Molecular Mobility Suppression of Ibuprofen-Rich Amorphous Nanodroplets by HPMC Revealed by NMR Relaxometry and Its Significance with Respect to Crystallization Inhibition

Abstract

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.

Effect of Polymer Species on Maximum Aqueous Phase Supersaturation Revealed by Quantitative Nuclear Magnetic Resonance Spectroscopy

“…Since the broadening of peaks arising from dissolved IBP was not observed for saturated solutions containing polymer (Figure 2), the broadening cannot be attributed to increases in solution viscosity caused by dissolved polymer. Instead, and consistent with previous reports, 29,37 the dissolved drug peaks are likely broadened due to drug exchange between the aqueous phase and the drug-rich phase. The spin−spin relaxation rate of dissolved components can be increased owing to lifetime line broadening and chemical exchange contributions, resulting in peak broadening.…”

“…Thus, two sets of IBP peaks, arising from IBP that is molecularly dissolved in the aqueous phase and IBP present in the IBP-rich phase, are observed in the 1 H NMR spectra, as noted previously. 29,30 The IBP peaks in the IBP-rich phase can be observed upfield from those arising from IBP in the aqueous phase (peaks from IBP-rich phase are represented by an asterisk in Figure 3). In solutions containing polymer, the drug peaks in the IBPrich phase were broadened and shifted downfield compared with the corresponding drug-rich phase peaks when polymer was absent.…”

“…38,39 Indeed, a previous study demonstrated that the spin−spin relaxation rate of dissolved IBP significantly increased due to the presence of the IBP-rich phase. 29 The peak shape of the exchanging nucleus between two different sites is determined by the chemical shift differences (Δω) and exchange rate constant (k ex ). 39 As k ex approaches Δω, individual peaks are broadened.…”

“…The amount of dissolved drug can be directly measured from the drug peak areas observed in the solution NMR spectrum since the dissolved drug peaks are observed separately from peaks arising from phase-separated drug, reflecting differences in their chemical environments. 29 Furthermore, the molecular state of the drug in the drug-rich phase can be directly investigated by solution NMR spectroscopy for drugs with sufficiently low glass-transition temperatures (T g s). This is because drugs with low T g s exist as highmobility supercooled liquids at the analysis temperature.…”

Interaction of Polymers with Enzalutamide Nanodroplets—Impact on Droplet Properties and Induction Times

“…Such reductions in amorphous solubility by polymer mixing with the drug-rich nanodroplet have been observed previously for some systems. 57,58 We note from Figure 5 that mixing of the polymers with the drug-rich nanodroplet does indeed reduce the drug amorphous solubility. However, there was no difference in the extent of reduction between the two polymers.…”