By: Laura I. Mosquera-Giraldo and Lynne S. Taylor
Imagine spending billions of dollars in the discovery of a new drug, and then realizing that it is impractical to administer it orally because it cannot reach the systemic circulation and achieve a therapeutic effect. This is the case for many emerging drugs that are insoluble in water, and it poses a challenge, because drugs must be firstly dissolved in order to be absorbed and reach their site of action.
In 2010, it was estimated that between 70% and 90% of novel drug candidates have solubility problems. Many of these drugs are even less soluble than sand or marble, which certainly gives you an idea about their extremely low solubility.
As pharmaceutical scientists, we explore different approaches that can help us to improve drug solubility and create an effective formulation. In Dr. Taylor’s lab, we use amorphous materials to tackle this problem. Amorphous solids lack long-range 3D order, allowing for improved solubility at the expense of a lower stability. The lower stability arises because molecules tend to reorder into crystalline structures, which then reduces solubility. Therefore, polymers are typically used to stabilize the amorphous state by hindering the rearrangement of drug molecules.
Interestingly, despite the fact that amorphous solid dispersions (ASDs) are a promising strategy to improve drug solubility, there are only a limited number of commercial formulations. This is mainly explained by concerns about the stability of the amorphous state and the poor understanding about how polymers inhibit crystallization from solution and from the solid state. In fact, this translates to an empirically driven process of polymer selection. As a consequence, the creation of new polymers is warranted to allow a mechanistic perspective of structural and chemical features needed to generate effective materials, and more importantly to increase the number of ASD products in the market.
My Ph.D. project intends to contribute to the understanding of polymer-drug interactions, to help in the design of more effective polymers that can be used for amorphous solid dispersions. To achieve this goal, in collaboration with Dr. Kevin Edgar’s group at Virginia Tech, we work on the design of novel polymers with greater chemical group diversity to establish which chemical substituents generate the most effective materials. In collaboration with Dr. Lyudmila Slipchenko’s group at Purdue University, we also use computational modeling to estimate the tendency of the polymer to self-interact versus the propensity to interact with the drug molecules. Then, we draw parallels between the crystallization inhibition results and the modeling analysis to better understand these systems at a fundamental level.
The AAPS Foundation Graduate Student Fellowship has been vital for the development of this project. It has allowed me to focus on developing essential skills to execute our research plan and to explore new methodologies, both experimental and computational, in order to obtain a more extensive perspective about the structural and chemical characteristics important in the creation of effective polymeric materials.