Table I: Compound solubility in Labrasol and the concentration upon dilution with simulated intestine fluid.
Compounds A and B were soluble in Labrasol at 29.6 and 34 mg/mL, respectively (see Table I). However, both compounds precipitated
out of the Labrasol formulations significantly when the Labrasol neat formulations were diluted in aqueous media. For example,
73% of Compound A precipitated out when the Labrasol formulation was diluted in SIF under the tested condition. The compound
concentration upon dilution decreased to 224.5 μg/mL at the loading of 833 μg/mL of Compound A (see Figure 1). The results
indicated that Labrasol could keep only 27% of Compound A soluble in the medium.
Figure 1: Compound A concentration upon dilution of Labrasol formulations with simulated intestine fluid (n = 3). (all figures
are courtesy of the authors)
In sharp contrast, after the addition of Pluronic F127 into the Labrasol formulation (Pluronic F127:Labrasol = 1:5, w/w),
more than 64% of compound A remained solubilized upon dilution. Compound concentration upon dilution reached 537.1 μg/mL,
compared with 1 μg/mL without any excipients. This increased concentration prompted by Pluronic F127 and Labrasol was much
higher than that resulting from Pluronic F127 (101.1 μg/mL) or Labrasol (224.5 μg/mL) alone. The increase was also statistically
significantly higher than the sum of the compound concentrations in the individual and Pluronic formulations (p < 0.001). The results suggested that a combination of Pluronic F127 and Labrasol resulted in a synergistic effect on inhibiting
compound precipitation under the tested conditions.
Figure 2: Compound B concentration upon dilution of Labrasol formulations with simulated intestine fluid (n = 3).
This synergistic effect was also demonstrated with Compound B. When Labrasol neat formulation was diluted with SIF, 88.5%
of Compound B precipitated despite a good compound solubility (i.e., 34 mg/mL) in Labrasol neat formulation. Similar to the
findings observed in the Compound A study, the addition of Pluronic F127 into the Labrasol formulation achieved a concentration
of 224.11 μg/mL in SIF, which was significantly higher than concentrations in Labrasol (i.e., 57.7 μg/mL) or Pluronic F127
(0.73 μg/mL) alone, and higher than the sum of the individual compound concentrations in Labrasol and Pluronic formulations
(p < 0.001) (see Figure 2).
Figure 3: The inhibitory effect of Pluronic 127 on precipitation of compound A in Labrasol–polyethylene glycol (PEG) 400 formulations
(n = 3).
In addition to Labrasol, the authors investigated whether Pluronic F127 inhibited drug precipitation out of the formulations
containing PEG 400 or NMP. Compound A had good solubility in PEG 400 (i.e., 53.8 mg/mL). However, most of the compound precipitated
quickly out of the PEG 400 formulation upon dilution in SIF. Interestingly, unlike the results with Labrasol, the addition
of Pluronic F127 into the Compound A–PEG 400 formulation only inhibited precipitation to a limited extent compared with the
PEG control (see Figure 3). Compound A's concentration upon dilution with the Pluronic F127–PEG 400 combination was 27.0 μg/mL.
The concentration was significantly higher than that in the PEG 400 formulation (i.e., 4.1 μg/mL), but lower than that in
the Pluronic F127 formulation (i.e., 101.1 μg/mL). The result suggested an absence of inhibitory synergy between Pluronic
F127 and PEG 400. Similarly, no synergistic inhibition effect on the precipitation of Compound B was observed when Pluronic
F127 was combined with the NMP formulation. Almost all compounds precipitated in all formulations (see Figure 4).
Figure 4: The inhibitory effect of Pluronic 127 on precipitation of compound A in Labrasol–1-methyl-2-pyrrolidinone (NMP)
formulations (n = 3).
To understand the inhibitory mechanism of Pluronic F127 in the Labrasol formulation, the micropolarity of the Labrasol formulation
with or without Pluronic F127 was characterized by the ratio of band I to band III (i.e., I333/I338) in a vibrational emission spectrum of pyrene. As shown in Table II, the I333/I338 value of the Pluronic F127–Labrasol mixture was significantly lower than that of Pluronic F127 or Labrasol alone (p < 0.02).