Influence of additives on phase transformations in highly supersaturated solutions of poorly water-soluble drug compounds
Abstract
Formulation of poorly water-soluble drugs is a challenging problem encountered during the drug development process. To improve drug delivery, the amorphous form of a poorly water-soluble drug compound is often used to generate supersaturated solutions. The supersaturated solutions generated from the dissolution of amorphous solids may lead to an increase in absorption compared to that of a saturated solution if supersaturation can be maintained for a physiologically-relevant type period. . The phase behavior of supersaturated solutions is complex and poorly understood, with the formation of drug colloidal aggregates often being reported. Little is known about the mechanism by which colloidal aggregates are produced from supersaturated solutions, although it has been suggested that they are important to the bioavailability enhancement often seen with amorphous solid dispersions. However, in order to maintain supersaturation, crystallization must be prevented and so the presence of an effective crystallization inhibitor in solution is desirable to prolong supersaturation. Maintaining supersaturation by using polymeric additives depends on their ability to inhibit nucleation and crystal growth. Although the inhibition of crystallization from aqueous supersaturated solutions by polymeric additives has been extensively documented, there is very little mechanistic understanding of the underlying factors that affect the ability of polymeric additives to inhibit nucleation and crystal growth for a given drug compound. The insights into that mechanism of colloidal aggregate formation has important implications for understanding the phase behavior of amorphous solid dispersions upon dissolution as well as the delivery of compounds with low aqueous solubility. The elucidation of the key polymer properties important for crystallization inhibition of chemically and structurally different drug molecules will provide important insights about how polymers inhibit the crystallization of molecular crystals, and help to guide the development of new excipients with superior crystallization inhibitory properties.
Degree
Ph.D.
Advisors
Taylor, Purdue University.
Subject Area
Chemical engineering|Pharmacy sciences
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