Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-Concentration Poly(ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility

Abstract

This study aims to investigate the crystallization behavior and molecular dynamics of amorphous griseofulvin (GSF) in the presence of low-concentration poly(ethylene oxide) (PEO). We observe that the addition of 3% w/w PEO remarkably increases the crystal growth rate of GSF by two orders of magnitude in both the supercooled liquid and glassy states. The liquid dynamics of amorphous GSF in the presence and absence of PEO are characterized by dielectric spectroscopy. With an increase of the PEO content, the α-relaxation times of the systems decrease, indicating the increase of global molecular mobility. The couplings between molecular mobility and crystallization kinetics of GSF systems show strong time-dependences below T. The overlapping of α-relaxation times of GSF in presence and absence of PEO as a function of T/T suggest the "plasticization" effect of PEO additives. However, the crystallization kinetics of amorphous GSF containing low-concentration PEO do not overlap with those of pure GSF on a T/T scale. The remarkable accelerating effect of crystal growth of amorphous GSF by low-concentration PEO can be partially attributed to the increase of global mobility. The high segmental mobility of PEO is expected to strongly affect the crystal growth rates of GSF. These findings are relevant for understanding and predicting the physical stability of amorphous pharmaceutical solid dispersions.

Diffusion-controlled and `diffusionless' crystal growth: relation between liquid dynamics and growth kinetics of griseofulvin

“…Here, the difference in the fragility of a liquid is attributed to the differences in vibrational heat capacity, harmonic and anharmonic (Martinez & Angell, 2001). In our previous work, the fragility parameter m of a supercooled liquid of GSF was calculated as 84.6, indicating liquid GSF is a 'moderately fragile' material (Shi, Zhang, Su et al, 2017). As shown in Fig.…”

“…Generally, the internal properties of a fluid, which reflect the cooperative nature of entire molecules, have been widely reported to play a crucial role in governing the physical stability of amorphous pharmaceutical formulations (Yu, 2001;Baird et al, 2012;Grzybowska et al, 2016;Sibik & Zeitler, 2016). Although considerable efforts have been made to explore the relation between liquid dynamics and crystallization kinetics, the relationship is still poorly understood (Grzybowska et al, 2016;Tu et al, 2019;Fung et al, 2018;Shi, Zhang, Su et al, 2017;. On the basis of the classic crystallization theory, the crystallization rate at the crystal-melt interface G(T) is given as G(T) = D(T)f(T), where D(T) and f(T) represent the temperature dependence of molecular diffusion and the free energy term of nucleation/crystal growth, respectively (Magill & Li, 1973;Ngai et al, 2000).…”

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

“…For the crystal growth in drug-polymer binary systems, one interesting phenomenon, polymer enrichment as a function of temperature and polymer concentration, could be observed at the advancing growth front of crystal using polarized light microscopy combined with a hot stage [29,30]. Visual observations can directly provide a reasonable explanation for the fact that the increase of global molecular mobility alone is insufficient to account for the accelerating effects of a low-T g polymer-e.g., poly (ethylene oxide) (PEO)-on the crystal growth of small-molecule drug griseofulvin and indomethacin [31,32]. In addition to the high global molecular mobility, PEO enrichment at the growth front could also accelerate the mass transport of drug molecules entering the crystalline phase by the high segmental mobility of PEO [29,30].…”

“…Recent studies revealed that molecular mobility of amorphous drug and ASD could be enhanced by the addition of water [79,80], glycerol [81], and low-T g polymer, e.g., poly(ethylene oxide) [31,32]. Mehta et al proposed that the increased molecular mobility of amorphous system by the sorbed water is attributed to the plasticization effect [79].…”

Advances in coamorphous drug delivery systems

“…In addition, the increased volume of final product may cause a problem for a high-dose drug formulation10., 11.. Furthermore, some polymers with low glass transition temperatures might accelerate rather than inhibit crystallizations of amorphous solids dispersions12., 13., 14., 15..…”