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

Purpose To present a calorimetry-based approach for estimating the initial (at the onset of annealing) relaxation time (τ ⁰) of organic amorphous solids at relatively low temperatures, and to assess the temperature where molecular mobility of the amorphous drug is reduced to a level comparable with the desired shelf-life of the product.Materials and Methods Values of τ ⁰ for six amorphous pharmaceutical compounds were estimated based on the nonlinear Adam–Gibbs equation. Fragility was determined from the scanning rate-dependence of the glass transition temperature (T _g). The initial enthalpic and entropic fictive temperatures were obtained from the T _g and the heat capacities (C _p) of the amorphous and crystalline forms.Results At a relatively low temperature (∼40°C or more below T _g), τ ⁰ for the different compounds varies by over an order of magnitude. For some materials, the practical storage temperature at T _g − 50 K was found to be still too high to ensure long-term stability. The estimated τ ⁰ is highly sensitive to the fragility of the material and the C _p of the crystalline and amorphous forms. Materials with high fragility or greater C _p differences between crystalline and amorphous forms tend to have longer τ ⁰.Conclusions The proposed method can be used to estimate molecular mobility at relatively low temperatures without having to conduct enthalpy recovery experiments. An accurate τ ⁰ determination from this method relies on faithful fragility measurements.     

Probing Beta Relaxation in Pharmaceutically Relevant Glasses by Using DSC

Purpose This study was conducted to demonstrate the use of differential scanning calorimetry (DSC) in detecting and measuring β-relaxation processes in amorphous pharmaceutical systems. Methods DSC was employed to study amorphous samples of poly(vinylpyrrolidone) (PVP), indomethacin (IM), and ursodeoxycholic acid (UDA) that were annealed at temperatures (T_a) around 0.8 of their glass transition temperatures (T_g). Dynamic mechanical analysis (DMA) was used to measure β-relaxation in PVP. Results Reheating the annealed samples gives rise to annealing peaks that occur below T_g. The peaks cannot be generated when annealing below the low temperature limit of β-relaxation. These limits are around 50°C for PVP, −20°C for IM, and 30°C for UDA. The effective activation energy (E) of the sub-T_g relaxation has been estimated for each T_a and found to increase with T_a, reflecting increasing contribution of the α-process. Estimates of E for β-relaxation have been obtained from the lowest T_a data, and are as follows: 68 (PVP), 56 (IM), 67 (UDA) kJ mol⁻¹. Conclusions DSC can be used for detecting β-relaxation processes and estimating its low temperature limit, i.e., the temperature below which amorphous drugs would remain stable. It can also provide comparative estimates of low temperature stability of amorphous drugs in terms of the activation energies of the β-relaxation.     

Significance of Local Mobility in Aggregation of β-Galactosidase Lyophilized with Trehalose,Sucrose or Stachyose

Purpose The purpose of this study is to compare the effects of global mobility, as reflected by glass transition temperature (T_g) and local mobility, as reflected by rotating-frame spin-lattice relaxation time (T_1ρ) on aggregation during storage of lyophilized β-galactosidase (β-GA). Materials and Methods The storage stability of β-GA lyophilized with sucrose, trehalose or stachyose was investigated at 12% relative humidity and various temperatures (40–90°C). β-GA aggregation was monitored by size exclusion chromatography (SEC). Furthermore, the T_1ρ of the β-GA carbonyl carbon was measured by ¹³C solid-state NMR, and T_g was measured by modulated temperature differential scanning calorimetry. Changes in protein structure during freeze drying were measured by solid-state FT-IR. Results The aggregation rate of β-GA in lyophilized formulations exhibited a change in slope at around T_g, indicating the effect of molecular mobility on the aggregation rate. Although the T_g rank order of β-GA formulations was sucrose < trehalose < stachyose, the rank order of β-GA aggregation rate at temperatures below and above T_g was also sucrose < trehalose < stachyose, thus suggesting that β-GA aggregation rate is not related to (T-T_g). The local mobility of β-GA, as determined by the T_1ρ of the β-GA carbonyl carbon, was more markedly decreased by the addition of sucrose than by the addition of stachyose. The effect of trehalose on T_1ρ was intermediate when compared to those for sucrose and stachyose. These findings suggest that β-GA aggregation rate is primarily related to local mobility. Significant differences in the second derivative FT-IR spectra were not observed between the excipients, and the differences in β-GA aggregation rate observed between the excipients could not be attributed to differences in protein secondary structure. Conclusions The aggregation rate of β-GA in lyophilized formulations unexpectedly correlated with the local mobility of β-GA, as indicated by T_1ρ, rather than with (T-T_g). Sucrose exhibited the most intense stabilizing effect due to the most intense ability to inhibit local protein mobility during storage.     

Time-Dependence of Molecular Mobility during Structural Relaxation and its Impact on Organic Amorphous Solids: An Investigation Based on a Calorimetric Approach

Purpose To develop a calorimetry-based model for estimating the time-dependence of molecular mobility during the isothermal relaxation of amorphous organic compounds below their glass transition temperature (T _g).Methods The time-dependent enthalpy relaxation times of amorphous sorbitol, indomethacin, trehalose and sucrose were estimated based on the nonlinear Adam‐Gibbs equation. Fragility was determined from the scanning rate dependence of T _g. Time evolution of the fictive temperature was determined from T _g, the heat capacity of the amorphous and crystalline forms, and from the enthalpy relaxation data.Results Relaxation time changes significantly upon annealing for all compounds studied. The magnitude of the increase in relaxation time does not depend on any one parameter but on four parameters: T _g, fragility, and the crystal–liquid and glass–liquid heat capacity differences. The obtained mobility data for indomethacin and sucrose, both stored at T _g−16 K, correlated much better with their different crystallization tendencies than did the Kohlrausch‐Williams‐Watts (KWW) equation.Conclusions The observed changes in relaxation time help explain and address the limitations of the KWW approach. Due consideration of the time-dependence of molecular mobility upon storage is a key element for improving the understanding necessary for stabilizing amorphous formulations.     

The Effect of Excipients on the Molecular Mobility of Lyophilized Formulations,as Measured by Glass Transition Temperature and NMR Relaxation-Based Critical Mobility Temperature

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 (T_mc) and glass transition temperature (T_g) is discussed in relation to the plasticizing effect of water in formulations. Methods. The T_mc and T_g of lyophilized -globulin formulations containing 6 different polymer excipients such as dextran, polyvinylpyrrolidone (PVP) and methylcellulose (MC) was determined by NMR and DSC. The molecular mobility of water in the formulations was determined by proton NMR and dielectric relaxation spectrometry (DRS). Results. T_mc varied with polymer excipients. T_mc increased as the ratio of bound water to mobile water increased and as the molecular mobility of mobile water decreased. The formulation containing MC exhibited a lower T_mc than the formulation containing dextran because of the smaller ratio of bound water and the higher molecular mobility of mobile water. The T_mc of the formulation containing PVP was higher than that expected from the higher T₂ values of water because of the lower molecular mobility of mobile water regardless of the higher ratio of mobile water. The T_mc of these lyophilized formulations was higher than their T_g by 23°C to 34°C, indicating that the formulations became a NMR-detected microscopically liquidized state below their T_g. Conclusions. The quantity and the molecular mobility of mobile water in lyophilized formulations can be considered to affect the T_mc of lyophilized formulations, which in turn governs their stability.     

Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures

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.     

Molecular Mobility in Mixtures of Absorbed Water and Solid Poly(vinylpyrrolidone)

Poly(vinylpyrrolidone) (PVP) was used as model system to examine molecular mobility in mixtures of absorbed water with solid amorphous polymers. Water vapor absorption isotherms were determined, along with diffusion and proton NMR relaxation measurements of absorbed water. Concurrently, measurements of glass transition temperatures (T _g) and carbon-13 NMR relaxation times for PVP were determined as a function of water content. Two water contents were used as reference points: W _m, obtained from the fit of water absorption isotherms to the BET equation, corresponding to the first shoulder in the sigmoid isotherm; and W _g, the amount of water necessary to depress T _g to the isotherm temperature. Translational diffusion coefficients of water, along with proton T ₁ relaxation time constants, show that both the translational and the rotational mobility of the water is hindered by the presence of the solid polymer and that the absorbed water is most likely represented by two or more populations of water with different modes or time scales of motion. The presence of "tightly bound or immobilized water at levels corresponding to W _m, however, is unlikely, since water molecules maintain a high degree of mobility, even at the lowest levels of water. Above W _g, water shows an increase in mobility with increasing water content, but it is always less mobile than bulk water. With increasing water content, carbon-13 T ₁ relaxation time constants for PVP, measured under the same conditions as above, indicate a major increase in the molecular mobility of carbon atoms associated with the pyrrolidone side chains.     

The Relationship Between Protein Aggregation and Molecular Mobility Below the Glass Transition Temperature of Lyophilized Formulations Containing a Monoclonal Antibody

Purpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. Methods. The temperature dependence of relaxation time constant, , was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, , in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. Results. For both sucrose and trehalose formulations, the variation in with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at t values <10, where t is the time of storage. Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 10⁸ and 10⁶ hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions.     

Different measures of molecular mobility: comparison between calorimetric and thermally stimulated current relaxation times below Tg and correlation with dielectric relaxation times above Tg

Stability of the amorphous state has been linked to molecular mobility of the matrix; however different techniques may capture different mobility substates. Our previous work suggested that two calorimetric techniques, Isothermal Microcalorimetry (TAM) and MDSC, measured different aspects of mobility with TAM measuring, in part, some faster modes of relaxation in addition to the modes mobilized at T(g). The aim of this work is to compare the relaxation times obtained using Thermally Stimulated Depolarization Current Spectroscopy (TSDC) with calorimetric mobility measured below T(g) and to determine if all measures of relaxation times below T(g) are consistent with relaxation times obtained above T(g) using Dielectric Spectroscopy (DRS). Model compounds were indomethacin, ketoconazole, nifedipine, flopropione, felodipine. For all compounds, relaxation times obtained using Thermal Windowing-TSDC technique below T(g) correlated well with relaxation times (tau) obtained above T(g) by DRS. At any given temperature below T(g), relaxation times measured depended upon the technique used and were in the following order TSDC < TAM < MDSC (tau). TSDC captures some faster relaxations not measured by calorimetric techniques, and therefore, different techniques give different measures of relaxation times below T(g). This information is important in understanding the relationships between mobility in the glassy solid and pharmaceutical stability.     

Comparison of Molecular Mobility in the Glassy State Between Amorphous Indomethacin and Salicin Based on Spin-Lattice Relaxation Times

Purpose. The purpose of the current study was to evaluate the molecular mobility of amorphous indomethacin and salicin in the relaxed glassy state based on spin-lattice relaxation times (T_1c) and to clarify the effects of molecular mobility on their physical stability.Methods. Pulverized glassy amorphous indomethacin and salicin samples were completely relaxed, and the T_1c values were investigated using solid-state ¹³C-nuclear magnetic resonance (NMR) at temperatures below the glass transition temperature (T_g). All NMR spectra were obtained using the T_1c measurement method combined with variable-amplitude cross-polarization, the Torchia method, and total sideband suppression method.Results. The T_1c value of amorphous indomethacin indicated that 73% of carbons were in a state of monodispersive relaxation, suggesting that the amorphous state was relatively homogeneous and restricted, particularly in backbone carbons. On the other hand, 92% of carbons of amorphous salicin exhibited both fast and slow biphasic relaxation. Individual structures of the salicin molecules behaved heterogeneously, and thus the entire molecule showed relatively fast local as well as slow mobility.Conclusions. At temperatures below T_g, amorphous salicin had relatively greater molecular mobility than amorphous indomethacin. This difference in the molecular mobility of the two compounds is correlated with their crystallization behavior. Solid-state ¹³C NMR provides valuable information on the physical stability of amorphous pharmaceuticals.     

Effect of Compaction Temperature on Consolidation of Amorphous Copolymers with Different Glass Transition Temperatures

Purpose. The purpose of this study was to relate the combination of glass transition temperature (T _g) and temperature of measurement with the mechanical and compaction properties of some test materials. Methods. Copolymers with different T _gs were synthesised by free radical copolymerisation of methyl methacrylate with lauryl methacrylate. Elastic moduli were measured by dynamic mechanical analysis at different strain rates and temperatures. Compaction experiments were performed at different compaction speeds and temperatures. Results. The difference between temperature of measurement and T _g appears to determine both elastic modulus and yield strength completely. They both decrease with decreasing difference between temperature of measurement and Tg and increase with strain rate. At temperatures of measurement higher than the T _g, the elastic modulus is extremely low because the materials behave as rubbers. Consequently, the amount of energy stored during compaction decreases when the compaction temperature approaches the T _g and increases with strain rate. When the compaction temperature is higher than the T _g, the amount of stored energy is extremely large. The compaction experiments show that the final tablet porosity is completely determined by stress relaxation phenomena. Consequently, the final tablet porosity follows exactly the same relation as that of stored energy. Conclusions. The final tablet porosity is unequivocally determined by the amount of stored energy. This implies that tablet production at a temperature of about 20 K under the glass transition temperature of the material yields tablets with minimum porosity.     

Correlationship of Drug-Polymer Miscibility,Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25 °C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τ^β) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP > DPD-HPMC P > DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25 ± 5 °C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (T_g) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing “physical stable” ASDs.     

Molecular Dynamics and Physical Stability of Pharmaceutical Co-amorphous Systems: Correlation Between Structural Relaxation Times Measured by Kohlrausch-Williams-Watts With the Width of the Glass Transition Temperature (ΔTg) and the Onset of Crystallization

The study aims to characterize the structural relaxation times of quench-cooled co-amorphous systems using Kohlrausch-Williams-Watts (KWW) and to correlate the relaxation data with the onset of crystallization. Comparison was also made between the relaxation times obtained by KWW and the width of glass transition temperature (ΔT_g) methods (simple and quick). Differential scanning calorimetry, Fourier-transformed infrared spectroscopy, and polarized light microscopy were used to characterize the systems. Results showed that co-amorphous systems yielded a single T_g and ΔC_p, suggesting the binary mixtures exist as a single amorphous phase. A narrow step change at T_g indicates the systems were fragile glasses. In co-amorphous nap-indo and para-indo, experimental T_gs were in good agreement with the predicted T_g. However, the T_g of co-amorphous nap-cim and indo-cim were 20°C higher than the predicted T_g, possibly due to stronger molecular interactions. Structural relaxation times below the experimental T_g were successfully characterized using the KWW and ΔT_g methods. The comparison plot showed that KWW data are directly proportional to the ½ power of ΔT_g data, after adjusting for a small offset. A moderate positive correlation was observed between the onset of crystallization and the KWW data. Structural relaxation times may be useful predictor of physical stability of co-amorphous systems.     

Electrolyte-Induced Changes in Glass Transition Temperatures of Freeze-Concentrated Solutes

Addition of electrolytes to solutions of non-crystallizing solutes can cause a significant decrease in the glass transition temperature (T_g) of the maximally freeze-concentrated solution. For example, addition of 2% sodium chloride to 10% solutions of dextran, PVP, lactose, and sucrose causes a decrease in T_g of 14° to 18°C. Sodium phosphate has a smaller effect on T_g, and is unusual in that 1% to 2% sodium phosphate in 10% PVP causes a second glass transition to be observed in the low-temperature thermogram, indicating a phase separation in the freeze concentrate. Comparison of DSC thermograms of fast-frozen solutions of sucrose with and without added sodium chloride shows that electrolyte-induced reduction of T_gis not caused by a direct plasticizing effect of the electrolyte on the freeze concentrate. Measurement of unfrozen water content as a function of temperature by a pulsed nmr method shows that the most likely mechanism for electrolyte-induced changes in T_g is by increasing the quantity of unfrozen water in the freeze concentrate, where the unfrozen water acts as a plasticizer and decreases T_g. The correlation time (_c) of water in the freeze concentrate is in the range of 10^–7 to 10^–8 seconds. The results underscore the importance of minimizing the amount of added salts to formulations in-tended for freeze drying.     

Effect of Glass Transition Temperature on the Stability of Lyophilized Formulations Containing a Chimeric Therapeutic Monoclonal Antibody

Purpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, T_g, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Results. Sucrose formulation (T_g ~ 59°C) when stored at 60°C was found to undergo significant aggregation, while the trehalose formulation (T_g ~ 80°C) was stable at 60°C. The instability observed with sucrose formulation at 60°C can be attributed to its T_g (~59°C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the T_gs of the formulations containing sucrose or trehalose, but to different degrees. Conclusions. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40°C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60°C) where one formulation is in the glassy state while the other is near or above its T_g.     

Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients,as Determined by High Resolution 13C Solid-State NMR

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. Methods. Protein aggregation of lyophilized bovine serum --globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T₁ of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution ¹³C NMR, and subsequently used to calculate the correlation time (_C) of each carbon. The spin-spin relaxation time (T₂) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (T_mc) was determined. Results. The _C of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the T_mc. The _C of BGG carbonyl carbon exhibited a similar temperature dependence to the _C of the dextran methin carbon and substantially decreased at temperatures above T_mc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than T_mc. Conclusions. High resolution ¹³C solid-state NMR indicated that the molecular motion of BGG was enhanced above T_mc in association with the increased global segmental motion of dextran molecules.     

Solid-State Stability of Spray-Dried Insulin Powder for Inhalation: Chemical Kinetics and Structural Relaxation Modeling of Exubera Above and Below the Glass Transition Temperature

The effect of temperature on the chemical stability of an amorphous spray-dried insulin powder formulation (Exubera)® was evaluated in the solid state at constant moisture content. The chemical stability of the powder was assessed using reversed-phase high-performance liquid chromatography (RP-HPLC) and high-performance-size exclusion chromatography (HP-SEC). The major degradants in spray-dried insulin produced during heat stressing were identified as A21-desamidoinsulin (A21) and high molecular weight protein (HMWP). As expected, the rates of formation of A21 and HMWP were observed to increase with temperature. A stretched-time kinetic model (degradation rate is proportional to the square root of time) was applied to the degradant profiles above and below the glass transition temperature (T_g) and apparent reaction rate constants were determined. Below T_g, isothermal enthalpy of relaxation measurements were used to assess the effect of temperature on molecular mobility. The formation of A21 and HMWP was found to follow an Arrhenius temperature dependence above and below the T_g. Comparison of reaction rate constants to those estimated from structural relaxation experiments suggests that the reaction pathways to form A21 and HMWP below the T_g may be coupled with the molecular motions involved in structural relaxation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3698–3710, 2010     

Measurement of Glass Transition Temperatures in Freeze Concentrated Solutions of Non-Electrolytes by Electrical Thermal Analysis

The electrical resistance (R) of frozen aqueous solutions was measured as a function of temperature in order to determine whether this technique can be applied for determination of glass transition temperatures of maximally freeze concentrated solutions (T_g) of non-electrolytes which do not crystallize during freezing. Electrical thermal analysis (ETA) thermograms of frozen solutions containing the solute alone show a gradual change in slope over the temperature range of interest, with no inflection point which corresponds to T_g. However, addition of low levels (about 0.1%) of electrolyte changes the shape of the thermogram into a biexponential function where the intersection of the two linear portions of the log (R) vs. T plot corresponds to the glass transition region. The total change in log (R) over the temperature range studied increases as the ionic radius of the reporter ion increases. The sharpest inflection points in the log (R) vs T curves, and the best correlation with DSC results, were obtained with ammonium salts. T_g values measured by ETA were compared with values measured by DSC. DSC thermograms of solutes with and without electrolyte (0.1%) show that the electrolyte decreases T_g by about 0.5 to 1.0°C. However, T_g values measured by ETA are somewhat higher than those measured by DSC, and difference between the two methods seems to increase as T_g decreases. T_g as measured by ETA is less heating rate dependent than DSC analysis, and ETA is a more sensitive method than DSC at low solute concentrations and at low heating rates. Results of electrical thermal analysis of frozen solutions are compared and contrasted with the electrical resistance vs. temperature behavior of polymer-electrolytes. ETA appears to be a useful complementary technique to DSC for characterizing formulations intended for freeze drying.     

Comparative Investigation by Two Analytical Approaches of Enthalpy Relaxation for Glassy Glucose,Sucrose, Maltose,and Trehalose

No HeadingPurpose. In an effort to understand the stability of glassy sugars such as glucose, sucrose, maltose, and trehalose, the molecular mobility below the glass transition temperature (T_g) was investigated by an enthalpy relaxation measurement with differential scanning calorimetry (DSC).Methods. The glassy sample was aged over several days at (T_g – 10) K to (T_g – 30) K, before a DSC heating scan was taken. The relaxed enthalpy (H_relax) was estimated from the endothermic peak area. The enthalpy relaxation time was analyzed from the time course of H_relax using two different approaches; Kohlrausch-Williams-Watts (KWW) and extended Adam-Gibbs (exAG).Results. ^KWW, which is defined as the mean average enthalpy relaxation time in a distribution, and ^eff₀ and ^eff, which correspond to the enthalpy relaxation time of the initial minimum and final maximum cooperative rearrangement region, were estimated by KWW and exAG, respectively. And three activation energies for enthalpy relaxation were calculated from the Arrhenius plot.Conclusions. Although these Es originated from different theoretical backgrounds, almost the same trend was observed for a comparison of the values of the four sugars. The finding that the Es of glassy trehalose were the largest among the four sugars may support the reason that glassy trehalose is an effective stabilizer.     

Characterisation of the Glass Transition of an Amorphous Drug Using Modulated DSC

Purpose. The use of modulated differential scanning calorimetry (MDSC) as a novel means of characterising the glass transition of amorphous drugs has been investigated, using the protease inhibitor saquinavir as a model compound. In particular, the effects of measuring variables (temperature cycling, scanning period, heating mode) have been examined. Methods. Saquinavir samples of known moisture content were examined using a TA Instruments 2920 MDSC at a heating rate of 2°C/min and an amplitude of ± 0.159°C with a period of 30 seconds. These conditions were used to examine the effects of cycling between - 50°C and 150°C. A range of periods between 20 and 50 seconds were then studied. Isothermal measurements were carried out between 85°C and 120°C using an amplitude of ± 0.159°C with a period of 30 seconds. Results. MDSC showed the glass transition of saquinavir (0.98 ± 0.05%w/w moisture content) in isolation from the relaxation endotherm to give an apparent glass transition temperature of 107.0° C ± 0.4C. Subsequent temperature cycling gave reproducible glass transition temperatures of approximately 105°C for both cooling and heating cycles. The enthalpic relaxation peak observed in the initial heating cycle had an additional contribution from a Tg 'shift' effect brought about by the difference in response to the glass transition of the total and reversing heat flow signals. Isothermal studies yield a glass transition at 105.9°C ± 0.1°C. Conclusions. MDSC has been shown to be capable of separating the glass transition of saquinavir from the relaxation endotherm, thereby facilitating measurement of this parameter without the need for temperature cycling. However, the Tg 'shift' effect and the number of modulations through the transition should be taken into account to avoid drawing erroneous conclusions from the experimental data. MDSC has been shown to be an effective method of characterising the glass transition of an amorphous drug, allowing the separate characterisation of the Tg and endothermic relaxation in the first heating cycle.