applyparastyle “fig//caption/p[1]” parastyle “FigCapt” PRACTICE RESEARCH REPORT Long-term stability of ready-to-use 1-mg/mL midazolam solution Downloaded from https://academic.oup.com/ajhp/article-abstract/77/9/681/5821086 by Biblioteca Nacional de Salud y Seguridad social user on 09 July 2020 Sixtine Gilliot (PharmD student), Groupe de Recherche sur les formes Purpose. Midazolam is a benzodiazepine derivative commonly used in Injectables et les Technologies Associées (GRITA), Centre Hospitalier Universitaire intensive care units to control sedation. Its use requires dilution of a 5-mg/ de Lille, ULR 7365, Lille, France mL commercial solution to a target concentration of 1 mg/mL. A study Morgane Masse, PharmD, Groupe was conducted to evaluate the stability of diluted ready-to-use 1-mg/mL de Recherche sur les formes Injectables midazolam solutions over 365 days when stored in cyclic olefin copolymer et les Technologies Associées (GRITA), vials or polypropylene syringes. Centre Hospitalier Universitaire de Lille, ULR 7365, Lille, France Methods. A specific stability-indicating high-performance liquid chroma- Frédéric Feutry, PharmD, Service of Pharmacy, Centre Oscar Lambret, Lille, tography coupled with UV detection method was developed for midazolam France hydrochloride and validated for selectivity, linearity, sensitivity, precision, Christine Barthélémy, PharmD, and accuracy. Three storage conditions were tested: –20°C ± 5°C, 5°C Groupe de Recherche sur les formes ± 3°C, and 25°C ± 2°C at 60% ± 5% relative humidity. Half of the vials Injectables et les Technologies Associées (GRITA), Centre Hospitalier Universitaire were stored upside down to test for the absence of interaction between de Lille, ULR 7365, Lille, France midazolam and the stopper. Particle contamination, sterility, and pH were Bertrand Décaudin, PharmD, Groupe assessed. de Recherche sur les formes Injectables et les Technologies Associées (GRITA), Results. The limit of stability was set at 90% of the initial concentration. Centre Hospitalier Universitaire de Lille, After 1 year’s storage at –20°C and 5°C, concentrations remained su perior ULR 7365, Lille, France to 90% under all storage conditions. At 25°C, stability was maintained Stéphanie Genay, PharmD, Groupe de Recherche sur les formes Injectables up to day 90 in syringes (mean [SD], 92.71% [1.43%]) and to day 180 in et les Technologies Associées (GRITA), upright and upside-down vials (92.12% [0.15%] and 91.57% [0.15%], re- Centre Hospitalier Universitaire de Lille, spectively). No degradation products were apparent, no variations in pH ULR 7365, Lille, France values were detected, and containers retained their sterility and conformity Pascal Odou, PharmD, Groupe de Recherche sur les formes Injectables with regard to any specific contamination during the study. et les Technologies Associées (GRITA), Centre Hospitalier Universitaire de Lille, Conclusion. The evaluated 1-mg/mL midazolam solution was stable ULR 7365, Lille, France over a 1-year period when stored at a refrigerated (5°C) or frozen (–20°C) temperature in both vials and syringes; with storage at 25°C, the stability duration was lower. The preparation of ready-to-use midazolam solutions by a hospital pharmacy is compatible with clinical practice and could help to decrease risks inherent in dilution in care units. Keywords: infusion, liquid chromatography, midazolam, stability- indicating method Am J Health-Syst Pharm. 2020;77:681-689 idazolam is a benzodiazepine be used without any preparation step Mderivative commonly used in in- for bolus injection. When administered tensive care units (ICUs) to control se- by continuous infusion, a 1-mg/mL dation. It is prescribed in preoperative midazolam solution can be prepared anesthesia for its intensive sedative and by mixing the contents of 5-mL vials or Address correspondence to Dr. Masse hypnotic action and administered intra- by diluting a 50 mg/10 mL commercial ([email protected]). venously by bolus or continuous infu- midazolam solution with 0.9% sodium Twitter: @MorganeMasse sion, depending on routines adopted in chloride injection in 50-mL polypro- ICUs. In France, injectable midazolam pylene (PP) syringes. The latter method © American Society of Health-System solutions are available at a concentra- is cheaper and is recommended in Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals. tion of 1 mg/mL packaged in 5-mL vials ICUs. Medication errors resulting from [email protected]. or a concentration of 5 mg/mL in 1-, 3-, manual preparation of injectable solu- DOI 10.1093/ajhp/zxaa040 or 10-mL vials. These presentations can tions are numerous. Multiple dilutions AM J HEALTH-SYST PHARM | VOLUME 77 | NUMBER 9 | MAY 1, 2020 681 PRACTICE RESEARCH REPORT STABILITY OF MIDAZOLAM SOLUTIONS by nurses several times a day can result The concentration of diazepam was in dilution errors, solvent errors, and KEY POINTS determined so that its peak was equiva- sterility disruption.1-4 These problems lent to that of the midrange midazolam • The stability of ready-to-use may compromise care safety and lead 1-mg/mL midazolam solution calibration (7.5 µg/mL). Downloaded from https://academic.oup.com/ajhp/article-abstract/77/9/681/5821086 by Biblioteca Nacional de Salud y Seguridad social user on 09 July 2020 to severe adverse effects,5-7 especially in depends on the storage tem- Solutions used for stability tests ICUs because of the weakness of criti- perature and type of container. were prepared at ambient temperature cally ill patients.8,9 Standardization of by diluting commercial midazolam so- • With storage at ambient preparations to remedy the lack of in- lution with 0.9% sodium chloride injec- temperature, the beyond-use dustrial products at the appropriate tion to reach a concentration of 1 mg/mL. interval for 1-mg/mL midazolam dosage would decrease the risks in- 150 PP syringes were filled manually, solution compounded in volved in the dilution step. and 300 COC vials were automatically polypropylene (PP) syringes (ie, To our knowledge there are no filled to the appropriate volume using 90 days after preparation) was published data on the stability of di- an automated filling stationl con- shorter than that for solution luted midazolam preparations (1 mg/ nected to a peristaltic pump.m Dilution kept in cyclic olefin copolymer mL) stored in PP syringes or in cyclic of stock solutions with 0.9% sodium (COC) vials (180 days). olefin copolymer (COC) vials; there chloride injection (from 1 mg/mL to are some published data for injectable • The stability of ready-to-use 10 µg/mL) was required for the dosage midazolam stored in PP syringes at 2-, 1-mg/mL midazolam solution method. 3-, and 5-mg/mL concentrations.10-12 was maintained in both PP syr- One hundred fifty COC vials were Several methods to analyze midazo- inges and COC vials for 365 stored upside down to guarantee con- lam in biological samples have been days with storage at –20°C or tact between the stopper and the so- developed.13-19 5°C. lution to determine the impact of the The study described here aimed to stopper on the stability of the prepara- evaluate the long-term stability of di- tion. The other vials were stored upright. luted, ready-to-use, 1-mg/mL mida- According to the nature of the mol- zolam solutions over 365 days in 2 ecule and respecting SFPC/GERPAC storage containers: PP syringes and ready-to-fill and meet the required and International Council for Harmo- COC vials. criteria for pharmaceutical primary nization (ICH) guidelines,24 3 storage containers. The filling process was con- conditions were tested for each of the 3 Materials and methods ducted in the same way as described by container types (syringes, upright vials, Products. Midazolama commer- Feutry et al.22 and upside-down vials) over 365 days: cial solution was compounded with Solution preparations. Quality –20°C ± 5°C, 5°C ± 3°C, and 25°C ± 2°C excipients such as water for injection, controls were prepared by dissolving at 60% ± 5% relative humidity (RH). 0.9% sodium chloride injection, hydro- midazolam standard reference (10 mg) Each syringe or vial was used for only chloric acid, and sodium hydroxide to in 10-mL graduated flasks with abso- 1 analysis. adjust the pH value to 3.3. Ultrapure lute ethanol to obtain 1-mg/mL pri- Chromatographic apparatus water (UPW)b and sterile 0.9% sodium mary stock solutions. and conditions. Measurements were chloride injectionc were used to obtain Midazolam solution for forced deg- made using an ultrafast liquid chro- clinical concentrations. A midazolam radation (10 µg/mL) was prepared from matographic (UFLC) systemn coupled standard referenced used for the val- a 1:100 dilution of an aliquot from the with a UV detector and equipped with idation step was of analytical grade. stock solution (1 mg/mL) with UPW a columno maintained at 25°C. The Diazepame was chosen as an internal and was submitted to high temperature. wavelength was optimized between standard (IS), and 20 mM acetate Another degradation midazolam 220 and 254 nm25 and was finally set at buffer,f trichloroacetic acid,g and solution (40 µg/mL) was prepared by 235 nm to obtain the best sensitivity. acetonitrileh were used for the mobile diluting with UPW and then subjected The mobile phase, consisting of (A) 20 phase; absolute ethanoli was used to to variations in pH and oxidative con- mM acetate buffer/trichloroacetic acid, dissolve midazolam and diazepam. ditions according to guidelines jointly with pH adjusted to 3.00, and (B) ace- Syringes were 50-mL PP luer-taper issued by the French Society of Clinical tonitrile was run at 65:35 vol/vol, with syringesj; vials were 50-mL AT-Closed Pharmacy (SFPC) and the Group of isocratic elution (0.2 mL/min).