Home Assessment of the relevance of osmolality measurement as a criterion for the stability of solutions
Article Open Access

Assessment of the relevance of osmolality measurement as a criterion for the stability of solutions

  • Jean Vigneron , Matthieu Sacrez , Élise D’Huart EMAIL logo and Béatrice Demoré
Published/Copyright: January 24, 2023
Download Article (PDF)
Become an author with De Gruyter Brill
Author Information
Pharmaceutical Technology in Hospital Pharmacy
From the journal Pharmaceutical Technology in Hospital Pharmacy Volume 8 Issue 1

Abstract

Objectives

The measurement of osmolality is used by many authors as an additional stability criterion of a drug in solution. In the current state of knowledge, no scientific publication correlates the osmolality values and the stability of a solution. To study the relevance of this analytical technique by measuring the osmolality of injectable solutions whose instability has been chemically demonstrated by high performance liquid chromatography (HPLC).

Methods

Selection of 13 drug preparations whose chemical instability has been demonstrated in the literature. Realization of three identical samples per selected preparation and measurements of the osmolality of the freshly prepared solutions, then, at various storage times until a chemical degradation of the molecule validated by HPLC of at least 10% and possibly up to 40%.

Results

Measurements of the osmolality were performed on five antibiotics (amoxicillin/clavulanic acid, cefepime, cefoxitine, meropenem and temocillin and cefoxitin) and five anticancer drugs (azacitidine, bendamustine, busulfan, fotemustine and oxaliplatin). Osmolality varied from −6.30 to 11.10% for antibiotics and from 0.57 to 2.04%.

Conclusions

Among the preparations tested, only two formulations have a variation in osmolality in accordance with the chemical degradation. For the other 11 formulas, the variations in osmolality values where not correlated with the degradation measured by HPLC. In view of these results, osmolality does not seem to be a criterion of choice for the study of drug stability. In the majority of the unstable solutions studied, the variation of osmolality measurements does not correlate with the loss of concentration and the appearance of degradation products.

Keywords: degradation; osmolality; stability

Introduction

Osmolality is a physical quantity that is expressed in osmoles per kilogram of solvent (osmol.kg−1). Osmolality can be quantified by an osmometer that measures the freezing point depression of a solution. The temperature difference (ΔT) from the freezing point is proportional to the osmolality (ΔT=ε.k with k the molar cryoscopic constant, which is a property of the solvent and ε the osmolality). The greater the cryoscopic depression is, the greater the value of osmolality.

Osmosis describes the movement of solvent, through a semi-permeable membrane, from a solution with a low solute concentration (=hypotonic) to a more concentrated solution (=hypertonic) until equilibrium is reached. If a pressure is applied to the more concentrated part of the solution to prevent the transfer of solute, this creates what is called osmotic pressure. The osmolality is therefore an indication of the osmotic pressure because it indicates the amount of solute per kilogram of solvent.

The European Pharmacopoeia defines osmolality as "[…] a measure of the total number of chemical entities per kilogram of solvent. It is therefore an indication of the osmotic pressure of the solution […]" [1].

In hospital pharmacy practice, the osmolality measurement is used in several fields in pharmacotechnics: (1) to determine the route of administration of parenteral nutrition according to the High Authority for Health (HAS) with the cut-off value of 850 mOsmol value below which a peripheral venous catheter is authorized and above which administration by a central line is mandatory [2], (2) to determine the feasibility of a preparation mainly for eyedrops or intrathecal injections because extreme values of osmolality can damage or destroy cells [3, 4] and (3) for the quality control of parenteral nutrition prepared specifically for pediatrics and neonatology departments. The NHS guideline: « A Standard protocol for derivation and assessment of stability – Part 4: Parenteral nutrition » recommends that osmolality measurement could be used to “[…] offer some indication of the correct compounding of the admixture […]”. Nevertheless, the authors inform that measurements of osmolality are “[…] non-specific and the measured values are influenced by all components present in the mixture, hence they are only indicative […]” [5].

In two documents, osmolality is suggested as a stability criterion. The SFPC/GERPAC stability guideline states that “A solution that does not degrade keeps constant osmolality. Within the scope of a stability study, measuring osmolality can be considered to provide an additional parameter to help confirm chemical stability” [6]. The ICH guideline Q6B Biotechnological advocates measurement of osmolality in stability studies “Physical description and the measurement of other quality attributes is often important for the evaluation of the drug product functions. Examples of such tests include pH and osmolality” [7]. However, other guidelines devoted to stability studies such as ICH Q1A or ICH Q1E or NHS guidelines do not mention osmolality as a potential stability criteria [8], [9], [10], [11], [12].

Many authors use this analytical technique to evaluate the stability of solutions mainly for eye drops. In the Stabilis database, there are 29 monographs of eye drop solutions including 52 publications. Among these 52 publications, 29 use osmolality as a stability criterion i.e. a percentage of 55.8%. However, stability studies of injectable solutions with 476 monographs and 2095 publications, the partially evaluation on 37 publications give a 1.77% of osmolality measurement as stability criterion.

In the absence of consensus on the use of this criterion to assess stability in the recommendations and in view of the use of this criterion in numerous publications, our objective was to assess the relevance of the measurement of osmolality as a criterion of stability of a solution.

Material et methods

A bibliographic search was carried out to select molecules whose chemical instability was demonstrated in the literature by a validated High Performance Liquid Chromatography (HPLC) method. The choice was also made for molecules studied in our pharmacy department. The molecules selected and the formulas are presented in Table 1. The percentages of the chemical degradation found in the publications are presented in Table 2.

Table 1:

Mode of preparation of selected samples.

Molecules + concentrations, mg/mL Vials (manufacturer, Batch) Reconstitution procedure Dilutions Storage conditions Containers (manufacturer, batch) Osmolality measurement times
Antibiotics
Amoxicillin/Clavulanic acid 2 g/200 mg/100 mL 1 × 2 g/200 mg (Sandoz, KS3429) 20 mL NS qs 100 mL NS 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T8H, T24H
Cefepime 125 mg/mL (6 g/48 mL) 3 × 2 g (Gerda, S-05) 10 mL SWFI qs 48 mL NS 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T24H, T48H
Cefepime 125 mg/mL (6 g/48 mL) 3 × 2 g (Gerda, S-05) 10 mL SWFI qs 48 mL D5W 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T24H, T48H
Cefepime 50 mg/mL (3 g/60 mL) 1 × 1 g (Gerda, R-08) + 1 × 2 g (Gerda, S-05) 10 mL SWFI qs 60 mL NS 37 °C Syringe (BD plastipak, 2,103,066) T0, T24H, T48H
Cefoxitin 125 mg/mL (6 g/48 mL) 3 × 2 g (panpharma, S4-03) 10 mL SWFI qs 48 mL D5W 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T48H, T72H
Cefoxitin 125 mg/mL (6 g/48 mL) 3 × 2 g (panpharma, S4-03) 10 mL SWFI qs 48 mL NS 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T48H, T72H
Meropenem 41.7 mg/mL (2 g/48 mL) 2 × 1 g (panpharma, MFR1081) 20 mL SWFI qs 48 mL D5W 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T8H, T24H
Temocilline 25 mg/mL (3 g/120 mL) 1 × 1 g (Eumedica, L163419) + 1 × 2 g (Eumedica, L166712) 20 mL NS qs 120 mL NS 37 °C Syringe (BD plastipak, 2,103,066) T0, T24H, T48H
Anticancer drugs
Azacitidine 2 mg/mL 1 × 100 mg (Mylan, 7U10030A) 20 mL SWFI 8 mL azacitidine qs 20 mL SWFI 20–25 °C Syringe (BD plastipak, 2,111,003) T0, T8H, T24H
Bendamustine 0.25 mg/mL 1 × 25 mg (Accord, P2004608) 10 mL SWFI 1 mL bendamustine qs 10 mL NS 20–25 °C Syringe (BD plastipak, 210,898) T0, T8H, T24H
Busulfan 0.12 mg/mL 1 × 60 mg/10 mL (Tilomed, BUAA21006) / 0.4 mL busulfan qs 20 mL NS 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T8H, T24H
Fotemustine 0.8 mg/mL 1 × 208 mg/4.16 mL (Serviers, S200003) / 0.8 mL qs 50 mL D5W 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T8H, T24H
Oxaliplatine 0.1 mg/mL 1 × 200 mg/40 mL (Accord, P2103167) / 1 mL oxaliplatine qs 50 mL NS 20–25 °C Syringe (BD plastipak, 2,103,066) T0, T8H, T24H

  1. NS, Normal Saline; SWFI, Sterile Water For Injection; D5W, Dextrose 5% in Water.

Table 2:

Percentage of chemical degradation of the preparation described in the literature.

Molecules Solvents Percentage of degradation Time References
Antibiotics
Amoxicillin/clavulanic acid 2 g/200 mg/100 mL NS 34.1% 24 h [14]
Cefepime 125 mg/mL (6 g/48 mL) NS 12.2% 48 h [15]
Cefepime 125 mg/mL (6 g/48 mL) D5W 14.4% 48 h [15]
Cefepime 50 mg/mL (3 g/60 mL) NS 40.5% 48 h [15]
Cefoxitin 125 mg/mL (6 g/48 mL) NS 10.2% 48 h [15]
Cefoxitin 125 mg/mL (6 g/48 mL) D5W 10.4% 48 h [15]
Meropenem 41.7 mg/mL (2 g/48 mL) D5W 14.1% 8 h [15]
Temocilline 25 mg/mL (3 g/120 mL) NS 98.6 °F 19.6% 48 h [15]
Anticancer drugs
Azacitidine 2 mg/mL NS 20% 6 h [16]
Bendamustine 0.25 mg/mL NS 27.3% 24 h [17]
Busulfan 0.12 mg/mL NS 35.9% 24 h [18]
Fotemustine 0.8 mg/mL D5W 30% 8 h [19]
Oxaliplatine 0.1 mg/mL NS 20.8% 2 h [20]

  1. NS, Normal Saline; SWFI, Sterile Water For Injection; D5W, Dextrose 5% in Water.

For each selected formula, three identical samples were prepared. Three measurements of osmolality per sample were performed on the freshly prepared solutions and then, at different storage times according to the results obtained by HPLC where a chemical degradation of the molecule of at least 10% and possibly up to 80% had been validated.

The osmolality measurements were performed by a Roebling micro-osmometer which uses the Peltier cooling system, a thermistor (resistance whose electrical variation depends on temperature) and a device to initiate solidification when supercooling occurs (freezing of the solution after an injection of ice-cold ultra-pure water).

Before each use, the osmometer was calibrated according to the manufacturer’s instructions and then 50 µL of each preparation was analyzed [13].

Results

The measurement times were selected according to the molecule and its degradation described in the literature with the exceptions of azacitidine and oxaliplatine with the osmolality measurement after 24 h instead of 6 and 2 h respectively. The results of osmolality measurements are presented in Table 3.

Table 3:

Average of osmolality measurements (mosmol/kg) of each sample.

Average of osmolality measurements (mosmol/kg) of each sample at: Variation rate
T0 T4 h T8 h T24 h T48 h
Antibiotics
Amoxicillin/Clavulanic acid 2 g/200 mg/100 mL NS 24 h
414.5 – 413.0 410.4 – −0.99%
Cefepime 125 mg/mL (6 g/48 mL) D5W 48 h
1,012.5 – – 1,027.4 1,024.1 1.14%
Cefepime 125 mg/mL (6 g/48 mL) NS 48 h
1,020.3 – – 1,042.0 1,025.8 0.53%
Cefepime 50 mg/mL (3 g/60 mL) 37 °C NS 48 h
575.0 – – 580.7 590.2 2.65%
Cefoxitin 125 mg/mL (6 g/48 mL) D5W 48 h
598.3 – – 664.7 699.6 11.10%
Cefoxitin 125 mg/mL (6 g/48 mL) NS 48 h
577.2 – – 628.4 663.2 8.87%
Cloxacillin 250 mg/mL (1 g/4 mL) SWFI 48 h
526.2 – – 528.0 544.6 3.51%
Meropenem 41.7 mg/mL (2 g/48 mL) D5W 8 h
331.7 – 310.8 306.1 – −6.30%
Temocilline 25 mg/mL (6 g/120 mL) 37 °C NS 48 h
471.3 – – 475.4 477.3 1.27%
Anticancer drugs
Azacitidine 2 mg/mL NS 24 h
192.2 – 193.1 195.7 – 1.85%
Bendamustine 0.25 mg/mL NS 24 h
260.8 – 260.6 266.2 – 2.04%
Busulfan 0.12 mg/mL NS 24 h
400.8 – 385.2 406.6 – 1.44%
Fotemustine 0.8 mg/mL D5W 8 h
510.2 – 513.1 519.2 – 0.57%
Oxaliplatine 0.1 mg/mL NS 24 h
277.4 – 266.6 281.8 – 1.60%

  1. Variation rate of osmolality at different times (h) are given in bold.

The summary of concentration decreases and of osmolality measurements are presented in Figure 1.

Figure 1: Comparison of the variation rate in osmolality with the rate of degradation measured by HPLC.
Figure 1:

Comparison of the variation rate in osmolality with the rate of degradation measured by HPLC.

Discussion

The molecules can be classified into two categories. Osmolality variations were in accordance with the chemical degradation described in the literature by HPLC for only two formulas. After 48 h, cefoxitin 125 mg/mL in NS and in D5W shows an osmolality variation of 8.87 and 11.10%, respectively, for a chemical degradation described in the literature of 10.22 and 10.44% [15].

Osmolality variations were in inadequacy with the chemical degradation described in the literature by HPLC for the 11 other formulas:

The small or non-existant variations in osmolality values can be explained by the number of molecules in the solution after degradation. As example, bendamustine degradation has been studied by Kasa S et al. [21]. For bendamustine hydrochloride, the variation in osmolality values is almost non-existent, only 2% in comparison with a chemical degradation of 27%. The molecule consists of an alkylating group, a benzimidazole ring and a butyric acid side chain. The hydrolysis of this molecule represented in Figure 2 shows the two main degradation products. A first chloride is replaced by a hydroxyle to produce monohydroxybendamustine and the second chloride of monihydroxybendamustine is replaced by a second hydroxyle to give dihydroxybendamustine. However, the total number of chemical entities is the same resulting with no variation of osmolality values when a 27%-chemical degradation is demonstrated.

Figure 2: Chemical degradation of the nitrogen mustard structure of bendamustine.
Figure 2:

Chemical degradation of the nitrogen mustard structure of bendamustine.

A limitation of our work is that we compared our osmolality measurements with published stability studies. HPLC analysis has not been verified in our laboratory. It could be interesting to continue measuring osmolality values in other stability studies for solutions whose instability is demonstrated by HPLC in order to confirm the irrelevance of osmolality measurement as a stability criterion.

Conclusions

Considering the evaluation of the stability of a solution, articles published on this topic and using osmolality measurement as stability criterium demonstrates that osmolality values stay stable when the solutions stay stable. If a solution is chemically stable by HPLC analysis with a variation of osmolality values during a stability study, the solution may not be stable and further investigations should be performed. However, for the unstable solutions selected for this work, osmolality stay also stable in the majority of cases. In view of these results, osmolality does not seem to be a pertinent criterion for the study of drug stability.

Corresponding author: Élise D’Huart, Pharmacy Department, Centre Hospitalier Régional Universitaire, Hôpital Brabois Adultes, Allée du Morvan, 54511 Vandœuvre-lès-Nancy, France: and Infostab, Non-profit Association, Heillecourt, France, Phone: +33 3 83 15 44 10, Fax: +33 3 83 15 35 27, E-mail:

Acknowledgments

Thank you to Franck Blaise, Nathalie Sobalak and Hubert Zenier for their help and their involvement throughout this stability and thank you to Jacques Kuhnlé for reading through it all and making corrections.

  1. Research funding: None declared.

  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. Presentation: Presented as a poster a European Congress of Oncology Pharmacy, 2022, Hambourg (Germany).

  5. Informed consent: Informed consent was obtained from all individuals included in this study.

  6. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

References

1. European Pharmacopoeia 10.0. 2.2.35. Osmolality, 10th ed. Strasbourg, France: Council of Europe; 2019:20235 p.Search in Google Scholar

2. Des Robert, C. Nutrition parentérale en néonatologie. Haute autorité de santé; 2018. Available from: https://www.has-sante.fr/upload/docs/application/pdf/2018-06/argu_np_neonat_2018-06-28_11-18-23_280.pdf.Search in Google Scholar

3. Akers, MJ. Basics of sterile compounding: excipients used in injections. Int J Pharm Compd 2017;214:301–8.Search in Google Scholar

4. Allen, LV. Quality-control analytical methods: osmolality and osmometry. Int J Pharm Compd 2004;8:143–5.Search in Google Scholar

5. Santillo, M. A Standard protocol for derivation and assessment of stability – Part 4: Parenteral nutrition. National Health Service; 2016. Available from: https://www.sps.nhs.uk/wp-content/uploads/2017/06/NHS-PQAC-YCD-Std-Protocol-Chemical-Stability-Part-.Search in Google Scholar

6. SFPC (French Society of Clinical Pharmacy). GERPAC (Evaluation and Research Group on Protection in Controlled Atmosphere). Methodological guidelines for stability studies of hospital pharmaceutical preparations; 2013. Available from: https://www.gerpac.net/plateforme/course/view.php?id=8.Search in Google Scholar

7. International Conference on Harmonisation. Q6B specifications: specifications: test procedures and acceptance criteria for biotechnological/biological products. guideline; 1999. Available from: https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf.Search in Google Scholar

8. International Conference on Harmonisation. Q1A(R2): stability studies of new drug substances and products; 2003. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1-r2-stability-testing-new-drug-substances-products-step-5_en.pdf.Search in Google Scholar

9. International Conference on Harmonisation. Q1E: evaluation for stability data; 2003. Available from: https://database.ich.org/sites/default/files/Q1E_Guideline.pdf.Search in Google Scholar

10. Santillo, M. NHS – Standard protocol for stability assessment. Part 1: aseptic preparation (small molecules), 5th ed.; 2019. Available from: https://www.sps.nhs.uk/wp-content/uploads/2013/12/Stability-part-1-small-molecules-5th-Ed-Sept-19.pdf.Search in Google Scholar

11. Santillo, M. NHS – A standard protocol for deriving and assessment of stability. Part 2: aseptic preparations (Biopharmaceuticals), 5th ed.; 2021. Available from: https://www.sps.nhs.uk/wp-content/uploads/2017/03/Stability-Part-2-Biopharmaceuticals-v5.pdf.Search in Google Scholar

12. Santillo, M. NHS – A standard protocol for deriving and assessment of stability. Part 3: oral liquid Medicines (Solutions, Emulsions, Suspensions and Syrups), 1st ed.; 2014. Available from: https://www.sps.nhs.uk/wp-content/uploads/2022/04/NHS-PQA-Standard-Protocol-for-Deriving-and-Assessment-of-Stability-Part-3-Oral-Liquid-Medicines.pdf.Search in Google Scholar

13. Micro-Osmometer type 15. user’s guide. Berlin. Germany: Löser Messtechnik. Available from: http://www.meteo-tech.co.il/ImagesDownloadFiles/Osmometer15.pdf.Search in Google Scholar

14. Kambia, NK. Stability studies of amoxicillin/clavulanic acid combination in polyolefin infusion bags. EJHP Practice Edition 2010;16:30–7.Search in Google Scholar

15. Loeuille, G, D’Huart, E, Vigneron, J, Nisse, YE, Beiler, B, Polo, C, et al.. Stability studies of 16 antibiotics for continuous infusion in intensive care units and for performing outpatient parenteral antimicrobial therapy. Antibiotics 2022;11:458. https://doi.org/10.3390/antibiotics11040458.Search in Google Scholar PubMed PubMed Central

16. Cheung, YW, Vishnuvajjala, BR, Morris, NL, Flora, KP. Stability of azacitidine in infusion fluids. Am J Hosp Pharm 1984;41:1156–9. https://doi.org/10.1093/ajhp/41.6.1156.Search in Google Scholar

17. Vigneron, J. Stability of bendamustine infusions: influence of sodium chloride concentration. temperature and container. Pharm Tech Hosp Pharm 2018;31:13–21. https://doi.org/10.1515/pthp-2017-0033.Search in Google Scholar

18. Xu, QA. Stability of busulfan injection admixtures in 5% dextrose injection and 0.9% sodium chloride injection. J Oncol Pharm Pract 1996;22:101–5. https://doi.org/10.1177/107815529600200202.Search in Google Scholar

19. Dine, T. Stability study of fotemustine in PVC infusion bags and sets under various conditions using a stability-indicating high-performance liquid chromatographic assay. J Pharm Biomed Anal 1998;18:373–81. https://doi.org/10.1016/s0731-7085(98)00096-x.Search in Google Scholar PubMed

20. Mehta, AM. Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy. Int J Pharm 2015;479:23–7. https://doi.org/10.1016/j.ijpharm.2014.12.025.Search in Google Scholar PubMed

21. Kasa, S. Stability-Indicating LC method for the estimation of bendamustine hydrochloride and its related impurities. J Chromatogr Sci 2014;52:579–83. https://doi.org/10.1093/chromsci/bmt075.Search in Google Scholar PubMed

Received: 2022-09-20
Accepted: 2022-11-22
Published Online: 2023-01-24

© 2023 the author(s), published by De Gruyter, Berlin/Boston

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

Articles in the same Issue

  1. Research Articles
  2. Air contamination, syringe contamination, and cross-contamination when using an automatic compounding device for sensitizing drugs
  3. Long term physicochemical stability study of novel ophthalmic formulations combining ceftazidime and vancomycin with and without cyclodextrins
  4. Semi-automatic COVID-19 vaccine preparation for upscaling of vaccination: a descriptive study
  5. Physicochemical stability of Cabazitaxel Zentiva® solution in vials after opening and diluted solutions in three infusion bags
  6. Physicochemical stability of durvalumab (Imfinzi®) concentrate for solution in original vials after first opening
  7. Physicochemical stability of urea-containing Mitomycin C preparations in glass vials (1.0 mg/mL) and plastic syringes (2.0, 0.4, 0.2 mg/mL)
  8. Physicochemical stability study of a biosimilar of Bevacizumab in vials and after dilution in 0.9% NaCl in polyolefin intravenous bags
  9. Assessment of the relevance of osmolality measurement as a criterion for the stability of solutions
  10. Short Communications
  11. An exploratory study of a simplified approach to evaluate drug solubility in milk related vehicles
  12. Use of a liquid chromatography-tandem mass spectrometry method to assess the concentration of epinephrine, norepinephrine, and phenylephrine stored in plastic syringes
https://doi.org/10.1515/pthp-2022-0008
Keywords for this article
degradation; osmolality; stability
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Air contamination, syringe contamination, and cross-contamination when using an automatic compounding device for sensitizing drugs
  3. Long term physicochemical stability study of novel ophthalmic formulations combining ceftazidime and vancomycin with and without cyclodextrins
  4. Semi-automatic COVID-19 vaccine preparation for upscaling of vaccination: a descriptive study
  5. Physicochemical stability of Cabazitaxel Zentiva® solution in vials after opening and diluted solutions in three infusion bags
  6. Physicochemical stability of durvalumab (Imfinzi®) concentrate for solution in original vials after first opening
  7. Physicochemical stability of urea-containing Mitomycin C preparations in glass vials (1.0 mg/mL) and plastic syringes (2.0, 0.4, 0.2 mg/mL)
  8. Physicochemical stability study of a biosimilar of Bevacizumab in vials and after dilution in 0.9% NaCl in polyolefin intravenous bags
  9. Assessment of the relevance of osmolality measurement as a criterion for the stability of solutions
  10. Short Communications
  11. An exploratory study of a simplified approach to evaluate drug solubility in milk related vehicles
  12. Use of a liquid chromatography-tandem mass spectrometry method to assess the concentration of epinephrine, norepinephrine, and phenylephrine stored in plastic syringes
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 14.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/pthp-2022-0008/html
Scroll to top button