Batch grinding kinetics and particle shape of active pharmaceutical ingredients by fluidized-bed jet-milling

Tadashi Fukunaka, Boris Golman, Kunio Shinohara

Research output: Contribution to conferencePaperpeer-review

1 Citation (Scopus)


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 dissolution rate. For low solubility APIs, or APIs for specialized formulations such as inhaled delivery, particle size requests are often in the 5-10 micron range. Quite often, the selection of process parameters to achieve a desired milling endpoint is done empirically rather than through engineering approaches. Fluidized-bed jet-mills are relatively new to the pharmaceutical industry compared to loop-style jet-mills and pin-mills. Two of the merits of fluidized-bed jet-mills are less deterioration of APIs quality due to thermal effect (e.g. melt-back) and less shut-down due to compaction over the internal surfaces during the long operation. Though it is known that the grinding mainly depends on inter-particle collision due to jet stream of gas, the grinding characteristics of API in this mill have not been investigated in detail. The present objectives 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, in the fluidized-bed jet-mill. Results of this study show that the variation of the residual fraction with the grinding time during milling can be 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 equation with respect to logarithmic particle diameter. The first Kapur function was found to be affected by such 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 of Ethenzamide was mainly caused by attrition, where small fragments are scraped off from the surface of the large particle. This is considered to result from the physical property of Ethenzamide, as it is expected that organic compounds are difficult to yield volumetric fracture because they have higher elastic properties than inorganic compounds. Shape index was also 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 particle size at a constant speed of the classifier rotor, the product particles are considered to become more spherical due to the selective grinding of large particles.

Original languageEnglish
Number of pages3
Publication statusPublished - Dec 1 2005
Event05AIChE: 2005 AIChE Annual Meeting and Fall Showcase - Cincinnati, OH, United States
Duration: Oct 30 2005Nov 4 2005


Other05AIChE: 2005 AIChE Annual Meeting and Fall Showcase
CountryUnited States
CityCincinnati, OH


  • Batch grinding
  • Ethenzamide
  • Fluidized-bed jet-mill
  • Kinetics
  • Mathematical model
  • Particle shape

ASJC Scopus subject areas

  • Engineering(all)

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