The effect of concentration, reconstitution solution and pH on the stability of a remifentanil hydrochloride and propofol admixture for simultaneous co-infusion.
BACKGROUND
There are scenarios where pre-mixing and infusing analgesic and anaesthetic agents as a single intravenous (IV) solution is highly desirable; however, it is important to ensure the agents are compatible when mixed. As such, the long-term stability of a remifentanil-propofol mixture, and means of improving this, were assessed across a range of remifentanil concentrations, diluents, and time points.


METHODS
Remifentanil was reconstituted with ultrapure water, 0.9% saline, 20% saline, or 8.4% sodium bicarbonate solution (the latter two chosen for their pH characteristics, rather than their use in pharmaceutical reconstitution) and then mixed with propofol (1%) or further diluted with water to derive concentrations of 10-50 μg mL- 1. Remifentanil and propofol concentrations were determined initially and then periodically for up to 24 h using high performance liquid chromatography (HPLC). Mass spectrometry (MS) was used to detect degradation products in solutions containing 30 μg mL- 1 of remifentanil. Statistical analysis was performed using ANOVA and Student's t-test, with a significance value of 0.05.


RESULTS
Isolated remifentanil (pH < 4) and propofol (pH 7.35) did not degrade significantly when reconstituted with water or saline solution over 24 h, while remifentanil reconstituted with sodium bicarbonate degraded significantly (P < 0.001, pH 8.65). Mixing with propofol substantially increased the pH of the mixture and resulted in significant remifentanil degradation for all reconstitution solutions used, while propofol remained stable (pH 6.50). The amount of degradation product detected in samples containing isolated remifentanil and a mixture of the drugs was proportional to the remifentanil degradation observed.


CONCLUSIONS
Remifentanil stability is affected by both the reconstitution solution used and when mixed with propofol, with pH appearing to be a contributing factor to degradation. If the pH of the solution and concentration of remifentanil are correctly controlled, e.g. through the use of a more acidic diluent, an admixture of remifentanil and propofol may be useful clinically.
['Henkel|Emily|E|0000-0002-7320-1378', 'Vella|Rebecca|R|', 'Behan|Kieran|K|', 'Austin|David|D|', 'Kruger|Peter|P|', 'Fenning|Andrew|A|']
D000701:Analgesics, Opioid D018686:Anesthetics, Intravenous D004305:Dose-Response Relationship, Drug D004338:Drug Combinations D004339:Drug Compounding D004355:Drug Stability D006801:Humans D006863:Hydrogen-Ion Concentration D015742:Propofol D000077208:Remifentanil D000077330:Saline Solution D017693:Sodium Bicarbonate D014867:Water
Remifentanil Propofol HPLC Chemical stability Drug-drug interaction(s) Pharmaceutical preparations