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.

co-amorphous system  /  dissolution  /  combination benefit  /  sodium dodecyl sulfate  /  hydroxypropyl methyl cellulose  /  baicalin  /  imperatorin  /  spray drying method  /  caking rate  /  dispersion time  /  contact angle  /  surface free energy