A Calorimetric Method to Estimate Molecular Mobility of Amorphous Solids at Relatively Low Temperatures

Chen, Mao; Chamarthy, Sai Prasanth; Byrn, Stephen R.; Pinal, Rodolfo

doi:10.1007/s11095-006-9071-9

Cited by 34 publications

(22 citation statements)

References 23 publications

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“…[109] This method is based on the non-linear Adam-Gibbs equation that requires an estimation of the fragility parameters of a glass and its fictive temperature: [110] τ…”

Section: The Adam-gibbs Equationmentioning

confidence: 99%

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Review: physical chemistry of solid dispersions

2009

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Objectives With poorly soluble drug candidates emerging in the drug discovery pipeline, the importance of the solid dispersion formulation approach is increasing. This strategy includes complete removal of drug crystallinity, and molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier. The potential of this technique to increase oral absorption and hence bioavailability is enormous. Nevertheless, some issues have to be considered regarding thermodynamic instability, as well in supersaturated solutions that are formed upon dissolution as in the solid state. Key findings After a brief discussion on the historical background of solid dispersions and their current role in formulation, an overview will be given on the physical chemistry and stability of glass solutions as they form supersaturated solutions, and during their shelf life. Conclusions Thorough understanding of these aspects will elicit conscious evaluation of carrier properties and eventually facilitate rational excipient selection. Thus, full exploitation of the solid dispersion strategy may provide an appropriate answer to drug attrition due to low aqueous solubility in later stages of development.

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“…[109] This method is based on the non-linear Adam-Gibbs equation that requires an estimation of the fragility parameters of a glass and its fictive temperature: [110] τ…”

Section: The Adam-gibbs Equationmentioning

confidence: 99%

“…[109] It was found that for two compounds with similar Tg but different fragility, the relaxation time constant can differ by several orders of magnitude. For glasses with similar Tg, the glass with the highest fragility will be more stable.…”

Section: Fragilitymentioning

confidence: 99%

Review: physical chemistry of solid dispersions

2009

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“…A recent study by Mao et al, had exposed the limitation of the commonly used KWW method to predict mobility of 'relatively' stable molecules with high T g and at aging temperatures T g -50 K. The concept of initial relaxation time (τ 0 ) has been discussed for cases where the relaxation process was too sluggish [15]. Therefore, τ 0 for IBS was calculated using the fragility parameters D (strength parameter), m (steepness parameter), and γC p .…”

Section: Molecular Mobility In 'Sluggish' Amorphous Systemsmentioning

confidence: 99%

Molecular Mobility and Physical Stability of Amorphous Irbesartan

Chawla

2009

Sci. Pharm.

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Amorphous systems have attracted considerable attention due to their favorable properties; however, their stability issues still pose a major challenge. The purpose of the present work was to investigate the role of molecular mobility and moisture in the physical stability of a selected pharmaceutical amorphous system. Irbesartan (IBS), a relatively stable glass, was chosen as the model drug, as it exhibits a good physical stability (resistance to crystallization) at temperatures below the glass transition (T g -50 K). The amorphous system was annealed at temperatures 298 K (25 °C) and 313 K (40 °C) at 0 and 75 % RH to study the effect of temperature and moisture on its relaxation behavior. Differential scanning calorimetry (DSC) was used to characterize both the crystalline and the freshly prepared glass, and to monitor the extent of relaxation at temperatures below glass transition (Tg) as well as heat capacity changes as a function of temperature. Molecular relaxation time constant (τ) decreased drastically from 302 years to 68 hours with the increase in annealing temperature as determined by Kohlrausch-William-Watts (KWW) equation. IBS was found to be 'relatively' stable in the amorphous state and presented a challenge for temporal measurements. Hence, at low annealing temperatures, (T g -50 K or below) initial relaxation time (τ 0 ) was estimated using the calorimetric based approach. Amorphous IBS was non-hygroscopic and retained its glassy nature under the accelerated stability conditions. The extent of relaxation in the amorphous drug in the presence of moisture was also estimated.

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“…The relative crystallinity, α( t ), was determined by the ratios of the melting enthalpies of sample with the final melting enthalpy without any change. The equations 31 are listed below:

x (t) = \frac{Δ H (t)}{Δ H (P . M .)}

where Δ H ( t ) is the melting enthalpy of the recrystallized solid dispersion sample and the Δ H ( P.M .) represents the melting enthalpies of physical mixtures of the API and polymers for each formulation.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the recrystallization kinetics of hot-melt extruded polymeric solid dispersions using an improved Avrami equation

Feng

Park

et al. 2014

Drug Development and Industrial Pharmacy

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The recrystallization of an amorphous drug in a solid dispersion system could lead to a loss in the drug solubility and bioavailability. The primary objective of the current research was to use an improved kinetic model to evaluate the recrystallization kinetics of amorphous structures and to further understand the factors influencing the physical stability of amorphous solid dispersions. Amorphous solid dispersions of fenofibrate with different molecular weights of hydroxypropylcellulose, HPC (Klucel™ LF, EF, ELF) were prepared utilizing hot-melt extrusion technology. Differential scanning calorimetry was utilized to quantitatively analyze the extent of recrystallization in the samples stored at different temperatures and relative humidity (RH) conditions. The experimental data were fitted into the improved kinetics model of a modified Avrami equation to calculate the recrystallization rate constants. Klucel LF, the largest molecular weight among the HPCs used, demonstrated the greatest inhibition of fenofibrate recrystallization. Additionally, the recrystallization rate (k) decreased with increasing polymer content, however exponentially increased with higher temperature. Also k increased linearly rather than exponentially over the range of RH studied.

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A Calorimetric Method to Estimate Molecular Mobility of Amorphous Solids at Relatively Low Temperatures

Abstract: The proposed method can be used to estimate molecular mobility at relatively low temperatures without having to conduct enthalpy recovery experiments. An accurate tau (0) determination from this method relies on faithful fragility measurements.

Cited by 34 publications

References 23 publications

Review: physical chemistry of solid dispersions

Review: physical chemistry of solid dispersions

Molecular Mobility and Physical Stability of Amorphous Irbesartan

Evaluation of the recrystallization kinetics of hot-melt extruded polymeric solid dispersions using an improved Avrami equation

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