School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China; School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
Int J Pharm. 2024 Dec 25;667(Pt A):124857. doi: 10.1016/j.ijpharm.2024.124857. Epub 2024 Oct 21.
Coamorphous drug delivery systems have received increasing interest owing to their potential to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs. However, the crystallization risk is one of major limitations in their application. It has been widely recognized that the coformer plays a vital role in physical stability of coamorphous formulation. Unfortunately, the screen of optimal coformer still adopts a trial-and-error method, which is time-consuming and expensive. Herein, a supramolecular synthon approach based on the interaction between functional groups, was exploited to design coamorphous systems (CMs) consisting of lurasidone hydrochloride (LH) and three coformers, saccharin (SAC), L-tryptophan (TRP), and L-cysteine hydrochloride (CYS). X-ray powder diffraction suggested the order of physical stability of the coamorphous systems was ranked as LH-CYS CM > LH-TRP CM > LH-SAC CM. The charge-assisted hydrogen bond between LH and coformer was confirmed by infrared spectroscopy and solid-state C NMR. Moreover, structural, electronic, and molecular interaction information, especially hydrogen bonding interactions, were quantified by theoretical calculations, including miscibility calculations, molecular dynamics simulations and quantum chemical calculations. It was revealed that LH-CYS CM exhibited the best miscibility, strongest binding energy and strongest H-bond with partially covalent character, demonstrating the significant role of supramolecular synthon in stabilizing coamorphous formulations. Interestingly, LH-TRP CM, not LH-CYS CM, exhibited the lowest molecular mobility among three coamorphous systems, which was inconsistent with their physical stability. But from thermodynamic perspective, the order of configurational entropy and physical stability of coamorphous systems was completely consistent. We shed light on the comprehensive effects of molecular mobility and configurational entropy on physical stability of coamorphous systems. Importantly, the relationship between supramolecular synthon and kinetic/thermodynamic mechanisms was also discussed, and the positive correlation between configurational entropy and intermolecular interactions was proposed in this paper. Our findings demonstrated the great potential of supramolecular synthon in designing coamorphous systems with tailored physical stability, and further provided a deeper insight into the mechanisms of physical stability of coamorphous systems.
无定形药物递送系统因其能够提高水溶性差的药物的溶解度、溶解率和生物利用度而受到越来越多的关注。然而，结晶风险是其应用的主要限制因素之一。人们普遍认识到共晶形成剂在共晶制剂的物理稳定性中起着至关重要的作用。不幸的是，最佳共晶形成剂的筛选仍然采用试错法，既耗时又昂贵。在此，我们利用基于官能团之间相互作用的超分子合成子方法，设计了由盐酸鲁拉西酮（LH）和三种共晶形成剂（糖精（SAC）、L-色氨酸（TRP）和 L-半胱氨酸盐酸盐（CYS））组成的无定形系统（CMs）。X 射线粉末衍射表明，无定形系统的物理稳定性顺序为 LH-CYS CM > LH-TRP CM > LH-SAC CM。红外光谱和固态 C NMR 证实了 LH 与共晶形成剂之间的电荷辅助氢键。此外，通过理论计算（包括混溶性计算、分子动力学模拟和量子化学计算）定量了结构、电子和分子相互作用信息，特别是氢键相互作用。结果表明，LH-CYS CM 表现出最佳的混溶性、最强的结合能和部分共价特征的最强氢键，表明超分子合成子在稳定无定形制剂中起着重要作用。有趣的是，在三种无定形系统中，LH-TRP CM 表现出最低的分子迁移率，而不是 LH-CYS CM，这与它们的物理稳定性不一致。但从热力学角度来看，无定形系统的构象熵和物理稳定性的顺序完全一致。我们揭示了分子迁移率和构象熵对无定形系统物理稳定性的综合影响。重要的是，本文还讨论了超分子合成子与动力学/热力学机制之间的关系，并提出了构象熵与分子间相互作用之间的正相关关系。我们的研究结果表明，超分子合成子在设计具有定制物理稳定性的无定形系统方面具有巨大潜力，并进一步深入了解了无定形系统物理稳定性的机制。
