Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Mol Pharm. 2019 Dec 2;16(12):4968-4977. doi: 10.1021/acs.molpharmaceut.9b00840. Epub 2019 Nov 11.
In the present study, the molecular state of drug-rich amorphous nanodroplets was evaluated using NMR techniques to reveal the mechanism underlying the crystallization inhibition of drug-rich amorphous nanodroplets by a polymer. Ibuprofen (IBP) with a low glass transition temperature was used for direct characterization of drug-rich amorphous nanodroplets. Highly supersaturated IBP formed IBP-rich amorphous nanodroplets through phase separation from aqueous solution. Increasing the concentration of hypromellose (HPMC) in the aqueous solution contributed to the inhibition of IBP crystallization and maintenance of supersaturation at IBP amorphous solubility. Solution H NMR measurements of IBP supersaturated solution containing IBP-rich amorphous nanodroplets clearly showed two kinds of H peaks derived from the dissolved IBP in bulk water phase and phase-separated IBP in IBP-rich amorphous nanodroplets. NMR spectral analysis indicated that HPMC did not affect the chemical environment and mobility of the dissolved IBP. However, H spin-spin relaxation time measurements clarified that the dissolved IBP in the bulk water phase was exchanged with the IBP-rich amorphous nanodroplets with an exchange lifetime of more than 10 ms. Moreover, the H peaks of HPMC partially disappeared due to the formation of IBP-rich amorphous nanodroplets, suggesting that a part of HPMC distributed into the IBP-rich amorphous nanodroplets from the bulk water phase. The incorporation of HPMC significantly changed the chemical environment of the phase-separated IBP in the IBP-rich amorphous nanodroplets and strongly suppressed molecular mobility. The resulting molecular mobility suppression effectively inhibited IBP crystallization from the IBP-rich amorphous nanodroplets. Thus, direct investigation of drug-rich amorphous nanodroplets using NMR can be a promising approach for selecting appropriate pharmaceutical excipients to suppress drug crystallization in supersaturated drug solutions.
在本研究中，使用 NMR 技术评估了富含药物的无定形纳米液滴的分子状态，以揭示聚合物抑制富含药物的无定形纳米液滴结晶的机制。具有低玻璃化转变温度的布洛芬（IBP）被用于直接表征富含药物的无定形纳米液滴。高过饱和的 IBP 通过从水溶液中相分离形成 IBP 丰富的无定形纳米液滴。增加水溶液中羟丙甲纤维素（HPMC）的浓度有助于抑制 IBP 结晶并维持 IBP 无定形溶解度的过饱和度。含有 IBP 丰富的无定形纳米液滴的 IBP 过饱和溶液的溶液 H NMR 测量清楚地显示了两个源自于在 bulk 水相中的溶解 IBP 和在 IBP 丰富的无定形纳米液滴中相分离的 IBP 的 H 峰。NMR 光谱分析表明 HPMC 不影响溶解的 IBP 的化学环境和迁移率。然而，H 自旋-自旋弛豫时间测量澄清了在 bulk 水相中的溶解的 IBP 与具有超过 10ms 的交换寿命的 IBP 丰富的无定形纳米液滴进行交换。此外，由于 IBP 丰富的无定形纳米液滴的形成，HPMC 的 H 峰部分消失，这表明一部分 HPMC 从 bulk 水相分配到 IBP 丰富的无定形纳米液滴中。HPMC 的掺入显著改变了 IBP 丰富的无定形纳米液滴中相分离的 IBP 的化学环境，并强烈抑制了分子迁移率。所得的分子迁移率抑制有效地抑制了 IBP 从 IBP 丰富的无定形纳米液滴中的结晶。因此，使用 NMR 对富含药物的无定形纳米液滴进行直接研究可能是选择合适的药物赋形剂来抑制过饱和药物溶液中药物结晶的有前途的方法。
