Preparation of glibenclamide nanocrystals by a simple laboratory scale ultra cryo-milling

Abstract

The objective of this study is to evaluate the ability to reduce the particle size of glibenclamide (GBC) to the nanometric scale through a very simple and well-known laboratory scale method, the laboratory scale ultra cryo-milling. The effect of milling on GBC crystalline properties and dissolution behaviour was deliberately evaluated in the absence of any surfactants as stabilizers. The milling procedure consisted in adding particles to liquid nitrogen and milling them by hand in a mortar with a pestle for different time intervals (15, 30, 40 min). For comparison, the same milling procedure was also applied without liquid nitrogen. The particle size reduction was evaluated for the coarsest samples (>3 μm) by measuring the particle Ferret’s diameter through scanning electron microscopy, while for the smallest one (<3 μm) by dynamic light scattering. A time grinding of 40 min in the presence of liquid nitrogen was revealed highly efficacious to obtain particles of nanodimensions, with a geometric mean particle size of 0.55 ± 0.23 μm and more than the 80 % of particles lower than 1,000 nm. Interestingly, non-agglomerated particles were obtained. Differential scanning calorimetry and X-ray powder diffractometry allowed to assess that under mechanical treatment no polymorphic transitions were observed, while a decrease in crystallinity degree occurred depending on the milling procedure (presence or absence of liquid nitrogen) and the milling time (crystallinity decreases at increasing milling time from 15 to 40 min). A comparison of the intrinsic dissolution rate and the dissolution from particles revealed an interesting improvement of particle dissolution particularly for particles milled in the presence of liquid nitrogen due to an increase in particle surface area and concentration gradient, according to the Noyes–Whitney equation.