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BY 4.0 license Open Access Published by De Gruyter April 1, 2022

Long-term stability of ready-to-use epinephrine 0.02 mg/mL injection solution in 50 mL glass vials

Rita Marina Heeb, Frank Erdnüß, Julia Reichhold and Irene Krämer



In adult intensive care patients, epinephrine is mostly administered by continuous injection with syringe pumps. The objective of this study was to investigate the physicochemical stability of pharmacy prepared ready-to-use epinephrine (E) 0.02 mg/mL injection solutions (total volume 50 mL) for assigning shelf-life.


E 0.02 mg/mL injection solution in 50 mL amber type l glass vials was produced batch-wise in the pharmacy department. Stability of the refrigerated (2–8 °C) product was investigated in real time over a period of 36 months by analyzing E concentrations, osmolality, pH, and sub-visible particles at predefined time-points. For E concentration measurements a stability-indicating, validated reversed-phase HPLC-PDA assay was used.


The autoclaving process of E 0.02 mg/mL injection solution in 50 mL amber type I glass vials caused 5% loss of the active substance. The finished product remained stable over the study period of 36 months when stored refrigerated.


Batch-wise production of ready-to-use E injection solution 0.02 mg/mL in 50 mL amber glass vials was successfully implemented in our pharmacy department. According to the stability tests, a shelf-life of 36 months can be assigned to the finished product stored refrigerated. Studies concerning stability at room temperature would be useful.


Epinephrine (E) is primarily used for its α-adrenergic stimulatory effects to increase blood flow during cardiopulmonary resuscitation and for the treatment of cardiac arrhythmias. In emergency cases diluted E solutions may be injected or infused intravenously, preferably via central venous catheters. E injection solution is categorized as high alert medication causing significant patient harm when used in error [1]. Medication errors have occurred due to confusion of the appropriate concentrations to be administered and erroneous performance of the dilution process [1]. To lower these risks, it is common sense that standard concentrations should be defined for medicinal products, especially when they are administered by continuous injection with syringe pumps. Patient individual dosing of standardized concentrations can be achieved by adjusting the injection rate. In order to increase patient safety and decrease the delay caused by erroneous dilution of the marketed injection concentrates (e.g., Suprarenin® 1 mg/mL (1:1,000), Adrenalin Aguettant 1 mg/10 mL (1:10,000)), ready-to-use (RTU) or ready-to-administer (RTA) medicinal products in standardized concentrations can be produced in advance by hospital pharmacies. Recently, we implemented the batch-wise production of RTU E injection solution 0.02 mg/mL sterilized in 50 mL amber glass vials as final containers in our pharmacy department. The production of the unlicensed pharmaceutical preparation made for the specific needs of patients follows Ph. Eur. 2619 and the resolution CM/Res (2016)1 [2, 3]. According to the recommendations, risk assessment was performed and a product dossier for stock preparation was compiled. Specified in-process controls, quality controls, and stability data of the finished products were developed and implemented. Obviously, the specifications of the active substance, excipient and primary containers were taken into account.

The active substance epinephrine degrades rapidly via oxidative reactions which are catalyzed by oxygen, pH>6, heavy metal ions, heat, and exposure to UV or daylight. Oxidation leads to adrenochrome and noradrenochrome [4, 5]. The degradation rates of E and norepinephrine (NE) in licensed pharmaceutical preparations vary according to the amount of antioxidative agent (e.g., sodium metabisulfite), pH, and the type of primary containers used. Moreover, temperature and the extent of light exposure are to be considered during storage and use of E injection solutions. To date, there are no acceptance limits defined for degradation products in the relevant pharmacopoeia monographs [6, 7].

The objective of our study was to investigate the long-term physicochemical stability of E 0.02 mg/mL injection solution in 50 mL amber glass vials produced batch-wise in the Pharmacy Department of the University Medical Center Mainz. Results were used for assigning shelf-lives.

Materials and methods

Preparation of epinephrine injection solution 0.02 mg/mL, 50 mL amber glass vials

A test batch amounting to 25 L bulk solution was prepared in the Pharmacy Department of the University Medical Center Mainz according to the Good Preparation Guide PIC/S PE 010-4 Annex 1 (preparation of terminally sterilized products) and the German Pharmacy Ordinance [8, 9]. Detailed information about the active substance, excipients, and packaging material is given in Table 1. The appropriate amount of Ph. Eur. E hydrogentartrate monohydrate was weighed. The ingredients were solved in the appropriate amount of water for injection which was pre-purged with nitrogen for 30 min. After the dissolution process purging was continued. The pH was adjusted to 3.6 (range 3.4–3.8) with HCl 10%, and water was added to achieve the exact overall volume of bulk solution. Type l amber glass vials (50 mL) were filled with the bulk solution using the Plümatex pump (Plümat, Espelkamp, Germany) and the filled vials were purged again with nitrogen to displace the oxygen in the headspace of the vials. Vials were closed with stoppers and caps. Finished products were autoclaved for 15 min at 121 °C, 2 bar. The vials were inspected for visible particles according to Ph. Eur., labeled, and the required analytical and sterility tests performed [10].

Table 1:

Formulation and packaging material E 0.02 mg/mL, 50 mL injection solution.

Epinephrine injection solution 0.02 mg/mL in 50 mL glass vials
Ingredients and packaging material Manufacturer Test batch 500 × 50 mL
Epinephrine hydrogentartrate monohydrate Ph. Eur. powder Caesar & Loretz GmbH, Hilden, Germany 0.955 g (0.53 g Epinephrine)
Sodium chloride Ph. Eur. Fagron GmbH & Co. KG, Barsbüttel, Germany or Caesar & Loretz GmbH, Hilden, Germany 2.50 g
Sodium metabisulfite Ph. Eur. Fagron GmbH & Co. KG, Barsbüttel, Germany 2.50 g
Sodium-EDTA VWR International GmbH, Darmstadt, Germany 2.50 g
HCl 10% Aug. Hedinger GmbH & Co. KG, Stuttgart, Germany q.s.
Water for injections in bulk Produced by the pharmacy department 24,971.5 g
Type I amber glass vials Zscheile & Klinger GmbH, Hamburg, Germany 500
Chlorobutyl flurotec stoppers Zscheile & Klinger GmbH, Hamburg, Germany 500
Yellow-green flip off caps Zscheile & Klinger GmbH, Hamburg, Germany 500

Storage of the test batch

The test batch (batch size 500 × 50 mL) was stored refrigerated at 2–8 °C for 36 months (whole study period) and the temperature monitored by loggers (Ebro®, Xylem Analytics Germany Sales GmbH & Co. KG, Ingolstadt). Stability tests were performed with 103 vials (50 mL each) randomly selected from the test batch at predefined time-points (compare Table 2).

Table 2:

Sampling time-points of E 0.02 mg/mL injection solution in 50 mL amber glass vials stored refrigerated.

E 0.02 mg/mL, 50 mL stored at 2–8 °C Day Month
0 Bulk solutiona 0 Finished product b 7 14 28 3 6 12 24 36
HPLC-analysis × × × × × × × × × ×
pH × × × × × × × × × ×
Osmolality × × × × × × × × × ×
Sub-visible particles × × × × × × × × ×

  1. abefore autoclaving; bafter autoclaving.

Sample preparation

Three samples were withdrawn from the bulk solution prior to filling and single samples were withdrawn after autoclaving from the vials of the finished product. For the HPLC, osmolality and pH analyses random sampling was performed by picking three vials at each predefined time-point as given in Table 2. For detection of sub-visible particles an extra vial was picked at each predefined time-point as given in Table 2.

HPLC assay

For quantitative analysis of E, the previously published stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with photodiode array-detection (PDA) was used [1112]. It comprises the µBondapak C18 column and a sodium dodecyl sulfate (SDS) containing mobile phase. Each sample was assayed in triplicate without further dilution.

The HPLC system consisted of a Waters Alliance 2695 with a Waters 996 PDA. Data were acquired and integrated by using Waters Empower 3 (Waters Eschborn, Germany). The characteristics are given in Table 3.

Table 3:

Characteristics of the RP-HPLC assay for quantitative analysis of E 0.02 mg/mL injection solution.

Column µBondapak C18,300 × 3.9 mm (MZ-Analysentechnik, Mainz, Germany)
Flow rate 1 mL/min
Injection volume 20 µL
Runtime 15 min
Detection wavelength 230 nm (adrenochrome 480 nm)
Mobile phase Isocratic elution of A/B = 70%/30% (v:v)

A: 3.4 mg/mL potassium dihydrogen phosphate (PanReac AppliChem GmBH, Darmstadt, Germany) buffer, 0.06 mg/mL sodium dodecyl sulfate (SDS, Sigma-Aldrich), adjusted to pH 3 with phosphoric acid 85% (PanReac AppliChem GmBH, Darmstadt, Germany)
B: 30% methanol (Fisher Scientific GmbH, Schwerte, Germany)

Validation of the RP-HPLC assay

The assay was validated with regard to the ICH Q2 (R1) guidelines for stability studies [13].


Suitability of the HPLC method was evaluated by analyzing forced degraded solutions. Aliquots of the E tartrate CRS (Epinephrine hydrogen tartrate powder (EDQM)) were heated, or acidified with 1N HCl, or 1 N NaOH, or oxidized with H2O2.


Linearity of the method was proven by analyzing seven different concentrations of E (10 μg/mL, 16 μg/mL, 18 μg/mL, 20 μg/mL, 22 μg/mL, 24 μg/mL, 30 μg/mL). Calibration standards containing E tartrate CRS (Epinephrine hydrogen tartrate powder (EDQM)) were prepared by dissolving and diluting with water HPLC grade (0.1 mg/mL epinephrine, Each calibration standard was injected in triplicate.

Accuracy and precision

Intraday accuracy and precision were validated with 10 quality control standards prepared from commercially available Suprarenin® [12]. Interday accuracy and precision were re-validated by analyzing five quality control standards with 13-fold-injection on two different days.


Robustness of the assay was evaluated by using different batches of mobile phase and different temperatures during the validation assays.


The test solutions were declared as chemically stable when the measured concentration of E was ≥90% of the initial E concentration designated as 100%. The concentration of the finished product measured on day 0 (initial content) was defined as 100% for the stability tests.

pH, osmolality

pH measurements were performed with a pH measuring module (AntonPaar, Ostfildern, Germany) equipped with a pH glass electrode (Hamilton Germany GmbH, Höchst, Germany), calibrated with Hamilton DuraCal buffer (pH 4.01 and 7.41).

Osmolality measurements were performed with Osmometer 3000 D (Gonotec GmbH, Serial no.: 300160266, Berlin, Germany) calibrated with calibration standard 1 mL 300 mosmol/kg NaCl/H2O (Gonotec GmbH, Berlin, Germany) according to Ph.Eur. 2.2.35 [14]. Osmolality and pH were determined in triplicate in each randomly picked vial.

Inspection for visible and sub-visible particles

Test solutions were visually inspected for particulate matter and changes in colour whenever they were picked and samples were withdrawn. Solutions without changes were defined as physically stable.

Sub-visible particles were counted with a calibrated PAMAS SVSS/SBSS (Partikelmess-und Analysesysteme GmbH, Rutesheim, Germany [Serial-Nr.:350-420]), equipped with an HCB-LD-50/50 sensor (Serial-Nr.: L-5050-5460) and the software USP V. 3.6.3. According to the Ph.Eur. 2.9.19 sub-visible particulate contamination should be within the limits of max. 6.000/vial (≥10 µm) and max. 600/vial (≥25 µm) [15]. Particulate matter was measured in quadruplicate in one test vial picked at each predefined time-point. The mean of run 2, 3, and 4 was calculated and given as result.

Figure 1: 
HPLC chromatogram (detection wavelength 230 nm) of Epinephrine tartrate CRS 0.02 mg/mL undegraded (1), degraded by heating (2), by acidification with 1 M HCl (3), by alkalization with 1 M NaOH (4), by oxidiation with H2O2 (5).

Figure 1:

HPLC chromatogram (detection wavelength 230 nm) of Epinephrine tartrate CRS 0.02 mg/mL undegraded (1), degraded by heating (2), by acidification with 1 M HCl (3), by alkalization with 1 M NaOH (4), by oxidiation with H2O2 (5).


RP-HPLC assay

Suitability of the assay was shown by forced degradation tests (compare Figure 1). None of the degradation peaks interfered with the parent peak of E.

Figure 2: 
HPLC chromatogram of E 0.02 mg/mL, 50 mL injection solution, PDA at 230 nm (2.3 and 2.6 min: sodium-EDTA, 2.6. min: sodium metabisulfite).

Figure 2:

HPLC chromatogram of E 0.02 mg/mL, 50 mL injection solution, PDA at 230 nm (2.3 and 2.6 min: sodium-EDTA, 2.6. min: sodium metabisulfite).

The HPLC method was successfully validated for quality control and stability tests of epinephrine hydrogen tartrate containing injection solutions (compare Figure 2). The correlation coefficient of the standard curve amounted to >0.999 and proved linearity over the defined concentration range. Intraday RSDr amounted to 0.68% and Interday RSDt to 0.76%. The results met the acceptance criteria of ICH Q2 (R1) and proved reproducibility.

Quality of epinephrine injection solution 0.02 mg/mL in 50 mL amber glass vials

The concentration of E amounted to 0.0216 mg/mL in the bulk solution and to 0.0204 mg/mL in the final vials. Hence, autoclaving potentially leads to a loss of about 5% of E and after recognition of this fact during formulation development we decided for compensation and increased E concentration in the bulk solution to 105%. Autoclaving did not cause any degradation peaks corresponding to adrenochromes in any of the HPLC-PDA chromatograms (compare Figure 2).

Stability of epinephrine injection solution 0.02 mg/mL in 50 mL amber glass vials

For stability studies the initial concentration of the finished product was defined as 100%. After 12, 24 and 36 months of storage under refrigerated conditions, the mean E content amounted to about 99.5, 95 and 94%, respectively. Detailed results are given in Table 4. Degradation peaks of adenochromes were not detected at the detection wavelength of 480 nm.

Table 4:

Stability of Epinephrine 0.02 mg/mL injection solution in 50 mL amber glass vials stored at 2–8 °C. Concentration expressed as mean ± relative standard deviation of triplicate assays of three test solutions (n=9). Drug concentrations of the finished product in samples taken at time zero were designated as 100%.

E 0.02 mg/mL injection solution stored 2–8 °C
Nominal concentration Measured concentration ± SD n=9 Initial conc. remaining ± RSD n=9
Storage period [µg/mL] [µg/mL] [%]
0 d Bulk solution (before autoclaving) 21 21.6 ± 0.05
0 d Finished product (autoclaved) 20 (0.02 mg/mL) 20.4 ± 0.31 100.00
7 d 20.3 ± 0.06 99.8 ± 0.3
14 d 20.5 ± 0.13 100.7 ± 0.7
28 d 20.3 ± 0.11 99.5 ± 0.6
3 m 20.7 ± 0.15 101.8 ± 0.8
6 m 20.3 ± 0.03 99.8 ± 0.2
12 m 20.3 ± 0.02 99.5 ± 0.1
24 m 19.3 ± 0.22 94.7 ± 1.2
36 m 19.2 ± 0.08 94.1 ± 0.5

  1. d = day; m = month.

Analyses of pH and osmolality indicated stability of the E test solutions over the whole study period. Values remained unchanged during autoclaving and storage (Table 5). No visible particulate matter or colour changes were detected in any of the test solutions during the 36 month study period. Moreover, results of sub-visible particle count lay within the limits defined in the Ph.Eur. (compare Table 5).

Table 5:

pH values, osmolality and sub-visible particles of E 0.02 mg/mL injection solutions in 50 mL amber glass vials stored at 2–8 °C.

Storage period pH [n=9] Ø Osmolality [n=9] Ø Sub-visible particles [n=3] Ø
Day [mOsmol/kg] ≥10 µm, n ≥25 µm, n
0 d Bulk solutionc 3.78 272 450 30
0 d Finished productd 3.35 274 183 20
7 d 3.29 275 80 0
14 d 3.31 275 150 17
28 d 3.30 b 173 30
3 m 3.22 b 57 3
6 m 3.28 b 117 3
12 m 3.17a 273 13 3
24 m 3.23 275
36 m 3.19 274 2 2

  1. an=3; bosmometer not available; cbefore autoclaving; dafter autoclaving.



Based on reliable methods [16, 17] we established a modified HPLC assay for quantitative analysis of E using the µBondapak C18 column and a sodium dodecyl sulfate (SDS) containing mobile phase [11, 12]. Due to the hydrophilic characteristics of E, addition of SDS is favorable, since it exchanges ions resulting in longer retention times and subsequently improved separation of E. This optimized HPLC assay turned out to be robust and met the validation criteria. Suitability of the assay was shown by forced degradation under heated, acidic, alkalized and oxidized conditions. Peaks of the resulting peaks did not interfere with the parent peak.

Epinephrine injection solution 0.02 mg in 50 mL amber glass vials

E is categorized as high alert medication and should preferably be provided as RTA or RTU pharmacy prepared injection solution. Since E injections are frequently used in the hospital, batch-wise pharmacy preparation in advance is rational. The parenteral manual of our hospital encompasses three standardized concentrations of E, each with 50 mL total volume for continuous administration with syringe pumps. Therefore, the decision was made to develop RTU E injection solution 0.02 mg/mL 50 mL in amber glass vials, sterilized by autoclaving. Prior to administration the total volume of the vial has to be withdrawn into a 50 mL plastic syringe. However, this is a safe procedure and more efficient than aseptic preparation of RTA syringes in series in the pharmacy department.

The product was developed based on the formulation of the licensed E injection concentrate 1 mg/mL. Degradation of E was decelerated by adjusting the pH to 3.4–3.8, addition of EDTA as antioxidative excipient, purging the bulk solution with nitrogen, and using amber Type I glass vials with flurotec stoppers as primary packaging material. The batch-wise produced injections are subject to analytical tests prior to the batch release. The test batch and each routinely prepared batch fulfilled the quality criteria. E concentrations measured in samples from routine batches after 12 months refrigerated storage correlate with the results of the test batch.

Physicochemical stability of the test batch was analyzed in real time by a stability-indicating HPLC assay, measurement of pH, osmolality, and visible and sub-visible particles. As the acceptance criteria were fulfilled over the whole observation period, a shelf-life of 36 months was assigned to refrigerated E 0.02 mg/mL in 50 mL amber glass vials. Considering the predefined 90% limit for stability and the measured E concentrations after 36 months of more than 94% of the initial concentrations one may argue for an even longer shelf-life. But, from a practical point of view there is no need for such an extension. However, long-term stability data regarding storage at room temperature (RT) are of interest for hospital pharmacies and wards, because storage capacity in refrigerators is limited.

But to our knowledge stability studies of comparable sterilized E pharmacy preparations in vials are not published. According to our own studies, E 0.02 mg/mL injection solution in 10 mL plastic syringes aseptically prepared by dilution of licensed E injection concentrate and stored at RT is only stable for 14 days [11]. Several other studies determined the stability of RTA preparations aseptically prepared by diluting marketed injection concentrates with saline or 5% dextrose solutions [18], [19], [20], [21], [22], [23]. Donelly et al. confirmed the stability for 14 days for a concentration of 0.1 mg/mL (E HCl 0.7 mg/mL: 54 days at RT) [18]. In two other studies, the stability of E RTA-preparations 0.016-0.064 µg/mL stored at RT was given for 30–45 d [1920]. For example, RTA E hydrochloride 0.016–0.064 mg/mL infusion solutions in prefilled 0.9% sodium chloride polyvinyl chloride bags showed stability (>90%) over 60 and 45 days when stored light protected under refrigeration and at RT, respectively [19]. Longer stability was measured for concentrations 0.3–1 mg/mL [21], [22], [23]. Wade reports stability of E hydrochloride 0.01 mg/mL in normal saline prepackaged syringes of 90 days at RT [21]. In addition, commercially available E 1 mg/mL injection solution filled into 1 mL plastic syringes was reported to be stable for at least 3 months when stored at RT (after 3 months E=101.2% of the nominal concentration) [22]. Varying stability data can be explained by different licensed medicinal products used as starting material, different types of primary containers associated with different air tightness, and by different E concentrations of different E salts. On the other hand it is known that licensed Suprarenin® injection solution 1 mg/mL remains stable for 6 months without refrigeration [24]. Given the 3-year shelf-life of the RTU E 0.02 mg/mL injection solution stored refrigerated, we started stability testing of E solutions stored at RT. Preliminary results of our ongoing studies with E injection solutions 0.2 mg/mL in 50 mL vials revealed E concentrations of 96.6% of the initial concentration after 6 months storage at RT.


Pharmacy preparation of ready-to-use E injection solution 0.02 mg/mL in 50 mL amber glass vials for stock is a feasible approach to increase medication safety. According to the results of the stability study, a shelf-life of 36 months can be assigned to the E injection solution when refrigerated storage is given. From a practical point of view, additional stability data concerning storage at room temperature would be useful.

Corresponding author: Rita Marina Heeb, Department of Pharmacy, University Medical Center Mainz, Johannes Gutenberg-University, Langenbeckstraße 1, D-55131 Mainz, Germany, Phone: +49 6131 17 7209, E-mail:


The authors thank the analytical staff of the pharmacy department for their support.

  1. Research funding: No Funding.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: The conducted research is not related to either human or animal use.


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Received: 2021-12-20
Accepted: 2022-03-14
Published Online: 2022-04-01

© 2022 Rita Marina Heeb et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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