Collaborative Research: How do biopolymers dissolve? Identification of rate-limiting steps as a framework to design polymers with tailored dissolution.

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Non-technical abstractPolymers are very long chains of molecules and are widely used in products ranging from paint to ice-cream. Nature provides an abundance of biopolymers such as cellulose and starch which are typically benign and can degrade to water and carbon dioxide in the environment. They can be chemically modified to produce, for example, broadly useful cellulose derivatives that are widely employed by society, including in medicines. Getting a medicine into the body by swallowing a tablet is becoming increasingly difficult because few modern drugs easily dissolve in water. It is important that a drug can be dissolved from a tablet in the right region of the digestive system so that it can be absorbed and exert its therapeutic effects on the body. Biopolymers can be used to help improve drug solubility and release. However, because new generations of drugs are increasingly difficult to absorb, it is important to understand more about how polymers dissolve and release their cargo, and how to chemically modify these polymers to make them even more effective at delivering drugs and other poorly soluble additives. This research investigates how polymers interact with water, and how this in turn impacts the rate of polymer dissolution. Polymers will be mixed with water-hating additives (many drugs can be described as water-hating), revealing how this changes dissolution. Finally, new biopolymer derivatives will be designed that maintain a good interaction with water, even in the presence of water-hating additives. The goal is to develop polymers that are more effective than existing polymers at releasing poorly water-soluble drugs (and other additives). Broad impacts of this work include training graduate and undergraduate students including under-represented minorities and women, including developing a professional skills program for graduate students. Technical abstractPolymer dissolution is both fundamentally and practically important. It differs significantly from small molecule dissolution and is often problematic. Key issues include slow or poorly controlled dissolution, and undesired gelation. Systems that also contain small molecule additives are common, for example amorphous solid dispersions (ASDs) for enhancement of aqueous solubility of hydrophobic additives. In these systems, mismatch of additive and polymer dissolution rates can lead to system failure (e.g. additive precipitation). Fundamental understanding of how additives impact polymer dissolution is lacking. Herein, we propose to elucidate the impact of additives on the rate limiting steps of biopolymer dissolution, in particular for polysaccharide (PS) derivatives, whose benign nature and potential for modification make them well suited for polymer/additive systems of technical importance. A set of novel PS derivatives will be designed and synthesized to test key hypotheses about the importance of hydration extent, as well as the impacts of specific functional groups upon dissolution rate. Selective PS oxidation and halogenation will permit substitution with omega-amino and omega-mercaptocarboxylic acids. PS dissolution rates will be measured in the presence and absence of model additives; tests of impact of ionization, counterion size/nature, and steric hindrance will reveal whether hydration rate/extent is the key rate limiting step. By elucidating polymer structural features necessary for release, the goal is to develop new oral delivery systems for poorly water-soluble compounds. Students will collaborate to elucidate rate-limiting steps in polymer dissolution, synthesize and characterize polymers, test dissolution rates with and without carefully selected additives, and apply the generated fundamental understanding to refine theory and enhance polymer design.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.