(446b) Batch Grinding Kinetics and Particle Shape of Active Pharmaceutical Ingredients by Fluidized-Bed Jet-Milling

As most of active pharmaceutical ingredients (APIs) developed in pharmaceutical industries have low solubility in water, production of fine particles by milling is performed for the main purpose of improvement of their solubility. Recently, requirements for properties of milled particles, such as mean particle diameter and particle size distribution, are getting stricter and stricter. However, the API milling process has not been developed so far by engineering approach, but mainly on the past experiences. In the pharmaceutical field, Fluidized-bed Jet-mill is relatively a new equipment comparing with the conventional ones, such as Jet-mill and Pin-mill. One of the merits is less troubles like the deterioration of API's quality due to thermal effect (e.g. melt-back) and the shut-down due to compaction over the internal surfaces during the long operation. Though the grinding mainly depends on inter-particle collision due to jet stream of gas, the grinding characteristics of API has not been investigated well. The present objects are to analyze the grinding mechanism and to find out the effect of the operating parameters on the breakage and selection functions and on the particle shape by the batch grinding test with a model API, Ethenzamide, and the Fluidized-bed Jet-mill. As a result, the variation of the residual fraction with the grinding time during milling was expressed by a mathematical model using only the first Kapur function to be consistent with experimental data satisfactorily. The shape of the function was characteristic of API and well fitted to a cubic function with respect to logarithmic particle diameter. The first Kapur function was found to be affected by the operating parameters as the grinding gas pressure, the charge weight of raw material and the linear velocity at the grinding nozzle. Although, under the low grinding pressure, the selection function tends to decrease with increasing charge weight, it was found to increase with decreasing charge under the high pressure. At the same gas flow rate, the selection function increases with the linear gas velocity. According to the assessments of the breakage and the selection functions derived from the first Kapur function, it was found that the grinding mechanism of Ethenzamide was mainly caused by attrition that large particle is selectively ground and small fragments are scraped off from the surface. This is considered to result from the physical property of Ethenzamide as organic compounds which are difficult to yield volumetric fracture due to higher elastic properties than inorganic compounds and metals. On the other hand, shape index was applied to the analysis of the mechanism. It describes a macroscopic shape of a particle outline using the ratio of minor- to major-axis of ellipse which is derived by Fourier transformation. The shape index of product particles by batch-grinding with the Fluidized-bed Jet-mill was found to increase with the grinding gas flow rate. Since higher gas flow rate leads to larger product particles due to centrifugal classification at a constant maximal speed of the rotor for the batch grinding, the product particles are considered to become more spherical due to the selective grinding of large particles.