Novel Ultra-Cryo Milling and Co-grinding Technique in Liquid Nitrogen to Produce Dissolution-Enhanced Nanoparticles for Poorly Water-Soluble Drugs

Abstract

A novel ultra-cryo milling micronization technique for pharmaceutical powders using liquid nitrogen (LN2 milling) was used to grind phenytoin, a poorly water-soluble drug, to improve its dissolution rate. LN2 milling produced particles that were much finer and more uniform in size and shape than particles produced by jet milling. However, the dissolution rate of LN2-milled phenytoin was the same as that of unground phenytoin due to agglomeration of the submicron particles. To overcome this, phenytoin was co-ground with polyvinylpyrrolidone (PVP). The dissolution rate of co-ground phenytoin was much higher than that of original phenytoin, single-ground phenytoin, a physical mixture of phenytoin and PVP, or jet-milled phenytoin. X-Ray diffraction showed that the crystalline state of mixtures co-ground by LN2 milling remained unchanged. The equivalent improvement in dissolution, whether phenytoin was co-ground or separately ground and then mixed with PVP, suggested that even when co-ground, the grinding of PVP and phenytoin occurs essentially independently. Mixing original PVP with ground phenytoin provided a slight improvement in dissolution, indicating that the particle size of PVP is important for improving dissolution. When mixed with ground phenytoin, PVP ground by LN2 milling aided the wettability and dispersion of phenytoin, enhancing utilization of the large surface area of ground phenytoin. Co-grinding phenytoin with other excipients such as Eudragit L100, hypromellose, hypromellose acetate-succinate, microcrystalline cellulose, hydroxypropylcellulose and carboxymethyl cellulose also improved the dissolution profile, indicating an ultra-cryo milling and co-grinding technique in liquid nitrogen has a broad applicability of the dissolution enhancement of phenytoin.Key words cryo-milling; media milling; liquid nitrogen; submicron; zirconia bead; co-grinding Combinatorial chemistry and high throughput screening have contributed to an increase in the number of poorly watersoluble drug candidates emerging from the discovery pipeline.1) Many technologies for reducing the particle size of drug substances have been developed and applied in pharmaceutical research in order to enhance the gastrointestinal dissolution and absorption of poorly water-soluble drug substances 2,3) or to reduce variations in uptake between fed and fasted conditions.4) Mechanical milling of dry drug substances by ball milling, hammer milling and jet milling has been traditionally used in pharmaceutical manufacturing because of its widespread application and the simplicity of the process. However, this approach can only reduce particle size to approximately 2-3 μm due to secondary co-aggregation between particles caused by van der Waals interactions and electrostatic forces. 5)In the past decade, the "1-micron limitation" in particle size has been overcome by micronization and nanonization strategies 6) by employing media milling and high pressure homogenization techniques conducted on aqueous suspensions. The resulting nanometer-sized drug ...

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