Dry mixing transformed micro-particles of a drug from a highly crystalline to a highly amorphous state

Abstract

In this paper, the degree of mechanical activation of particles due to mechanical straining without subsequent breakage has been studied. Griseofulvin micro-particles of about 2 microm in size were mixed with glass beads (proportion 1:99) in a tumbling mixer. After a series of mixing times, ranging from 2-96 hours, samples were withdrawn and the particle size and the degree of crystallinity were assessed. The mixing process gave no detectable change in particle size. The degree of disorder of the drug particles increased with mixing time and highly amorphous particles were obtained after about 24 h of mixing. The results thus indicate that particles can be completely activated by mechanical treatment without a parallel size reduction of the particles. It is suggested that the activation is caused by repeated deformation of the particles, gradually transforming the crystalline state into an amorphous state.

Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin

“…For crystalline GSF samples, mechanical activation occurring due to dry mixing was found to begin at the particle surface and gradually form a surface layer with higher energy (18). The thickness of this layer was suggested to be around 0.1-1 μm corresponding to a depth of 100-1000 molecules (19).…”

Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer

“…). According to earlier reported data, their size were about 2 μm, expressed as a volume diameter. The SEM image supports that the particles can be described as micro‐particles and they showed a very large specific surface area (Table ).…”

“…Griseofulvin with a melting point of 218°C and an approximate particle size of 2 μm, acid‐washed glass beads with a labelled particle size range of 425 –600 μm and calcium nitrate tetrahydrate were obtained from Sigma‐Aldrich, Stockholm, Sweden. Magnesium stearate powder (Ph.…”

“…From the crystallisation enthalpies, an indication of the degree of amorphisation ( A %) was calculated as:where H x is the crystallisation enthalpy of particles mixed or compressed, and H q is the crystallisation enthalpy of the melt‐quenched material. In this calculation, a value of 60 J/g, obtained from the crystallisation of griseofulvin by a melt‐quenching procedure, was used.…”

“…Thus, the particle processes causing amorphisation can be categorised as particle failure and inter‐particulate sliding. Since the seminal articles of Hüttenrauch, numerous papers on mechanical amorphisation of organic solids have appeared in the literature . In the pharmaceutical literature, the process of mechanical amorphisation is almost without exceptions discussed as a result of the breakage of particles during application of a force, for example during milling and compaction.…”