Dissolution Amelioration by Small Amounts of HPMC in the Difficult-to-solve Drug Combination Baicalein-imperatorin Co-Amorphous System: Dispersion and Crystallization Inhibition.

Drug-drug co-amorphous systems (CAS) represent an emerging co-delivery strategy for combination therapy. Current research primarily explores combinations of poorly water-soluble drugs with water-soluble counterparts, while CAS comprising exclusively poorly water-soluble drugs remains underexplored. Such systems may exhibit unique dissolution behaviors due to the absence of hydrophilic components. In prior work, we developed a co-amorphous system of two poorly water-soluble drugs, baicalin (Bai) and imperatorin (Imp). However, this system demonstrated significant agglomeration during dissolution and limited dissolution enhancement. To address this, we incorporated trace hydroxypropyl methylcellulose (HPMC) into the Bai-Imp-CAS via spray drying. This study investigates HPMC's impact on dissolution behavior and underlying mechanisms through comprehensive analyses of supersaturation dissolution, dispersion kinetics, agglomeration rate, contact angle, surface free energy, nucleation time, and crystal growth rate. Results indicate that trace HPMC significantly enhances dissolution performance by reducing contact angles and increasing surface free energy, thereby improving dispersibility and inhibiting recrystallization. Additionally, HPMC elevates the glass transition temperature (Tg), improving physical stability. These findings provide a novel theoretical framework for optimizing poorly soluble drug combinations and offer practical solutions for co-delivery system development.Finally, it is also important to note that the degree of improvement of HPMC on the dissolution of the two drugs in the difficult-to-dissolve drug combination is also related to the solubility of the drugs themselves, their crystallization properties and the ratio of the two drugs.