Quercetin (QUE) has recently attracted increasing interest as a co-former in co-amorphous systems owing to its multiple hydrogen-bonding functionalities. However, the relationship between its intermolecular interactions and co-amorphous performance remains poorly understood. This study investigated the influence of co-former chemistry on the molecular interactions, stability, and aqueous performance of quercetin-based co-amorphous systems using arginine (ARG) and glutamic acid (GLU) as model amino acid co-formers. Co-amorphous formulations were prepared by spray drying and characterized using molecular modelling, solution-state 1H NMR titration, FTIR spectroscopy, PXRD, mDSC, dynamic vapour sorption, solubility, and dissolution studies. Molecular simulations predicted stronger miscibility and intermolecular interactions in the QUE-ARG systems than in the corresponding QUE-GLU systems, which was supported by NMR and FTIR analyses. Although all formulations were initially amorphous, the QUE-GLU systems crystallized within one week of storage, whereas the QUE-ARG systems remained amorphous for at least three months. Notably, the QUE-GLU formulations exhibited comparable or higher glass-transition temperatures, indicating that Tg alone was not predictive of physical stability. The stronger interactions observed in the QUE-ARG systems were also associated with substantially improved saturated solubility and dissolution performance. These findings demonstrate that the effectiveness of quercetin as a co-former depends on the nature and specificity of intermolecular interactions and highlight their importance in the rational design of quercetin-based co-amorphous systems.
The current research aimed at designing mesoporous silica nanoparticles (MSNs) for a controlled coadministration of salicylic acid (SA) and ketoconazole (KCZ) to effectively treat highly resistant fungal infections. The sol-gel method was used to formulate MSNs, which were further optimized using central composite rotatable design (CCRD) by investigating mathematical impact of independent formulation variables such as pH, stirring time, and stirring speed on dependent variables entrapment efficiency (EE) and drug release. The selected optimized MSNs and pure drugs were subjected to comparative in vitro/in vivo antifungal studies, skin irritation, cytotoxicity, and histopathological evaluations. The obtained negatively charged (-23.1), free flowing spherical, highly porous structured MSNs having a size distribution of 300-500 nm were suggestive of high storage stability and improved cell proliferation due to enhanced oxygen supply to cells. The physico-chemical evaluation of SA/KCZ-loaded MSNs performed through powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA) indicates absolute lack of any interaction between formulation components and successful encapsulation of both drugs in MSNs. The EESA, EEKCZ, SA release, and KCZ release varied significantly from 34 to 89%, 36 to 85%, 39 to 88%, and 43 to 90%, respectively, indicating the quadratic impact of formulation variables on obtained MSNs. For MSNs, the skin tolerability and cell viability percentage rate were also having an extraordinary advantage over suspension of pure drugs. The optimized SA/KCZ-loaded MSNs demonstrated comparatively enhanced in vitro/in vivo antifungal activities and rapid wound healing efficacy in histopathological evaluation without any skin irritation impact, suggesting the MSNs potential for the simultaneous codelivery of antifungal and keratolyic agents in sustained release fashion.