Physicochemical properties and structural aspects of aluminum-containing adjuvants: I. Constant pH precipitation; II. Stability; and III. Effect of autoclaving

Lana Sharie Burrell, Purdue University

Abstract

The only adjuvants approved by the Food and Drug Administration for use in human vaccines are aluminum-containing adjuvants. These adjuvants have a long history of safe and effective use. Despite this, aluminum-containing adjuvants have been described as being difficult to manufacture with reproducible physiochemical properties. The purpose of this research was to study the precipitation process of aluminum phosphate adjuvants. The constant pH precipitation process and the physicochemical properties of aluminum phosphate adjuvants produced by this method were examined. The stability of aluminum-containing adjuvants upon aging at room temperature and the effect of autoclaving were also examined. In an attempt to produce a more consistent adjuvant, aluminum phosphate adjuvants were produced by a constant pH precipitation process at intervals of 0.5 pH units from pH 3.0 to 7.5. The aluminum phosphate adjuvants were characterized by the following techniques: X-ray diffraction, true density, acid reactivity, infrared, Raman and NMR spectroscopy. Results of this study indicate that the properties of aluminum phosphate adjuvants are influenced by the pH of precipitation, thus suggesting that the current batch method of aluminum phosphate adjuvant production results in a heterogeneous mixture. Reproducibility studies indicate that the constant pH precipitation method minimizes batch to batch variations. The pH of adjuvants produced by the batch method was unstable. However, the pH of adjuvants produced by the constant pH precipitation method was stable. The stability of aluminum-containing adjuvants was monitored for 15 months at room temperature. The results of this study indicate that the particle size of the solid phase increases with aging, which results in a decreased protein adsorptive capacity. The polymerization of particles, via the formation of double hydroxide bridges, is believed to be the cause of this increase in particle size. Autoclaving adjuvants also cause an increase particle size. The protein adsorptive capacity of both the aluminum hydroxide and aluminum phosphate adjuvants decreased after autoclaving. X-ray diffraction, viscosity changes, acid reactivity, and pH changes all support the hypothesis that polymerization reactions are occurring during autoclaving resulting in a larger particle size.

Degree

Ph.D.

Advisors

Hem, Purdue University.

Subject Area

Pharmaceuticals

COinS