Using Thermally Stimulated Current (TSC) to Investigate Disorder in Micronized Drug Substance Produced at Different Milling Energies

Abstract

TSC proves sensitive to the crystal defects in the micronized drug substance studied here. The technique is able to differentiate distinct types of disorder and can be used to characterize noncrystalline regions arising from milling processes which are physically distinct from amorphous material.

Effect of milling temperatures on surface area, surface energy and cohesion of pharmaceutical powders

“…Milling is one the most common particle size reduction step. The effect of milling parameters, such as milling frequency, impact velocity, milling time on particle bulk and surface properties, is well documented in the literature Adrjanowicz et al, 2011;Forcino et al, 2010;Vegt et al, 2009;Shariare et al, 2011;Perkins et al, 2009;Kwan et al, 2004;Kwan et al, 2003;Leleux and Williams, 2014;Newman and Zografi, 2014). Kwan et al investigated the effect of milling frequency and propensity of breakage for microcrystalline cellulose and α-lactose monohydrate.…”

Milling induces disorder in crystalline griseofulvin and order in its amorphous counterpart

“…Such a combination determines whether a given length of milling time or milling intensity (type of mill used) will result in crystal dislocations or the amorphous form. For example, Forcino et al 10 were able to produce the amorphous form and crystal defects of the same API using ball milling and jet milling, respectively. Most significantly, the long-term relaxation of the milled drug with low levels of crystal lattice defects (jet milling) did not exhibit the unmistakable decrease in relaxation time, characteristic of aging in glasses.…”

“…Most significantly, the long-term relaxation of the milled drug with low levels of crystal lattice defects (jet milling) did not exhibit the unmistakable decrease in relaxation time, characteristic of aging in glasses. 10,31 Whether or not griseofulvin can be turned into the amorphous form (i.e., exhibiting a glass transition) by a specific milling process and/or length of milling time remains an open possibility, but such a transformation is not achieved during the early stages of cryomilling. It seems that some materials like griseofulvin, possessing a strong crystal lattice, can store sizable amounts of energy in the form of crystal dislocations before becoming amorphous.…”

“…One approach is the two-state model of partial crystallinity, where the material under study is assumed to consist of a mixture of regions that are either completely crystalline or completely amorphous. 9 While this view is not satisfactory in the study of some milled crystalline materials, 10 the two-state model has received considerable acceptance from practitioners, since it readily lends itself to the use of calibration curves from the chosen analytical technique. An alternative view of partial crystallinity is offered by the one-state model, where the reduction in crystallinity is viewed as a gradual and continuous decrease in the degree of orderly arrangement in the crystal lattice, corresponding to a gradual increase in the free energy of the material.…”

“…In some instances, the one-state model may be more appropriate for characterizing the effects of milling. 10 A number of published reports have investigated the difference between amorphous, milled, and crystalline materials. Two differently prepared amorphous samples of simvistatin (cryomilled and the quenched-melt) were characterized and it was found that the cryomilled form was physically less stable, based on a lower onset temperature of recrystallization (46 vs. 80 C) and a lower recrystallization enthalpy (32 vs. 46 J g À1 ).…”