Document Type


Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In


First Advisor

Flanagan, Douglas R.

First Committee Member

MacGillivray, Leonard R.

Second Committee Member

Wurster, Dale Eric

Third Committee Member

Donovan, Maureen D.

Fourth Committee Member

Zhang, Geoff G.Z.

Fifth Committee Member

Stevens, Lewis L.


Cocrystals have two or more neutral components (drug and cocrystal former) in the same crystal lattice which are held together via non-covalent bonds. Since the presence of the cocrystal former alters the energy of the drug molecules and their physicochemical properties, the drug dissolution characteristics can be manipulated by cocrystallization. A diffusion-convection-reaction (DCR) model has been developed to predict cocrystal intrinsic dissolution rates from the rotating disk system. In this work, the DCR model was used to further analyze the dissolution characteristics of 1:1 and 2:1 cocrystals. The effects of diffusion, convection and complexation kinetics and equilibrium were evaluated. In addition, the sublimation properties of cocrystals were also studied in order to evaluate the importance of solute-solute and solute-solvent interactions during solid dissolution.

In the first study, the phase-solubility study was performed for the acetaminophen(ACE)-2,4-pyridinedicarboxylic acid(PDA) and thymol(THY)2-4,4’-dipyridyl(DP) cocrystals. The aqueous dissolution rates of cocrystals ACE-PDA, THY2-DP, acetaminophen(ACE)-theophylline(THP) and theophylline(THP)-salicylic acid(SA) and their individual components were measured at various disk rotation speeds. The DCR model could predict their dissolution rates and the convection effect with proper model parameters. Moreover, the dissolution rate was predicted to be proportional to the apparent solubility (Sapp), emphasizing solubility as the dominant factor in a cocrystal’s reactive dissolution even with possible variation in reaction kinetics.

In the second study, cocrystal dissolution was further analyzed by the DCR model for unionized 1:1 AB and 2:1 A2B cocrystals. For model analysis purpose, the model parameters were varied by several orders of magnitude to describe the dependencies of cocrystal dissolution more accurately. The congruent dissolution behavior can be predicted if all dissociated species are equally diffusive. If all diffusing species have the same diffusion coefficient (D), the cocrystal dissolution rate is independent of the complexation equilibrium and proportional to Sapp or D0.66, as expected. Otherwise, it is dependent upon the complexation equilibrium and all diffusivities. The dissociation kinetics appeared to not affect cocrystal dissolution rates, but it can affect the maintenance of reaction equilibrium in the diffusion layer.

The third study focused on the ACE-PDA cocrystal dissolution into various media. Its dissolution rates in 0.05 M NaCl and 0.5 M pH 3.5 phosphate buffer showed that the presence of ions can affect diffusivities of cocrystal components. In pH 1.8-7 media, the cocrystal dissolved faster with higher medium pH or more concentrated buffer solutions, due to more PDA ionized at solid surface. The DCR model predicted the dissolution rate with adjusted diffusion coefficients. It also simulated that the medium effect on cocrystal dissolution rate arose from the change in apparent solubility.

In the fourth study, the dissolution and sublimation characteristics of two thymol cocrystals (THY2-DP and thymol(THY)2-1,2-di(4-pyridyl)ethylene (BPE)) were evaluated and compared with their individual components. The sublimation rate was taken as the rate of weight loss at constant temperature. It was found that both cocrystals were less soluble than their components but they sublimed faster than the cocrystal formers and more slowly than thymol. This indicates that after forming cocrystals, the escaping tendency of thymol was reduced while that of cocrystal formers were increased. But during dissolution, the solute-solvent interaction also plays a role. Water may interact with cocrystal formers more than with the cocrystal complexes, enhancing the dissolution.


xiii, 175 pages


Includes bibliographical references (pages 171-175).


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