Constant pH precipitation of aluminum hydroxide adjuvant: I. Effect of precipitation conditions. II. Effect of hydrothermal treatment
Abstract
Aluminum-containing adjuvants are the only adjuvant approved by Food and Drug Administration for use in human vaccines, due to their long history of safe use and low cost. However, aluminum-containing adjuvants have been reported to be difficult to manufacture reproducibly because of the difficulty of achieving batch uniformity, in terms of pH and salt concentration, during precipitation process. The goal of this study was to produce aluminum hydroxide adjuvant with prolonged stability and consistent physicochemical properties by constant pH precipitation. Effect of precipitation conditions was investigated and stabilization studies were performed on the aluminum hydroxide adjuvants. In order to study the effect of precipitation conditions on aluminum hydroxide during constant pH precipitation, thirteen precipitates were produced at different temperatures, sodium chloride concentrations and OH/Al molar ratios and were characterized by x-ray powder diffraction, ammonium oxalate selective dissolution, protein adsorptive isotherm and transmission electron microscopy. The results showed that temperature, sodium chloride concentration and OH/Al molar ratio had significant effects on the physicochemical properties and polymorphic forms of the aluminum hydroxide precipitates. A reproducibility study showed that the constant pH precipitation was able to produce uniform aluminum hydroxide adjuvant with consistent physicochemical properties. The aluminum hydroxide adjuvants produced by constant pH precipitation were not stable as crystalline aluminum hydroxide formed during aging. Thus, stabilizing aluminum hydroxide adjuvant by addition of salt was tried. The results showed that addition of 3 M of sodium chloride or sodium acetate stabilized the aluminum hydroxide adjuvant, but this level of salt was too high to be applied in vaccine formation. Next, hydrothermal treatment was tried to stabilize the aluminum hydroxide adjuvant. It was found that hydrothermal treatment at 80°C did not stabilize the aluminum hydroxide adjuvant. On the other hand, the aluminum hydroxide adjuvants hydrothermally treated at 110°C or above were stable for 12 weeks. In summary, constant pH precipitation produced aluminum hydroxide adjuvant with consistent properties. Applying hydrothermal treatment at 110°C for 4 hours was recommended to stabilize the aluminum hydroxide adjuvant.
Degree
Ph.D.
Advisors
Hem, Purdue University.
Subject Area
Pharmaceuticals|Chemistry
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