Infrared (IR), Raman, and nuclear magnetic resonance (NMR) spectroscopic techniques were used to investigate the nature of molecular aggregation of indomethacin (I) in acetonitrile and ethanol solutions. Spectroscopic data provided no evidence for self-aggregation of I in supersaturated solutions of acetonitrile or ethanol. As the concentration of I was increased by more than 130 fold, from 5 × 10-4 to 0.067 M in acetonitrile, the diffusion coefficients of I and water (residual) measured by pulse field gradient spin echo nuclear magnetic resonance (PFGSE-NMR) showed a decrease of about 5 and 27%, respectively, while the diffusion coefficient of acetonitrile did not change. The chemical shift and Nuclear Overhauser Effect Spectroscopy data confirmed formation of hydrogen bonds between the carboxyl group of I and residual water at low concentrations of I in acetonitrile, while IR-Raman data suggest formation of weak hydrogen bonds between I and acetonitrile at higher concentrations. In contrast, the diffusion coefficients of I and ethanol decreased by up to 15% as the concentration of I in ethanol was increased from 3.6 × 10-4 to 0.3 M. This together with IR and Raman data suggest formation of strong intermolecular hydrogen bonds between I and ethanol. In summary, our data suggest that solute-solvent interactions determine the critical supersaturation at the onset of nucleation (σcr) and thereby control the preferential crystallization of I polymorphs from supersaturated solutions of acetonitrile and ethanol. Furthermore, our data highlight the importance of intermolecular interactions between solute and residual water in aprotic solvents, such as acetonitrile.