Characterization of the Particle Size and Polydispersity of Dicumarol Using Solid-State NMR Spectroscopy.
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 (1H T1) 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 shorter1H T1times than larger ones. Additionally, cryomilled particles had the shortest1H T1times encountered (8 s). SSNMR1H T1times of all the samples were measured and showed as-received dicumarol to have a T1of 1500 s, whereas the1H T1times 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 on1H T1values. 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 in1H T1times. 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 its1H T1time was proposed.
Department of Pharmaceutical Chemistry, University of Kansas , 2095 Constant Drive, Lawrence, Kansas 66047, United States.|Department of Pharmaceutical Sciences, University of Kentucky , 789 South Limestone, Lexington, Kentucky 40509, United States.
Kassibla Elodie
0000-0002-5204-9290
KE
Dempah
Department of Small Molecules Pharmaceutical Sciences, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Joseph W
0000-0002-5806-0204
JW
Lubach
Department of Pharmaceutical Sciences, University of Kentucky , 789 South Limestone, Lexington, Kentucky 40509, United States.
Eric J
EJ
Munson
D011232:Chemical Precipitation; D001728:Dicumarol / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008855:Microscopy, Electron, Scanning / Q000379:methods; D010316:Particle Size; D011522:Protons
D011522:Protons; D001728:Dicumarol
1H T1 time; cryogrinding; milling; particle size; relaxation; solid-state NMR; spin diffusion; stability