Controlling drug crystallization, polymorphism, and physicochemical properties using mechanochemistry

University Of Missouri-Columbia, Columbia MO

Investigators

Abstract

Project Summary Our research program focuses on understanding the relationship between the structure and function of organic solid-state materials. We are especially interested in understanding this relationship in the context of drug polymorphism, physicochemical properties, and crystallization mechanisms. Crystallization and structural determination are exceptionally important aspects of chemical synthesis, biochemistry, and pharmaceutics. While many compounds can be crystallized through standard techniques, some compounds such as oils, chiral compounds, and natural products are difficult to crystallize. Two additional challenges that arise when developing drug molecules include polymorphism and poor physicochemical properties (e.g., aqueous solubility). Polymorphism is the ability of a compound to exist in more than one form or crystal structure, and polymorphs often exhibit different properties. Poor aqueous solubility impacts bioavailability and causes many drugs to be rejected during discovery. Our group has taken a multifaceted approach toward addressing the structure-function relationship by using cocrystallization, mechanochemistry, and structural analysis as strategies for controlling and tuning behaviors of drug molecules. Cocrystallization involves combining at least two compounds into a unique solid phase, and the components typically interact through noncovalent bonds. Mechanochemistry is a chemical transformation that is either initiated or sustained by mechanical force, and the field has undergone a rapid re-emergence because it is a green technique and has shown promise in controlling polymorphism. Cocrystallization and mechanochemistry offer our group platforms for preparing pharmaceutical materials of interest, while interrogating how the resulting structure gives rise to drug function. Our laboratory recently developed a mechanochemical method to facilitate crystallization of beta blocker drugs that otherwise form oils when standard crystallization methods are used. We have also used cocrystallization to improve aqueous solubility of a biopharmaceutics classification system (BCS) Class II (low solubility) antibiotic while maintaining drug safety. Most recently, we demonstrated that mechanical methods can be used to reversibly interconvert pharmaceutical polymorphs. Over the next five years, our goals are to use mechanochemistry to control crystallization and polymorphism of drug molecules, elucidate mechanisms by which mechanochemistry facilitates such crystallization, and determine structural characteristics that afford enhanced physicochemical properties in BCS Class II and IV drugs. The methods outlined above will be complemented with several characterization techniques to determine how structural modification impacts drug behavior. Our long-term goal is to use the insight gained from this work to enhance our understanding of the crystallization process, develop novel strategies for synthesizing pharmaceutical solids with improved treatment efficacy, and address fundamental challenges in controlling drug polymorphism. Overall, we aim to impact the future of disease treatments by determining the role that the solid-state structure plays in drug function and efficacy.