Physical emulsion stability of mixtures of propofol

and remifentanil hydrochloride

Niklas Nilsson
PhD-candidate, Clinical Pharmacist
Dept. of Pharmacy, University of Oslo
Hospital Pharmacy of Oslo

Supervisors:
Prof. Ingunn Tho
Dr. Katerina Nezvalova-Henriksen
(Clinical Pharmacist)
 Background
Propofol (general anaesteticum) Remifentanil hydrochloride (opioid analgesic)

Mixed in plastic syringe shown to

be chemically stable for 36 h (22-
24 ºC)
Stewart et al., Anesth. Analg. 2000; 90:1450-451
Objective
Assess and compare the physical emulsion stability of
propofol formulations when mixed with remifentanil
hydrochloride (Ultiva®)

Three propofol formulations with different type and amount

of excipients (Diprivan®, Propofol-Lipuro®, Propolipid®)

Physical stability was assessed according to USP <729>, i.e.

percentage of fat with droplet size larger than 5 µm (PFAT5)

USP <729> Globule Size Distribution in Injectable Emulsions

Propofol formulation composition
An early sign of emulsion destabilization is an increase in
droplet size in the large diameter tail of the size distribution

Small capillaries has a

diameter of around 5 µm
< 0.05%
Propofol (o/w) Remifentanil (NaCl 9 mg/mL)
• 10 mg/ml • 50 µg/ml
• 20 mg/ml
Mixing ratio (remifentanil+propofol)
• 10+1
• 20+1
• 1+1
• 1+20

Analysis after mixing

• 0h
• 4h
Mixed solution
(n=3)
Assessment methods
• Droplet charge
• pH
• Zeta potential

• Droplet size (DLS)

• Mean droplet diameter (MDD)
• Polydispersity index (PDI)

• Number of droplet > 5 µm (light obscuration)

• PFAT5 < 0.05%
USP <729> Globule Size Distribution in Injectable Emulsions
 Results - PFAT5 < 0.05%
0h 4h
10+1 10+1
Remifentanil + 20+1 20+1
Propofol 10 mg/ml C 1+1 I 1+1
1+20 1+20
PFAT5
10+1
10+1 20+1 0.945
Remifentanil + 1+1 10+1
20+1 1+20
20+1
Propofol 20 mg/ml I 1+1 I
1+1
1+20 1+20

C = compatible, I = incompatible, mixing ratio: R+P (v/v)

Conclusion
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

Differences were observed between the

propofol formulations, but could not be
related to the lipid phase alone

These results is also alerting when it comes to

co-administration of propofol and remifentanil
in the same i.v. line
 To mix or not to mix
-
that is the question

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