Thermodynamics, Molecular Mobility and Crystallization Kinetics of Amorphous Griseofulvin

Abstract

Griseofulvin is a small rigid molecule that shows relatively high molecular mobility and small configurational entropy in the amorphous phase and tends to readily crystallize from both rubbery and glassy states. This work examines the crystallization kinetics and mechanism of amorphous griseofulvin and the quantitative correlation between the rate of crystallization and molecular mobility above and below Tg. Amorphous griseofulvin was prepared by rapidly quenching the melt in liquid N2. The thermodynamics and dynamics of amorphous phase were then characterized using a combination of thermal analysis techniques. After characterization of the amorphous phase, crystallization kinetics above Tg were monitored by isothermal differential scanning calorimetry (DSC). Transformation curves for crystallization fit a second-order John-Mehl-Avrami (JMA) model. Crystallization kinetics below Tg were monitored by powder X-ray diffraction and fit to the second-order JMA model. Activation energies for crystallization were markedly different above and below Tg suggesting a change in mechanism. In both cases molecular mobility appeared to be partially involved in the rate-limiting step for crystallization, but the extent of correlation between the rate of crystallization and molecular mobility was different above and below Tg. A lower extent of correlation below Tg was observed which does not appear to be explained by the molecular mobility alone and the diminishing activation energy for crystallization suggests a change in the mechanism of crystallization.

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

“…GRIS has been shown to undergo rapid crystallization below and above the T g of the drug (31,58); however, in this study, ASDs were able to be prepared at 10% and 20% drug Fig. 6.…”

“…Polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) of increasing molecular weight were utilized as the carrier polymers and recrystallization inhibitors. Griseofulvin (GRIS) was utilized as the model drug, as it has a relatively high melting point and is known to rapidly recrystallize from its amorphous state (31)(32)(33). ASDs of increasing drug load were prepared by HME, if possible, and by KSD.…”

Comprehensive studies on physical and chemical stability in liquid and glassy states of telmisartan (TEL): solubility advantages given by cryomilled and quenched material

“…For many amorphous pharmaceuticals it was reported that crystallization rate is comparable or even faster than structural relaxation [ 58 ]. Unfortunately, the mechanism of crystallization from the glassy state is till now not fully understand and remain an open issue.…”

Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution

“…For example, one major issue associated with amorphous APIs is that they are inherently metastable, which can lead to phase transformations during storage as well as during dissolution. Although there has been a significant amount of research conducted on the physical stability of amorphous pharmaceuticals under storage conditions (10)(11)(12)(13)(14), much less attention has been given to the in vitro and in vivo behavior of these amorphous materials during dissolution. As a result, there is an insufficient understanding of the processes governing the resultant concentration-time profiles.…”