Dempah Kassibla Elodie, Lubach Joseph W, Munson Eric J
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.
Mol Pharm. 2017 Mar 6;14(3):856-865. doi: 10.1021/acs.molpharmaceut.6b01073. Epub 2017 Feb 15.
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.
制备并表征了模型化合物双香豆素的多种粒径，以研究粒径与固态核磁共振（SSNMR）质子自旋晶格弛豫（HT）时间之间的相关性。使用传统的激光衍射和扫描电子显微镜作为粒径测量技术，结果显示结晶双香豆素样品的粒径范围从几十微米到几微米。通过反溶剂微沉淀和冷冻研磨，采用自下而上和自上而下的粒径控制方法制备了双香豆素样品。观察到，一般来说，较小的双香豆素颗粒的HT时间比较大的颗粒短。此外，冷冻研磨颗粒的HT时间最短（8秒）。测量了所有样品的SSNMR HT时间，结果显示，收到的双香豆素的T为1500秒，而沉淀样品的HT时间在20到80秒之间，双香豆素的物理形态没有明显变化。还分析了不同粒径颗粒的物理混合物，以确定样品不均匀性对HT值的影响。冷冻研磨的双香豆素和收到的双香豆素的混合物明显不均匀，因为它们不太符合单组分弛豫模型，但可以更好地拟合具有快速和慢速弛豫机制的双组分模型。结果表明，仅根据结晶双香豆素样品中两种粒径明显不同的群体在HT时间上的差异，就可以对其进行去卷积。每个粒径范围的相对群体也可以使用双组分拟合模型进行近似。以自旋扩散的核磁共振理论为参考，并考虑到晶体缺陷的存在，提出了双香豆素粒径与其HT时间之间的相关性模型。
