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.     

Molecular Mobility of Supercooled Amorphous Indomethacin,Determined by Dynamic Mechanical Analysis

Purpose. To determine the viscosity and the frequency-dependent shear modulus of supercooled indomethacin as a function of temperature near and above its glass transition temperature and from these data to obtain a quantitative measure of its molecular mobility in the amorphous state. Methods. Viscoelastic measurements were carried with a controlled strain rheometer in the frequency domain, at 9 temperatures from 44° to 90°C. Results. The viscosity of supercooled indomethacin shows a strong non-Arrhenius temperature dependence over the temperature range studied, indicative of a fragile amorphous material. Application of the viscosity data to the VTF equation indicates a viscosity of 4.5 × 10¹⁰ Pa.s at the calorimetric Tg of 41°C, and a T₀ of –17°C. From the complex shear modulus and the Cole-Davidson equation the shear relaxation behaviour is found to be non-exponential, and the shear relaxation time at Tg is found to be approximately 100 sec. Conclusions. Supercooled indomethacin near and above its Tg exhibits significant molecular mobility, with relaxation times similar to the timescales covered in the handling and storage of pharmaceutical products.     

Effect of Temperature History on the Freeze-Thawing Process and Activity of LDH Formulations

Purpose. The purpose of the study was to investigate the effect of freeze-thawing processes with different temperature histories on thermal transformations and on protein activity of lactate dehydrogenase (LDH) formulations. Polyethylene glycol (PEG 6000) and maltodextrin were used as cryoprotectants. Methods. The thermal characterization was made by oscillating DSC (ODSC). LDH activity assays were performed spectrophotometrically. Results. The crystallization of the solutions and the melting of the frozen samples occurred at fairly constant heat of crystallisation and heat of fusion values and temperatures. The main difference between the two investigated temperature cycles was an exothermic peak at –45°C, which might reflect the transition between the cubic and hexagonal ice structures. When PEG was added to the system an additional endothermic peak appeared at –15°C in the heating program. It was transformed into the shape of a glass transition at the same temperature when the heating rate was increased. The degree of crystallinity of the samples was evaluated as the quota between the c_p component of heat of transformation and the total heat of transformation values. Only minor differences between the two temperature histories and between the samples were observed. The c_p component of the melting endotherm revealed a complex melting process with two overlapping endothermic transformations. The good protein protecting ability of PEG obtained when cooling and heating rate was low, was greatly reduced with increasing rate. The addition of maltodextrin to PEG-containing solutions lowered the activity recovery. Conclusions. The endothermic transformation of a PEG-ice structure at –15°C in the heating process is strongly correlated to the protective ability of PEG 6000 in the freeze-thawing process of LDH. To obtain the highest protein activity after the freeze-thawing process, the formulation shall be transformed by a low cooling and heating rate. The crystallinity of the system melting at about 2°C is independent of temperature history. The c_p component of the melting endotherm, however, shows a complex transformation, where two phases of different crystallinity and stability might be involved.     

Effect of thermal history on the glassy state of indapamide

The effects of thermal history, e.g. cooling rate, annealing, etc., on the thermal behaviour of indapamide glass were determined by differential scanning calorimetry (DSC). The glass was prepared by heating indapamide crystals (m.p. 162 degrees C) to 180 degrees C, and then cooling the melt to room temperature. The glass transition temperature (Tg) of the material was 98 degrees C. An endotherm, due to thermal relaxation of the glass, was observed in the DSC thermogram when indapamide glass was prepared by slow cooling or was annealed isothermally at a temperature below Tg. Such enthalpy relaxation may be observed during ageing of pharmaceutical glasses and might influence their physico-chemical properties.     

Physical Aging of Progesterone-Loaded Poly(D,L,-lactide-co-glycolide) Microspheres

Purpose. To study the interactions between a polymeric matrix and a drug during storage at a temperature lower than the glass transition temperature of the polymers. Methods. Poly(lactide-co-glycolide) microspheres loaded with different progesterone ratios were stored at 4, 20 and 40°C. DSC-scans were recorded at regular intervals, depending on the storage temperature. Results. The physical aging of the polymeric matrix, as monitored by the amplitude of the endotherm associated with the glass transition, is slowed down by crystalline progesterone. The development of the progesterone polymorphic depends on the interface/volume ratio of the crystals. Conclusions. For polymeric drug delivery systems, the determination of all studies parameters must take into account an effect of dispersed drugs which are more sensitive as the storage temperature is lower than the glass transition temperature of the matrix.     

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.     

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.     

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.     

Measurement of Glass Transition Temperatures of Freeze-Concentrated Solutes by Differential Scanning Calorimetry

Thermal analysis of aqueous solutions in which the solute does not crystallize immediately upon freezing was carried out to define the effects of experimental parameters on thermograms in the glass transition region. The intensity of enthalpy relaxations in the glass transition region is related to both the rate of cooling and the rate of heating through the glass transition region—slow cooling or slow heating increases the extent of structural relaxation in the glassy state and increases the intensity of the endotherm. Plots of the logarithm of heating rate versus l /Tg are linear, and activation enthalpies for structural relaxation are in the range of 210–350 kJ/mol. For polymeric solutes, both the activation enthalpies for structural relaxation and the heat capacity change accompanying the glass transition increase with increasing molecular weight of the solute. Molecular weight dependence of the observed midpoint of the glass transition agrees with the Fox–Flory relationship. Results are compared and contrasted with glass transitions in solid polymers and with the glass transition of hyperquenched water. Practical implications for characterization of formulations intended for freeze-drying are discussed.     

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.     

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.     

The Molecular Mobility of Supercooled Amorphous Indomethacin as a Function of Temperature and Relative Humidity

Purpose. To determine the relaxation times of supercooled indomethacin as a function of temperature and relative humidity above Tg, and to analyze the results in the context of being able to predict such behavior at various storage conditions. Methods. Dielectric relaxation times were measured in the frequency domain (12 to 10⁵ Hz) for amorphous indomethacin equilibrated at 0, 56, and 83% relative humidity. The heating rate dependence of Tg for dry supercooled indomethacin was measured with differential scanning calorimetry and used to determine relaxation times. The results were compared with previously published shear relaxation times and enthalpy recovery data. Results. Very good agreement was observed between dielectric and shear relaxation times, and those obtained from the heating rate dependence of the Tg, for dry indomethacin as a function of temperature above Tg. The introduction of water lowered the dielectric relaxation times of supercooled indomethacin without significantly affecting its fragility. The relaxation times below Tg, found to be lower than those predicted by extrapolation of the data obtained above Tg, were analyzed in the context of the Adam-Gibbs-Vogel equation. Conclusions. The relaxation times of amorphous indomethacin obtained from the heating rate dependence of Tg were in good agreement with those obtained from shear and dielectric measurements, thus validating a relatively simple approach of assessing molecular mobility. The significant molecular mobility of amorphous indomethacin observed below Tg, and the significant plasticizing effects of sorbed water, help to explain why amorphous indomethacin crystallizes well below Tg over relatively short time scales.     

Effects of a Citrate Buffer System on the Solid-State Chemical Stability of Lyophilized Quinapril Preparations

Purpose. The objective of this study was to examine the effect of a citric acid-citrate buffer system on the chemical instability of lyophilized amorphous samples of quinapril hydrochloride (QHCl). Methods. Molecular dispersions of QHCl and citric acid were prepared by colyophilization from their corresponding aqueous solutions with a molar ratio of QHCl to citric acid from 1:1 to 6:1 and solution pH from 2.49 to 3.05. Solid samples were subjected to a temperature of 80°C and were analyzed for degradation using high-performance liquid chromatography. The glass transition temperature, Tg, of all samples was measured by differential scanning calorimetry. Results. Samples were first examined by varying the Tg and maintaining the initial solution pH constant. At pH 2.49 the rate of reaction was found to be less dependent on the sample Tg, whereas at pH 2.75 the rate decreased with an increase in Tg. In a second set of experiments at a constant Tg of 70°C, the reaction rate increased as the pH increased. Conclusion. The overall solid-state chemical reactivity of amorphous quinapril depends on the relative amount of QHCl and Q^+–, the zwitterionic form of quinapril. At high proportions of Q^+– (higher pH values) the reaction rate seems to be strongly influenced by the Tg of the mixture, and hence the molecular mobility, whereas at higher proportions of QHCl (lower pH) the reaction rate is less sensitive to Tg, presumably because of different mechanistic rate determining steps for the two sets of conditions.     

Neotame anhydrate polymorphs. II: Quantitation and relative physical stability

Purpose. To study the relative thermodynamic and kinetic stabilities of neotame anhydrate polymorphs A, D, F, and G, and to develop a quantitative method for analyzing polymorphic mixtures of A and G by powder X-ray diffractometry (PXRD). Methods. Based on the melting points, heats of fusion, and densities of the four polymorphs, thermodynamic rules were applied to study their thermodynamic relationships. The phase transition temperature of Forms A and G was estimated from their heats of solution and intrinsic dissolution rates (J) in 2-propanol. Using PXRD, a method for the quantitative analysis of polymorphic mixtures of Forms A and G was developed. Binary polymorphic mixtures of Forms A, D, F, or G were stored under zero relative humidity at 23 or 70°C, and their compositions were monitored by PXRD. Results. The endothermic enthalpy of solution of A, D, F, and G follows the rank order: G (29.71 ± 0.82 kJ/mol, n = 4) > A (28.48 ± 0.51 kJ/mol, n = 4) > D (20.43 ± 0.45 kJ/mol, n = 4) > F (18.77 ± 0.31 kJ/mol, n = 4). The van't Hoff plots of ln(J) against 1/T for A and G show good linearity between 25°C and 32°C. At 23°C polymorphic mixtures remain unchanged for 4 months. However, at 70°C the phase transition is fast and the relative stability of the four polymorphs follows the rank order: G > D > F and G > A. Conclusions. PXRD provides a reliable and accurate technique for the quantitative analysis of polymorphic mixtures of Forms A and G. Among the four polymorphs, A-G and A-D are enantiotropic pairs, whereas D-F, D-G, F-G are monotropic pairs. The phase transition temperature between A and G lies within the range 35-70°C.     

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.     

Real-Time in Situ Monitoring of Lysozyme During Lyophilization Using Infrared Spectroscopy: Dehydration Stress in the Presence of Sucrose

Purpose. First, to investigate the role of sucrose in stabilizing protein structure (as measured by changes in the amide I band of lysozyme) caused by dehydration encountered during lyophilization. Second, to demonstrate the utility of internal reflection spectroscopy as a tool for conducting controlled lyophilization experiments. Methods. A custom-built internal reflection FTIR accessory was used to follow the entire freeze-drying process of solutions consisting of 49.4 mg/mL lysozyme in the presence and absence of 10% sucrose in real-time. Studies were carried out using D₂O as a transparent medium in the infrared region of the protein amide bands. Potential self-association of the protein in the presence of sucrose was investigated using dynamic light scattering. Hydration levels were determined using a multiple regression equation. Differential scanning calorimetry (DSC) permitted characterization of the final lyophilized product. Moisture content was determined using Karl Fischer titration. Results. Throughout freezing and drying, minimal changes were observed both in frequency (1647 ± 1 cm^–1) and bandwidth (46 ± 1 cm^–l) of the amide I band in the presence of sucrose. In contrast, greater changes in frequency and band width were seen in the absence of sucrose. A successfully lyophilized cake was obtained which had properties of a glass as measured by DSC, with a Tg of 50°C. The lyophilized product containing sucrose had 4% moisture by weight. Three distinct rates of water desorption were discovered during drying under vacuum (50 mg/hr within the sample temperature range from –35° to –25°C; 30 mg/hr from 10° to 25°C; 1.2 mg/hr from 27° to 38°C). Conclusions. The inclusion of sucrose served to minimize perturbations of protein structure caused by freezing and dehydration stresses encountered during lyophilization (compared to studies conducted in the absence of sucrose). The results support the water replacement hypothesis and underscore the role of the sugar in preserving a native structure in the dried state. This investigation demonstrates the usefulness of infrared spectroscopy in evaluating lyophilization process parameters and formulation design.     

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.     

Influence of storage temperature and moisture on the performance of microsphere/hydrogel composites

The current study involved investigation of the effect of storage temperature and moisture on the performance of poly(lactide-co-glycolide) (PLGA) microsphere/poly(vinyl-alcohol) (PVA) hydrogel composites. Physical aging occurred in composites stored at 25 °C due to structural relaxation. The glass transition temperature (Tg) and enthalpy of relaxation of the composites increased leading to a slower cumulative % release. The Tg of composites incubated at 40 °C, 75% RH decreased significantly due to the plasticization effect of absorbed water, whereas no change was observed in the Tg of microspheres alone; indicating that the hydrogel component enhanced water absorption. PLGA degradation occurred leading to significantly faster dexamethasone release following incubation at 40 °C, 75% RH for 1 month. No significant change was observed in the in vitro release profiles of composites after 6 months storage at 25 °C, 60% RH, however, release was accelerated following 12 months storage. Accordingly, exposure of the composites to ambient temperature/moisture during storage, shipping or handling may cause physical aging, plasticization, and degradation and hence, their performance may be affected. The extent to which the performance of the composite is affected by storage temperature and moisture is a net effect of physical aging and moisture induced plasticization/hydrolytic degradation.     

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.