Preparation of Transparent Injectable Formulation for Lipid A Analog E5531

Abstract

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 pK_a:pKK_al= 6.0 and pK_a2 = 9.3. At pH 11.0, E5531 was dispersed as a dissociated form, and the phase transition temperature T_c of E5531 was determined to be 30°C using differential scanning calorimetry (DSC). Based on these results, the pH-jump method procedure involves dispersing E5531 at pH 11.0 (above pK_a2) at 50°C (above T_c) and mixing with a phosphate buffer to neutralize the pH. No degradated products of E5531 were observed at 50°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.

Key Words:

• Aggregates
• Dispersing
• Lipid A
• pH
• Turbidity