Spontaneous Crystalline-to-Amorphous Phase Transformation of Organic or Medicinal Compounds in the Presence of Porous Media

Date of Completion

January 2011

Keywords

Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

Many new drug candidates have low aqueous solubilities, which presents challenges to effective delivery and can compromise product performance such as bioavailability. Amorphization, or crystalline-to-amorphous phase transformation, of drug molecules in the presence of a mesoporous material is a promising approach. Crystalline compounds became amorphous spontaneously when physically mixed with mesoporous materials. The pathway of phase transformation was via the vapor state, i.e., sublimation of the crystalline compound, followed by adsorption on the surface of porous media. In order to successfully apply this unique phenomenon to commercial uses, a better understanding of the underlying mechanisms of vapor-phase mediated amorphization is necessary. ^ Thermodynamics of spontaneous amorphization was rigorously evaluated, using mesoporous silicon dioxide (SiO2) and crystalline naphthalene as a model system. The enthalpy of adsorption of naphthalene on SiO2 was more exothermic than the enthalpy of naphthalene vapor-solid condensation. This exothermic net enthalpy was the driving force responsible for the spontaneous phase transformation. Similar amorphization was observed for compounds with a wide range of melting points, vapor pressures and structures.^ The properties of both the porous media and crystalline adsorbates on amorphization were evaluated. The amorphization capacity of naphthalene was found to be a function of the degree of surface curvature, i.e., the smaller the pore diameter and the higher the degree of surface curvature, the greater the amorphization capacity. As a consequence, amorphization appeared to be facilitated through capillary condensation. The amorphization capacity was enhanced by the silanol groups on the surface of porous materials.^ Moisture was found to have a significant effect on the capacity of amorphization. Moisture suppressed the capacity of amorphization, and induced recrystallization of previously amorphized drug through competitive interaction. That same competitive interaction resulted in improved solubility when the amorphous formulations were dispersed in an aqueous medium. Furthermore, SiO2 was found by analysis of adsorption enthalpies to possibly react with water vapor, changing its surface chemistry. This effect will require further analysis.^ In conclusion, mesoporous materials have a unique functionality in amorphous formulation. Our improved understanding of the phase transformation mechanism will facilitate the use of amorphous drug delivery systems to translate potential therapeutic molecules into drug products to treat patients. ^

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