Thalidomide treats multiple myeloma and protracts life-span of patient, but its bioavailability is limited as it is poorly water soluble. Thalidomide nano-flakes are produced to improve the drug dissolution rate. Two nanoflake production methods are utilized for a comparative study:a supercritical antisolvent (SAS) method and a supercritical antisolvent with enhanced mass transfer (SAS-EM). SAS-EM utilizes ultrasonication to improve dispersion upon injection within the supercritical carbon dioxide. Comparative study of SAS and SAS-EM thalidomide confirmed that the application of ultrasonication improved the micro/nano particles produced by SAS. The effects of ultrasound power on the formation of thalidomide particles are examined. The particle size and morphology were characterized by SEM. The thalidomide nano-flakes produced by SAS-EM were smaller than the particles produced by SAS. Dissolution rates of the produced particles, evaluated by HPLC, demonstrated an increase in the thalidomide dissolution rate for the SAS-EM produced particles. The polymorphs and crystallinity of thalidomide particles (flakes) were observed by FTIR and XRD. In this research, the supercritical processing significantly modified the crystal formation of thalidomide from an original state of a β-polymorph to the amorphous state β-polymorph after supercritical processing. Thalidomide treats multiple myeloma and protracts life-span of patient, but its bioavailability is limited as it is poorly water soluble. Thalidomide nano-flakes are produced to improve the drug dissolution rate. Two nanoflake production methods are utilized for a comparative study: a supercritical antisolvent (SAS) method and a supercritical antisolvent with enhanced mass transfer (SAS-EM). SAS-EM enabled ultrasonication to improve dispersion upon injection within the supercritical carbon dioxide. Comparative study of SAS and SAS-EM thalidomide confirmed that the application of ultrasonication The effects of ultrasound power on the formation of thalidomide particles are examined. The particle size and morphology were characterized by SEM. The thalidomide nano-flakes produced by SAS-EM were smaller than the particles produced by SAS. Dissolution rates of the produced particles, evaluated by HPLC, demonstrated an increase in the thalido The polymorphs and crystallinity of thalidomide particles (flakes) were observed by FTIR and XRD. In this research, the supercritical processing significantly modified the crystal formation of thalidomide from an original state of a β- polymorph to the amorphous state β-polymorph after supercritical processing.