What is the stability of bupivicaine diluted and stored in a syringe for storage?

Comment by InpharmD Researcher

The stability of bupivacaine diluted in 0.9% sodium chloride varies between different concentrations. One study reported bupivacaine 1.25 mg/mL in polypropylene syringes was stable for up to 32 days at 3 or 23 °C (Table 1), whereas bupivacaine 1 mg/mL had an acceptable pH range for 30 days at 4 °C, 21 °C, and 35 °C in both Omnifix and Terumo syringes (Table 2).

PubMed: ("bupivacain"[All Fields] OR "bupivacaine"[MeSH Terms] OR "bupivacaine"[All Fields] OR "bupivacaine s"[All Fields]) AND ("syringe s"[All Fields] OR "syringed"[All Fields] OR "syringes"[MeSH Terms] OR "syringes"[All Fields] OR "syringe"[All Fields]) = 104 results (2 relevant)



Background

A 2018 study evaluated the physical and chemical stability of hydromorphone 15 mg/mL and bupivacaine 10 mg/mL in 0.9% sodium chloride. Solutions were all aseptically prepared, and test samples of the mixture were stored at 37°C for 90 days in 20 mL plastic syringes. Physical stability was assessed by visual observation, while chemical stability was evaluated with stability-indicating high-performance liquid chromatographic (HPLC) analytical technique; pH and osmolarity were measured electronically. After 3 months, no visible haze, particulate formation, or gas evolution was discovered. The pH and osmolality were maintained stable. The HPLC revealed no significant change in concentration of either hydromorphone or bupivacaine, with less than 5% variability over the 3 months. [1]

A 2000 stability study evaluated the microbiological stability of fentanyl, bupivacaine, and clonidine diluted in a 0.9% sodium chloride to a total of 1,200 mL and a final concentration of 35 mcg/mL for fentanyl, 1 mg/mL bupivacaine, and 9 mcg/mL for clonidine. The solutions were prepared in eight syringes (polypropylene syringes, 50 mL, B. Braun, Germany) and eight reservoirs (Pharmacia Deltec PVC medication cassettes, 50 mL, Pharmacia, Sweden) and stored at 4, 21, and 36°C. After 12 hours and 28 days of sample incubation, the samples were clear, and no precipitation or change in color was observed during the 28-day storage period. Although there was also no change in pH of the mixtures stored in the PVC medication cassettes, a substantial increase in pH (from pH 4.60 to pH 6.06) was seen when bupivacaine was mixed with fentanyl and clonidine and stored in polypropylene syringes at 36°C after 28 days. The change in pH is likely due to the polypropylene syringes leaching from the natural rubber material of the piston. Overall, there was no in situ antimicrobial activity during the seven days of incubation, and all mixtures retained the acceptable microbiological stability for at least 28 days at 4, 21, and 36°C when prepared under aseptic conditions. [2]

References:

[1] Macorigh C, Guibbert V, Casanova M, Haenni C. Stability study of hydromorphone and bupivacaine mixture by HPLC-UV. Eur J Hosp Pharm. 2020 Mar;27(2):95-99. doi: 10.1136/ejhpharm-2018-001553. Epub 2018 Oct 15. PMID: 32133135; PMCID: PMC7043245.
[2] Jappinen A, Naaranlahti T, Kokki H, Ojanen T, Rasi A. Microbiological stability of a fentanyl, bupivacaine and clonidine mixture in a 0.9% sodium chloride infusion stored in syringes and reservoirs. Int J Pharm Compd. 2000 Jul-Aug;4(4):318-9. PMID: 23985396.

Literature Review

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

What is the stability of bupivicaine diluted and stored in a syringe for storage?

Please see Tables 1-2 for your response.


 

Stability of bupivacaine hydrochloride in polypropylene syringes

Design

Stability study 

Objective

To assess the stability of bupivacaine hydrochloride 1.25 mg/mL in 0.9% sodium chloride injection in disposable polypropylene syringes during and after storage 

Study Groups

Storage temperature at 23 °C

Storage temperature at 3 °C 

Methods

To prepare bupivacaine hydrochloride 1.25 mg/mL stock solution, preservative-free bupivacaine hydrochloride 5 mg/mL injection and 0.9% sodium chloride injection were mixed. The stock solution was then drawn up into 35 mL polypropylene syringes sealed with syringe caps or into a sterile empty glass vial (30 mL) sealed with a pharmaceutical-grade rubber stopper. Prefilled syringes of bupivacaine hydrochloride and the 0.9% sodium chloride control solution were refrigerated at 3 °C in the dark or stored at 23 °C in light. All samples were examined visually for precipitation and color change. The pH of solutions was measured with a pH meter, and concentrations of bupivacaine were tested with reverse-phase isocratic high-performance liquid chromatography (HPLC). 

Duration

Up to 32 days 

Outcome Measures

Visual changes, pH, and concentrations after 5,11,15, and 32 days of storage

Baseline Characteristics

 

Storage temperature at 23 °C

Storage temperature at 3 °C

 

Actual initial concentration, mg/mL

1.24 ± 0.04 1.23 ± 0.06  

Results

Endpoint

Storage temperature at 23 °C

Storage temperature at 3 °C

 

% initial concentration remaining 

Day 5

Day 11

Day 15

Day 32

 

99.01 ± 4.94

99.57 ± 7.09

97.28 ± 1.52

99 52 ± 6.15 

 

98.83 ± 2.81

101.87 ± 6.58

104.34 ± 0.94

99.32 ± 7.03

 

No significant differences were observed after 32 days between the solutions stored at room temperature and the solutions stored under refrigeration. Under the conditions of the HPLC assay, no decomposition products were detected at any of the assay times. No visible color change or precipitation was observed, and there were no significant changes in pH.

Study Author Conclusions

Bupivacaine hydrochloride 1.25 mg/mL in 0.9% sodium chloride injection in polypropylene syringes was stable for up to 32 days when stored at 3 or 23 °C.

InpharmD Researcher Critique

The stability results may only apply to a final concentration of bupivacaine hydrochloride at 1.25 mg/mL diluted with 0.9% sodium chloride injection. The study does not specify how many syringes were prepared from the stock solution and tested for analysis. 



References:

Jones JW, Davis AT. Stability of bupivacaine hydrochloride in polypropylene syringes. Am J Hosp Pharm. 1993;50(11):2364-2365.

 

pH Stability of Injectable Fentanyl, Bupivacaine, or Clonidine Solution or a Ternary Mixture in 0.9% Sodium Chloride in Two Types of Polypropylene Syringes

Design

Stability study 

Objective

To evaluate the potential interaction, under laboratory conditions, of fentanyl, bupivacaine, or clonidine solution and a mixture of those three drugs, all of which were stored in polypropylene syringes for 30 days at 4 °C, 21 °C, and 35 °C

Study Groups

Omnifix 50-mL syringes (n= 58)

Terumo 20- mL syringes (n= 120)

Methods

Sufficient amount of bupivacaine hydrochloride was diluted with 0.9 % sodium chloride injection to a total volume of 1,200 mL of bupivacaine hydrochloride 1 mg/mL. Admixture was then drawn up into 12 sets of Omnifix syringes and 30 sets of Terumo syringes with fill volumes in each syringe type of 20 mL and 50 mL, respectively. The Omnifix syringe had a synthetic latex-free polyisoprene piston, and Terumo did not contain natural rubber or synthetic rubber. 

Four sets of Omnifix and 10 sets of Terumo syringes of bupivacaine solution were stored at 4 °C, 21 °C, and 35 °C. All samples were immediately examined for precipitation and color change and were analyzed for pH and analyzed for pH at 1, 2, 5, 7, 9, 12, 16, 23, and 30 days after preparation. 

Duration

Up to 30 days 

Outcome Measures

Visual changes and pH 

Results

Endpoint

Bupivacaine 

pH changes 

25.3 °C

22.5 °C

 

5.75

5.85

There was no change in color, precipitation, or change in the pH of the fentanyl, bupivacaine, clonidine solutions, or the ternary mixture stored in Terumo syringes for 30 days at 4 °C, 21 °C, and 35 °C. 

Bupivacaine stored in Omnifix syringes is stable between pH 4.0 and 6.5.12. In this study, the bupivacaine solution in Omnifix syringes had an acceptable pH range for 30 days when stored at 4 °C, 21 °C, and 35 °C. 

Study Author Conclusions

According to the results of this study, the pH of individual solutions of fentanyl and bupivacaine and a mixture of fentanyl, bupivacaine, and clonidine is within an acceptable pH range for 30 days at 4 °C, 21 °C, and 35 °C in both Omnifix and Terumo syringes. 

InpharmD Researcher Critique

The study did not report specific pH values of bupivacaine solutions at all time assessment points. Stability results at different conventions other than 1 mg/mL can not be extrapolated from this study. 



References:

Jappinen A, Kokki H, Naaranlahti T. pH stability of injectable fentanyl, bupivacaine, or clonidine solution or a ternary mixture in 0.9% sodium chloride in two types of polypropylene syringes. Int J Pharmaceut Compound. 2002;6:471-4.