目的 明确十二烷基硫酸钠（sodium dodecyl sulfate，SDS）与羟丙基甲基纤维素（hydroxypropyl methyl cellulose，HPMC）联用能否改善黄芩苷-欧前胡素共无定形系统（baicalin-imperatorin co-amorphous system，Bai-Imp-CAS）的溶出行为，并探讨其联合增益机制。方法 运用喷雾干燥法制备SDS与HPMC不同比例的Bai-Imp-CAS，通过粉末X射线衍射（powder X-ray diffraction，PXRD）、差示扫描量热（differential scanning calorimetry，DSC）确认固态形态；以结块率、分散时间评价分散性能，用接触角和表面自由能表征润湿性；基于分散性能确定SDS与HPMC最优比例并参照《中国药典》2025年版溶出度法考察最优比例SDS/HPMC (2∶1)-CAS与单用SDS或HPMC的溶出行为；采用紫外分光光度法研究药物成核及晶体生长速率。结果 各喷雾干燥产物均为共无定形态。SDS/HPMC (2∶1)-CAS的结块率（15.30±1.55）%显著低于单辅料组，分散时间与SDS单用组无显著差异；其水接触角低至24.23°，表面自由能达57.54 mJ/m²，润湿性最佳。体外溶出显示，SDS/HPMC (2∶1)-CAS中黄芩苷和欧前胡素的溶出曲线下面积（area under the curve，AUC）分别为（38 661.00±375.32）和（4 565.00±434.65）μg·h/mL，均显著高于SDS-CAS和HPMC-CAS；溶出前期趋势与SDS组相近，中后期溶出衰减速率与HPMC组一致。结晶动力学表明，HPMC（单用或联用）显著抑制两药成核及黄芩苷的晶体生长，但对欧前胡素晶体生长无显著影响；SDS对成核和生长均无作用。结论 SDS/HPMC (2∶1)-CAS分散性能最优，SDS与HPMC可对2种药物的溶出实现联合增益，其机制为通过时序性功能互补改善Bai-Imp-CAS的溶出：SDS主导初期快速分散与抗团聚，并通过降低局部过饱和度产生间接抑晶作用；HPMC于溶出中后期直接抑制晶体生长。两者在抑晶层面形成“间接＋直接”的叠加效应，共同维持过饱和状态。该策略为难溶性药物组合的共无定形系统设计提供了新思路，且可减少SDS用量，具有“减量增效”的临床转化优势。

Objective To clarify whether the combined use of sodium dodecyl sulfate (SDS) and hydroxypropyl methylcellulose (HPMC) can improve the dissolution behavior of baicalin-imperatorin co-amorphous system (Bai-Imp-CAS), and explore the mechanism of combination benefit. Methods A series of Bai-Imp CAS with different ratios of SDS and HPMC were prepared by the spray-drying method. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were adopted to characterize the solid-state properties of samples. Dispersion performance was evaluated by determining caking rate and dispersion time, and wettability was analyzed via contact angle and surface free energy measurements. The optimal ratio of SDS to HPMC was determined based on dispersion performance. According to the requirements of the 2025 Edition of Chinese Pharmacopoeia, the in vitro dissolution of the optimal SDS/HPMC (2∶1)-CAS was investigated and compared with those of SDS-CAS and HPMC-CAS. UV-visible spectrophotometry was used to detect the nucleation time and crystal growth rate of the two drugs. Results All spray-dried products were identified as co-amorphous systems. The caking rate of SDS/HPMC (2∶1)-CAS was (15.30 ± 1.55)%, which was significantly lower than that of single excipient groups. There was no significant difference in dispersion time between SDS/HPMC (2∶1)-CAS and SDS-CAS. The water contact angle of SDS/HPMC (2∶1)-CAS was 24.23°, with a surface free energy of 57.54 mJ/m², indicating favorable wettability. The in vitro dissolution results showed that the area under curve (AUC) values of baicalin and imperatorin in SDS/HPMC (2∶1)-CAS were (38 661.00 ± 375.32) and (4 565.00 ± 434.65) μg·h/mL, respectively, both significantly higher than those of SDS-CAS and HPMC-CAS. The early dissolution profile of SDS/HPMC (2∶1)-CAS was similar to that of SDS-CAS, while its dissolution decline rate in the middle and late stages was consistent with HPMC-CAS. Crystallization kinetics demonstrated that HPMC alone or combined with SDS could inhibit the nucleation of the two drugs and the crystal growth of baicalin, but exert no obvious effect on the crystal growth of imperatorin. SDS had no significant influence on the nucleation and crystal growth of both drugs. Conclusion SDS/HPMC (2∶1)-CAS shows the best dispersibility, and SDS and HPMC can jointly boost the dissolution of both drugs. The mechanism works by sequentially complementing each other's functions to improve the dissolution of Bai-Imp-CAS: SDS mainly drives fast initial dispersion and prevents aggregation, while also indirectly inhibiting crystallization by lowering local supersaturation; HPMC directly inhibits crystal growth during the mid to late stages of dissolution. Together, they create a combined “indirect and direct” effect on crystal inhibition, helping to maintain a supersaturated state. This strategy offers a fresh approach for designing co-amorphous systems for poorly soluble drug combinations, and it can reduce the amount of SDS needed, giving a “less is more” advantage for clinical translation.

R283.6

国家自然科学基金资助项目（82160751）；江西中医药大学中药制剂传承创新与转化团队（CXTD22006）