Combination of a propofol emulsion with alpha-2 adrenergic receptor agonists used for multimodal analgesia or sedation in intensive care units: a physicochemical stability study

Marine Roche; Damien Rousseleau; Cécile Danel; Héloïse Henry; Gilles Lebuffe; Pascal Odou; Damien Lannoy; Nicolas Simon

doi:10.1136/ejhpharm-2023-004027

Combination of a propofol emulsion with alpha-2 adrenergic receptor agonists used for multimodal analgesia or sedation in intensive care units: a physicochemical stability study

Eur J Hosp Pharm. 2024 Jan 30:ejhpharm-2023-004027. doi: 10.1136/ejhpharm-2023-004027. Online ahead of print.

Authors

Marine Roche^{1

2}, Damien Rousseleau^{2

3}, Cécile Danel^{1

2}, Héloïse Henry^{1

2}, Gilles Lebuffe^{2

3}, Pascal Odou^{1

2}, Damien Lannoy^{4

2}, Nicolas Simon^{1

2}

Affiliations

¹ Pharmacy, Lille University Hospital, Lille, Nord, France.
² ULR 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille University, Lille, France.
³ Anaesthesia and Intensive Care Department, Hospital Claude Huriez, Lille University Hospital, Lille, France.
⁴ Pharmacy, Lille University Hospital, Lille, Nord, France damien.lannoy@univ-lille.fr.

PMID: 38290833
DOI: 10.1136/ejhpharm-2023-004027

Abstract

Objectives: To assess the physicochemical stability of the combination of a propofol emulsion with an alpha-2 (α2) adrenergic receptor agonist (α2A; clonidine or dexmedetomidine) under conditions mimicking routine practice in an intensive care unit or in multimodal analgesia procedures.

Methods: We developed and validated three stability-indicating methods based on high-performance liquid chromatography with ultraviolet (HPLC-UV) detection. Eight different conditions per combination were evaluated in triplicate, with variations in the simulated, bodyweight-adjusted dose level and the drugs' flow rate. The drugs were mixed in clinically relevant concentrations and proportions and then stored unprotected from light, in clear glass vials at room temperature for 96 hours. At each sampling point, we assessed the chemical stability (the HPLC-UV drug level, pH, and osmolality) and physical compatibility (visual aspect, zeta potential (ZP), mean droplet diameter (MDD, Z-average) and polydispersity index (PDI)). We validated our stability findings in positive and negative control experiments.

Results: Over the 96-hour test, the concentrations of propofol, clonidine and dexmedetomidine did not fall below 90% of the initial value, and the pH and osmolality were stable. The visual aspect of the mixed propofol emulsions did not change. The MDD remained below 500 nm (range 165-195 nm). The PDI was always below 0.4; 78.7% of the measurements were below 0.1 and 21.3% were between 0.1 and 0.4. The ZP measurements (-31.3 to -42.9 mV) suggested that the emulsion was stable. The MDD and PDI increased slightly at 96 hours under some conditions, which might indicate early destabilisation of the emulsion. Given that the MDD remained below 500 nm, these emulsions are compatible with intravenous administration.

Conclusions: Our results demonstrate the chemical and physical compatibility of propofol-α2 agonist mixtures at concentrations and in proportions representative of standard protocols when stored unprotected from light at room temperature for 96 hours.

Keywords: ANESTHESIA AND ANALGESIA; DRUG INCOMPATIBILITY; PAIN MANAGEMENT; PHARMACY SERVICE, HOSPITAL; Safety.