(303b) Continuous Synthesis of Drug Particles through Spray-Drying of Nano-Emulsion

In the pharmaceutical field, nanoparticle synthesis is an effective means of improving the water solubility of poorly water-soluble drugs. Spray-drying is one of the methods to synthesize fine drug particles. The particle size obtained by the spray-drying method generally depends on the diameter of the sprayed droplets. The synthesis of metallic nanoparticles with single nanometers from micro-droplets generated with electrostatic spraying has been reported. However, the yield of particles obtained by electrostatic spraying is too small, 0.050-15 mL/h. Although spray-drying using a two-fluid nozzle is desirable owing to its high productivity, the diameter of droplets sprayed by two-fluid nozzles is limited to 4µm, leading to a difficulty of synthesis of nanoparticles.

In this study, the “emulsion spray-drying method” was proposed as a novel method for the nanoparticle synthesis. First, nano-sized oil in water (O/W) emulsions with oil-soluble drugs were prepared. Spraying the O/W emulsions generated nano-sized oil droplets within the water droplets. The nano-sized oil droplets dried then to produce fine particles. In this study, nifedipine (NFD) and polyvinylpyrrolidone were used as model powders. Chloroform and Tween 80 were used as the oil component and the surfactant, respectively. These were mixed and stirred with mechanical external force to generate O/W emulsions. The obtained O/W emulsions were confirmed to have monodisperse fine oil droplets with the size of 165 nm. The O/W emulsions were spray-dried, obtaining the NFD particles with the size of ca. 122 nm. To verify the micritization by the emulsion spray-drying method, chloroform solutions of NFD without emulsion were spray-dried. The NFD particles obtained by spray-drying chloroform solutions were 2.5 µm in diameter, demonstrating that fine particles can be obtained by emulsion spray-drying.

Furthermore, ouzo emulsion, which is the self-emulsification method, was investigated to improve the particle yield. Ouzo emulsions are generated through the mixing of oil, water, and co-soluble surfactants. Co-soluble surfactants are well soluble in both oil and water. Phenytoin (PHT), 1-hexanol, and ethanol were used as model powders, the oil component, and the co-soluble surfactant, respectively. These were just mixed to generate ouzo emulsions. The obtained ouzo emulsions had monodispersed fine oil droplets with the size of 7.06 nm. The ouzo emulsion was spray-dried, obtaining the PHT particles with the size of ca. 300 nm. Here, high yields of 2.2 g/min were achieved compared with spray-drying of O/W emulsions. 1-hexanol solutions of PHT without emulsion were also spray-dried. The PHT particles obtained by spray drying a 1-hexanol solution were 1 µm in diameter, demonstrating that fine particles can be obtained by spray-drying of ouzo emulsions. Moreover, dissolution tests were performed to evaluate the solubility of the three PHT particles, including the raw powder. The PHT particles obtained via the spray-drying of ouzo emulsions were confirmed to indicate the highest dissolution rate.

In summary, the spray-drying of O/W emulsions with chloroform and ouzo emulsions with 1-hexanol demonstrated the production of fine drug particles.