Mechanism of solid state amorphization of glucose upon milling.

Crystalline α-glucose is known to amorphize upon milling at -15 °C while it remains structurally invariant upon milling at room temperature. We have taken advantage of this behavior to compare the microstructural evolutions of the material in both conditions in order to identify the essential microstructural features which drive the amorphization process upon milling. The investigations have been performed by differential scanning calorimetry and by powder X-ray diffraction. The results indicate that two different amorphization mechanisms occur upon milling: an amorphization at the surface of crystallites due to the mechanical shocks and a spontaneous amorphization of the crystallites as they reach a critical size, which is close to 200 Å in the particular case of α-glucose.

Solid state mutarotation of glucose.

It has been recently shown that mechanical milling can amorphize D-glucose without any mutarotation, giving rise to an anomerically pure amorphous sample. We have taken advantage of this exceptional possibility to study the kinetic of mutarotation in the amorphous solid state. The investigations have been performed in situ by time-resolved Raman spectroscopy. The results reveal an unexpected coupling between the mutarotation process and the structural relaxations involved in the glassy state.

Amorphization of sugar hydrates upon milling.

The possibility to amorphize anhydrous crystalline sugars, like lactose, trehalose and glucose, by mechanical milling was previously reported. We test here the possibility to amorphize the corresponding crystalline hydrates: lactose monohydrate, trehalose dihydrate and glucose monohydrate using fully identical milling procedures. The results show that only the first hydrate amorphizes while the other two remain structurally invariant. These different behaviours are attributed to the plasticizing effect of the structural water molecules which can decrease the glass transition temperature below the milling temperature. The results reveal clearly the fundamental role of the glass transition in the solid-state amorphization process induced by milling, and they also explain why crystalline hydrates are systematically more difficult to amorphize by milling than their anhydrous counterpart. The investigations have been performed by differential scanning calorimetry and powder X-ray diffraction.

First obtaining of glass solutions and phase diagram of glucose with fully tunable anomeric concentration.

In this article we show the possibility to form amorphous alpha-glucose/beta-glucose molecular alloys directly in the solid state by comilling crystalline alpha-glucose and crystalline beta-glucose. Contrary to the usual melt quenching process, milling does not induce any mutarotation so that alloys can be obtained for the whole range of anomeric concentration. This offers the unique possibility to explore the phase diagram of this binary system which appears to be a eutectic mixture. The structural and thermodynamic investigations have been performed by powder X-ray diffraction and differential scanning calorimetry.

Transformation of pharmaceutical compounds upon milling and comilling: the role of T(g).

Milling is a usual process used in the course of drug formulation, which however may change the physical nature of the end product. The diversity of the transformations of organic compounds upon milling has been widely demonstrated in the pharmaceutical literature. However, no effort has still been devoted to study the correlation between the nature of the transformation and the milling conditions. Results clarifying such transformations are shortly reviewed with special attention paid to the temperature of milling. The importance of the position of the glass transition temperature compared with that of milling is demonstrated. It is shown that decreasing the milling temperature leads to an increase of the amorphization tendency whereas milling above T(g) can produce a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual suggestion that milling transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are also presented, which demonstrate the possibility for milling to form low temperature solid-state alloys that offer new promising ways to stabilize amorphous molecular solids.