Physical and chemical properties of boronic acids: Formulation implications

The research described in this dissertation was undertaken in order to better understand the formulation relevant properties of boronic acids. Many boronic acid containing molecules are currently under investigation as possible therapeutics. An increase in the knowledge of the physical and chemical properties of these compounds will lead to their improved formulation into usable dosage forms.; The aqueous solubility of a model boronic acid, 4-methoxybenzeneboronic acid (4-MBBA), alone and in the presence of mannitol was investigated as a function of pH. These studies revealed a decrease of the intrinsic solubility and of the apparent pKa value when 4-MBBA was in the presence of mannitol. The lowered intrinsic solubility was determined to be caused by the formation of a boronic acid ester with mannitol. This caused an increase in size and crystal strength relative to the free boronic acid species.; The lower observed pKa value of the boronic acid esters was studied further. Several techniques were used to describe the binding of model boronic acids with polyols. Several hypotheses for the increased binding of larger linear polyols over smaller linear polyols were tested. In general the boronic acid ester has a pKa value 3.0-3.5 units lower than its parent boronic acid. The boronic acid esters rapidly hydrolyze to yield the parent boronic acid in dilute aqueous solution.; The formation and characterization of the 4-MBBA anhydride, called a boroxine, was also described. The implications of forming a boroxine on the dissolution characteristics of boronic acids were also discussed. The dissolution rate of the boroxine was only slightly decreased compared to the dissolution rate of the monomer. The rapid hydrolysis of the boroxine in aqueous solution to yield the monomer is one likely explanation for this behavior.