Document Type


Date of Degree

Spring 2015

Access Restrictions

Access restricted until 07/13/2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Douglas R. Flanagan


The objective of this study is to investigate cocrystal solubility and dissolution behavior to elucidate the factors affecting these processes in various media. Six cocrystals with xanthines (theophylline (THP), caffeine (CAF) and theobromine (THB)) were prepared and characterized by powder X-ray diffraction and thermal methods. Two cocrystals (CAFCA I and THBSA) are new solids and their crystal structures were determined by single crystal X-ray diffraction.

Cocrystal solubility behavior depended on the dissolving complex solubility and its dissociation behavior in solution. Two THP cocrystals - one with acetaminophen (ACE) and one with citric acid (CA) created different degrees of free THP supersaturation in solubility and dissolution studies. High transient THP supersaturation caused almost immediate THP hydrate crystallization from THPCAH and led to non-congruent solubility behavior. Such behavior was not observed with the ACETHP because free THP supersaturation was not sufficient to induce rapid crystallization but did so over longer equilibration times.

Three salicylic acid (SA) cocrystals with xanthines (THP, CAF, and THB) were prepared; two (THPSA and CAFSA) had low aqueous solubility compared to their pure components and one (THBSA) had higher solubility. Both cocrystal components in these cocrystals produced higher solubility/dissolution rates in alkaline media due to ionization. Also, at higher pH, THB precipitated from THBSA solutions because of higher THB supersaturation under alkaline conditions.

Caffeine (CAF) and theophylline (THP) both form cocrystals with citric acid (CA) which is a highly water-soluble cocrystal former. Both CAFCA Form I and II solubility and dissolution behavior were studied. THPCAH exhibited non-congruent dissolution because of rapid precipitation of THP hydrate on the dissolving cocrystal surface. CAFCA exhibited congruent dissolution because it did not produce sufficient supersaturation to precipitate CAF hydrate during dissolution. CA cocrystals also have the unusual behavior of high viscosities produced in the dissolution boundary layer due to CA’s high solubility. These viscosities alter diffusion coefficients which reduce dissolution rates from that expected based purely on solubility.

To further understand cocrystal dissolution, a diffusion-convection-reaction (DCR) model was developed to predict cocrystal dissolution rates in various media. This model predicted concentration profiles of all species (complex, free components and reactive species) in the diffusion layer of a rotating disk intrinsic dissolution system. Predicted dissolution rates had varying degrees of agreement with experimental data depending on the cocrystal model and the medium into which the cocrystal dissolved.


Cocrystal, Complex, Dissociation, Dissolution Behavior, Modeling, Solubility


xxv, 251 pages


Includes bibliographical references.


Copyright © 2015 Hong-Guann Lee

Available for download on Saturday, July 13, 2019