Abstract For several decades nanoparticle formulations of molecules used for diagnostics and/or therapy have been intensively developed to improve and control their bioavailability and pharmacokinetics. This is particularly important for the large number of new drugs developed that have poor solubility in water. A common form of such formulations consists of small molecules of an active pharmaceutical ingredient (API) encapsulated in a polymer nanoparticle carrier. Despite the advantages of this type of nanoparticle formulation for many materials, there is a lack of predictive quantitative models for determining the optimum method, processing conditions and excipients needed to effectively encapsulate a given API. Instead, much of the development and optimization are based on qualitative and/or trial-and-error methods. This proposal aims to address this by a systematic study of the encapsulation efficiency of small molecules into polymer nanoparticles using the method of flash nanoprecipitation. This simple method, in which a solution is rapidly mixed with a second, miscible solvent in which the API has poor solubility, yields nanoparticle dispersions with sizes in the range of 10’s to 100’s of nanometers. It has several advantages, including ease of scaleup, the possibility of incorporating multiple components into single particles, and the ability to use the processing conditions to kinetically trap molecules that might otherwise not be encapsulated. We propose to develop a general model for predicting the encapsulation efficiency of a given molecule into a polymer nanoparticle based on the molecular properties of the API, polymer, and solvents and as a function of the processing conditions such as concentration, mixing rates and temperature. Our model will be based on both thermodynamics (partitioning of the molecules into the polymer phase due to non-specific van der Waals interactions) and kinetics (trapping of molecules in the polymer due to the glass transition), as well as the interplay between the two. The model will be tested using a range of molecules, polymers, and solvents by measuring encapsulation efficiencies and effects of the small molecule on the particle size and morphology. A second aim will be to apply this model to the development of various potentially useful systems. Finally, we will use this project as an opportunity train undergraduate students in highly multidisciplinary research, exposing students with backgrounds in physics to applications in biomedicine and giving biology or biochemistry students experience in fundamental materials characterization.