Characterization of the Particle Size and Polydispersity of Dicumarol Using Solid-State NMR Spectroscopy

Abstract

A variety of particle sizes of a model compound, dicumarol, were prepared and characterized in order to investigate the correlation between particle size and solid-state NMR (SSNMR) proton spin-lattice relaxation (H T) times. Conventional laser diffraction and scanning electron microscopy were used as particle size measurement techniques and showed crystalline dicumarol samples with sizes ranging from tens of micrometers to a few micrometers. Dicumarol samples were prepared using both bottom-up and top-down particle size control approaches, via antisolvent microprecipitation and cryogrinding. It was observed that smaller particles of dicumarol generally had shorter H T times than larger ones. Additionally, cryomilled particles had the shortest H T times encountered (8 s). SSNMR H T times of all the samples were measured and showed as-received dicumarol to have a T of 1500 s, whereas the H T times of the precipitated samples ranged from 20 to 80 s, with no apparent change in the physical form of dicumarol. Physical mixtures of different sized particles were also analyzed to determine the effect of sample inhomogeneity on H T values. Mixtures of cryoground and as-received dicumarol were clearly inhomogeneous as they did not fit well to a one-component relaxation model, but could be fit much better to a two-component model with both fast-and slow-relaxing regimes. Results indicate that samples of crystalline dicumarol containing two significantly different particle size populations could be deconvoluted solely based on their differences in H T times. Relative populations of each particle size regime could also be approximated using two-component fitting models. Using NMR theory on spin diffusion as a reference, and taking into account the presence of crystal defects, a model for the correlation between the particle size of dicumarol and its H T time was proposed.

Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems

“…To put it bluntly, if the recorded T 1 ( 1 H) relaxation times of different components in a multicomponent system differ considerably, then the system is phase-separated with large domains the size of which usually exceeds 100-500 nm. On the contrary, if the recorded T 1 ( 1 H) relaxation times of these components are similar or identical, it means that the system is rather homogenous with the size of domains smaller than 10 nm [50–53]. In general, the rate of magnetization equilibration reflects the extent of phase separation in multicomponent and multiphase systems.…”

1H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR

“…Among these, SSNMR provides valuable information concerning the crystalline state from the perspective of molecular mobility, compared with other methods such as PXRD; however, running costs are high and measurements are very time consuming. [16][17][18][19] Time domain NMR (TD-NMR) is a benchtop instrument aiming at measuring 1 H NMR relaxation. Whereas analysis of precise molecular structures can be carried out with SSNMR, for example, TD-NMR can be used rapidly and easily to measure the T 1 and T 2 relaxation times of samples.…”

Reply to “Comment on ‘Chirality-Induced Electron Spin Polarization and Enantiospecific Response in Solid-State Cross-Polarization Nuclear Magnetic Resonance’”

“…These sizes are much larger than the nanoparticle radii where size-dependent NMR intensities have been reported in the literature. 11 Hence, we conclude that the size dependency can be ruled out as a potential cause of the observed L/D signal differences.…”