Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland.
Institute of Physics, University of Silesia, 75 Pulku Piechoty 1a, 41-500 Chorzow, Poland.
Mol Pharm. 2020 Mar 2;17(3):990-1000. doi: 10.1021/acs.molpharmaceut.9b01244. Epub 2020 Feb 6.
In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature (), reveal the presence of two secondary relaxations (β, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (β) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, ), as well as annealing at two temperatures in the vicinity of and further heating up to , showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (Tominaka, S.; Kawakami, K.; Fukushima, M.; Miyazaki, A.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-T Temperature 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.), who demonstrated that the sub- annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.
本文应用宽带介电谱（BDS）研究了降脂活性药物成分（API）吉非罗齐（GEM）及其氘代（dGEM）和甲基化（metGEM）衍生物的分子动力学和结晶动力学，这些衍生物具有不同类型和强度的分子间相互作用。此外，还进行了量热和红外测量，分别对所研究样品的热特性和 GEM 中氢键模式的变化进行了表征。我们发现，所有被检测化合物的介电谱，在玻璃化转变温度（Tg）以下收集，揭示了存在两个二级松弛（β、γ）。根据耦合模型（CM）的预测，假设较慢的过程（β）是 JG 型，而较快的过程（γ）具有分子内起源。有趣的是，在应用两种途径后进行的广泛结晶动力学测量，即标准程序（冷却并随后加热到适当温度），以及在和附近的两个温度下退火并进一步加热到，表明退火增加了天然 API 的结晶速率，而样品的热历史对这两个 GEM 衍生物的结晶过程速度没有显著影响。对退火过程中α-过程的介电强度（Δε）的分析，以及傅里叶变换红外光谱（FTIR）测量的结果表明，GEM 分子之间形成的二聚体结构内的重排是导致观察到的行为的原因。重要的是，我们的结果与 Tominaka 等人的结果不同（Tominaka，S.；Kawakami，K.；Fukushima，M.；Miyazaki，A.。基于亚温度下氢键重排的药物玻璃物理稳定化 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.），他们证明了能够形成广泛超分子氢键的利托那韦（RTV）的亚-退火可以保护这种活性物质免受结晶。因此，基于这些相互矛盾的报告，可以假设在玻璃化转变温度附近退火后，形成氢键结构的材料，其结构不同，可能表现不同。
