The amorphous state of pharmaceuticals obtained or transformed by milling: Sub-Tg features and rejuvenation

The industrial formulation processes used to prepare drugs impose high energy mechanical constraints which involve dynamic aspects in addition to temperature or pressure variations. Materials which are driven by dynamic stresses undergo modifications of their physical state which affect solubility and bioavailability. In the present paper we are concerned with the very nature of the amorphous end products resulting from a high energy milling. Information is obtained by investigating with (DSC) the relaxation behavior of the glass when heating it over the glass transition at Tg. Two different situations are considered: 1) That of a crystalline compound-trehalose (TRE)-amorphized by milling. In that case further characterization is achieved by looking at the effects of temperature and duration of subsequent aging steps. 2) That of high energy cryomilling on a long aged quench cooled amorphous indomethacine (IDM). The specificities of the activated glass are revealed by Tg and sub-Tg events. Milling induces some relaxation capabilities within the glass. An interesting result is that cryomilling is able to fastly rejuvenate an aged amorphous sample and to modify its local structure. Impacts on recrystallization are demonstrated. Such mechanically induced modifications of the physical state can induce physical and chemical instabilities.