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Physical stability of highly concentrated injectable drugs solutions used in intensive care units
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ORIGINAL ARTICLE
Physical stability of highly concentrated injectable drugs solutions used in intensive care units Stabilité physique de principes actifs en solutions concentrées pour utilisation en unités de soins intensifs M. Closset b,∗, J.D. Hecq a,c, L. Soumoy a, J. Simar b, E. Gonzalez b, L. Charlet a, C. Declave a, P. Gillet a, L. Galanti b,c a
Department of Pharmacy, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium b Medical Laboratory, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium c Drug Stability Research Group, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium Received 1st August 2016; accepted 19 December 2016
KEYWORDS Drug stability; Spectrophotometry; pH-meter; Microscope
∗
Summary Background. — The intensive care department of the institution use drug solutions within higher concentration to avoid fluid overload. The purpose of the study is to prove the physical stability of different injectable drugs within high concentration (amiodarone 25 mg/mL, isosorbide 0.60 mg/mL, lorazepam 0.16 mg/mL, noradrenalin 0.120 and 0.240 mg/mL, salbutamol 0.06 mg/mL and sodium valproate 12 mg/mL) to ensure the patients safety. Methods. — Five of 30 or 50 mL polypropylene syringes were prepared for each solution under aseptic conditions and stored at room temperature. Immediately after the preparation (hour 0) and after 1, 4, 8, 24 and 48 hours, 2 mL of each solution were withdrawn from each syringe and placed in glass tubes to proceed to the stability test. All specimens were visually inspected in front of a black and of a white background and aliquots of each solution were centrifuged
Corresponding author. Department of Medical Laboratory, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium. E-mail address: [email protected] (M. Closset).
http://dx.doi.org/10.1016/j.pharma.2016.12.004 0003-4509/© 2016 Acad´ emie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
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M. Closset et al. to proceed to microscopic inspection with a ten-fold magnification. The pH of each solution was measured with glass electrode pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Switzerland) and spectrophotometric measurements (Genesys 10 series, New-York, USA) were performed at three wavelengths (350, 410 and 550 nm) to avoid the apparition of turbidity. Results. — For all the drugs included in the study, there was no significant change in pH, no color change, no turbidity or opacity and no precipitation observed in the solutions during the storage at room temperature for 48 hours. No microaggregates were detected by microscope neither revealed by a change of absorbance. Conclusion. — Within these limits, the preparations of amiodarone in 5% glucose polypropylene syringes and isosorbide, lorazepam, noradrenalin, salbutamol, valproate in 0.9% sodium chloride polypropylene syringes are physically stable at room temperature for 48 hours. These results allow us to consider a study of chemical stability by high-performance liquid chromatography (HPLC). © 2016 Acad´ emie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Stabilité d’injectables ; Spectrophotométrie ; pH-mètre ; Microscope
Résumé Contexte. — Le département des soins intensifs de l’institution utilise des solutions de principes actifs en solutions concentrées afin d’éviter la surcharge hydrique des patients. Le but de cette étude est de prouver la stabilité physique d’une série de principes actifs utilisés à des concentrations élevées (amiodarone 25 mg/mL, isosorbide 0,60 mg/mL, lorazépam 0,16 mg/mL, noradrénaline 0,120 and 0,240 mg/mL, salbutamol 0,06 mg/mL et acide valproïque 12 mg/mL) afin d’assurer la sécurité des patients. Méthode. — Pour chaque solution, cinq seringues en polypropylène de 30 ou 50 mL ont été préparées dans des conditions d’asepsie et stockées à température ambiante pour une durée de 48 heures. Tout de suite près la préparation (heure 0) et après 1, 4, 8, 24 et 48 heures, 2 mL ont été prélevés de chaque solution et placés dans des tubes en verre afin de procéder au test de stabilité. Tous les échantillons ont été inspectés visuellement devant un fond noir et un fond blanc. Des aliquots de chaque solution ont été centrifugés afin de réaliser un examen microscopique à un grossissement 10 ×. Le pH de chaque solution a été mesuré au moyen d’électrodes en verre pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Suisse) et les mesures spectrophotométriques (Genesys 10 series, New York, ÉtatsUnis) ont été réalisées à trois longueurs d’ondes différentes (350, 410 et 550 nm) afin d’exclure l’apparition d’un trouble. Résultats. — Pour tous les principes actifs inclus dans l’étude, il n’y a pas eu de modification significative du pH ni de la couleur. Aucun trouble, aucune opacité ni aucune précipitation n’ont été observés dans les solutions lors du stockage à température ambiante pendant 48 heures. Aucun micro-agrégat n’a été détecté au microscope ni révélé par une modification d’absorbance. Conclusion. — Dans ces limites, les préparations d’amiodarone dans des seringues en polypropylène de glucosé 5 % et d’isosorbide, lorazépam, noradrénaline, salbutamol, acide valproïque dans des seringues en polypropylène de NaCl 0,9 % sont physiquement stables à température ambiante pour une durée de 48 heures. Ces résultats nous permettent d’envisager une étude de stabilité chimique par chromatographie liquide à haute performance (HPLC). © 2016 Acad´ emie Nationale de Pharmacie. Publi´ e par Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction The total volume of infusion administrated to patients admitted into intensive care units is often important [1]. Fluid overload is commonly implicated in fluid resuscitation
and is associated with increased hospital costs, morbidity and mortality [2]. Sometimes fluid overload can also induce other side effects, such as hypernatremia [3]. There is a huge interest to build strategies that reduce excessive fluid infusions.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
+Model PHARMA-490; No. of Pages 4
ARTICLE IN PRESS
Physical stability of highly concentrated injectable drugs solutions One possible way to avoid such type of adverse effects is to reduce the global volume of infusion by using drugs solution within higher concentrations. The intensive care department of the institution is actually using such a way to reduce fluid overload in patients. The drugs administrated at high concentration and preliminary selected for the study are: amiodarone 25 mg/mL, isosorbide 0.60 mg/mL, lorazepam 0.16 mg/mL, noradrenalin 0.120 and 0.240 mg/mL, salbutamol 0.06 mg/mL and sodium valproate 12 mg/mL. In order to ensure patients safety [4,5], the physical stability of those injectable drugs at high concentration must be proved. This physical stability study fits into the update of the standardization of reconstitution and administration of injectable drugs in our institution [6—9].
Aims of the study The aim of this study is to determine the physical stability [10,11] of a range of concentrated injectable drugs solutions, individually prepared in polypropylene syringes and stored at room temperature.
Method Solutions preparation Five of 30 or 50 mL polypropylene syringes were prepared for each solution under aseptic conditions.
Amiodarone Fifty-millilitre syringes (Becton Dinckinson (BD), lot 1505236) were prepared containing each one 600 mg of ® amiodarone (Cordarone , Sanofi, lot AY003) diluted into 12 mL of glucose solution (Glucose 5%, Baxter, Lot 15D24G61) for a total volume of 24 mL and a final concentration of 25 mg/mL.
Isosorbide
3
lot15J13G60) for a total volume of 50 mL and a final concentration of 0.120 mg/mL and 0.240 mg/mL, respectively.
Salbutamol Fifty-millilitre syringes (BD, lot1508258) were prepared con® taining each one 3 mL of salbutamol (Ventolin , Glaxo Smith Kline, lot 3501A) diluted into 47 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J12G60) for a total volume of 50 mL and a final concentration of 0.06 mg/mL.
Valproate Fifty-millilitre syringes (BD, lot 1507241) were prepared con® taining each one 600 mg of Valproate (Valproate Sodique , Mylan, lot 080147) diluted into 44 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J13660) for a total volume of 50 mL and a final concentration of 12 mg/mL.
Storage The syringes were stored at room temperature in order to suit to the clinical conditions of administration in the intensive care unit. Immediately after the preparation (hour 0) and after 1, 4, 8, 24 and 48 hours, 2 mL of each solution were withdrawn from each syringe and placed in glass tubes to proceed to the stability test.
pH The pH of the solutions was measured at each time by a glass electrode pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Switzerland).
Spectrophotometric analyse At each time, all specimens went under spectrophotometric measurements (Genesys 10 series, New-York, USA) at three wavelengths (350, 410 and 550 nm).
Visual observation
Fifty-millilitre syringes (BD, lot 1508258) were prepared con® taining each one 30 mg of isosorbide (Cedocard , Tadeka, lot 14D10/1) diluted into 20 mL of sodium chloride solution (NaCl 0.9% 100 mL, Baxter, lot 15I22G61) for a total volume of 50 mL and a final concentration of 0.60 mg/mL.
All specimens were visually inspected at each time in front of white and black backgrounds to avoid the apparition of crystals or small particles.
Lorazepam
As well, aliquots of each solution were systematically withdrawn and then centrifuged to proceed to microscopic inspection with a ten-fold magnification.
Thirty-millilitre syringes (BD, lot 1510205) were prepared ® containing each one 4 mg of lorazepam (Temesta , Pfizer, lot 4034) diluted into 23 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J13G60) for a total volume of 24 mL and a final concentration of 0.16 mg/mL.
Noradrenalin Fifty-millilitre syringes (BD, lot 1508258) were prepared containing each one 6 mg or 12 mg of noradrenalin (Noradrenaline, Aguettant, lot4301834) diluted into 44 mL or 38 mL of sodium chloride solution (NaCl 250 mL, Baxter,
Microscopic observation
Results and discussion For all the drugs included in the study, the measurements of pH at each time did not show any significant change in pH during storage (cf. Table 1). There was no color change, no turbidity or opacity and no precipitation observed in the solutions during the storage at room temperature for 48 hours.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
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M. Closset et al. Table 1 Results of pH measurements and spectrophotometric analyses (mean ± SD) of highly concentrated drugs solutions over the time. Résultats des mesures de pH et des analyses spectrophotométriques (moyenne ± SD) des principes actifs en solutions concentrées au cours du temps. Spectrophotometry (x ± SD)
pH x ± SD Isosorbide 0.6 mg/mL Noradrenaline 0.12 mg/mL Noradrenaline 0.24 mg/mL Amiodarone 25 mg/mL Lorazepam 0.16 mg/mL Valproate 12 mg/mL Salbutamol 0.06 mg/mL
6.52 3.79 3.62 3.86 7.30 7.22 5.65
± ± ± ± ± ± ±
0.116 0.016 0.014 0.049 0.23 0.07 0.045
Min
Max
350 nm
6.39 3.77 3.61 3.80 7.06 7.15 5.58
6.71 3.81 3.65 3.94 7.54 7.34 5.69
0.0026 0.0028 0.0029 2.9447 0.07 0.0002 0.0034
No microaggregates were detected by microscope neither revealed by a change of absorbance. Visual compatibility was defined as the absence of particulate formation, haze, precipitation, colour change and gas evolution [12]. Various tests were performed to detect the development of particles at each level. Visual inspection in front of a black and a white background is useful to detect macroscopically particles of various colours. The microscopic inspection is important to ensure the absence of microscopically crystals that cannot be visually observed. The purpose of the spectrophotometric analysis is to detect the apparition of turbidity, which may sign the presence of a precipitate in the solution [13]. The interest of the pH measurements of the injectable drug solution remains suitable to the stability of its active principle. But there is also a clinical interest, which means that the injection has to be well tolerated by the patient. The pH of the solution must be greater than or equal to 3 and less than or equal to 9 (3 ≤ pH ≤ 9) [14].
Conclusion Within these limits, the preparations of amiodarone in 5% glucose polypropylene syringes and isosorbide, lorazepam, noradrenalin, salbutamol, valproate in 0.9% sodium chloride polypropylene syringes are physically stable at room temperature for 48 hours. For each molecule, these results allow us to consider a study of chemical stability by high-performance liquid chromatography (HPLC).
Disclosure of interest The authors declare that they have no competing interest.
References [1] Besen BA, Gobatto AL, Melro LM, Maciel AT, Park M. Fluid an electrolyte overload in critically ill patients: an overview. World J Crit Care Med 2015;4(2):116—29.
410 nm ± ± ± ± ± ± ±
0.002 0.0016 0.0009 0.0027 0.001 0.0025 0.0027
—0.001 0.0006 0.0004 0.152 0.001 —0.0009 —0.0009
550 nm ± ± ± ± ± ± ±
0.0006 0.0012 0.0006 0.668 0.0007 0.0018 0.0008
—0.0008 0.0003 —0.00003 0.0031 0.00003 —0.001 —0.0005
± ± ± ± ± ± ±
0.0007 0.0009 0.00008 0.0010 0.0001 0.0023 0.0007
[2] Ogbu OC, Murphy DJ, Martin GS. How to avoid fluid overlaod. Curr Opin Crit Care 2015;21(4):315—21. [3] Choo WP, Groenevel ABJ, Driessen RH, Swart EL. Normal saline to dilute parenteral drugs and to keep catheters open is a major and preventable source of hypernatremia acquired in the intensive care unit. J Crit Care 2014;29:390—4. [4] Clarck C. Safety with injectable medicines. Clin Pharm Eur 2007;7:13—6. [5] Hecq JD. Stabilité des médicaments injectables en perfusion. Brussels: Association belge des pharmaciens hospitaliersBelgische Vereniging van Ziekenhuis Apothekers (ABPH-BVZA); 2015. [6] Hecq JD. Centralized intravenous additive services (CIVAS): the state of the art in 2010. Ann Pharm Fr 2011;69:30—7. [7] Hecq JD, Evrard JM, Gillet P, Gilain M, Crucifix MB, Gardin C, et al. Standardisation de la procédure de dilution et d’administration des antiinfectieux intraveineux utilisés aux cliniques universitaires UCL de Mont-Godinne. Pharmakon 1998;114:72—80. [8] Hecq JD, Limbort V, Lecoq MC, Gillet P, Bary M, Jacquet S, et al. Mise à jour de la standardisation des procédures de dilution et d’administration des anti-infectieux utilisés aux cliniques universitaires UCL de Mont-Godinne. Pharmakon 2005;37(1): 7—10. [9] Hecq JD, Vastrade Ch, Perrad J, Garc ¸ous R, Amant F, Artoisenet Ch, et al. Standardisation des méthodes de dilution des médicaments injectables en unités de soins intensifs et unités conventionnelles. J Pharm Belg 2016;98:26—35. [10] Anrys P, Magnette A, Jamart J, Galanti L, Hecq JD. Compatibilité physique d’un mélange d’alizapride et de clorazépate dans des poches souples de 100 mL glucose 5 % pour perfusion. J Pharm Belg 2014;96:38—9. [11] Huvelle S, Godet M, Gillet P, Jamart J, Galanti l, Hecq JD. Compatibilité physique d’un mélange d’alizapride et de déxaméthasone dans des poches souples de 100 mL glucose 5 % pour perfusion. J Pharm Belg 2015;97:38—9. [12] Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American society of Health-System Pharmacy; 2013. [13] Lahlou A, Blanchet B, Carvalho M, Paul M, Astier A. Mechanically-induced aggregation of the monoclonal antibody cetuximab. Ann Pharm Fr 2009;67(5):340—52. [14] Wouessi Djewe D. Formes galéniques administrées par voies parentérales. UE6 — Pharmacie Galénique : voies d’administration et formes pharmaceutiques, chapitre 6. Université Joseph-Fourier de Grenoble; 2011—2012.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
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PHARMA-490; No. of Pages 4
Annales Pharmaceutiques Françaises (2017) xxx, xxx—xxx
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ORIGINAL ARTICLE
Physical stability of highly concentrated injectable drugs solutions used in intensive care units Stabilité physique de principes actifs en solutions concentrées pour utilisation en unités de soins intensifs M. Closset b,∗, J.D. Hecq a,c, L. Soumoy a, J. Simar b, E. Gonzalez b, L. Charlet a, C. Declave a, P. Gillet a, L. Galanti b,c a
Department of Pharmacy, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium b Medical Laboratory, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium c Drug Stability Research Group, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium Received 1st August 2016; accepted 19 December 2016
KEYWORDS Drug stability; Spectrophotometry; pH-meter; Microscope
∗
Summary Background. — The intensive care department of the institution use drug solutions within higher concentration to avoid fluid overload. The purpose of the study is to prove the physical stability of different injectable drugs within high concentration (amiodarone 25 mg/mL, isosorbide 0.60 mg/mL, lorazepam 0.16 mg/mL, noradrenalin 0.120 and 0.240 mg/mL, salbutamol 0.06 mg/mL and sodium valproate 12 mg/mL) to ensure the patients safety. Methods. — Five of 30 or 50 mL polypropylene syringes were prepared for each solution under aseptic conditions and stored at room temperature. Immediately after the preparation (hour 0) and after 1, 4, 8, 24 and 48 hours, 2 mL of each solution were withdrawn from each syringe and placed in glass tubes to proceed to the stability test. All specimens were visually inspected in front of a black and of a white background and aliquots of each solution were centrifuged
Corresponding author. Department of Medical Laboratory, CHU Dinant Godinne, UCL Namur, avenue Therasse, 1, 5530 Yvoir, Belgium. E-mail address: [email protected] (M. Closset).
http://dx.doi.org/10.1016/j.pharma.2016.12.004 0003-4509/© 2016 Acad´ emie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
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M. Closset et al. to proceed to microscopic inspection with a ten-fold magnification. The pH of each solution was measured with glass electrode pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Switzerland) and spectrophotometric measurements (Genesys 10 series, New-York, USA) were performed at three wavelengths (350, 410 and 550 nm) to avoid the apparition of turbidity. Results. — For all the drugs included in the study, there was no significant change in pH, no color change, no turbidity or opacity and no precipitation observed in the solutions during the storage at room temperature for 48 hours. No microaggregates were detected by microscope neither revealed by a change of absorbance. Conclusion. — Within these limits, the preparations of amiodarone in 5% glucose polypropylene syringes and isosorbide, lorazepam, noradrenalin, salbutamol, valproate in 0.9% sodium chloride polypropylene syringes are physically stable at room temperature for 48 hours. These results allow us to consider a study of chemical stability by high-performance liquid chromatography (HPLC). © 2016 Acad´ emie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.
MOTS CLÉS Stabilité d’injectables ; Spectrophotométrie ; pH-mètre ; Microscope
Résumé Contexte. — Le département des soins intensifs de l’institution utilise des solutions de principes actifs en solutions concentrées afin d’éviter la surcharge hydrique des patients. Le but de cette étude est de prouver la stabilité physique d’une série de principes actifs utilisés à des concentrations élevées (amiodarone 25 mg/mL, isosorbide 0,60 mg/mL, lorazépam 0,16 mg/mL, noradrénaline 0,120 and 0,240 mg/mL, salbutamol 0,06 mg/mL et acide valproïque 12 mg/mL) afin d’assurer la sécurité des patients. Méthode. — Pour chaque solution, cinq seringues en polypropylène de 30 ou 50 mL ont été préparées dans des conditions d’asepsie et stockées à température ambiante pour une durée de 48 heures. Tout de suite près la préparation (heure 0) et après 1, 4, 8, 24 et 48 heures, 2 mL ont été prélevés de chaque solution et placés dans des tubes en verre afin de procéder au test de stabilité. Tous les échantillons ont été inspectés visuellement devant un fond noir et un fond blanc. Des aliquots de chaque solution ont été centrifugés afin de réaliser un examen microscopique à un grossissement 10 ×. Le pH de chaque solution a été mesuré au moyen d’électrodes en verre pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Suisse) et les mesures spectrophotométriques (Genesys 10 series, New York, ÉtatsUnis) ont été réalisées à trois longueurs d’ondes différentes (350, 410 et 550 nm) afin d’exclure l’apparition d’un trouble. Résultats. — Pour tous les principes actifs inclus dans l’étude, il n’y a pas eu de modification significative du pH ni de la couleur. Aucun trouble, aucune opacité ni aucune précipitation n’ont été observés dans les solutions lors du stockage à température ambiante pendant 48 heures. Aucun micro-agrégat n’a été détecté au microscope ni révélé par une modification d’absorbance. Conclusion. — Dans ces limites, les préparations d’amiodarone dans des seringues en polypropylène de glucosé 5 % et d’isosorbide, lorazépam, noradrénaline, salbutamol, acide valproïque dans des seringues en polypropylène de NaCl 0,9 % sont physiquement stables à température ambiante pour une durée de 48 heures. Ces résultats nous permettent d’envisager une étude de stabilité chimique par chromatographie liquide à haute performance (HPLC). © 2016 Acad´ emie Nationale de Pharmacie. Publi´ e par Elsevier Masson SAS. Tous droits r´ eserv´ es.
Introduction The total volume of infusion administrated to patients admitted into intensive care units is often important [1]. Fluid overload is commonly implicated in fluid resuscitation
and is associated with increased hospital costs, morbidity and mortality [2]. Sometimes fluid overload can also induce other side effects, such as hypernatremia [3]. There is a huge interest to build strategies that reduce excessive fluid infusions.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
+Model PHARMA-490; No. of Pages 4
ARTICLE IN PRESS
Physical stability of highly concentrated injectable drugs solutions One possible way to avoid such type of adverse effects is to reduce the global volume of infusion by using drugs solution within higher concentrations. The intensive care department of the institution is actually using such a way to reduce fluid overload in patients. The drugs administrated at high concentration and preliminary selected for the study are: amiodarone 25 mg/mL, isosorbide 0.60 mg/mL, lorazepam 0.16 mg/mL, noradrenalin 0.120 and 0.240 mg/mL, salbutamol 0.06 mg/mL and sodium valproate 12 mg/mL. In order to ensure patients safety [4,5], the physical stability of those injectable drugs at high concentration must be proved. This physical stability study fits into the update of the standardization of reconstitution and administration of injectable drugs in our institution [6—9].
Aims of the study The aim of this study is to determine the physical stability [10,11] of a range of concentrated injectable drugs solutions, individually prepared in polypropylene syringes and stored at room temperature.
Method Solutions preparation Five of 30 or 50 mL polypropylene syringes were prepared for each solution under aseptic conditions.
Amiodarone Fifty-millilitre syringes (Becton Dinckinson (BD), lot 1505236) were prepared containing each one 600 mg of ® amiodarone (Cordarone , Sanofi, lot AY003) diluted into 12 mL of glucose solution (Glucose 5%, Baxter, Lot 15D24G61) for a total volume of 24 mL and a final concentration of 25 mg/mL.
Isosorbide
3
lot15J13G60) for a total volume of 50 mL and a final concentration of 0.120 mg/mL and 0.240 mg/mL, respectively.
Salbutamol Fifty-millilitre syringes (BD, lot1508258) were prepared con® taining each one 3 mL of salbutamol (Ventolin , Glaxo Smith Kline, lot 3501A) diluted into 47 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J12G60) for a total volume of 50 mL and a final concentration of 0.06 mg/mL.
Valproate Fifty-millilitre syringes (BD, lot 1507241) were prepared con® taining each one 600 mg of Valproate (Valproate Sodique , Mylan, lot 080147) diluted into 44 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J13660) for a total volume of 50 mL and a final concentration of 12 mg/mL.
Storage The syringes were stored at room temperature in order to suit to the clinical conditions of administration in the intensive care unit. Immediately after the preparation (hour 0) and after 1, 4, 8, 24 and 48 hours, 2 mL of each solution were withdrawn from each syringe and placed in glass tubes to proceed to the stability test.
pH The pH of the solutions was measured at each time by a glass electrode pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Switzerland).
Spectrophotometric analyse At each time, all specimens went under spectrophotometric measurements (Genesys 10 series, New-York, USA) at three wavelengths (350, 410 and 550 nm).
Visual observation
Fifty-millilitre syringes (BD, lot 1508258) were prepared con® taining each one 30 mg of isosorbide (Cedocard , Tadeka, lot 14D10/1) diluted into 20 mL of sodium chloride solution (NaCl 0.9% 100 mL, Baxter, lot 15I22G61) for a total volume of 50 mL and a final concentration of 0.60 mg/mL.
All specimens were visually inspected at each time in front of white and black backgrounds to avoid the apparition of crystals or small particles.
Lorazepam
As well, aliquots of each solution were systematically withdrawn and then centrifuged to proceed to microscopic inspection with a ten-fold magnification.
Thirty-millilitre syringes (BD, lot 1510205) were prepared ® containing each one 4 mg of lorazepam (Temesta , Pfizer, lot 4034) diluted into 23 mL of sodium chloride solution (NaCl 0.9% 250 mL, Baxter, lot 15J13G60) for a total volume of 24 mL and a final concentration of 0.16 mg/mL.
Noradrenalin Fifty-millilitre syringes (BD, lot 1508258) were prepared containing each one 6 mg or 12 mg of noradrenalin (Noradrenaline, Aguettant, lot4301834) diluted into 44 mL or 38 mL of sodium chloride solution (NaCl 250 mL, Baxter,
Microscopic observation
Results and discussion For all the drugs included in the study, the measurements of pH at each time did not show any significant change in pH during storage (cf. Table 1). There was no color change, no turbidity or opacity and no precipitation observed in the solutions during the storage at room temperature for 48 hours.
Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004
+Model
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M. Closset et al. Table 1 Results of pH measurements and spectrophotometric analyses (mean ± SD) of highly concentrated drugs solutions over the time. Résultats des mesures de pH et des analyses spectrophotométriques (moyenne ± SD) des principes actifs en solutions concentrées au cours du temps. Spectrophotometry (x ± SD)
pH x ± SD Isosorbide 0.6 mg/mL Noradrenaline 0.12 mg/mL Noradrenaline 0.24 mg/mL Amiodarone 25 mg/mL Lorazepam 0.16 mg/mL Valproate 12 mg/mL Salbutamol 0.06 mg/mL
6.52 3.79 3.62 3.86 7.30 7.22 5.65
± ± ± ± ± ± ±
0.116 0.016 0.014 0.049 0.23 0.07 0.045
Min
Max
350 nm
6.39 3.77 3.61 3.80 7.06 7.15 5.58
6.71 3.81 3.65 3.94 7.54 7.34 5.69
0.0026 0.0028 0.0029 2.9447 0.07 0.0002 0.0034
No microaggregates were detected by microscope neither revealed by a change of absorbance. Visual compatibility was defined as the absence of particulate formation, haze, precipitation, colour change and gas evolution [12]. Various tests were performed to detect the development of particles at each level. Visual inspection in front of a black and a white background is useful to detect macroscopically particles of various colours. The microscopic inspection is important to ensure the absence of microscopically crystals that cannot be visually observed. The purpose of the spectrophotometric analysis is to detect the apparition of turbidity, which may sign the presence of a precipitate in the solution [13]. The interest of the pH measurements of the injectable drug solution remains suitable to the stability of its active principle. But there is also a clinical interest, which means that the injection has to be well tolerated by the patient. The pH of the solution must be greater than or equal to 3 and less than or equal to 9 (3 ≤ pH ≤ 9) [14].
Conclusion Within these limits, the preparations of amiodarone in 5% glucose polypropylene syringes and isosorbide, lorazepam, noradrenalin, salbutamol, valproate in 0.9% sodium chloride polypropylene syringes are physically stable at room temperature for 48 hours. For each molecule, these results allow us to consider a study of chemical stability by high-performance liquid chromatography (HPLC).
Disclosure of interest The authors declare that they have no competing interest.
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410 nm ± ± ± ± ± ± ±
0.002 0.0016 0.0009 0.0027 0.001 0.0025 0.0027
—0.001 0.0006 0.0004 0.152 0.001 —0.0009 —0.0009
550 nm ± ± ± ± ± ± ±
0.0006 0.0012 0.0006 0.668 0.0007 0.0018 0.0008
—0.0008 0.0003 —0.00003 0.0031 0.00003 —0.001 —0.0005
± ± ± ± ± ± ±
0.0007 0.0009 0.00008 0.0010 0.0001 0.0023 0.0007
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Please cite this article in press as: Closset M, et al. Physical stability of highly concentrated injectable drugs solutions used in intensive care units. Ann Pharm Fr (2017), http://dx.doi.org/10.1016/j.pharma.2016.12.004