An Evaluation of the Use of Modulated Temperature DSC as a Means of Assessing the Relaxation Behaviour of Amorphous Lactose

Purpose. To evaluate the use of Modulated Temperature DSC(MTDSC) as a means of assessing the relaxation behaviour ofamorphous lactose via measurement of the heat capacity, glasstransition (Tg) and relaxation endotherm. Methods. Samples of amorphous lactose were prepared by freezedrying. MTDSC was conducted using a TA Instruments 2920 MDSCusing a heating rate of 2°C/minute, a modulation amplitude of ±0.3°Cand a period of 60 seconds. Samples were cycled by heating to 140°Cand cooling to a range of annealing temperatures between 80°C and100°C, followed by reheating through the Tg region. Systems werethen recooled to allow for correction of the Tg shift effect. Results. MTDSC enabled separation of the glass transition from therelaxation endotherm, thereby facilitating calculation of the relaxationtime as a function of temperature. The relative merits of using MTDSCfor the assessment of relaxation processes are discussed. In addition,the use of the fictive temperature rather than the experimentally derivedTg is outlined. Conclusions. MTDSC allows assessment of the glass transitiontemperature, the magnitude of the relaxation endotherm and the valueof the heat capacity, thus facilitating calculation of relaxation times.Limitations identified with the approach include the slow scanningspeed, the need for careful choice of experimental parameters and theTg shift effect.     

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.     

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.     

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.     

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.     

A Pragmatic Test of a Simple Calorimetric Method for Determining the Fragility of Some Amorphous Pharmaceutical Materials

Purpose. To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region. Methods. The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC). Results. Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration. Conclusions. The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.     

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.     

Evaluation of the Physical Stability of Freeze-Dried Sucrose-Containing Formulations by Differential Scanning Calorimetry

Freeze-dried samples of sucrose with buffer salts, amino acids, or dextran have been analyzed with differential scanning calorimetry (DSC) to evaluate the use of DSC thermograms in predicting the physical storage stability. The glass transition temperature, T _g, of the amorphous cake, crystallization, and melting of sucrose are observed with DSC. T _g appeared to be an important characteristic of the physical stability of the amorphous freeze-dried cake. A storage temperature above T _g results in collapse or shrinkage of the cake, which for a sucrose-based formulation, may be accompanied by crystallization of the sucrose. The T _g of the amorphous sucrose is influenced by other components present in the cake. Dextran-40 raised T _g, while the addition of glycine to the formulation lowered T _g. The residual moisture content strongly influences T _g, since water acts as a plasticizer of the system; the higher the moisture content, the lower the T _g and the less physically stable the freeze-dried cake. Crystallization of amorphous sucrose is shown to be inhibited by high molecular weight components or ionic compounds. DSC analysis of freeze-dried cakes proved to be a powerful tool in formulation studies.     

Solid-State Characteristics of Amorphous Sodium Indomethacin Relative to Its Free Acid

Purpose. Having previously studied the amorphous properties of indomethacin (IN) as a model compound for drugs rendered amorphous during processing, we report on the formation and characterization of its sodium salt in the amorphous state and a comparison between the two systems. Methods. Sodium indomethacin (SI) was subjected to lyophilization from aqueous solution, rapid precipitation from methanol solution, and dehydration followed by grinding to produce, in each case, a completely amorphous form. The amorphous form of SI was analyzed using DSC, XRD, thermomicroscopy and FTIR. The method of scanning rate dependence of the glass transition temperature, Tg, was used to estimate the fragility of the SI system. Enthalpy relaxation experiments were carried out to probe the molecular mobility of the SI system below Tg. Results. The amorphous form of SI formed by different methods had a Tg equal to 121°C at a scanning rate of 20°C/min. This compares with a Tgfor indomethacin of 45°C. Estimation of fragility by the scanning rate dependence of Tg indicates no significant differences in fragility between ionized and unionized forms. Enthalpy relaxation measurements reveal very similar relaxation patterns between the two systems at the same degree of supercooling relative to their respective Tg values. Conclusions. The amorphous form of SI made by various methods has a Tg that is about 75°C greater than that of IN, most likely because of the greater density and hence lower free volume of SI. Yet, the change of molecular mobility as a function of temperature relative to Tgis not very different between the ionized and unionized systems.     

The Impact of Thermal Treatment on the Stability of Freeze Dried Amorphous Pharmaceuticals: I. Dimer Formation in Sodium Ethacrynate

The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T_g. Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T_g–15°C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:663–682, 2010     

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.     

Molecular Mobility in Raffinose in the Crystalline Pentahydrate Form and in the Amorphous Anhydrous Form

Purpose The aims of the study are to characterize the slow molecular mobility in solid raffinose in the crystalline pentahydrate form, as well as in the anhydrous amorphous form (T_g = 109°C at 5°C/min), and to analyze the differences and the similarities of the molecular motions in both forms.Methods Thermally stimulated depolarization current (TSDC) is used to isolate the individual modes of motion present in raffinose, in the temperature range between −165 and +60°C. From the experimental output of the TSDC experiments, the kinetic parameters associated with the different relaxational modes of motion were obtained, which allowed a detailed characterization of the distribution of relaxation times of the complex relaxations observed in raffinose. The features of the glass transition relaxation in raffinose were characterized by differential scanning calorimetry (DSC).Results A complex mobility was found in the crystalline form of raffinose. From the analysis of the TSDC data, we conclude that these molecular motions are local and noncooperative. A sub-T_g relaxation, or secondary process, was also detected and analyzed by TSDC in the amorphous phase. It has low activation energy and low degree of cooperativity. The glass transition was studied by DSC. The fragility index (Angell’s scale) of raffinose obtained from DSC data is m = 148.Conclusions TSDC proved to be an adequate technique to study the molecular mobility in the crystalline pentahydrate form of raffinose. In the amorphous form, on the other hand, the secondary relaxation was analyzed by TSDC, but the study of the glass transition relaxation was not possible by this experimental technique as a consequence of conductivity problems. The DSC study of the glass transition indicates that raffinose is an extremely fragile glass former.     

Enthalpy Relaxation Studies of Celecoxib Amorphous Mixtures

Purpose. The purpose of this study was to compare the structural relaxation and molecular mobility of amorphous celecoxib (CEL) with that of CEL amorphous mixtures consisting of various excipients and to study the effect of different excipients on the relaxation of high-energy amorphous systems. Methods. The measurement of glass transition temperatures (Tg) and enthalpy relaxation were performed using differential scanning calorimetry. The interactions between drug and excipients and the absence of crystalline forms were further confirmed by conducting Fourier transform infrared spectroscopic and X-ray powder diffraction studies on same samples. Results. All samples exhibited a single Tg value. Polymers had a prominent effect on the lowering of the relaxation rate in amorphous CEL. The lowering of the rate of relaxation was directly dependent on the concentration and type of polymer used. The total enthalpy required for relaxation was same, although additives affected the rate of relaxation. Conclusions. In absence of any specific interactions during Fourier transform infrared studies, it was concluded that the antiplasticizing activity of polymers is responsible for the stabilization of CEL amorphous systems. Glassy amorphous dispersions of CEL exhibited a complex type of relaxation pattern, which failed to fit in Kohlrausch-Williams-Watts equation with respect to calculation of relaxation time constants.     

A Mechanistic Investigation of An Amorphous Pharmaceutical and Its Solid Dispersions,Part II: Molecular Mobility and Activation Thermodynamic Parameters

Purpose. The ability of TSDC to characterize further amorphous materials beyond that possible with DSC was presented in part I (16) of this work. The purpose of part II presented here is to detect and quantitatively characterize time-scales of molecular motions (relaxation times) in amorphous solids at and below the glass transition temperature, to determine distributions of relaxation times associated with different modes of molecular mobility and their temperature dependence, and to determine experimentally the impact upon these parameters of combining the drug with excipients (i.e., solid dispersions at different drug to polymer ratios). The knowledge gleaned may be applied toward a more realistic correlation with physical stability of an amorphous drug within a formulation during storage. Methods. Preparation of amorphous drug and its solid dispersions with PVPK-30 was described in part I (16). Molecular mobility and dynamics of glass transition for these systems were studied using TSDC in the thermal windowing mode. Results. Relaxation maps and thermodynamic activation parameters show the effect of formulating the drug in a solid dispersion on converting the system (drug alone) from one with a wide distribution of motional processes extending over a wide temperature range at and below Tg to one that is homogeneous with very few modes of motion (20% dispersion) that becomes increasingly less homogeneous as the drug load increases (40% dispersion). This is confirmed by the high activation enthalpy (due to extensive intra- and intermolecular interactions) as well as high activation entropy (due to higher extent of freedom) for the drug alone vs. a close to an ideal system (lower enthalpy), with less extent of freedom (low entropy) especially for the 20% dispersion. The polymer PVPK-30 exhibited two distinct modes of motion, one with higher values of activation enthalpies and entropy corresponding to -relaxations, the other with lower values corresponding to -relaxations characterized by local noncooperative motional processes. Conclusions. Using thermal windowing, a distribution of temperature-dependent relaxation times encountered in real systems was obtained as opposed to a single average value routinely acquired by other techniques. Relevant kinetic parameters were obtained and used in mechanistically delineating the effects on molecular mobility of temperature and incorporating the drug in a polymer. This allows for appropriate choices to be made regarding drug loading, storage temperature, and type of polymer that would realistically correlate to physical stability.     

Effects of Lyophilization on the Physical Characteristics and Chemical Stability of Amorphous Quinapril Hydrochloride

Purpose. To prepare amorphous quinapril hydrochloride(QHCl) by lyophilization and to compare its physical characteristics andchemical stability as a function of the initial pH of the pre-lyophilizedsolution. Methods. Amorphous QHCl samples were prepared bylyophilization from aqueous solutions. Solid-state characteristics wereevaluated by DSC, PXRD, and optical microscopy. Chemical degradation wasmonitored by an HPLC assay. Results. Amorphous QHCl samples obtained fromlyophilization exhibited variable glass transition temperatures, dependingon the pH and/or concentration of the starting aqueous solutions.Neutralized quinapril (Q) in the amorphous form, which has a T_gof 51°C, lower than that of its HCl salt (91°C), was significantlymore reactive than QHCl at the same temperature. The T_g oflyophilized samples prepared at various initial pH values correlated wellwith values predicted for mixtures of QHCl and Q. Their different reactionrates were related to their glass transition temperature, consistent withthe results from earlier studies obtained with amorphous samples made byprecipitation from an organic solution and grinding of the crystalsolvate. Conclusions. Lyophilization of different QHCl solutionsproduces mixtures of amorphous QHCl and its neutralized form Q, withT_g values intermediate to the values of QHCl and Q. As thefraction of Q increases the overall rate of chemical degradation increasesrelative to QHCl alone, primarily due to the increase in molecular mobilityinduced by the plasticizing effects of Q.     

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.     

Investigation of the impact of annealing on global molecular mobility in glasses: optimization for stabilization of amorphous pharmaceuticals

The purpose of this research was to investigate the effect of annealing on the molecular mobility in lyophilized glasses using differential scanning calorimetry (DSC) and isothermal microcalorimetry (IMC) techniques. A second objective that emerged was a systematic study of the unusual pre-T(g) thermal events that were observed during DSC warming scans after annealing. Aspartame lyophilized with three different excipients; sucrose, trehalose and poly vinyl pyrrolidone (PVP) was studied. The aim of this work was to quantify the decrease in mobility in amorphous lyophilized aspartame formulations upon systematic postlyophilization annealing. DSC scans of aspartame:sucrose formulation (T(g) = 73 degrees C) showed the presence of a pre-T(g) endotherm which disappeared upon annealing. Aspartame:trehalose (T(g) = 112 degrees C) and aspartame:PVP (T(g) = 100 degrees C) showed a broad exotherm before T(g) and annealing caused appearance of endothermic peaks before T(g). This work also employed IMC to measure the global molecular mobility represented by structural relaxation time (tau(beta)) in both un-annealed and annealed formulations. The effect of annealing on the enthalpy relaxation of lyophilized glasses, as measured by DSC and IMC, was consistent with the behavior predicted using the Tool-Narayanaswamy-Moynihan (TNM) phenomenology (Luthra et al., 2007, in press). The results show that the systems annealed at T(g) -15 degrees C to T(g) -20 degrees C have the lowest molecular mobility.     

Enthalpy Relaxation in Binary Amorphous Mixtures Containing Sucrose

Purpose. To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. Methods. Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVP/VA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. Results. Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran PVP > PVP/VA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (H) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). Conclusions. The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a T_g that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below T_g, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.     

Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams-Watts decay function.

The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam was studied using differential scanning calorimetry for ageing temperatures which were below the glass transition temperature, and ageing times up to 16 h. Experimental determination of the relaxation enthalpy and the heat capacity change, both accompanying the glass transition, enabled us to calculate the extent of relaxation of the amorphous drugs at specific ageing conditions. Fitting of the relaxation function to the Williams-Watts two parameter decay function led to calculation of the mean relaxation time constant tau and the molecular relaxation time distribution parameter beta. The mean relaxation time constants for the three drugs increased from approximately ten h at the glass transition temperature with more than eight orders of magnitude at 66 K below the glass transition temperature. It was found that the benzodiazepines exhibited significant molecular mobility until approximately 50 K below the glass transition temperature; below this temperature molecular mobility becomes unimportant with respect to the shelf life stability. Hence the presented procedure provides the formulation scientist with a tool to set storage conditions for amorphous drugs and glassy pharmaceutical products.     

Effects of annealing on enthalpy relaxation in lyophilized disaccharide formulations: mathematical modeling of DSC curves

The overall objective of these studies was to investigate, by experimental studies and theoretical analysis, the optimum annealing conditions to obtain maximum structural relaxation in lyophilized glasses of pharmaceutical significance. The model formulations used in this work were aspartame: sucrose and aspartame: trehalose (1:10 w/w) freeze-dried glasses. In this article, structural relaxation in amorphous systems was described in terms of the change in the fictive temperature (T(f)) and was measured using the enthalpy relaxation endotherm in a differential scanning calorimeter (DSC). The theoretical analysis was performed using the Tool-Narayanaswamy-Moynihan (TNM) model. The effect of different annealing conditions (temperature and time) on fictive temperature obtained from the theoretical analysis was calculated and compared with the experimental results. The model reproduced the experimental data very well for samples that were quench cooled from the liquid. However, the model fits were poor for lyophilized samples, indicating an inability to incorporate the complex thermal history of freeze-drying in the TNM model. The optimum aging conditions were determined from both DSC and approximated best-fit parameters of the TNM model, and it was found that annealing when done at a temperature about 15-25 degrees C below T(g) resulted in maximum structural relaxation.