The present study focused on comparing the efficacy of two novel techniques, lyophilization and spray drying, which were proposed to overcome the solubility drawbacks of the highly effective antihypertensive drug, bosentan monohydrate. Solid dispersion approach is the most globally acknowledged and successful method for improving solubility. Poloxamer 188 was used as the carrier to prepare the solid dispersions. The results indicated that the particle size, solubility, and dissolution profiles of formulated amorphous systems varied significantly. Lyophilized solid dispersions demonstrated the highest level of solubility in the prepared solid dispersions. The solid dispersion formulations FL10 and FS10 prepared using lyophilization and spray drying techniques were optimized using a 32 full factorial design approach. The resulting amorphous solid dispersions were characterized using Fourier-transform infrared spectroscopy (FTIR), particle size analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The optimized solid dispersion (FL10) prepared via lyophilization had an average particle size of 450.9 nm in particle size analysis. X-ray diffraction analyses of both FL10 and FS10 revealed a decrease in peak intensity compared to the drug and polymer, indicating the transformation of the crystalline form to amorphous. The outcomes of this study allow us to conclude that even though lyophilization and spray drying can be used to enhance solubility, lyophilization showed superior results.