Nanoparticle preparation of active pharmaceutical ingredients (APIs) by emulsion solvent diffusion method with cyclodextrins

摘要

The objective of the present work is to prepare nanocrystals of APIs using emulsion solvent diffusion method in the existence of cyclodextrin, and to evaluate the effect of cyclodextrin on the particle formation process.A stable crystalline form of indomethacin (IMC) was used as a model drug substance. Several types of cyclodextrin (CyD) solutions, e.g., α-, Β-,γ-CyD solutions, are used as a candidate for outer phase solution. IMC nanoparticles were prepared by the emulsion solvent diffusion method established by Kawashima et al.1) The ethanol solution containing IMC was added into 100 ml of aqueous CyD solution (0.1-1.0 %, w/w) in a 100 mL glass flask using a peristaltic pump at a flow rate of 2.5 mL/min while continuously stirring at 400 rpm with a propeller mixer. The aqueous dispersion was freeze-dried in a vacuum to obtain powdered particles. Freeze dried samples were then dispersed into an aqueous solution to estimate their redispersibility.IMC crystals with a mean diameter of ca. 400 nm were produced by the crystallization process. The freeze dried sample showed porous and braided structure on SEM photograph. These crystals were found to be a methastable form of IMC by using X-ray diffractometry and differential scanning caloriemetry. The freeze dried sample was well dispersed into an aqueous solution as nanocrystals. Although it is well known that CyDs have an ability to form inclusion complexes with a variety of organic compounds due to their peculiar structure, we could not find any evidence for the inclusion complex formation on this method. Interestingly, the nanoparticles of IMC could be formed regardless of types of CyDs used. These results suggest that CyDs in the outer phase suppress the crystal growth and/or aggregation during the emulsion solvent diffusion process, leading to formation of nanosized crystals of IMC in the aqueous solution.