Itraconazole suspension for intravenous injection: determination of the real component of complete refractive index for particle sizing by static light scattering.

The purpose of this study is to assess the impact of real refractive indices, using different itraconazole suspensions, on the associated particle size distributions. Instrumental particle size measurement remains the practical option for determining the particle size distribution of a suspension. In this study, the suspension particle size distribution was measured by static light scattering, which requires knowledge of both the real and imaginary components of the complete refractive index. The real refractive indices of micronized itraconazole raw material, as well as vacuum-dried itraconazole suspension samples obtained from different formulations, polymorphs, manufacturing methods and particle size distributions, were determined using the Becke line method. Identical samples were analyzed by two contract laboratories in order to assess consistency. For the static light scattering equipment used in this study, the complete relative refractive index (RRI = n(particte) / n(dispersant) - ik) input required for software calculation is denoted by a refractive index kernel (RRI input) comprising a relative real component and an imaginary component. The reported real refractive indices for the itraconazole raw material as well as vacuum dried itraconazole suspension samples were different, ranging from 1.608 to 1.65 (selected kernel range of 120A010I to 124A010I). The imaginary component of itraconazole suspension was determined in a previous study to be 010I. The average real refractive index was calculated to be 1.62 (122A010I). The particle size distributions obtained using 120A010I and 124A010I were in good agreement with one generated using 122A010I. Therefore, itraconazole suspensions that were produced using different manufacturing methods/formulations or exhibited different particle size distributions/polymorphic forms may use 122A010I in determining particle size distribution. The particle size distributions determined using RRI input outside the range of 120A010I to 124A010I may not be reliable. However, it is recommended that similar investigations be conducted for other drug suspensions on a case-by-case basis.

Suspension for intravenous injection: image analysis of scanning electron micrographs of particles to determine size and volume.

The purpose of this study is to determine the size and volume of large particles in a drug suspension by performing an image analysis of digital micrographs obtained by field emission, low voltage scanning electron microscopy (FE-LVSEM). The data obtained by this method are then used to select the appropriate imaginary component of the complete refractive index necessary for the software computation of particle size distribution measured using laser light diffraction. The application of FE-LVSEM involves four major elements: 1) the use of Anodisc inorganic aluminum oxide membrane filters for the image analysis of drug crystal particles > or = 350 nm having been isolated from suspension in order to determine the area, length, width, and other particle measurements; 2) the use of either a Thornley Everhart secondary electron detector or a MCP detector in the secondary electron mode directly above the specimen so as to produce a shadow-free digital image; 3) recording digital images as viewed normal to the crystal surface and at 45 degrees so as to image the edge of the crystal at a known angle; and 4) determination of drug particle volume from both views and the conversion of those volumes to an equivalent spherical volume.