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theses

To maximize the pharmacological effect of a pain reliever such as ibuprofen, early onset of action is critical. Unfortunately, the acidic nature of ibuprofen minimizes the amount of drug that can be solubilized in the stomach and would be available for immediate absorption upon entry into the intestine. Although the sodium salt of ibuprofen has high aqueous solubility, rapid conversion from the salt to the poorly soluble free acid phase occurs under gastric conditions. In order to prolong the solubility enhancement initially afforded by the salt, the impact of polymers on ibuprofen supersaturation was evaluated in vitro and in vivo, with a focus on establishing a mechanistic understanding for how polymers enabled supersaturation. For this research, dissolution profiles of ibuprofen sodium in the presence of polymers were examined in order to assess degree and duration of supersaturation. In addition, the roles that polymers played in altering drug solubility, pKa, physical form, particle morphology, solution speciation, and media viscosity were probed. Finally in vivo studies were conducted in order to understand the influence of supersaturation on pharmacokinetic parameters. Supersaturation of ibuprofen was effectively prolonged in the presence of a variety of polymers. This was the first example of work that demonstrated prolonged supersaturation when combining a salt form of a drug with a polymeric precipitation inhibitor in the absence of surfactant. Characterization during dissolution demonstrated that mechanism of supersaturation was dependent on specific drug-polymer interactions. In situ formation of stabilized amorphous colloids enabled supersaturation in the presence of PVP-VA64. Intermolecular hydrogen bonding was driving supersaturation in the presence of HPMC by inhibiting nucleation and altering crystal growth. Alternatively, increased media viscosity effectively prolonged supersaturation of ibuprofen when combined with MC. In vitro supersaturation observed with these ibuprofen-polymer formulations translated to an increase in Cmax and an earlier Tmax for the PVP-VA64, MC, and HPC formulations relative to ibuprofen only controls when administered orally to rats. Based on these observations, combining ibuprofen sodium with polymers is a viable formulation approach to prolong supersaturation in the stomach and enable an optimized pharmacokinetic profile in vivo where rapid onset of action is desired.

ETD_5356

doi:10.7282/T3930RHR

Ph.D.

Includes bibliographical references

by Jenna Leschek Terebetski

ETD doctoral

The author owns the copyright to this work.