Success in delivering high quality preclinical candidates with properties amenable to development requires a strong understanding of the interconnectivity between critical attributes such as potency, pharmacokinetics, and physicochemical properties. Elucidation of structure-property relationships can lead to the identification of compounds with improved molecular properties such as solubility, permeability, and stability which can then translate to desirable bioperformance and the probability of progressing these compounds toward clinical development. This talk will cover a diverse set of case studies that link physicochemical properties with bioperformance for oral and inhaled small molecules. The first case study will summarize the design of molecules with a balance of optimal properties resulting in decreased half-life and increased solubility in biorelevant media to improve the oral bioperformance and drive down the projected human dose. This reduction in dose was critical to increase the feasibility of achieving the desired product profile which required a fixed dose combination with a second active pharmaceutical ingredient. Modifications of physical properties can also influence the ability to deliver a compound via a targeted route of administration. In the second case study, key physical attributes including phase and particle size will be discussed to achieve the desired bioperformance for inhaled delivery. Finally, when chemical modifications are no longer an option and drug delivery strategies need to be leveraged to achieve the desired pharmacokinetic profile, a fundamental understanding of the physical properties of the compound can inform on a robust drug delivery strategy. In the final case study, combining a highly soluble salt with polymers proved to be a viable formulation approach to prolong supersaturation in the stomach and enable the optimal pharmacokinetic profile <i>in vivo</i> where rapid onset of action was desired. Overall, understanding the link between potency, bioperformance, and physical properties is required to influence the selection of high quality preclinical candidates with pharmaceutical properties amenable to development.

Want to improve your (bio)performance? Take a closer look at the physical properties

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.