Sulfasalazine-quercetin co-amorphous systems: Sustained release behaviors and enhanced pharmacokinetics

Sulfasalazine (SULF) is a well-established therapeutic agent for rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), but its oral absorption is limited by efflux transporters, particularly MRP2 and BCRP. Consequently, high daily doses (1-3 g) and frequent administration (three to four times daily) are required, increasing the risk of adverse effects during long-term therapy. To overcome these limitations, co-amorphous systems (CASs) of SULF with quercetin (QUE) were developed in this study. The CASs were systematically characterized using powder X-ray diffraction (PXRD), polarized light microscopy (PLM), scanning electron microscopy (SEM), and temperature-modulated differential scanning calorimetry (mDSC). The molecular-level formation mechanism was further elucidated via Fourier-transform infrared spectroscopy (FTIR) and molecular dynamics (MD) simulations. All SULF-QUE CASs exhibited glass transition temperatures around 113 °C and demonstrated sustained-release behavior, with markedly lower SULF dissolution (24.5-42.9 %) compared to the crystalline form (89.8 %) after 6 h. This reduction was attributed to the in situ formation of a dense "shell-like" recrystallized QUE surface structure resulting from its incongruent dissolution. Importantly, co-amorphous forms demonstrated enhanced oral bioavailability (1.52-2.80-fold) and prolonged T_max (1.84-5.52-fold) compared to crystalline SULF, fulfilling the original goal of their development. Moreover, these systems exhibited satisfactory physical stability over time. Overall, the SULF-QUE CASs present a promising strategy to optimize the clinical dosage of SULF, reduce side effects, and offer a synergistic therapeutic approach for RA and IBD.