Inverse gas chromatography a tool to follow physicochemical modifications of pharmaceutical solids: Crystal habit and particles size surface effects.

Powders are complex systems and so pharmaceutical solids are not the exception. Nowadays, pharmaceutical ingredients must comply with well-defined draconian specifications imposing narrow particle size range, control on the mean particle size, crystalline structure, crystal habits aspect and surface properties of powders, among others. The different facets, physical forms, defects and/or impurities of the solid will alter its interaction properties. A powerful way of studying surface properties is based on the adsorption of an organic or water vapor on a powder. Inverse gas chromatography (IGC) appears as a useful method to characterize the surface properties of divided solids. The aim of this work is to study the sensitivity of IGC, in Henry's domain, in order to detect the impact of size and morphology in surface energy of two crystalline forms of an excipient, d-mannitol. Surface energy analyses using IGC have shown that the α form is the most energetically active form. To study size and shape influence on polymorphism, pure α and ß mannitol samples were cryomilled (CM) and/or spray dried (SD). All forms showed an increase of the surface energy after treatment, with a higher influence for ß samples (γs(d) of 40-62 mJ m(-2)) than for α mannitol samples (γs(d) of 75-86 mJ m(-2)). Surface heterogeneity analysis in Henry's domain showed a more heterogeneous ß-CM sample (62-52 mJ m(-2)). Moreover, despite its spherical shape and quite homogeneous size distribution, ß-SD mannitol samples showed a slightly heterogeneous surface (57-52 mJ m(-2)) also higher than the recrystallized ß pure sample (∼40 mJ m(-2)).

Physicochemical characterization of D-mannitol polymorphs: the challenging surface energy determination by inverse gas chromatography in the infinite dilution region.

Nowadays, it is well known that surface interactions play a preponderant role in mechanical operations, which are fundamental in pharmaceutical processing and formulation. Nevertheless, it is difficult to correlate surface behaviour in processes to physical properties measurement. Indeed, most pharmaceutical solids have multiple surface energies because of varying forms, crystal faces and impurities contents or physical defects, among others. In this paper, D-mannitol polymorphs (α, ß and δ) were studied through different characterization techniques highlighting bulk and surface behaviour differences. Due to the low adsorption behaviour of ß and δ polymorphs, special emphasis has been paid to surface energy analysis by inverse gas chromatography, IGC. Surface energy behaviour has been studied in Henry's domain showing that, for some organic solids, the classical IGC infinite dilution zone is never reached. IGC studies highlighted, without precedent in literature, dispersive surface energy differences between α and ß mannitol, with a most energetically active α form with a γ(s)(d) of 74.9 mJ·m⁻². Surface heterogeneity studies showed a highly heterogeneous α mannitol with a more homogeneous ß (40.0 mJ·m⁻²) and δ mannitol (40.3 mJ·m⁻²). Moreover, these last two forms behaved similarly considering surface energy at different probe concentrations.