Multi-method coamorphous systems of lumefantrine with alpha ketoglutaric acid: Comprehensive characterization, biological evaluation and stability analysis.

The coamorphous systems (CAM) of lumefantrine (LMF) and alpha-ketoglutaric acid (KGA) were developed using three different methods to address the solubility and bioavailability limitations of LMF. Powder X-ray diffraction spectroscopy (PXRD) and the differential scanning calorimetry (DSC) confirmed the complete amorphization of the three CAM by the halo pattern and glass transition temperature (Tg), respectively. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance spectroscopy (NMR) results indicated that intermolecular interactions existed in the three CAM. Solid-state molecular dynamics simulations revealed the different intermolecular disordered environments present in all three CAM. Solubility analysis showed 14.73×, 12.8× and 9.81× improvement in the liquid-assisted grinding-based coamorphous system (CAM LAG), solvent evaporation-based coamorphous system (CAM SE) and quench-cool-based coamorphous system (CAM QC), respectively, compared to LMF crystalline (LMF CRY). In the in-vitro dissolution experiment 2.63-, 2.16- and 2.17-times increments were observed in CAM LAG, CAM SE and CAM QC compared to LMF CRY, respectively. In-vivo pharmacokinetics study revealed 10.86-, 9.24- and 8.46- folds increments in C of CAM LAG, CAM SE and CAM QC, respectively, compared to LMF CRY. All three CAM illustrated anti-cancer activity in the A549 lung cancer cell line. Molecular dynamics simulation of LMF and KGA with Epidermal growth factor receptor (EGFR), a target for lung cancer treatment, revealed good binding affinity and stability. Stability studies performed under accelerated storage (40°C/75% RH) and extreme environmental conditions indicated that all three CAM have good stability. Different methods based prepared CAM have shown different physicochemical properties, bioavailability and stability profiles. These findings suggest that LMF-KGA CAM effectively addresses the solubility and bioavailability challenges of LMF, potentially leading to better therapeutic outcomes in lung cancer treatment.