Abstract: OBJECTIVE To improve the pharmaceutical attributes of the hydrophobic drug HNN as the model drug by the Ultrasonic spray-drying technique while BÜCHI ultrasonic controller was using as the main equipment. The main properties of the drugs HNN, powder properties, crystal morphology and chemical stability were compared to evaluate the fuction of the ultrasonic spray drying. METHODS The main powder properties such as drug particle size distribution, density and angle of repose were measured, and the microstructure was investigated by scanning electron microscopy. Characterization spectrum of drugs were detected by DSC, IR, XRPD and Raman analysis. HPLC was used to determine the contents of the related substances of drugs. RESULTS The particle size of the drug substance was 4.44-1 710 μm, that of spray dried drug was 50-300 μm, the size distribution was narrower and more uniform, and showed a normal distribution. The bulk density of spray dried drug was increased by 9.5 times from 0.054 5 g·cm^-3 to 0.515 4 g·cm^-3. Angle of repose was discreased from 57.26° to 37.21° that had been close to the requirements of direct compression of the powder. The microscopic morphology structure of the drug substance was needle-like, chaotic, but the spray-dried drug exhibits spherical round particles in the same size. The DSC showed no change in melting point. IR, XRPD and Raman showed consistent in drug characteristic peaks. These results told that there were no significantly different in the crystal types of drugs. The results of the relevant substances chemical stability test indicated that the spray drying process had any negative inflence on drug stability. CONCLUSION The spray-dried particles produced by ultrasonic nozzle are observed to be more rounded and uniform in terms of size and shape. Moreover, the pharmaceutical attributes of drug have been greatly optimized. The ultrasonic nozzle used in this study provide more protection on polymorphs and stability based on the low shear mode of ultrasonic energy atomization. The Ultrasonic spray-drying technique can be used as an alternative method to optimize the pharmaceutical attributes for the study of similar drug.