One-step preparation of pharmaceutical nanocrystals using ultra cryo-milling technique in liquid nitrogen

A novel micronization technique for pharmaceutical powders has been established using liquid nitrogen (LN2). Different from the conventional dry milling while cooling the milling pot by LN2, the materials were directly suspended in LN2 together with hard small spherical balls, called beads, and broken down by agitating intensively. The present beads milling in LN2 was named “ultra cryo-milling” in this paper. The operational conditions including the size/amount of beads made of zirconia and agitation speed were optimized to obtain the finer particles. It was found that the original crystals were effectively broken down into submicron particles, and the ultra cryo-milled particles were much finer and more uniform in size and shape than the conventional jet-milled particles. Dried powder was recovered continuously after milling process because LN2 was spontaneously evaporated at ambient temperature/pressure. Further, it was shown that this technique is applicable to the drugs with wide range of physicochemical features including heat-sensitive and water-soluble drugs. However, the resultant fine particles intrinsically tended to form the agglomerated masses. The crystalline analysis indicated that the both crystal form and crystallinity of the original bulk drugs completely remained after ultra cryo-milling process. The results demonstrated that the ultra cryo-milling would be a fundamental technique to produce the pharmaceutical nanocrystals by one step.