Kaminska E, Tarnacka M, Kaminski K, Ngai K L, Paluch M
Department of Pharmacognosy and Phytochemistry, Medical University of Silesia in Katowice, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland.
Institute of Physics, University of Silesia, ul. Uniwersytecka 4, 40-007 Katowice, Poland; Silesian Center of Education and Interdisciplinary Research, University of Silesia, ul. 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland.
Eur J Pharm Biopharm. 2015 Nov;97(Pt A):185-91. doi: 10.1016/j.ejpb.2015.09.010. Epub 2015 Sep 30.
Some molecular glass-formers can crystallize in the glassy state, some of which are van der Waals molecules and some are pharmaceuticals. The molecular mechanism responsible for this glass-to-crystal mode of crystallization is of interest to the glass transition research community as well as to the pharmaceutical industry because the effect is detrimental to stability of amorphous form of the drugs stored below the glass transition temperature. Two prominent models have been proposed for the molecular mechanism. In the homogeneous nucleation-based crystallization model, the molecular mechanism is the secondary relaxation, and the other model assumes that the molecular process responsible for crystal growth in the glassy state is from the local molecular motions. Crystal growth requires motion of the entire molecule, and in the glassy state the only such local molecular motion is engendered by the secondary relaxation of the Johari-Goldstein (JG) kind. While the JG secondary relaxation is the crux in the two models of glass-to-crystal growth, it has not been found in the glassy state of the pharmaceuticals studied so far. The examples include 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), indomethacin (IMC) and nifedipine (NIF). In the absence of any evidence of the JG secondary relaxation, the conundrum is that the two models of glass-to-crystal growth cannot be validated. It turns out these pharmaceuticals all have structural α-relaxations with narrow frequency dispersion. Empirically, glass-formers with narrow α-dispersion have JG secondary relaxation with weak relaxation strength, not well separated from the α-relaxation, and hence cannot be resolved. Theoretically, the narrow width of the α-dispersion is due to weak intermolecular coupling. In this article we enhance the intermolecular coupling of NIF by mixing with octaacetylmaltose to enhance the intermolecular coupling of NIF. In this way we have successfully resolved the JG secondary relaxation in the dielectric loss spectra of the NIF component in the glassy state, and validated the two models of glass-to-crystal growth.
一些分子玻璃形成体能够在玻璃态下结晶，其中一些是范德华分子，还有一些是药物。这种玻璃态到晶体态的结晶分子机制引起了玻璃化转变研究领域以及制药行业的兴趣，因为这种效应不利于储存于玻璃化转变温度以下的药物无定形形式的稳定性。针对该分子机制，已经提出了两种主要模型。在基于均相成核的结晶模型中，分子机制是次级弛豫，另一种模型则假定在玻璃态下负责晶体生长的分子过程源于局域分子运动。晶体生长需要整个分子的移动，而在玻璃态下，唯一的这种局域分子运动是由乔哈里 - 戈尔茨坦（JG）型次级弛豫产生的。虽然JG次级弛豫是玻璃态到晶体生长的两种模型的关键所在，但在目前所研究的药物玻璃态中尚未发现。这些例子包括5 - 甲基 - 2 - [(2 - 硝基苯基)氨基] - 3 - 噻吩甲腈（ROY）、吲哚美辛（IMC）和硝苯地平（NIF）。在没有任何JG次级弛豫证据的情况下，难题在于玻璃态到晶体生长的两种模型无法得到验证。结果表明，这些药物都具有频率色散较窄的结构α - 弛豫。根据经验，α - 色散较窄的玻璃形成体具有弛豫强度较弱的JG次级弛豫，与α - 弛豫没有很好地分离，因此无法分辨。从理论上讲，α - 色散较窄是由于分子间耦合较弱。在本文中，我们通过与八乙酰麦芽糖混合来增强硝苯地平的分子间耦合。通过这种方式，我们成功地在玻璃态下硝苯地平组分的介电损耗谱中分辨出了JG次级弛豫，并验证了玻璃态到晶体生长的两种模型。
