Abstract：
Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the \"deep eutectic\" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds\' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the \"deep eutectic\" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound\'s glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the \"deep eutectic\" region there was still an ideal, or thermodynamically preferrable \"THEDES point\", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the \"therapeutic deep eutectic\" phenomenon. Through correlation between parent reagents\' physicochemical properties and the synthesised products\' characteristics, we establish a more educated process for the prediction and engineering of THEDES.
摘要：
治疗性深共晶溶剂(THDES)作为能够改善难以递送的药物化合物的物理化学和生物制药性质的有希望的使能技术在药物文献中引起越来越多的关注。目前的文献已经探索了酰胺局部麻醉剂和羧酸非甾体抗炎药（NSAIDs）作为其活性氢键键合功能的常用THEDES形成剂。然而,对“深共晶”区域内发生的事情知之甚少，在该区域中，一系列二元成分仅作为液体存在，在实验可实现的条件下没有可检测到的熔化事件。对母体化合物的物理化学性质如何影响地层的理解也非常有限，相互作用机制，和形成的液体系统的稳定性，尽管这些信息在剂量调整中具有重要意义，工业处理，以及这些液体的放大。在目前的工作中,我们通过研究某些选定的利多卡因-NSAID系统在各种组成比范围内的形成和物理化学行为，探讨了“深共晶”现象。我们的数据表明，成功形成的THDES表现出与组成相关的Tg变化，并且使用Gordon-Taylor理论与预测的Tg值存在明显的正偏差，表明在形成的超分子结构内存在实质性的相互作用。有趣的是,发现母体化合物的玻璃形成能力对这种深刻的相互作用有明显的影响，因此可以决定THDES形成的成功。还已经证实，所有成功的系统都是基于其THEDES网络内的电荷辅助氢键形成的。肯定了部分质子化对实现深度熔点下降的重要作用。更重要的是,这项工作发现，在“深共晶”区域内仍然有一个理想的，或热力学上优选的“thedes点”，其在暴露于应力储存条件时将表现出优异的稳定性。这项研究的发现使文献离充分理解“治疗性深共晶”现象更近了一步。通过母体试剂的物理化学性质和合成产物的特性之间的相关性，我们为theges的预测和工程建立了一个更有教养的过程。
