Evaluation of Individual and Crystal Population Dissolution Rates by Time-Resolved X-ray Microtomography.

The intrinsic dissolution rate (IDR) is an important parameter in pharmaceutical science that measures the rate at which a pure crystalline active pharmaceutical ingredient dissolves in the absence of diffusion limitations. Traditional IDR measurement techniques do not capture the complex interplay between particle morphology, fluid flow, and dissolution dynamics. The dissolution rate of individual particles can differ from the population average because of factors such as particle size, surface roughness, or exposure of individual crystal facets to the dissolution medium. The aim of this work was to apply time-resolved X-ray microtomography imaging and simultaneously measure the individual dissolution characteristics of a large population of crystalline particles placed in a packed bed perfused by the dissolution medium. Using NaCl crystals in three different size fractions as a model, time-resolved microtomography made it possible to visualize the dissolution process in a custom-built flow cell. Subsequent 3D image analysis was used to evaluate changes in the shape, size, and surface area of individual particles by tracking them as they are dissolved. Information about the particle population statistics and intrabatch variability provided a deeper insight into the dissolution process that can complement established IDR measurements.

Surface stabilization determines macrophage uptake, cytotoxicity, and bioactivity of curcumin nanocrystals.

Pharmaceutical nanocrystals represent a promising new formulation that combines the benefits of bulk crystalline materials and colloidal nanoparticles. To be applied in vivo, nanocrystals must meet several criteria, namely colloidal stability in physiological media, non-toxicity to healthy cells, avoidance of macrophage clearance, and bioactivity in the target tissue. In the present work, curcumin, a naturally occurring poorly water-soluble molecule with a broad spectrum of bioactivity has been considered a candidate substance for preparing pharmaceutical nanocrystals. Curcumin nanocrystals in the size range of 40-90 nm were prepared by wet milling using the following combination of steric and ionic stabilizers: Tween 80, sodium dodecyl sulfate, Poloxamer 188, hydroxypropyl methylcellulose, phospholipids (with and without polyethylene glycol), and their combination. Nanocrystals stabilized by a combination of phospholipids enriched with polyethylene glycol proved to be the most successful in all evaluated criteria; they were colloidally stable in all media, exhibited low macrophage clearance, and proved non-toxic to healthy cells. This curcumin nanoformulation also exhibited outstanding anticancer potential comparable to commercially used cytostatics (IC50 = 73 µM; 24 h, HT-29 colorectal carcinoma cell line) which represents an improvement of several orders of magnitude when compared to previously studied curcumin formulations. This work shows that the preparation of phospholipid-stabilized nanocrystals allows for the conversion of poorly soluble compounds into a highly effective "solution-like" drug delivery system at pharmaceutically relevant drug concentrations.