Preparation of transparent injectable formulation for lipid A analog E5531.
We developed a "pH-jump method" to obtain transparent solutions of E5531, a synthetic lipid A analog, at neutral pH for pharmaceutical injection. E5531 has two pKa: pKa1 = 6.0 and pKa2 = 9.3. At pH 11.0, E5531 was dispersed as a dissociated form, and the phase transition temperature Tc of E5531 was determined to be 30 degrees C using differential scanning calorimetry (DSC). Based on these results, the pH-jump method procedure involves dispersing E5531 at pH 11.0 (above pKa2) at 50 degrees C (above Tc) and mixing with a phosphate buffer to neutralize the pH. No degradated products of E5531 were observed at 50 degrees C for 3 hr during dispersing in the alkaline solution. The turbidity of samples prepared with the pH-jump method was similar to that of water and superior to the samples dispersed directly in neutral pH. This method does not need mechanical power and is suitable for large-scale production.
Asai
Y
Y
Formulation Research Laboratory, Kawashima, Eisai Company, Limited, Gifu, Japan.
Watanabe
S
S
D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007267:Injections / Q000379:methods*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry; D009391:Nephelometry and Turbidimetry; D013696:Temperature
D008050:Lipid A; C092845:E 5531