The Activation Energy at T g and the Fragility Index of Indomethacin,Predicted from the Influence of the Heating Rate on the Temperature Position and on the Intensity of Thermally Stimulated Depolarization Current Peak

Purpose. The purpose of this study was to estimate the activation energy at the glass transition temperature (and the fragility index) of amorphous indomethacin from the influence of heating rate on the features of the relaxation peaks obtained by thermally stimulated depolarization currents (TSDC) and to compare the obtained results with those obtained by other procedures based on TSDC data. Methods. The glass transition temperature region of amorphous indomethacin was characterized at different heating rates by TSDC in a way similar to that used to determine the kinetics of the glass transition relaxation by differential scanning calorimetry. The features of a thermal sampled TSDC peak, namely the temperature location and the intensity, depend on the heating rate. Results. The activation energy for structural relaxation (directly related to glass fragility) was estimated from the heating rate dependence of the TSDC peak location, T _m, and of the maximum intensity of the TSDC peak, I(T _m). Conclusions. The methods for determining the activation energy for structural relaxation and fragility of indomethacin from TSDC data obtained with different heating rates were compared with other procedures previously proposed. TSDC, which is not a very familiar technique in the community of pharmaceutical scientists, proved to be a very convenient technique to study molecular mobility and to determine the fragility index in glass-forming systems. The value of 60 appears as a reasonable value of the fragility index of indomethacin.     

Determination of the Viscosity of an Amorphous Drug Using Thermomechanical Analysis (TMA)

Purpose. To evaluate thermomechanical analysis (TMA) as a technique for determining the viscosity of amorphous pharmaceutical materials. This property of amorphous drugs and excipients is related to their average rate of molecular mobility and thus to their physical and chemical stability. Methods. Indomethacin was selected as a model amorphous drug whose viscosity has previously been reported in the literature. A Seiko TMA 120C thermomechanical analyzer was utilized in isothermal penetration mode to determine the viscosity of the amorphous drug over the maximum possible range of temperatures. Results. Using a cylindrical penetration geometry it was possible to accurately determine the viscosity of amorphous indomethacin samples by TMA over the temperature range from 35 to 75°C. The results were consistent with those reported in the literature using a controlled strain rheometer over the range 44–75°C. The limiting lower experimental temperature for the TMA technique was extended to significantly below the calorimetric glass transition temperature (T_g 42°C), thus allowing a direct experimental determination of the viscosity at T_g to be made. Conclusions. Thermomechanical analysis can be used to accurately determine the viscosity of amorphous pharmaceutical materials at temperatures near and above their calorimetric glass transition temperatures.     

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.     

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.     

Molecular Mobility and Fragility in Indomethacin: A Thermally Stimulated Depolarization Current Study

Purpose. To show that thermally stimulated depolarization currents (TSDC), which is a dielectric experimental technique relatively unknown in the pharmaceutical scientists community, is a powerful technique to study molecular mobility in pharmaceutical solids, below their glass transition temperature (T_g). Indomethacin (T_g = 42°C) is used as a model compound. Methods. TSDC is used to isolate the individual modes of motion present in indomethacin, in the temperature range between –165°C 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 indomethacin. Results. Two different relaxational processes were detected and characterized: the glass transition relaxation, or -process, and a sub-T_g relaxation, or secondary process. The lower temperature secondary process presents a very low intensity, a very low activation energy, and a very low degree of cooperativity. The fragility index (Angell's scale) of indomethacin obtained from TSDC data is m = 64, which can be compared with other values reported in the literature and obtained from other experimental techniques. Conclusions. TSDC data indicate that indomethacin is a relatively strong glass former (fragility similar to glycerol but lower than sorbitol, trehalose, and sucrose). The high-resolution power of the TSDC technique is illustrated by the fact that it detected and characterized the secondary relaxation in indomethacin, which was not possible by other techniques.     

Direct Observation of the Enthalpy Relaxation and the Recovery Processes of Maltose-Based Amorphous Formulation by Isothermal Microcalorimetry

Purpose. The applicability of isothermal microcalorimetry (IMC) for evaluating enthalpy relaxation and recovery processes of amorphous material was assessed. Methods. A maltose-based formulation was prepared by freeze-dry method. Differential scanning calorimetry (DSC) was used to investigate its glass transition and relaxation behaviors. IMC was applied to quantitatively analyze the relaxation and the recovery processes. The IMC data were analyzed using a derivative of the Kohlrausch-Williams-Watts equation. Results. The glass transition temperature of the formulation and its fictive temperature stored at 15°C for 1 year were 62 and 32°C, respectively. DSC study showed that annealing below the fictive temperature increased the enthalpy recovery, but it was decreased by annealing at higher temperatures. IMC enabled direct observation of the heat flow during both the relaxation and the recovery processes. The decay constant for the recovery process (recovery time) was much smaller and less sensitive to the temperature than that for the relaxation process (relaxation time). Conclusions. IMC was successfully used to obtain quantitative information on both relaxation and recovery processes of amorphous material. The relaxation parameters obtained by this method could explain the thermodynamic behavior of the formulation.     

Prediction of Glass Transition Temperature of Freeze-Dried Formulations by Molecular Dynamics Simulation

Purpose. To examine whether the glass transition temperature (T_g) of freeze-dried formulations containing polymer excipients can be accurately predicted by molecular dynamics simulation using software currently available on the market. Molecular dynamics simulations were carried out for isomaltodecaose, a fragment of dextran, and -glucose, the repeated unit of dextran, in the presence or absence of water molecules. Estimated values of T_g were compared with experimental values obtained by differential scanning calorimetry (DSC). Methods. Isothermal-isobaric molecular dynamics simulations (NPTMD) and isothermal molecular dynamics simulations at a constant volume (NVTMD) were carried out using the software package DISCOVER (Material Studio) with the Polymer Consortium Force Field. Mean-squared displacement and radial distribution function were calculated. Results. NVTMD using the values of density obtained by NPTMD provided the diffusivity of glucose-ring oxygen and water oxygen in amorphous -glucose and isomaltodecaose, which exhibited a discontinuity in temperature dependence due to glass transition. T_g was estimated to be approximately 400K and 500K for pure amorphous -glucose and isomaltodecaose, respectively, and in the presence of one water molecule per glucose unit, T_g was 340K and 360K, respectively. Estimated T_g values were higher than experimentally determined values because of the very fast cooling rates in the simulations. However, decreases in T_g on hydration and increases in T_g associated with larger fragment size could be demonstrated. Conclusions. The results indicate that molecular dynamics simulation is a useful method for investigating the effects of hydration and molecular weight on the T_g of lyophilized formulations containing polymer excipients, although the relationship between cooling rates and T_g must first be elucidated to predict T_g vales observed by DSC measurement. January 16     

Determination of Glass Transition Temperature and in Situ Study of the Plasticizing Effect of Water by Inverse Gas Chromatography

Purpose. To use an inverse gas chromatographic (IGC) method to determine the glass transition temperature (Tg) of some amorphous pharmaceuticals and to extend this technique for the in situ study of the plasticizing effect of water on these materials. Methods. Amorphous sucrose and colyophilized sucrose-PVP mixtures were the model compounds. Both IGC and differential scanning calorimetry (DSC) were used to determine their Tg. By controlling the water vapor pressure in the IGC sample column, it was possible to determine the Tg of plasticized amorphous phases. Under identical temperatures and vapor pressures, the water uptake was independently quantified in an automated water sorption apparatus. Results. The Tg of the dry phases, determined by IGC and by DSC, were in very good agreement. With an increase in the environmental relative humidity (RH), there was a progressive decrease in Tg as a result of the plasticizing effect of water. Because the water uptake was independently quantified, it was possible to use the Gordon-Taylor equation to predict the Tg values of the plasticized materials. The predicted values were in very good agreement with those determined experimentally using IGC. A unique advantage of this technique is that it provides complete control over the sample environment and is thus ideally suited for the characterization of highly reactive amorphous phases. Conclusions. An IGC method was used (a) to determine the glass transition temperature of amorphous pharmaceuticals and (b) to quantify the plasticizing effect of water on multicomponent systems.     

Thermophysical Properties of Trehalose and Its Concentrated Aqueous Solutions

Purpose. To address the lack of fundamental thermophysical data for trehalose and its aqueous systems by measuring equilibrium and non-equilibrium properties of such systems. Methods/Results. Differential scanning calorimetry (DSC) and dynamic mechanical analysis were used to measure glass transition temperatures of trehalose and its solutions. X-ray diffractometry was used to verify the structure of amorphous trehalose. Controlled-stress rheometry was used to measure viscosity of several aqueous trehalose systems at ambient and sub-ambient temperatures. Over this temperature range, the density of these solutions was also measured with a vibrating tube densimeter. The equilibrium phase diagram of aqueous trehalose was determined by measuring the solubility and freezing point depression. Conclusions. Our solubility measurements, which have allowed long times for attainment of chemical equilibrium, are substantially different from those reported earlier that used different techniques. Our measurements of the glass transition temperature of trehalose are higher than reported values. A simple model for the glass transition is presented to describe our experimental observations.     

Predicting Plasticization Efficiency from Three-Dimensional Molecular Structure of a Polymer Plasticizer

Purpose. In polymeric coatings, plasticizers are used to improve the film-forming characteristic of the polymers. In this study, a computerized method (VolSurf with GRID) was used as a novel tool for the prediction plasticization efficiency () of test compounds, and for determining the critical molecular properties needed for polymer plasticization. Methods. The film-former, starch acetate DS 2.8 (SA), was plasticized with each of 24 tested compounds. A decrease in glass transition temperature of the plasticized free films (determined by differential scanning calorimeter (DSC)) was used as an indicator for . Partial least squares discriminant analysis was used to correlate the experimental data with the theoretical molecular properties of the plasticizers. Results. A good correlation (r² = 0.77, q² = 0.58) between the molecular modeling results and the experimental data demonstrated that can be predicted from the three-dimensional molecular structure of a compound. Favorable structural properties identified for the potent SA plasticizer were strong hydrogen bonding capacity and a definitive hydrophobic region on the molecule. Conclusions. The VolSurf method is a valuable tool for predicting the plasticization efficiency of a compound. The correlation between experimental and calculated glass transition temperature values verifies that physicochemical properties are primary factors influencing plasticization efficiency of a compound.     

Crystallization of Mannitol below Tg′ during Freeze-Drying in Binary and Ternary Aqueous Systems

Purpose. To characterize the phase transitions in a multicomponent system during the various stages of the freeze-drying process and to evaluate the crystallization behavior below Tg (glass transition temperature of maximally freeze-concentrated amorphous phase) in frozen aqueous solutions and during freeze-drying. Methods. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study frozen aqueous solutions of mannitol with or without trehalose. By attaching a vacuum pump to the low-temperature stage of the diffractometer, it was possible to simulate the freeze-drying process in situ in the sample chamber of the XRD. This enabled real-time monitoring of the solid state of the solutes during the process. Results. In rapidly cooled aqueous solutions containing only mannitol (10% w/w), the solute was retained amorphous. Annealing of frozen solutions or primary drying, both below Tg, resulted in crystallization of mannitol hydrate. Similar effects were observed in the presence of trehalose (2% w/w). At higher concentrations (5% w/w) of this noncrystallizing sugar, annealing below Tg led to nucleation but not crystallization. However, during primary drying, crystallization of mannitol hydrate was observed. Conclusions. The combination of in situ XRD and DSC has given a unique insight into phase transitions during freeze-drying as a function of processing conditions and formulation variables. In the presence of trehalose, mannitol crystallization was inhibited in frozen solutions but not during primary drying.     

Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization

Purpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30°C Methods. The glass transition temperatures (Tg) of molecular dispersions were measured using differential scanning calorimetry (DSC). FT-IR spectroscopy was used to investigate possible differences in interactions between indomethacin and polymer in the various dispersions. The enthalpy relaxation of 5% w/w and 30% w/w polymer dispersions was determined following various aging times. Quantitative isothermal crystallization studies were carried out with pure indomethacin and 5% w/w polymers in drug as physical mixtures and molecular dispersions. Results. All coprecipitated mixtures exhibited a single glass transition temperature. All polymers interacted with indomethacin in the solid state through hydrogen bonding and in the process eliminated the hydrogen bonding associated with the carboxylic acid dimers of indomethacin. Molecular mobility at 16.5°C below Tg was reduced relative to indomethacin alone, at the 5% w/w and 30% w/w polymer level. No crystallization of indomethacin at 30°C was observed in any of the 5% w/w polymer molecular dispersions over a period of 20 weeks. Indomethacin alone and in physical mixtures with various polymers completely crystallized to the form at this level within 2 weeks. Conclusions. The major basis for crystal inhibition of indomethacin at 30°C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indomethacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the crystal form of indomethacin.     

Freeze-Concentration Separates Proteins and Polymer Excipients Into Different Amorphous Phases

Purpose. To study the miscibility of proteins and polymer excipients in frozen solutions and freeze-dried solids as protein formulation models. Methods. Thermal profiles of frozen solutions and freeze-dried solids containing various proteins (lysozyme, ovalbumin, BSA), nonionic polymers (Ficoll, polyvinylpyrrolidone [PVP]), and salts were analyzed by differential scanning calorimetry (DSC). The polymer miscibility was determined from the glass transition temperature of maximally freeze-concentrated solute (T_g) and the glass transition temperature of freeze-dried solid (T_g). Results. Frozen Ficoll or PVP 40k solutions showed T_g at –22°C, while protein solutions did not show an apparent T_g. All the protein and nonionic polymer combinations (5% w/w, each) were miscible in frozen solutions and presented single T_gs that rose with increases in the protein ratio. Various salts concentration-dependently lowered the single T_gs of the proteins and Ficoll combinations maintaining the mixed amorphous phase. In contrast, some salts induced the separation of the proteins and PVP combinations into protein-rich and PVP-rich phases among ice crystals. The T_gs of these polymer combinations were jump-shifted to PVP's intrinsic T_g at certain salt concentrations. Freeze-dried solids showed varied polymer miscibilities identical to those in frozen solutions. Conclusions. Freeze-concentration separates some combinations of proteins and nonionic polymers into different amorphous phases in a frozen solution. Controlling the polymer miscibility is important in designing protein formulations.     

Structural and Dynamic Properties of Crystalline and Amorphous Phases in Raffinose-Water Mixtures

Purpose. To obtain an improved characterisation of the raffinose-water solid-solid and solid-liquid state diagram, and to study the thermophysical behaviour of the solid amorphous phase. This information is expected to shed light on the potential of rafTinose as a pharmaceutical excipient, for stabilising labile preparations at high temperatures. Methods. X-ray diffraction, scanning electron microscopy, polarised-light microscopy, differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA) were applied to study raffinose pentahydrate and its behaviour during progressive dehydration. Results. Isothermal dehydration of raffinose pentahydrate led to its gradual amorphisation, but also to minor changes in the diffractograms, suggesting the probability of lower stable hydrates. Their existence was confirmed by DSC. Anhydrous raffinose was found to be completely amorphous, and this was supported by the gradual disappearance of birefringence during dehydration. In contrast, electron micrographs, taken during the dehydration process, exhibited no changes in the original ultrastructural crystal morphology. The widths of the glass-to-fluid transitions and the absolute specific heats of crystalline and amorphous phases in the vitreous and fluid states were used to estimate some structural and relaxation characteristics of amorphous raffinose-water mixtures. Conclusions. Raffinose forms the most 'fragile' glass of those pharmaceutical excipients for which data are available. In its thermomechanical properties, it is superior to trehalose and should therefore be effective as a long-term stabiliser for dried biopharmaceutical preparations at temperatures up to 65°C.     

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.     

Crystallization Behavior of Mannitol in Frozen Aqueous Solutions

Purpose. To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions. Methods. Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions. Results. Rapid cooling (20°C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10°C and 5°C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32°C and -25°C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of 100 mM, the buffer salts significantly inhibited mannitol crystallization. Conclusions. The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.     

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.     

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.     

Detection of Low Levels of the Amorphous Phase in Crystalline Pharmaceutical Materials by Thermally Stimulated Current Spectrometry

Purpose. To demonstrate the applicability of thermally stimulated current (TSC) spectrometry for the detection of low levels of the amorphous phase in crystalline pharmaceutical materials.Methods. A crystalline drug substance was melt quenched to produce an amorphous material. Blends of the crystalline and amorphous phases in different ratios (from 75:25 to 99:01) were prepared by serial dilution. TSC studies were performed by applying an electric field at a temperature above the glass transition temperature (T_g) to orient the dipoles, rapidly cooling to 0°C, short circuiting for 1 min, and scanning at 7°C/min to measure the depolarization current. The temperature of the peak in the spectrum corresponds to the T_g of the amorphous phase. Modulated differential scanning calorimtery (DSC) studies were performed using three different test protocols (varying linear heating rate, modulation amplitude, and time period). Powder X-ray diffraction (XRD) studies were performed using a Siemens D500 diffractometer.Results. The ability to detect the amorphous phase by powder XRD is beset with problems due to indirect inference, orientation effects, and instrument-related intensity variations. Even using a consistent sampling procedure and an internal standard, the XRD could quantify the amorphous phase at a level of 5%. In the conventional or modulated DSC, the amorphous phase manifests itself as a shift in the baseline. Using modulated DSC it was possible to detect the amorphous phase at a level of 5% when tested at a heating rate of 2°C/min and an amplitude of ±1.0°C with a period of 30 s. The moisture sorption method appears to have a similar detection capability. In TSC scans, the glass transition event due to molecular/segmental mobility in the amorphous phase was manifested as a peak/shoulder on the low-temperature side of the depolarization peak of the crystalline phase. The amorphous phase was unambiguously detected at 2% with a lower detection limit of 1%.Conclusions. On the basis of the results of this preliminary investigation, TSC appears to be capable of detecting the amorphous phase at as low as 1% in crystalline pharmaceuticals, thus offering a much needed capability in discerning factors.     

Real Time Detection of Photoreactivity in Pharmaceutical Solids and Solutions with Isothermal Microcalorimetry

Purpose. In this study an irradiation cell made as an accessory for an isothermal microcalorimeter is introduced, and its suitability for detection photoreactivity in pharmaceutical solutions and solids is demonstrated. The pharmaceuticals employed are chosen as sample materials to evaluate the usefulness and stability of the irradiation cell. Methods. An irradiation cell has been constructed and tested in an isothermal microcalorimeter with pharmaceutical solutions and solids known to be sensitive to daylight or UV light. Light is produced with an Xe-arc lamp, split into two parts and introduced into calorimetric vessels with optical light cables. One of the vessels containing the reference sample gives the response to the heat absorbed by the material (radiant power), and the other vessel containing the sample material gives the response also to the photoreaction. The two irradiation cells are positioned in the sample sides of two separate twin microcalorimetric units. Results. Nifedipine and L-ascorbic acid were found to be photosensitive in solutions and solid states, the extent of the degradation depending on the irradiation intensity and wavelength. The threshold values of the wavelength for the photoreactions, as well as the wavelengths for the maximum reaction rates, were estimated via the scanning irradiation measurements. The ability of photons with different energies to produce heat in the photosensitive reaction of nifedipine was calculated using constant measurements. Conclusions. The technique introduced offers a rapid and versatile method to study the photosensitivity of materials in any state. In the measurements, various conditions can be simulated and thus provide information on the real behavior of materials.