Understanding crystallization tendency of organic molecules from the undercooled melt and glassy state

Jared A Baird, Purdue University

Abstract

Formulating a drug compound in the amorphous state is increasingly being applied as a formulation strategy to improve the oral bioavailability of pharmaceutical compounds exhibiting low aqueous solubility. Cooling the material from the melt state (e.g. melt extrusion) is a common method used to trap a material in the amorphous state; however, solidification of the active pharmaceutical ingredient (API) during cooling can result in the formation of a crystalline phase, an amorphous solid, or some combination thereof. Thus, understanding the inherent crystallization tendency of the API from the undercooled melt state is an important criterion to assess a drug compound's suitability for an amorphous formulation. Current knowledge of the inherent crystallization tendency of organic molecules upon cooling from the undercooled melt (glass-forming ability or GFA) and the relationship between this and the long term physical stability of any resultant glass (glass stability or GS) is marginal at best. Furthermore, there is a current knowledge gap in understanding why certain polymeric additives are very effective at disrupting crystallization from both the undercooled melt and glassy solid, while others are relatively ineffective. This research aims to bridge this knowledge gap by investigating the critical molecular properties governing the crystallization tendency of organic molecules, and how these properties influence the ability of polymeric additives to alter their crystallization behavior. It is hypothesized that for organic molecules cooled from the undercooled melt state: · The crystallization tendency of a compound is inherently dependent on its molecular structure (i.e. molecular weight (MW), # of rotatable bonds, etc.), and that this intrinsic crystallization ability will impact a polymer's ability to alter crystallization behavior. · There is a relationship between the glass-forming ability of a compound from the undercooled melt state and its resultant glass stability, and low glass stability of certain compounds is due in large part to the presence of quenched-in nuclei. To test these working hypotheses, the crystallization tendency from the undercooled melt state was evaluated for a large number of compounds (∼ 50) using calorimetric techniques. The relationship between the physio-chemical properties of the compounds and their crystallization tendency was evaluated using multivariate analysis in an effort to establish a model to predict the crystallization tendency of new chemical entities a priori. The presence of quenched-in nuclei for compounds was assessed using a prototype rapid heat/cool differential scanning calorimeter. Finally, the crystallization tendency of compounds formulated as solid dispersions was investigated, and the relationship between the ability of polymers to alter crystallization behavior and the inherent crystallization tendency of the compound was probed.

Degree

Ph.D.

Advisors

Taylor, Purdue University.

Subject Area

Physical chemistry|Pharmaceutical sciences

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