In the present study, the molecular state of drug-rich amorphous nanodroplets was evaluated using NMR techniques to reveal the mechanism underlying the crystallization inhibition of drug-rich amorphous nanodroplets by a polymer. Ibuprofen (IBP) with a low glass transition temperature was used for direct characterization of drug-rich amorphous nanodroplets. Highly supersaturated IBP formed IBP-rich amorphous nanodroplets through phase separation from aqueous solution. Increasing the concentration of hypromellose (HPMC) in the aqueous solution contributed to the inhibition of IBP crystallization and maintenance of supersaturation at IBP amorphous solubility. Solution 1H NMR measurements of IBP supersaturated solution containing IBP-rich amorphous nanodroplets clearly showed two kinds of 1H peaks derived from the dissolved IBP in bulk water phase and phase-separated IBP in IBP-rich amorphous nanodroplets. NMR spectral analysis indicated that HPMC did not affect the chemical environment and mobility of the dissolved IBP. However, 1H spin-spin relaxation time measurements clarified that the dissolved IBP in the bulk water phase was exchanged with the IBP-rich amorphous nanodroplets with an exchange lifetime of more than 10 ms. Moreover, the 1H peaks of HPMC partially disappeared due to the formation of IBP-rich amorphous nanodroplets, suggesting that a part of HPMC distributed into the IBP-rich amorphous nanodroplets from the bulk water phase. The incorporation of HPMC significantly changed the chemical environment of the phase-separated IBP in the IBP-rich amorphous nanodroplets and strongly suppressed molecular mobility. The resulting molecular mobility suppression effectively inhibited IBP crystallization from the IBP-rich amorphous nanodroplets. Thus, direct investigation of drug-rich amorphous nanodroplets using NMR can be a promising approach for selecting appropriate pharmaceutical excipients to suppress drug crystallization in supersaturated drug solutions.
Crystallization Hypromellose Derivatives