Morphological and Structural Properties of Amorphous Lactulose Studied by Scanning Electron Microscopy, Polarized Neutron Scattering, and Molecular Dynamics Simulations.

Morphological and structural properties of amorphous disaccharide lactulose (C12H22O11), obtained by four different amorphization methods (milling, quenching of the melt form, spray-drying, and freeze-drying), are investigated by scanning electron microscopy, polarized neutron scattering, and molecular dynamics simulations. While major differences on the morphology of the different amorphous samples are revealed by scanning electron microscopy images, only subtle structural differences have been found by polarized neutron scattering. Microstructure of the milled sample appears slightly different from the other amorphized materials with the presence of remaining crystalline germs which are not detected by X-ray diffraction. Quantitative phase analysis shows that these remaining crystallites are present in a ratio between 1 and 4%, and their size remains between 20 and 30 nm despite a long milling time of about 8 h. The impact of the change in tautomeric concentrations on the physical properties of lactulose in the amorphous state has been investigated from molecular dynamics simulations. It is suggested that chemical differences between lactulose tautomers could be at the origin of small structural differences detected by polarized neutron scattering.

Impact of Amorphization Methods on the Physicochemical Properties of Amorphous Lactulose.

The influence of the amorphization technique on the physicochemical properties of amorphous lactulose was investigated. Four different amorphization techniques were used: quenching of the melt, milling, spray-drying, and freeze-drying, and amorphous samples were analyzed by differential scanning calorimetry, NMR spectroscopy, and powder X-ray diffraction analysis. Special attention was paid to the tautomeric composition and to the glass transition of amorphized materials. It was found that the tautomeric composition of the starting physical state (crystal, liquid, or solution) is preserved during the amorphization process and has a strong repercussion on the glass transition of the material. The correlation between these two properties as well as the plasticizing effect of the different tautomers was clarified by molecular dynamics simulations.

Lactulose: A Model System to Investigate Solid State Amorphization Induced by Milling.

In this article, we show that crystalline lactulose can be amorphized directly in the solid state by mechanical milling. Moreover, compared to similar materials, the amorphization kinetics of lactulose is found to be very rapid and the amorphous state thus obtained appears to be very stable against recrystallization on heating. These features make lactulose a model compound for this type of solid state transformation. The ease of crystalline lactulose to be amorphized on milling is explained by comparing elastic constants of lactulose with those of several other disaccharides. These constants have been determined by molecular dynamics simulations. The article also shows how isothermal dissolution calorimetry can be used effectively for the determination of amorphization kinetics during grinding when the usual characterization techniques (differential scanning calorimetry and powder X-ray diffraction) fail.