Therapeutic deep eutectic solvents (THEDSs) are the best exemplification of green alternative formulations of active pharmaceutical ingredients (APIs) that offer superlative properties of APIs. Previously, THEDESs of risperidone, fentanyl and levofloxacin with capric acid (CA) were developed by our group. These APIs share cyclic tertiary amine nuclei. Herein, DESs of two drugs bearing cyclic tertiary amine nucleus, namely, droperidol and aripiprazole, in the presence of CA, were investigated as model drugs. Comprehensive analyses were conducted using liquid-state 1D and 2D NMR and differential scanning calorimetry (DSC) to elucidate the regiochemistry and thermodynamic mechanisms bringing about those THEDESs. Everted gut sac technique was used to study the flux of the developed THEDESs. 1D and 2D NMR techniques analyses revealed the importance of cyclic tertiary amine nuclei in forming interactions with CA. This was confirmed by the downfield shift of the protons proximal to the tertiary amine groups compared to the individual drugs. Diffusion NMR analysis (DOSY) showed a significant reduction in the diffusion coefficient of CA in the mixed system compared with CA in isolation. Thermal analysis of the two drugs revealed that the drugs have a low tendency to recrystallise upon melting but rather vitrify from a melt to form an amorphous solid. Interestingly, the superior absorption and flux of the THEDES formulation of droperidol was demonstrated using the ERIS. Collectively, this work provides a green method to attain liquid formulations of APIs with enhanced pharmacokinetic features.

中文翻译：

---

使用具有优异肠道渗透性的 1D、2D NMR 和 DSC 技术对新型治疗性深共晶体系与癸酸的结构见解

治疗性低共熔溶剂 (THEDS) 是活性药物成分 (API) 绿色替代配方的最佳例证，可提供 API 的卓越特性。此前，我们课题组开发了利培酮、芬太尼、左氧氟沙星与癸酸（CA）的THEDES。这些 API 共享环状叔胺核。本文以两种带有环状叔胺核的药物氟哌利多和阿立哌唑在 CA 存在下的 DES 作为模型药物进行了研究。使用液态一维和二维核磁共振以及差示扫描量热法 (DSC) 进行综合分析，以阐明产生这些 THEDES 的区域化学和热力学机制。使用外翻肠囊技术来研究所开发的 THEDES 的通量。一维和二维核磁共振技术分析揭示了环状叔胺核在与 CA 形成相互作用中的重要性。与单个药物相比，靠近叔胺基团的质子的低场位移证实了这一点。扩散核磁共振分析 (DOSY) 显示，与单独的 CA 相比，混合体系中 CA 的扩散系数显着降低。对两种药物的热分析表明，这些药物在熔化时重结晶的倾向较低，而是从熔化物玻璃化形成无定形固体。有趣的是，使用 ERIS 证明了氟哌利多 THEDES 制剂具有优异的吸收和通量。总的来说，这项工作提供了一种绿色方法来获得具有增强药代动力学特征的 API 液体制剂。