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.     

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.     

The Use of Inverse Phase Gas Chromatography to Study the Glass Transition Temperature of a Powder Surface

PURPOSE: To measure the glass transition temperature (Tg) at the surface of a hydrophobic particle at different temperatures and humidities, on the hypothesis that the surface may be plasticized to a different extent to the bulk due to slow water sorption giving a concentration gradient of water through the particles. METHODS: Amorphous indomethacin was exposed to a range of relative humidities (RH) and temperatures in an inverse gas chromatograph (IGC). The retention volumes of decane were calculated at all conditions using center of mass (Vcom) and peak height (Vmax) methods. The extent of water sorption was determined gravimetrically. RESULTS: The Vcom retention volumes were found to deviate from Vmax results at certain critical humidities at each temperature. This was taken as a novel method for determining the Tg of the sample surface at different experimental conditions. Extrapolating the critical RH to lower the Tg to experimental temperature to 0% RH yeilded a Tg similar to literature values. Water sorption data provided valuable information on changes in mobility of the amorphous form as a function of temperature and RH. CONCLUSIONS: It is possible to use IGC to determine the Tg of the surface of particles at defined conditions. This overcomes the problems of conventional methods of assessing Tg, relating to disruption of water sorption on heating. This helps in the understanding of the physical form of the surface of hydrophobic particles and how and when the surface will start to crystallize.     

Microcalorimetric Measurement of the Interactions Between Water Vapor and Amorphous Pharmaceutical Solids

Purpose. Use a microcalorimetric technique to measure the interactions between water vapor and amorphous pharmaceutical solids and describe the relationship between long-term physical stability and the storage relative humidity (RH) at constant temperature. Methods. A thermal activity monitor was used to characterize interactions of water vapor with spray-dried amorphous sucrose, lactose, raffinose, and sodium indomethacin. Differential scanning calorimetry was used to measure glass transition temperature, T _g. X-ray powder diffraction was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy was used to examine particle morphology. Specific surface area was determined by BET analysis of nitrogen and krypton adsorption isotherms. Results. The moisture-induced thermal activity traces (MITATs) of the materials in this study exhibit general behavior that helps explain the effect of moisture content on the physical stability of the glassy phase at a given storage temperature. At some RH threshold, RH _m, the MITAT exhibits a dramatic increase in the energy of interaction between water vapor and the glass that cannot be explained by a phase or morphology change. Calorimetric data indicate that water vapor-solid interactions are reversible below RH _m; above RH _m, energetic hysteresis is observed and water-water interactions predominate. In addition, the MITAT was deconvoluted into sorptive and nonsorptive components, making it possible to assign the observed heat flow to unique thermal events. Samples stored at a RH just below RH _m for more than 2 months show no evidence of morphology or phase change. In addition, the MITAT can be deconvoluted into sorptive and nonsorptive components by using a twin-calorimeter arrangement. This analysis provides specificity to the microcalorimetric analysis and helps explain the nature of the physical changes that occur during the hydration glassy phase. Conclusions. The MITAT is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and may find a broad application to determine appropriate storage conditions to ensure long-term physical stability.     

The Use of Solution Theories for Predicting Water Vapor Absorption by Amorphous Pharmaceutical Solids: A Test of the Flory–Huggins and Vrentas Models

The limitations of traditional gas adsorption models for describing water vapor sorption by amorphous pharmaceutical solids are described and an alternative approach based on polymer solution theories is proposed. The approach is tested by comparing a priori predicted isotherms with literature data for the poly(vinylpyrrolidone)(PVP)–water system. The well-known Flory– Huggins model is able to describe the water vapor sorption isotherm only when the PVP–water mixture is in the rubbery state (i.e., above its glass transition temperature). However, a newer model developed by Vrentas and co-workers, which takes into account the plasticizing effect of water on the polymer, is able to describe the entire form of the isotherm. Consideration of the parameters in this model allows a number of critical variables to be identified and also enables the characteristic shape of the water vapor sorption isotherm to be explained.     

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.     

Effect of Aging on the Physical Properties of Amorphous Trehalose

PURPOSE: The purpose of this investigation was i) to study the effect of physical aging on crystallization and water vapor sorption behavior of amorphous anhydrous trehalose prepared by freeze-drying, and ii) to determine the effects of water sorption on the relaxation state of the aged material. METHODS: Freeze-dried trehalose was aged at 100 dgrees C for varying time periods to obtain samples with different degrees of relaxation. The glass transition temperature (Tg) and enthalpic relaxation were determined by differential scanning calorimetry, and the rate and extent of water uptake at different relative humidity values were quantified using an automated vapor sorption balance. RESULTS: Annealing below the Tg caused nucleation in the amorphous trehalose samples, which decreased the crystallization onset temperature on subsequent heating. However, no crystallization was observed below the Tg even after prolonged annealing. Physical aging caused a decrease in the rate and extent of water vapor sorption at low relative humidity values. Moreover, the water sorption removed the effects of physical aging, thus effectively causing enthalpic recovery in the aged samples. This recovery occurred gradually in the glassy phase and was not associated with a glass to rubber transition. We believe this aging reversal to be due to volume expansion during water sorption in the amorphous structure. CONCLUSIONS: Thermal history of amorphous materials is a crucial determinant of their physical properties. Aging of amorphous trehalose led to nucleation below the Tg, and decrease in rate and extent of water sorption. Sorption of water resulted in irreversible changes in the relaxation state of the aged material.     

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.     

Determining the critical relative humidity for moisture-induced phase transitions

A new method to determine the onset relative humidity for a glass transition and crystallization processes in amorphous or partially amorphous materials was developed using dynamic gravimetric vapor sorption (DVS). Water vapor can act as a plasticizing agent in amorphous materials, thus lowering the glass transition temperature below room temperatures. Additional water sorption can lead to a crystallization event below the glass transition temperature. On spray-dried lactose the glass transition RH and crystallization RH values were 30 and 58% at 25 degrees C, respectively. Glass transition and crystallization RH values were also measured at 5, 15, 25, 35, and 45 degrees C on a spray-dried salbutamol sulfate sample. The glass transition RH values for the salbutamol sulfate sample ranged from 64.5% RH (5 degrees C) to 32.8% RH (45 degrees C) while the crystallization RH values ranged from 81.0% RH (5 degrees C) to 50.4% RH (45 degrees C). The results clearly show that the glass transition and crystallization humidity values decrease as the sample temperature increases.     

Effect of Preparation Method on Physical Properties of Amorphous Trehalose

PURPOSE: To determine the effect of preparation method on the physical properties of amorphous trehalose. METHODS: Amorphous anhydrous trehalose was prepared by four different methods. viz., freeze-drying, spray-drying, dehydration, and melt quenching. The glass transition temperature (Tg), enthalpic relaxation behavior, and crystallization were studied by differential scanning calorimetry, whereas X-ray diffractometry was used for phase identification. The rate and extent of water uptake at different relative humidity values were also obtained. RESULTS: Though the enthalpic relaxation and crystallization behaviors were influenced by the method of preparation of amorphous trehalose, the Tg and fragility were not. The phase prepared by dehydration showed the highest enthalpic recovery at Tg, indicating that aging may have occurred during preparation. Among the four methods used, trehalose prepared by dehydration had the highest tendency to crystallize, whereas there was no crystallization in melt-quenched amorphous trehalose. The method of preparation influenced not only the rate and extent of water sorption but also the phase crystallized. Water vapor sorption removed the effects of structural history in the amorphous phase formed by dehydration. CONCLUSIONS: The method of preparation strongly influenced the pharmaceutically relevant properties of amorphous trehalose. The resistance to crystallization can be rank ordered as trehalose prepared by dehydration < freeze-dried approximately spray-dried < melt-quenched. The rate of water sorption can be rank ordered as trehalose prepared by dehydration < freeze-dried < spray-dried.     

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.     

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.     

Influence of Environmental Conditions on the Kinetics and Mechanism of Dehydration of Carbamazepine Dihydrate

ABSTRACT

The object of this project was to study the influence of temperature and water vapor pressure on the kinetics and mechanism of dehydration of carbamazepine dihydrate and to establish the relationship between the dehydration mechanism and the solid-state of the anhydrous phase formed, Three experimental techniques were utilized to study the kinetics of dehydration of carbamazepine dihydrate (C₁₅H₁₂N₂O·2H₂O)-thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VYXRD). These techniques respectively provide information about the changes in weight, heat flow and solid-state (phase) during the dehydration process. The instrumental setup was modified so that simultaneous control of both the temperature and the water vapor pressure was possible. The experiments were carried out at different temperatures, ranging from 26 to 64°C. In the absence of water vapor, the dehydration followed the 2-dimen-sional phase boundary controlled model at all the temperatures studied. In the next stage, the water vapor pressure was altered while the studies were carried out at a single temperature of 44°C. The dehydration was 2-dimensional phase boundary controlled at water vapor pressures ≤5.1 torr while the Avrami-Erofeev kinetics (3-dimensional nucleation) was followed at water vapor pressures ≥ 12.0 torr. In the former case, the anhydrous phase formed was X-ray amorphous while it was the crystalline anhydrous γ-carbamazepine in the latter. Thus a relationship between the mechanism of dehydration and the solid-state of the product phase was evident. The dehydration conditions influence not only the mechanism but also the solid-state of the anhydrous phase formed. While the techniques of TGA and DSC have found extensive use in studying dehydration reactions, VTXRD proved to be an excellent complement in characterizing the solid-states of the reactant and product phases.     

Rapid Assessment of the Structural Relaxation Behavior of Amorphous Pharmaceutical Solids: Effect of Residual Water on Molecular Mobility

Purpose Use RH-perfusion microcalorimetry and other analytical techniques to measure the interactions between water vapor and amorphous pharmaceutical solids; use these measurements and a mathematical model to provide a mechanistic understanding of observed calorimetric events.Materials Isothermal microcalorimetry was used to characterize interactions of water vapor with a model amorphous system, spray-dried raffinose. Differential scanning calorimetry was used to measure glass transition temperature, T _g. High-sensitivity differential scanning calorimetry was used to measure enthalpy relaxation. X-ray powder diffraction (XRPD) was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy (SEM) was used to examine particle morphology. Gravimetric vapor sorption was used to measure moisture sorption isotherms. Thermogravimetric analysis (TGA) was used to measure loss on drying.Results A moisture-induced thermal activity trace (MITAT) provides a rapid measure of the dependence of molecular mobility on moisture content at a given storage temperature. At some relative humidity threshold, RH_m, the MITAT exhibits a dramatic increase in the calorimetric rate of heat flux. Simulations using calorimetric data indicate that this thermal event is a consequence of enthalpy relaxation.Conclusions RH-perfusion microcalorimetry is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and could find a broad application to determine appropriate storage conditions to ensure long-term physical stability. Remarkably, thermal events measured on practical laboratory timescales (hours to days) are relevant to the stability of amorphous materials on much longer, pharmaceutically relevant timescales (years). The mechanistic understanding of these observations in terms of enthalpy relaxation has added further value to the use of RH-perfusion calorimetry as a rapid means to characterize the molecular mobility of amorphous solids.     

The Effect of Temperature on Hydrogen Bonding in Crystalline and Amorphous Phases in Dihydropyrine Calcium Channel Blockers

Purpose: To investigate the effect of temperature on hydrogen bonding in a series of structurally related amorphous and crystalline compounds to gain a better molecular-level understanding of structural differences in the various phases. Methods: FT-infrared spectra of seven 1,4-dihydropyridine calcium channel blockers were obtained at temperatures between 0 and 200°C using a temperature-controlled attenuated total reflection accessory. Thermal behavior was characterized using differential scanning calorimetry. Results: Hydrogen bonding was investigated by monitoring the position of the NH stretching vibration, where an increase in peak wavenumber was taken to indicate a weakening of hydrogen bonding. Heating resulted in a reduction in hydrogen bonding strength, which was greatest for liquids and less for glassy and crystalline phases. For the amorphous samples, a plot of NH peak position vs. temperature displayed a discontinuity in the region of the glass transition (determined using differential scanning calorimetry) indicating that hydrogen bonding weakened abruptly as the material passed through the glass transition. This effect was more pronounced for some samples than for others. Conclusions: The variation in the decrease in hydrogen-bonding interactions with increasing temperature for the different phases is consistent with greater configurational freedom as one moves from crystal to glass to liquid.     

Non-Isothermal and Isothermal Crystallization of Sucrose from the Amorphous State

The crystallization of a model compound, sucrose, from the amorphous solid state has been studied non-isothermally using differential scanning calorimetry to determine crystallization temperature, Tc, and isothermally at 30°C by subjecting samples to 32.4% relative humidity and gravimetrically monitoring water vapor uptake and subsequent loss with time due to crystallization. From the measurement of glass transition temperature, Tg, and melting temperature, Tm, for sucrose alone and in the presence of absorbed water it was possible to predict Tc and thus to directly relate the plasticizing effects of water to its tendency to promote crystallization. Colyo-philization of sucrose with lactose, trehalose, and raffinose, all having Tg values greater than that of sucrose, increased Tc significantly, even at levels as low as 1 – 10% w/w. In the isothermal studies the time required for crystallization to commence, due to the plasticizing effects of water, i.e., the induction time, assumed to be mostly affected by rates of nucleation, was greatly increased by the presence of the additives at these low levels, with raffinose producing a greater effect than lactose and trehalose. Similarly, these additives reduced the rate of water loss, i.e., the rate of crystal growth, but now no significant differences were noted between the three additives. The possible relationships of nucleation and crystal growth and the effects of additives on molecular mobility are discussed.     

What is the True Solubility Advantage for Amorphous Pharmaceuticals?

Purpose. To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterparts.Methods. The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry. From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis. These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperatures.Results. By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold. The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted. It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behavior.Conclusions. Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations. This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution.     

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.     

The Effects of Absorbed Water on the Properties of Amorphous Mixtures Containing Sucrose

Purpose. To measure the water vapor absorption behavior of sucrose-poly(vinyl pyrrolidone) (PVP) and sucrose-poly(vinyl pyrrolidone co-vinyl acetate) (PVP/VA) mixtures, prepared as amorphous solid solutions and as physical mixtures, and the effect of absorbed water on the amorphous properties, i.e., crystallization and glass transition temperature, T_g, of these systems. Methods. Mixtures of sucrose and polymer were prepared by co-lyophilization of aqueous sucrose-polymer solutions and by physically mixing amorphous sucrose and polymer. Absorption isotherms for the individual components and their mixtures were determined gravimetrically at 30°C as a function of relative humidity. Following the absorption experiments, mixtures were analyzed for evidence of crystallization using X-ray powder diffraction. For co-lyophilized mixtures showing no evidence of crystalline sucrose, T_g was determined as a function of water content using differential scanning calorimetry. Results. The absorption of water vapor was the same for co-lyophilized and physically mixed samples under the same conditions and equal to the weighted sums of the individual isotherms where no sucrose crystallization was observed. The crystallization of sucrose in the mixtures was reduced relative to sucrose alone only when sucrose was molecularly dispersed (co-lyophilized) with the polymers. In particular, when co-lyophilized with sucrose at a concentration of 50%, PVP was able to maintain sucrose in the amorphous state for up to three months, even when the T_g was reduced well below the storage temperature by the absorbed water. Conclusions. The water vapor absorption isotherms for co-lyophilized and physically mixed amorphous sucrose-PVP and sucrose-PVP/VA mixtures at 30°C are similar despite interactions between sugar and polymer which are formed when the components are molecularly dispersed with one another. In the presence of absorbed water the crystallization of sucrose was reduced only by the formation of a solid-solution, with PVP having a much more pronounced effect than PVP/VA. The effectiveness of PVP in preventing sucrose crystallization when significant levels of absorbed water are present was attributed to the molecular interactions between sucrose, PVP and water.     

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.