Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang KM 21, Sumedang 45363, Indonesia.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Int J Pharm. 2021 May 1;600:120492. doi: 10.1016/j.ijpharm.2021.120492. Epub 2021 Mar 17.
In this study, the molecular state of ritonavir (RTN)-saccharin (SAC) coamorphous incorporated into mesoporous silica by solvent evaporation and the effect of SAC on the RTN dissolution from mesopores were investigated. The amorphization of RTN-SAC was confirmed as a halo pattern in powder X-ray diffraction measurements and a single glass transition event in the modulated differential scanning calorimetry (MDSC) curve. C solid-state NMR spectroscopy revealed a hydrogen bond between the thiazole nitrogen of RTN and the amine proton of SAC. The glass transition of the RTN-SAC coamorphous in mesoporous silica was not found in the MDSC curve, indicating that RTN and SAC were monomolecularly incorporated into the mesopores. Solid-state NMR measurements suggested that the co-incorporation of SAC into the mesopores decreased the local mobility of the thiazole group of RTN via hydrogen bond formation. The RTN-SAC 1:1 coamorphous in mesoporous silica retained the X-ray halo-patterns after 30 d of storage, even under high temperature and humidity conditions. In the dissolution test, the RTN-SAC 1:1 coamorphous in mesoporous silica maintained RTN supersaturation for a longer time than the RTN amorphous in mesoporous silica. This study demonstrated that the drug-coformer interaction within mesoporous silica can significantly improve drug dissolution.
在这项研究中，通过溶剂蒸发法将利托那韦（RTN）-糖精（SAC）共无定形物掺入介孔硅中，并研究了 SAC 对 RTN 从介孔中溶解的影响。通过粉末 X 射线衍射测量证实了 RTN-SAC 的无定形化为晕环图案，在调制差示扫描量热法（MDSC）曲线上为单个玻璃化转变事件。固态 NMR 光谱表明 RTN 的噻唑氮和 SAC 的胺质子之间存在氢键。在 MDSC 曲线上未发现介孔硅中 RTN-SAC 共无定形的玻璃化转变，表明 RTN 和 SAC 以单分子形式掺入介孔中。固态 NMR 测量表明，SAC 共掺入介孔会通过氢键形成降低 RTN 的噻唑基团的局部迁移率。即使在高温高湿条件下，介孔硅中的 RTN-SAC 1:1 共无定形物在 30 天后仍保留 X 射线晕环图案。在溶解测试中，与介孔硅中的 RTN 无定形相比，介孔硅中的 RTN-SAC 1:1 共无定形物能更长时间维持 RTN 的过饱和状态。这项研究表明，药物共晶剂在介孔硅内的相互作用可显著提高药物的溶解速率。
