Nanosizing of Poorly Water Soluble Compounds Using Rotation/Revolution Mixer

Abstract

Synthesis of water soluble compounds with high pharmacological activity is becoming increasingly difficult. Pulverization is one of the methods that can be used to enhance the dissolution rate of poorly water soluble compounds and improve their bioavailability. 1) Pulverization is an important process, especially during the discovery, clinical, and developmental stages of a drug to salvage from the dropout of compound.Phenytoin is a highly crystalline compound with a high melting point of 295-298°C and poor solubility in water. Because of its poor solubility in water, there are very few cases where the concentration of phenytoin in blood reaches the desired levels when administered at a conventional dosage. 2,3) According to a few reports, however, the dissolution rate of phenytoin was improved by reducing its particle size, thereby increasing its concentration in blood to the desired level. [4][5][6] Reducing the particle size makes the increase of surface area and as a result of it, dissolution rate of drug increases according to the Nernst-Brunner and Levich modification of the Noyes-Whitney model of dissolution. 7,8) Solubility problem could be solved by reducing particle size to nanometer range. 9)There are different techniques for pulverizing compounds to obtain nanoparticles-wet-grinding in agitated media milling, stirred media milling, wet co-grinding.10,11) However, in most cases, these techniques are difficult to be carried out. Wet milling is one of the various methods used to obtain nanoparticles of a given compound. The use of the wet mill, NanoCrystal, brought about a remarkable improvement in bioavailability by reducing the size of the particles to the nanometer range.12,13) Conventional beads milling is timeconsuming and requires a large amount of beads for pulverizing a given compound in the grinding chamber. Moreover, troublesome tasks such as the cleaning of balls and machine have to be carried out after the pulverization. The rotation/revolution mixer is used to homogenize materials such as epoxy resins, silicone resins, acrylic resins, metal pastes, inks, cosmetics, pastes, and foodstuff. In the pharmaceutical field, beads milling is used for preparing oral formulations for preclinical safety studies.14) Beads milling helps improve product quality and reduce its manufacturing process. Rotation/revolution mixer does not need much amount of compounds and can pulverize a small amount of them (mg order). It can easily scale up from very small volume to large volume. This paper reports on a method to reduce the size of the particles to the nanometer range by using a rotation/revolution mixer and zirconia balls. ExperimentalManufacturing Instruments A rotation/revolution mixer (Nano Pulverizer NP-100, Thinky Co., Ltd., Tokyo, Japan) was used to pulverize the compounds. Two types of vessels made of polyacetal were used-one was convex and the other was circular, as shown in Figs. 3a, b. Zirconia (zirconium oxide) balls with diameters of 0.05 mm, 0.1 mm, 0.3 mm, 0.5 mm, and 1 mm (YTZ-0.05, -0.1, -0.3...

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

“…Following this, some selected formulations were scaled up to 0.5 g/batch using a rotation/revolution mixer 33) that was able to mill drug substances rapidly (approximately 2-15 min) at proper scale for toxicology studies in the discovery stage (approximately 0.1-10 g/batch). The dispersing agents of 0.5% Tween 80 and 0.5% HPMC (3 cP)-0.5% Tween 80 were used in the scale-up study.…”

Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies – Development of particle design method

“…Especially, the nanosuspension, which whole particle distribution was in the submicron range, was successfully produced using 0.1 and 0.3 mm beads. Takatsuka et al reported that the total collision energy was a function of both the weight of a bead and the number of collisions between the beads and particles of compound (Takatsuka et al, 2009). However, the present results suggested that the number of collisions might be more predominant to pulverize the particles than the weight of a bead in the current oscillating system because the correlation between the bead diameter and the milled particle size was a monotone function and there was no local minimum of the milled size.…”

Development of High-Energy Amorphous Solid Dispersion of Nanosized Nobiletin, a Citrus Polymethoxylated Flavone, with Improved Oral Bioavailability

“…11,13 Briefly, 100 mg of NOB was weighed into the vessel of a rotation/revolution mixer (NP-100; Thinky Company Ltd., Tokyo, Japan). Zirconia (zirconium oxide) balls with a diameter of 0.1 mm (Nikkato Company, Ltd., Osaka, Japan) were put into the vessel and the indicated volume of HPC-SSL solution (10 mg/mL) was added.…”