Leon Farber

Use of X-ray tomography to study the porosity and morphology of granules

Abstract X-ray computed tomography (XRCT) is a technique that uses X-ray images to reconstruct the internal microstructure of objects. Known as a CAT scan in medicine, it has found wide application for whole-body and partial-body imaging of hard tissues (e.g., bone). A modern tabletop XRCT system with a resolution of about 4 μm was used to characterize some pharmaceutical granules. Total porosity, pore size distribution, and geometric structure of pores in granules produced using different conditions and materials were studied. The results were compared to data obtained from mercury porosimetry. It was found that while XRCT is less precise in the determination of total porosity in comparison to mercury porosimetry, it provides detailed morphological information such as pore shape, spatial distribution, and connectivity. The method is nondestructive and accurate down to the resolution of the instrument. Tomographic images show that the pore network of individual granules comprises relatively large cavities connected by narrow pore necks. The major structural difference between granules produced at different conditions of compaction and shear is a reduction in the pore neck diameter; the cavity size is relatively insensitive to these conditions. Comparison of pore size distributions determined from tomographic images and mercury porosimetry indicates that mercury intrusion measures the pore neck size distribution, while tomography measures the true size distribution of pores ca. 4 μm or larger (the instrument resolution).

Characterization of Crystalline Drug Nanoparticles Using Atomic Force Microscopy and Complementary Techniques

AbstractPurpose. The purpose of this work was to image crystalline drug nanoparticles from a liquid dispersion and in a solid dosage form for the determination of size, shape, and distribution. Methods. Crystalline drug nanoparticles were adsorbed from a colloidal dispersion on glass for atomic force microscopy (AFM) imaging. Nanoparticles that were spray coated onto a host bead were exposed by ultramicrotomy for scanning electron microscopy and AFM examination. Results. The adsorbed drug nanoparticles were measured by AFM to have a mean diameter of 95 nm and an average aspect ratio of 1.3. Nanoparticles observed in the solid dosage form had a size and shape similar to drug nanoparticles in the dispersion. Particle size distribution from AFM measurement agreed well with data from field emission scanning electron microscopy, static light scattering, and X-ray powder diffraction. Conclusions. AFM is demonstrated to be a valuable tool in visualization and quantification of drug nanoparticle crystals in formulations. In addition to accurate size measurement, AFM readily provides shape and structural information of nanoparticles, which cannot be obtained by light scattering. Ultramicrotomy is a good sample preparation method to expose the interior of solid dosage forms with minimal structural alteration for microscopic examination.

Chapter 26 Morphology and strength development in solid and solidifying interparticle bridges in granules of pharmaceutical powders

Publisher Summary Granulation is used extensively in the pharmaceutical industry to produce larger granules from fine powdery particles to improve flowability and appearance, reduce dustiness, and to ensure thorough mixing of different ingredients. This last application is a very important unit operation in the pharmaceutical industry to produce non-segregating mixtures of dry powders that would otherwise strongly segregate because of differences in size, shape, density, and surface properties. The so-called “wet” granulation process uses liquids that are dripped, sprayed, or poured into a shearing mass of powder. The granulating fluid is typically composed of water and/or alcohol and may contain surfactants and polymeric binders such as hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP). The process by which large dry granules are formed from fine powders by using liquid binders is quite complex. An accepted view holds that the liquid solution wets and spreads in the interstices among primary particles, forming liquid bridges that hold them together by capillary and viscous forces. These wet or “green” granules are subsequently dried and the liquid evaporated from the bridges to leave behind solid bridges or “necks” that impart mechanical strength to the dry granule.