution was recovered.

Diazepam diluted in intralipid 10%:

The potency of the infusate was 100% of the initial concentration.

Part 2

i) Glucose 5.5%:

No significant increase in particle size. No creaming was observed.

ii) Glucose 10%:

No significant increase in particle size. No creaming was observed.

iii) Sodium Chloride 0.9%:

Increased emulsion particle size observed. Creaming was observed.

Part 3

Storage time in plastic syringes	Percentage of initial concentration – diazepam emulsion	Percentage of initial concentration – diazepam injection
0 min	100%	100%
20 min	98%	100%
40 min	99%	100%
1 hour	97%	101%
2 hours	98%	100%
4 hours	100%	100%

No significant change in diazepam concentrations was found.

Study Author Conclusions

The two infusion sets did not show any significant differences in diazepam adsorption. Diazepam emulsion can be added to glucose 5.5% or glucose 10% with no great changes in particle size and no evidence of creaming. No detectable adsorption of diazepam to the syringes could be measured.

InpharmD Researcher Critique

Choice of infusion solution, infusion rate, and diazepam formulation can affect adsorption levels.

References:

Winsnes M, Jeppsson R, Sjöberg B. Diazepam adsorption to infusion sets and plastic syringes. Acta Anaesthesiol Scand. 1981;25(2):93-6.