Master of Engineering Science
Chemical and Biochemical Engineering
Approximately 75% of new molecular entities approved by the Food and Drug Administration (FDA) for use in the pharmaceutical industry are found to have poor aqueous solubility. This undesirable attribute leads to consequences such as higher doses required to reach therapeutic levels, greater vulnerability to food effects, lesser fraction absorbed in the small intestine and damage to the environment due to increased quantity of excretion. The addition of an excipient (i.e. a FDA approved inactive ingredient) to the molecular structure of an active pharmaceutical ingredient (API) through intermolecular bonding is of growing interest because the properties of the API can be tuned without further clinical testing. Crystal engineering utilizes the knowledge of intermolecular interactions to design new solids with improved properties (e.g. solubility, stability, bioavailability, dissolution rates). In this thesis, these techniques are applied to increase the solubility of three APIs with low solubility: esomeprazole magnesium, curcumin and rufinamide. Through an intense screening process, novel solid states were discovered including a water/butanol solvate of esomeprazole magnesium and a co-amorphous mixture comprised of curcumin and folic acid dihydrate. The co-amorphous mixture was found to have increased dissolution rate compared to curcumin and can be repositioned as a prenatal drug. Characterization of these products include powder and single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier Transform infrared spectroscopy, solution nuclear magnetic resonance spectroscopy and dynamic vapour sorption. Screening of rufinamide did not lead to the discovery of any new forms, but the refined molecular structure of the metastable form is reported.
Skieneh, Jenna M., "Crystal Engineering of Active Pharmaceutical Ingredients with Low Aqueous Solubility and Bioavailability" (2017). Electronic Thesis and Dissertation Repository. 4708.