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Richard D. Ludescher - One of the best experts on this subject based on the ideXlab platform.
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Effects of glycerol on the Molecular Mobility and hydrogen bond network in starch matrix.
Carbohydrate polymers, 2014Co-Authors: Jun Liang, Richard D. LudescherAbstract:Abstract The effects of glycerol on Molecular Mobility and hydrogen bonding network in an amorphous glassy starch matrix were studied using phosphorescence and IR spectroscopy. Amorphous potato starch films containing varying amounts of glycerol (0, 5, 10, 20 and 30 wt.%) were formulated by rapidly dehydrating aqueous potato starch gel (5%, w/v) with a corresponding content of glycerol; X-ray diffraction data confirm that the films contained negligible content of crystalline starch. Erythrosin B (Ery B) phosphorescence was used to monitor the Molecular Mobility of these matrices over the temperature range from 0 to 100 °C. Analysis of Ery B emission peak frequency, band width and intensity decay provided information about thermally-activated modes of Molecular Mobility in the matrix. Dipolar relaxation around the triplet state of Ery B was enhanced by addition of glycerol and the extent of relaxation increased at low and intermediate but decreased at higher temperature. The glycerol content-dependent onset temperature for this transition was 70 °C for pure starch and decreased to 40 °C for a matrix with 30% glycerol. Measurements of the rate of non-radiative decay from the Ery B triplet state indicated that glycerol plasticized the starch matrix above ∼10 wt.% while acting as an antiplastizer to increase the matrix Molecular Mobility at lower content. These matrix properties were related to glycerol-dependent increases in hydrogen bond strength as measured by IR.
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Influence of antioxidant structure on local Molecular Mobility in amorphous sucrose.
Carbohydrate research, 2013Co-Authors: Jun Liang, Maria G. Corradini, Richard D. LudescherAbstract:Abstract The effect of the antioxidants gallic acid and methyl, propyl, and octyl gallate on the Molecular Mobility and hydrogen bond network in amorphous sucrose was studied. Solid amorphous sucrose films with and without the addition of antioxidants at a mole ratio of 1:5 (antioxidant/sucrose) were cast from solution onto quartz slides. Local Molecular Mobility from 0 to 70 °C was measured using tryptophan amino acid as a luminescent probe dispersed in the films. Phosphorescence from the tryptophan probe provides spectroscopic characteristics—emission spectrum and lifetime—that are sensitive to changes in Molecular Mobility induced by the addition of antioxidants. Local Molecular Mobility detected by tryptophan increased in the following order: sucrose sucrose–gallic acid > sucrose–propyl gallate > sucrose > sucrose–octyl gallate) that was nearly the reverse of that seen in matrix Mobility. Analysis of the differential effects of the antioxidants suggests that the presence of the hydroxyl benzoyl head group increased matrix Molecular Mobility and hydrogen bond strength while the saturated carbon chain decreased Mobility and bond strength. The influence of the carboxyl group on matrix properties was comparable to that of the formyloxy group. These results indicate that the addition of specific functional ingredients such as antioxidants may significantly affect the physical properties and consequently functional properties of amorphous edible films in ways that might condition their use. The observed changes are closely related to the chemical structure of the added species.
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Molecular Mobility in a homologous series of amorphous solid glucose oligomers
Food Chemistry, 2012Co-Authors: Rashmi Tiwari, Richard D. LudescherAbstract:Abstract The Molecular Mobility of amorphous solid biomaterials influences the stability of dried foods and pharmaceuticals, the viability of seeds and spores, and the desiccation-tolerance of organisms during anhydrobiosis. Current understanding of how structure correlates with Molecular Mobility in the glassy state is inadequate. We used phosphorescence from vanillin dispersed in amorphous films to study the effect of temperature on Molecular Mobility in the homologous series of oligosaccharides glucose, maltose, maltotriose, maltotetraose, maltopentaose, maltohexaose, and maltoheptaose. Phosphorescence emission spectra and intensity decays were collected from −10 to as high as 130 °C. Emission peak energy, a measure of the extent of dipolar relaxation around the excited state prior to emission, decreased monotonically with temperature, decreasing more significantly in the glassy state in larger sugars (higher degree of polymerisation). The intensity decays were well fitted with sums of either four (glucose, maltose, maltotriose) or three exponentials (maltotetraose, maltopentaose, maltohexaose, maltoheptaose); fit lifetimes at each temperature varied over nearly two orders of magnitude, suggesting a comparable range in matrix dynamic heterogeneity. The lifetimes decreased monotonically with temperature, while the lifetime amplitudes favoured the long lifetime components at lower and short lifetime components at higher temperatures near T g . Arrhenius analysis indicated that the rate of non-radiative decay, which reflects coupling of probe vibrations with matrix motions and thus provides an estimate of the matrix Molecular Mobility, increased with Molecular size in the glassy state. Both apparent activation energy and activation entropy increased systematically with temperature in all sugars. These data provide additional evidence that the rate and extent of Molecular Mobility in glassy state carbohydrates is higher in sugars of greater Molecular size (mass) and thus higher glass transition temperature and provides additional insight into the Molecular dynamics of the glassy state in carbohydrates.
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Effect of starch on the Molecular Mobility of amorphous sucrose.
Journal of agricultural and food chemistry, 2011Co-Authors: Yumin You, Richard D. LudescherAbstract:Molecular Mobility in amorphous solid biomaterials is modulated by the composition and environment (primarily temperature). Phosphorescence of the triplet probe erythrosin B was used to generate a Mobility map within amorphous sucrose films doped with starch ranging from 0.001 to 0.1 g starch/g sucrose. Data on the emission energy and lifetime of erythrosin B in sucrose and sucrose-starch films over the temperature range from 5 to 100 °C indicates that starch influences the Molecular Mobility as well as dynamic site heterogeneity of amorphous sucrose in a dose-dependent manner. At a starch/sucrose weight (wt) ratio below 0.005, both emission energy and lifetime decreased, and both the dipolar relaxation rate and nonradiative quenching rate k(TS0) increased, indicating that starch increased the matrix Molecular Mobility. At a ratio above 0.005, both emission energy and lifetime increased, and the dipolar relaxation rate and nonradiative quenching rate decreased, indicating that starch decreased the matrix Mobility both in the glass and in the melt. The Mobility showed a minimum value at a ratio of 0.01. The interactions existing in the sucrose-starch matrix are considered as the determining factor to influence the Molecular Mobility of sucrose-starch mixtures. Changes in the distribution of emission energies (emission bandwidth) and lifetimes indicated that starch increased the spectral heterogeneity at high contents while showing insignificant change or a slight decrease in the heterogeneity at low starch contents. These data illustrate the complex effects of a polymer with mainly linear structure and flexible conformation on the Mobility of an amorphous, hydrogen bonded sugar matrix.
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The Effect of Molecular Size on Molecular Mobility in Amorphous Oligosaccharides
Food Biophysics, 2010Co-Authors: Richard D. LudescherAbstract:The physical properties and especially the Molecular Mobility of amorphous carbohydrate matrixes directly influence the stability of foods, feeds, and pharmaceuticals and the dessication tolerance of animals and plants during anhydrobiosis. Phosphorescence of the sodium salt of erythrosin B was used to investigate the local Molecular Mobility in pure amorphous solids of a homologous series of malto-oligosaccharides (maltose, G_2; maltotriose, G_3; maltotetraose, G_4; maltopentaose, G_5; maltohexaose, G_6; and maltoheptaose, G_7); sucrose and maltodextrin DE18 (a hydrolytic fraction of starch) were investigated for comparison. Measurements of the temperature-dependence of the phosphorescence emission energy, an indicator of the extent of local dipolar relaxation, and the phosphorescence emission lifetime, an indicator of the rate of collisional quenching of the excited state by matrix molecules, demonstrate that the local matrix Molecular Mobility increases with Molecular size, and thus, with an increase in T _g, in these glucose oligosaccharides. Master curves of the spectroscopic measures of matrix Mobility for each oligosaccharide, plotted against T – T _g, were not superimposable, suggesting that local properties of the amorphous sugar matrixes, rather than T _g per se, influence local matrix Mobility. Indicators of spectral heterogeneity also varied with Molecular size, indicating that dynamic site heterogeneity also increased with Molecular size and thus, T _g. These results emphasize the importance of additional research in developing appropriate “Molecular rules” for designing amorphous matrix systems with better long-term stability for foods, feeds, or pharmaceuticals.
Raj Suryanarayanan - One of the best experts on this subject based on the ideXlab platform.
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Molecular Mobility in glassy dispersions
The Journal of chemical physics, 2016Co-Authors: Mehak Mehta, Gregory B. Mckenna, Raj SuryanarayananAbstract:Dielectric spectroscopy was used to characterize the structural relaxation in pharmaceutical dispersions containing nifedipine (NIF) and either poly(vinyl) pyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS). The shape of the dielectric response (permittivity versus log time) curve was observed to be independent of temperature. Thus, for the pure NIF as well as the dispersions, the validity of the time-temperature superposition principle was established. Furthermore, though the shape of the full dielectric response varied with polymer concentration, the regime related to the α- or structural relaxation was found to superimpose for the dispersions, though not with the response of the NIF itself. Hence, there is a limited time-temperature-concentration superposition for these systems as well. Therefore, in this polymer concentration range, calculation of long relaxation times in these glass-forming systems becomes possible. We found that strong drug-polymer hydrogen bonding interactions improved the physical stability (i.e., delayed crystallization) by reducing the Molecular Mobility. The strength of hydrogen bonding, structural relaxation time, and crystallization followed the order: NIF−PV P>NIF−HPMCAS>NIF. With an increase in polymer concentration, the relaxation times were longer indicating a decrease in Molecular Mobility. The temperature dependence of relaxation time, in other words fragility, was independent of polymer concentration. This is the first application of the superposition principle to characterize structural relaxation in glassy pharmaceutical dispersions.
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the role of polymer concentration on the Molecular Mobility and physical stability of nifedipine solid dispersions
Molecular Pharmaceutics, 2015Co-Authors: Khushboo Kothari, Vishard Ragoonanan, Raj SuryanarayananAbstract:We investigated the influence of polymer concentration (2.5–20% w/w) on the Molecular Mobility and the physical stability in solid dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With an increase in polymer concentration, the α-relaxation times measured by broadband dielectric spectroscopy were longer, which reflects a decrease in Molecular Mobility. In the supercooled state, at a given temperature (between 55 and 75 °C), the relaxation time increased linearly as a function of polymer concentration (2.5–20% w/w). The temperature dependence of the relaxation time indicated that the fragility of the dispersion, and by extension the mechanism by which the polymer influences the relaxation time, was independent of polymer concentration. The time for NIF crystallization also increased as a function of polymer concentration. Therefore, by using Molecular Mobility as a predictor, a model was built to predict NIF crystallization from the dispersions in the supercooled state. The predicted crystal...
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Correlation between Molecular Mobility and physical stability of amorphous itraconazole
Molecular pharmaceutics, 2013Co-Authors: Sunny P. Bhardwaj, Kapildev K. Arora, Elizabeth Kwong, Allen C. Templeton, Sophie-dorothee Clas, Raj SuryanarayananAbstract:The goal was to investigate the correlation between Molecular Mobility and physical stability in amorphous itraconazole and identify the specific Mobility mode responsible for its instability. The Molecular Mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5–40 °C temperature range revealed a β-relaxation which exhibited Arrhenius temperature dependence. As the temperature approached Tg, β-relaxation became progressively less resolved due to interference from the high frequency tail of the α-relaxation and then transformed into an excess wing. Above Tg, nonlinear temperature dependence of the α-relaxation was described by the Vogel–Tammann–Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ∼4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 °C, was best described by...
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Molecular Mobility as a Predictor of the Water Sorption by Annealed Amorphous Trehalose
Pharmaceutical research, 2012Co-Authors: Sunny P. Bhardwaj, Raj SuryanarayananAbstract:Purpose The work aims at investigating the correlation of water sorption potential with different measures of Molecular Mobility in an annealed amorphous model compound (trehalose).
Sumie Yoshioka - One of the best experts on this subject based on the ideXlab platform.
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Feasibility of 19F-NMR for assessing the Molecular Mobility of flufenamic acid in solid dispersions.
Chemical & pharmaceutical bulletin, 2009Co-Authors: Yukio Aso, Sumie Yoshioka, Tamaki Miyazaki, Toru KawanishiAbstract:The purpose of the present study was to clarify the feasibility of 19F-NMR for assessing the Molecular Mobility of flufenamic acid (FLF) in solid dispersions. Amorphous solid dispersions of FLF containing poly(vinylpyrrolidone) (PVP) or hydroxypropylmethylcellulose (HPMC) were prepared by melting and rapid cooling. Spin-lattice relaxation times (T1 and T(1rho)) of FLF fluorine atoms in the solid dispersions were determined at various temperatures (-20 to 150 degrees C). Correlation time (tauc), which is a measure of rotational Molecular Mobility, was calculated from the observed T1 or T1rho value and that of the T1 or T1rho minimum, assuming that the relaxation mechanism of spin-lattice relaxation of FLF fluorine atoms does not change with temperature. The tauc value for solid dispersions containing 20% PVP was 2-3 times longer than that for solid dispersions containing 20% HPMC at 50 degrees C, indicating that the Molecular Mobility of FLF in solid dispersions containing 20% PVP was lower than that in solid dispersions containing 20% HPMC. The amount of amorphous FLF remaining in the solid dispersions stored at 60 degrees C was successfully estimated by analyzing the solid echo signals of FLF fluorine atoms, and it was possible to follow the overall crystallization of amorphous FLF in the solid dispersions. The solid dispersion containing 20% PVP was more stable than that containing 20% HPMC. The difference in stability between solid dispersions containing PVP and HPMC is considered due to the difference in Molecular Mobility as determined by tauc. The Molecular Mobility determined by 19F-NMR seems to be a useful measure for assessing the stability of drugs containing fluorine atoms in amorphous solid dispersions.
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Correlations between Molecular Mobility and chemical stability during storage of amorphous pharmaceuticals
Journal of pharmaceutical sciences, 2007Co-Authors: Sumie Yoshioka, Yukio AsoAbstract:Recent studies have demonstrated that Molecular Mobility is an important factor affecting the chemical stability of amorphous pharmaceuticals, including small-Molecular-weight drugs, peptides and proteins. However, quantitative correlations between Molecular Mobility and chemical stability have not yet been elucidated. The purpose of this article is to review literature describing the effect of Molecular Mobility on chemical stability during storage of amorphous pharmaceuticals, and to seek a better understanding of the relative significance of Molecular Mobility and other factors for chemical reactivity. We first consider the feature of chemical stability often observed for amorphous pharmaceuticals; changes in temperature dependence of chemical stability around matrix glass transition temperature (Tg), and greater stability associated with higher Tg. Secondly, we review papers which quantitatively studied the effects of the global Mobility (often referred to as structural relaxation or α-relaxation) of amorphous pharmaceuticals on chemical stability, and discuss correlations between chemical stability and global Mobility using various equations that have thus far been proposed. Thirdly, the significance of local Mobility of drug and excipient molecules in chemical reactivity is discussed in comparison with that of global Mobility. Furthermore, we review literature reports which show no relationship between chemical stability and Molecular Mobility. The lack of apparent relationship is discussed in terms of the effects of the contribution of excipient molecules as reactants, the specific effects of water molecules, the heterogeneity of the matrix, and so on. The following summary has been obtained; the chemical stability of amorphous pharmaceuticals is affected by global Mobility and/or local Mobility, depending on the length scale of Molecular Mobility responsible for the chemical reactivity. In some cases, when activation energy for degradation processes is high and when other factors such as the specific effects of water and/or excipients contribute the degradation rate, stability seems to be largely independent of Molecular Mobility.
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Negligible contribution of Molecular Mobility to the degradation rate of insulin lyophilized with poly(vinylpyrrolidone).
Journal of pharmaceutical sciences, 2006Co-Authors: Sumie Yoshioka, Yukio Aso, Tamaki MiyazakiAbstract:Abstract The purpose of this study is to confirm the speculation which arose in our previous study that the degradation rate of insulin lyophilized with poly(vinylpyrrolidone) is mainly governed by the chemical activational barrier rather than Molecular Mobility. This speculation was based on the degradation data of insulin lyophilized with poly(vinylpyrrolidone) K-30 (PVP K-30), which was obtained at temperatures well below the glass transition temperature ( T g ). In this study, the degradation rate of insulin at temperatures below and above T g was determined using PVP 10k as an excipient, instead of PVP K-30, in order to examine whether or not the temperature dependence of the degradation rate changes around T g . The relative contributions of Molecular Mobility and the activational barrier, calculated from the temperature- and T g -dependence of the degradation rate, indicated that the contribution of Molecular Mobility to the degradation rate was negligible. Furthermore, the negligible contribution of Molecular Mobility was confirmed by the lack of significant change observed in the temperature- and T g -dependence of the rate around T g .
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A quantitative assessment of the significance of Molecular Mobility as a determinant for the stability of lyophilized insulin formulations.
Pharmaceutical research, 2005Co-Authors: Sumie Yoshioka, Yukio AsoAbstract:The purpose was to explore a method for quantitatively assessing the contribution of Molecular Mobility to the chemical reactivity of amorphous solids. Degradation of insulin in lyophilized formulations containing trehalose and poly(vinylpyrrolidone)(PVP) was chosen as a model system, and the temperature- and glass transition temperature (Tg)-dependence of the degradation rate was analyzed to obtain the relative contributions of Molecular Mobility and that of the chemical activational barrier reflected in the energy of activation. Insulin degradation and dimerization in lyophilized trehalose and PVP formulations were monitored at various relative humidities (6–60% RH) and temperatures (10–60°C) by reverse-phase high-performance liquid chromatography (HPLC) and high-performance size-exclusion chromatography (HP-SEC), respectively. The Tg and fragility parameter of the lyophilized insulin formulations were determined by differential scanning calorimetry (DSC). Insulin degradation in the initial stage was describable with first-order kinetics for both of the trehalose and PVP formulations. The temperature- and Tg-dependence of the degradation rate indicated that the reactivity of insulin in the trehalose formulation is affected by Molecular Mobility at low humidity (12% RH), such that the ratio of the observed rate constant (k′) to the rate constant governed only by the activational barrier (k) was 0.051 at the Tg. At higher humidities, in contrast, the value of k′/k was much higher (0.914, 0.978, and 0.994 for 23% RH, 33% RH, and 43% RH, respectively), indicating that insulin degradation rate is determined predominantly by the activational barrier. For insulin degradation in the PVP formulation at temperatures below Tg, the contribution of Molecular Mobility to the degradation rate appeared to be negligible, as the extrapolated value of t90 at the Tg exhibited a large difference between the formulations with differing Tg values (because of differing water contents). The reactivity of insulin in the trehalose and PVP formulations can be described by an equation including factors reflecting the activational barrier (activation energy and frequency coefficient) and factors reflecting the Molecular Mobility (Tg, fragility parameter and a constant representing the relationship between the Molecular Mobility and the reaction rate). Thus, analysis of temperature dependence based on the proposed equation allows quantitative assessment of the significance of Molecular Mobility as a factor affecting chemical reactivity.
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The effect of excipients on the Molecular Mobility of lyophilized formulations, as measured by glass transition temperature and NMR relaxation-based critical Mobility temperature.
Pharmaceutical Research, 1999Co-Authors: Sumie Yoshioka, Shigeo KojimaAbstract:Purpose. The dependence of the Molecular Mobility of lyophilized formulations on pharmaceutical polymer excipients was studied. Molecular Mobility as determined by NMR relaxation-based critical temperature of Molecular Mobility (Tmc) and glass transition temperature (Tg) is discussed in relation to the plasticizing effect of water in formulations.
George Zografi - One of the best experts on this subject based on the ideXlab platform.
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Molecular Mobility of supercooled amorphous indomethacin determined by dynamic mechanical analysis
Pharmaceutical Research, 1997Co-Authors: Vlassios Andronis, George ZografiAbstract:Purpose. To determine the viscosity and the frequency-dependent shear modulus of supercooled indomethacin as a function of temperature near and above its glass transition temperature and from these data to obtain a quantitative measure of its Molecular Mobility in the amorphous state.
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Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures
Pharmaceutical Research, 1995Co-Authors: Bruno C. Hancock, Sheri L. Shamblin, George ZografiAbstract:Purpose . To measure the Molecular Mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds. Methods . Differential scanning calorimetry (DSC) was used to measure enthalpic relaxation of the amorphous samples after storage at temperatures 16-47 K below Tg for various time periods. The measured enthalpy changes were used to calculate Molecular relaxation time parameters. Analogous changes in specimen dimensions were measured for PVP films using thermomechanical analysis. Results . For all the model materials it was necessary to cool to at least 50 K below the experimental Tg before the Molecular motions detected by DSC could be considered to be negligible over the lifetime of a typical pharmaceutical product. In each case the temperature dependence of the Molecular motions below Tg was less than that typically reported above Tg and was rapidly changing. Conclusions . In the temperature range studied the model amorphous solids were in a transition zone between regions of very high Molecular Mobility above Tg and very low Molecular Mobility much further below Tg. In general glassy pharmaceutical solids should be expected to experience significant Molecular Mobility at temperatures up to fifty degrees below their glass transition temperature.
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Molecular Mobility of amorphous pharmaceutical solids below their glass transition temperatures
Pharmaceutical Research, 1995Co-Authors: Bruno C. Hancock, Sheri L. Shamblin, George ZografiAbstract:Purpose. To measure the Molecular Mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds.
Yukio Aso - One of the best experts on this subject based on the ideXlab platform.
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Feasibility of 19F-NMR for assessing the Molecular Mobility of flufenamic acid in solid dispersions.
Chemical & pharmaceutical bulletin, 2009Co-Authors: Yukio Aso, Sumie Yoshioka, Tamaki Miyazaki, Toru KawanishiAbstract:The purpose of the present study was to clarify the feasibility of 19F-NMR for assessing the Molecular Mobility of flufenamic acid (FLF) in solid dispersions. Amorphous solid dispersions of FLF containing poly(vinylpyrrolidone) (PVP) or hydroxypropylmethylcellulose (HPMC) were prepared by melting and rapid cooling. Spin-lattice relaxation times (T1 and T(1rho)) of FLF fluorine atoms in the solid dispersions were determined at various temperatures (-20 to 150 degrees C). Correlation time (tauc), which is a measure of rotational Molecular Mobility, was calculated from the observed T1 or T1rho value and that of the T1 or T1rho minimum, assuming that the relaxation mechanism of spin-lattice relaxation of FLF fluorine atoms does not change with temperature. The tauc value for solid dispersions containing 20% PVP was 2-3 times longer than that for solid dispersions containing 20% HPMC at 50 degrees C, indicating that the Molecular Mobility of FLF in solid dispersions containing 20% PVP was lower than that in solid dispersions containing 20% HPMC. The amount of amorphous FLF remaining in the solid dispersions stored at 60 degrees C was successfully estimated by analyzing the solid echo signals of FLF fluorine atoms, and it was possible to follow the overall crystallization of amorphous FLF in the solid dispersions. The solid dispersion containing 20% PVP was more stable than that containing 20% HPMC. The difference in stability between solid dispersions containing PVP and HPMC is considered due to the difference in Molecular Mobility as determined by tauc. The Molecular Mobility determined by 19F-NMR seems to be a useful measure for assessing the stability of drugs containing fluorine atoms in amorphous solid dispersions.
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Correlations between Molecular Mobility and chemical stability during storage of amorphous pharmaceuticals
Journal of pharmaceutical sciences, 2007Co-Authors: Sumie Yoshioka, Yukio AsoAbstract:Recent studies have demonstrated that Molecular Mobility is an important factor affecting the chemical stability of amorphous pharmaceuticals, including small-Molecular-weight drugs, peptides and proteins. However, quantitative correlations between Molecular Mobility and chemical stability have not yet been elucidated. The purpose of this article is to review literature describing the effect of Molecular Mobility on chemical stability during storage of amorphous pharmaceuticals, and to seek a better understanding of the relative significance of Molecular Mobility and other factors for chemical reactivity. We first consider the feature of chemical stability often observed for amorphous pharmaceuticals; changes in temperature dependence of chemical stability around matrix glass transition temperature (Tg), and greater stability associated with higher Tg. Secondly, we review papers which quantitatively studied the effects of the global Mobility (often referred to as structural relaxation or α-relaxation) of amorphous pharmaceuticals on chemical stability, and discuss correlations between chemical stability and global Mobility using various equations that have thus far been proposed. Thirdly, the significance of local Mobility of drug and excipient molecules in chemical reactivity is discussed in comparison with that of global Mobility. Furthermore, we review literature reports which show no relationship between chemical stability and Molecular Mobility. The lack of apparent relationship is discussed in terms of the effects of the contribution of excipient molecules as reactants, the specific effects of water molecules, the heterogeneity of the matrix, and so on. The following summary has been obtained; the chemical stability of amorphous pharmaceuticals is affected by global Mobility and/or local Mobility, depending on the length scale of Molecular Mobility responsible for the chemical reactivity. In some cases, when activation energy for degradation processes is high and when other factors such as the specific effects of water and/or excipients contribute the degradation rate, stability seems to be largely independent of Molecular Mobility.
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Negligible contribution of Molecular Mobility to the degradation rate of insulin lyophilized with poly(vinylpyrrolidone).
Journal of pharmaceutical sciences, 2006Co-Authors: Sumie Yoshioka, Yukio Aso, Tamaki MiyazakiAbstract:Abstract The purpose of this study is to confirm the speculation which arose in our previous study that the degradation rate of insulin lyophilized with poly(vinylpyrrolidone) is mainly governed by the chemical activational barrier rather than Molecular Mobility. This speculation was based on the degradation data of insulin lyophilized with poly(vinylpyrrolidone) K-30 (PVP K-30), which was obtained at temperatures well below the glass transition temperature ( T g ). In this study, the degradation rate of insulin at temperatures below and above T g was determined using PVP 10k as an excipient, instead of PVP K-30, in order to examine whether or not the temperature dependence of the degradation rate changes around T g . The relative contributions of Molecular Mobility and the activational barrier, calculated from the temperature- and T g -dependence of the degradation rate, indicated that the contribution of Molecular Mobility to the degradation rate was negligible. Furthermore, the negligible contribution of Molecular Mobility was confirmed by the lack of significant change observed in the temperature- and T g -dependence of the rate around T g .
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A quantitative assessment of the significance of Molecular Mobility as a determinant for the stability of lyophilized insulin formulations.
Pharmaceutical research, 2005Co-Authors: Sumie Yoshioka, Yukio AsoAbstract:The purpose was to explore a method for quantitatively assessing the contribution of Molecular Mobility to the chemical reactivity of amorphous solids. Degradation of insulin in lyophilized formulations containing trehalose and poly(vinylpyrrolidone)(PVP) was chosen as a model system, and the temperature- and glass transition temperature (Tg)-dependence of the degradation rate was analyzed to obtain the relative contributions of Molecular Mobility and that of the chemical activational barrier reflected in the energy of activation. Insulin degradation and dimerization in lyophilized trehalose and PVP formulations were monitored at various relative humidities (6–60% RH) and temperatures (10–60°C) by reverse-phase high-performance liquid chromatography (HPLC) and high-performance size-exclusion chromatography (HP-SEC), respectively. The Tg and fragility parameter of the lyophilized insulin formulations were determined by differential scanning calorimetry (DSC). Insulin degradation in the initial stage was describable with first-order kinetics for both of the trehalose and PVP formulations. The temperature- and Tg-dependence of the degradation rate indicated that the reactivity of insulin in the trehalose formulation is affected by Molecular Mobility at low humidity (12% RH), such that the ratio of the observed rate constant (k′) to the rate constant governed only by the activational barrier (k) was 0.051 at the Tg. At higher humidities, in contrast, the value of k′/k was much higher (0.914, 0.978, and 0.994 for 23% RH, 33% RH, and 43% RH, respectively), indicating that insulin degradation rate is determined predominantly by the activational barrier. For insulin degradation in the PVP formulation at temperatures below Tg, the contribution of Molecular Mobility to the degradation rate appeared to be negligible, as the extrapolated value of t90 at the Tg exhibited a large difference between the formulations with differing Tg values (because of differing water contents). The reactivity of insulin in the trehalose and PVP formulations can be described by an equation including factors reflecting the activational barrier (activation energy and frequency coefficient) and factors reflecting the Molecular Mobility (Tg, fragility parameter and a constant representing the relationship between the Molecular Mobility and the reaction rate). Thus, analysis of temperature dependence based on the proposed equation allows quantitative assessment of the significance of Molecular Mobility as a factor affecting chemical reactivity.
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Molecular Mobility of protein in lyophilized formulations linked to the Molecular Mobility of polymer excipients, as determined by high resolution 13C solid-state NMR.
Pharmaceutical research, 1999Co-Authors: Sumie Yoshioka, Shigeo Kojima, Yukio Aso, Satoshi Sakurai, Toshimichi Fujiwara, Hideo AkutsuAbstract:Purpose. The Mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T1) of each molecule determined by high resolution 13C solid-state NMR. The relationship between Molecular Mobility and protein stability is discussed.