School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China.
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, China.
J Pharm Biomed Anal. 2018 May 30;154:198-206. doi: 10.1016/j.jpba.2018.03.006. Epub 2018 Mar 8.
In this study, a new cocrystal of felodipine (Fel) and glutaric acid (Glu) with a high dissolution rate was developed using the solvent ultrasonic method. The prepared cocrystal was characterized using X-ray powder diffraction, differential scanning calorimetry, thermogravimetric (TG) analysis, and infrared (IR) spectroscopy. To provide basic information about the optimization of pharmaceutical preparations of Fel-based cocrystals, this work investigated the thermal decomposition kinetics of the Fel-Glu cocrystal through non-isothermal thermogravimetry. Density functional theory (DFT) simulations were also performed on the Fel monomer and the trimolecular cocrystal compound for exploring the mechanisms underlying hydrogen bonding formation and thermal decomposition. Combined results of IR spectroscopy and DFT simulation verified that the Fel-Glu cocrystal formed via the NH⋯OC and CO⋯HO hydrogen bonds between Fel and Glu at the ratio of 1:2. The TG/derivative TG curves indicated that the thermal decomposition of the Fel-Glu cocrystal underwent a two-step process. The apparent activation energy (E) and pre-exponential factor (A) of the thermal decomposition for the first stage were 84.90 kJ mol and 7.03 × 10 min, respectively. The mechanism underlying thermal decomposition possibly involved nucleation and growth, with the integral mechanism function G(α) of α. DFT calculation revealed that the hydrogen bonding between Fel and Glu weakened the terminal methoxyl, methyl, and ethyl groups in the Fel molecule. As a result, these groups were lost along with the Glu molecule in the first thermal decomposition. In conclusion, the formed cocrystal exhibited different thermal decomposition kinetics and showed different E, A, and shelf life from the intact active pharmaceutical ingredient.
在这项研究中，使用溶剂超声法开发了一种具有高溶解速率的新型非洛地平（Fel）和戊二酸（Glu）共晶。使用 X 射线粉末衍射、差示扫描量热法、热重（TG）分析和红外（IR）光谱对制备的共晶进行了表征。为了提供基于 Fel 的共晶药物制剂优化的基本信息，通过非等温热重法研究了 Fel-Glu 共晶的热分解动力学。还对 Fel 单体和三聚体共晶化合物进行了密度泛函理论（DFT）模拟，以探索氢键形成和热分解的机制。IR 光谱和 DFT 模拟的综合结果验证了 Fel-Glu 共晶是通过 Fel 和 Glu 之间的 NH⋯OC 和 CO⋯HO 氢键以 1:2 的比例形成的。TG/导数 TG 曲线表明，Fel-Glu 共晶的热分解经历了两步过程。第一阶段的热分解表观活化能（E）和指前因子（A）分别为 84.90 kJ/mol 和 7.03×10 min。热分解的可能机制涉及成核和生长，其中积分机制函数 G(α)为 α。DFT 计算表明，Fel 和 Glu 之间的氢键削弱了 Fel 分子中的末端甲氧基、甲基和乙基基团。结果，这些基团与 Glu 分子一起在第一次热分解中丢失。总之，形成的共晶表现出不同的热分解动力学，与完整的活性药物成分相比具有不同的 E、A 和保质期。
