Functional ionic liquids for use in pharmaceutical applications

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For years, the pharmaceutical industry has relied heavily on crystalline active pharmaceutical ingredients (APIs) that can be approved by the Federal Drug Administration (FDA) as neutral compounds, salts, or solvates of said neutral compounds and salts. Yet, the solid crystalline form can have unexpected and unfavorable effects on properties such as solubility, bioavailability, efficacy, etc., due to different polymorphic forms of the API. A drug can be present in multiple forms and interconvert between forms during isolation, manufacturing, storage, and transport of the end product. These unwelcome problems could be alleviated or even eliminated by the formation of a liquid drug, which possesses no crystal structure. Unfortunately, research in this area has been limited to solubilization of solid drugs into various drug delivery vehicles such as emulsions, suspensions, and liposomes. However, it is possible for a drug to crystallize from these vehicles during the manufacturing, storage, and transportation. Thus, a new method to liquefy pharmaceuticals, thereby reducing problems associated with the solid-state, is needed. A potential solution is the use of ionic liquids (IL), defined as salts that melt below 100 °C. Since ILs are salts it is possible to combine a pharmaceutical ion with any desired counter ion, thereby, providing a level of tunablity that is not possible with current techniques. This IL modular strategy was the basis for the research discussed here, in which APIs with known problems were combined with GRAS (generally regarded as safe) compounds or FDA-approved APIs, which resulted in ILs displaying dual biological functionality. This strategy was successful in producing a wide range of ILs, all containing at least one pharmaceutically active ion. The physical property set for these synthesized ILs was varied, as it is difficult to predict how two ionic organic compounds will interact. However, common trends regarding melting point depression, thermal stability, and solubility were determined. The most exciting results were exhibited during the biological testing, as several of the synthesized ILs demonstrated improved biological activity over the precursor ions. Additionally, the drug mechanism, at a cellular level, was found to be modified when contained within an IL. This indicates that ILs behavior differently in the body than simple halide containing salts. Overall, the obtained results signify that ILs can serve as pharmaceuticals, in which these liquid salts eliminate problems associated with the solid-state and displayed to synergistic physical and biological properties.

Electronic Thesis or Dissertation
Chemistry, Pharmaceutical