Physical emulsion stability of mixtures of propofol and remifentanil hydrochloride

Propofol, a general anaesthetic, and remifentanil, an opioid analgesic, are used to induce and/or maintain sedation, and they are often used together. It has been shown that from a chemical point of view a mixture of 50 µg/ml remifentanil with 10 mg/ml propofol was stable for 36 h (22-24 ºC) when mixed in plastic syringes, but only for 3 h when mixed in PVC bags [1]. Propofol is formulated as an oil-in-water, and droplet stability is vital for parenteral emulsions to avoid undesirable consequences, e.g. catheter obstruction and embolism. Droplets that reach a diameter of 5 μm or more have an increased tendency to become entrapped in small capillaries. According to USP <729> the percentage of fat residing in globules larger than 5 µm (PFAT5) should not exceed 0.05% for injectable emulsions [2].

The objective of this study was to assess and compare the physical emulsion stability of the three propofol formulations Propolipid^®, Propofol-Lipuro^® and Diprivan^®(10 mg/ml and 20 mg/ml) when mixed with remifentanil hydrochloride (Ultiva^®) 50 µg/ml. The three propofol formulations differed in the type and amount of excipients.

Remifentanil (R) was reconstituted in 9 mg/ml sodium chloride to a final concentration of 50 µg/ml and mixed with each of the propofol (P) formulations, respectively. Mixing ratios (R:P) were 20+1, 10+1, 1+1 and 1+20. Mixing was done in 50 ml sterile, particle free polypropylene centrifuge tubes at room temperature (n=3). Emulsion stability was assessed by measuring pH, mean droplet diameter (MDD), polydispersity index (PI) and calculating PFAT5. Analyses was conducted on unmixed propofol, mixed samples immediately upon mixing and mixed samples stored for 4 hours at room temperature.

Differences in stability between the propofol formulations were identified by elevated PFAT5-values 4 hours after mixing. In mixing ratios where remifentanil was in abundance (10+1 and 20+1), all of the propofol formulations resulted in PFAT5 > 0.05%. No difference in mean droplet diameter and PI was noticed. The first signs of droplet growth appears in the large diameter tail of the size distribution, and a considerable amount of large droplets will have to be formed before it can be recognized as an increased MDD. The pH of the reconstituted remifentanil solution was 3.5, whereas all propofol formulations were around 7.5, and the pH-value of the mixt reflected the ratio of R:P.

Development of larger droplets after 4 hours contact time suggests that premixing propofol and remifentanil, e.g.in syringes or admixtures, should be avoided as it affects the stability of the emulsion.

[1] Stewart JT, Warren FW, Maddox FC, Viswanathan K, Fox JL, The stability of remifentanil hydrochloride and propofol mixtures in polypropylene syringes and polyvinylchloride bags at 22-24 C, Anesth. Analg. 2000 ; 90:1450-451
[2] Driscoll DF, Globule-size distribution in injectable 20% lipid emulsions : Compliance with USP requirements, Am. J. Health. Syst. Pharm. 2007 ; 64 : 2032-2036

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