Graduation Year

2009

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Chemistry

Major Professor

Michael J. Zaworotko, Ph.D.

Co-Major Professor

Mohamed Eddaoudi, Ph.D.

Committee Member

Wayne C. Guida, Ph.D.

Committee Member

Joanna A. Bis, Ph.D.

Keywords

Supramolecular chemistry, Pharmaceutical cocrystal, Crystal form, Crystal engineering, Lamotrigine, Meloxicam

Abstract

With a greater understanding of the fundamentals of crystal engineering lays the

potential for the development of a vast array of novel materials for a plethora of

applications. Addressed herein is the latent potential of the current knowledge base with

an emphasis upon cocrystallization and the desire for scientific exploration that will lead

to the development of a future generation of novel cocrystals. The focus of this

dissertation is to expand the cocrystallization knowledge base in two directions with the

utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state

synthesis and in the development of active pharmaceutical ingredients.

Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive

moieties in such a way that the reaction occurs more quickly and in higher yield than the

typical solution methodology. The focus herein is upon cocrystal controlled solid-state

synthesis of imides where an anhydride and primary amine were the reactive moieties.

Forty-nine reactions were attempted and thirty-two resulted in successful imide

formation. In addition, the cocrystal was isolated as part of the reaction pathway in three

cases and is described in detail.

The impact of cocrystals upon active pharmaceutical ingredients is also addressed

with a focus upon generating novel crystal forms of lamotrigine and meloxicam.

Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including

three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate,

and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded

seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a

selected set of lamotrigine and meloxicam crystal forms to determine the crystal form

with the most desirable properties. Properties between crystal form and cocrystal former

were also examined.

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