Ricarte Ralm G, Lodge Timothy P, Hillmyer Marc A
Department of Chemical Engineering and Materials Science and ‡Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455-0431, United States.
Mol Pharm. 2015 Mar 2;12(3):983-90. doi: 10.1021/mp500682x. Epub 2015 Feb 20.
We explored the use of transmission electron microscopy (TEM) to evaluate the crystallinity of griseofulvin (GF)/hydroxypropyl methylcellulose acetate succinate (HPMCAS) solid dispersions. TEM, which provides both real-space images and electron diffraction patterns, was used to unambiguously identify GF crystals in spray dried GF. Using TEM, we were also able to detect GF crystals in a physical mixture of spray dried GF particles and spray dried HPMCAS particles with an overall crystallinity of ∼3 vol %, below the practical lower limit of detection for laboratory-scale wide-angle X-ray scattering (WAXS). Using TEM and WAXS, we did not find crystals in GF/HPMCAS solid dispersions with GF loadings of 5, 10, and 50 wt %. However, we detected GF crystals in annealed 5 wt % GF solid dispersion using TEM, whereas we did not detect crystals using in situ WAXS and modulated differential scanning calorimetry, thereby establishing the superior crystal detection sensitivity of TEM. We also performed TEM analysis of the in situ growth of GF crystals in a TEM sample of 50 wt % GF solid dispersion. Based on this study, TEM has significant potential for characterizing even small degrees of crystallinity in solid dispersions.
我们探索了使用透射电子显微镜（TEM）来评估灰黄霉素（GF）/醋酸羟丙基甲基纤维素琥珀酸酯（HPMCAS）固体分散体的结晶度。TEM既能提供实空间图像又能提供电子衍射图谱，用于明确鉴定喷雾干燥的GF中的GF晶体。使用TEM，我们还能够在喷雾干燥的GF颗粒和喷雾干燥的HPMCAS颗粒的物理混合物中检测到GF晶体，其总体结晶度约为3体积％，低于实验室规模广角X射线散射（WAXS）的实际检测下限。使用TEM和WAXS，我们在GF含量为5、10和50 wt％的GF/HPMCAS固体分散体中未发现晶体。然而，我们使用TEM在退火的5 wt％GF固体分散体中检测到了GF晶体，而使用原位WAXS和调制差示扫描量热法未检测到晶体，从而确立了TEM卓越的晶体检测灵敏度。我们还对50 wt％GF固体分散体的TEM样品中GF晶体的原位生长进行了TEM分析。基于这项研究，TEM在表征固体分散体中即使很小程度的结晶度方面具有巨大潜力。
