Despite the significant advancements in the pharmaceutical manufacturing process, the aqueous solubility of most of the potent drugs has remained as an unresolved problem during the formulation development and drug delivery processes. To address this critical issue, we modified the continuous-rapid expansion of supercritical solution (RESS-C) process, which is incessant, stable and well-regulated. Initially, the solubility of lonidamine (LND) in supercritical carbon dioxide (SC-CO2) was tested using a static analytical method at altered critical conditions (T: 308.15-328.15 K, P: 10.0-30.0 MPa). Under optimized conditions (LND conc.- 0.5% (w/v), flow rate- 1.0 mL/min, T- 328.15 K, P- 20.0 MPa and CO2 flow rate- 30.0 g/min), the modified RESS-C process resulted in nano-sized spheres with a smooth surface and a narrow particle size distribution. Further, the crystal properties of the samples and their molecular interactions were elucidated. The altered physical state of RESS-C processed LND from crystalline to amorphous resulted in the solubility improvement and also enhanced the in vitro antiproliferative effects compared to the unprocessed LND, demonstrating the potential of the modified RESS-C process in improving the bioavailability of poorly water-soluble drugs.