Surface acidity and solid-state compatibility of excipients with an acid-sensitive API: case study of atorvastatin calcium.

The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pHeq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pHeq. No lactone formation was observed in mixtures with excipients having pHeq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pHeq < 3. The three pHeq regions (> 6, 3-6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pHeq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pHeq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.

Optimization of a Raman microscopy technique to efficiently detect amorphous-amorphous phase separation in freeze-dried protein formulations.

A confocal Raman microscopic technique was optimized to more efficiently detect amorphous-amorphous phase separation in freeze-dried protein formulations. A Renishaw Raman inVia confocal microscope was used to collect 100-200 µm line maps (2 µm step size) of freeze-dried protein-excipient formulations. At each point across the line map, the composition was evaluated from the intensity of the nonoverlapping peaks representative of each component. Collection aperture, scan time, and line map length significantly contributed to the phase-separation analysis, whereas different sample preparation methods did not affect the analysis. Using the optimized parameters (i.e., large aperture 5 s scan time, 200 µm line map), phase separation was successfully detected in binary polymer formulations and was comparable to the previously developed Raman method. However, the previous method required 2.5 h/sample, whereas the optimized method only requires 0.5 h/sample. Phase separation was detected in the following protein-excipient formulations: lysozyme-trehalose (1:1), lysozyme-isomaltose (1:1), ß-lactoglobulin-dextran (1:1), ß-lactoglobulin-dextran (1:3), and ß-lactoglobulin-trehalose (1:1). Phase separation was not detected in lysozyme-sucrose (1:1) and ß-lactoglobulin-sucrose (1:1) formulations. The optimized method successfully detected phase separation in several protein formulations, where phase separation was previously suspected, and promised to be a useful tool for detection of phase separation in amorphous therapeutic formulations.

Water clusters in amorphous pharmaceuticals.

Amorphous materials, although lacking the long-range translational and rotational order of crystalline and liquid crystalline materials, possess certain local (short-range) structure. This paper reviews the distribution of one particular component present in all amorphous pharmaceuticals, that is, water. Based on the current understanding of the structure of water, water molecules can exist in either unclustered form or as aggregates (clusters) of different sizes and geometries. Water clusters are reported in a range of amorphous systems including carbohydrates and their aqueous solutions, synthetic polymers, and proteins. Evidence of water clustering is obtained by various methods that include neutron and X-ray scattering, molecular dynamics simulation, water sorption isotherm, concentration dependence of the calorimetric Tg , dielectric relaxation, and nuclear magnetic resonance. A review of the published data suggests that clustering depends on water concentration, with unclustered water molecules existing at low water contents, whereas clusters form at intermediate water contents. The transition from water clusters to unclustered water molecules can be expected to change water dependence of pharmaceutical properties, such as rates of degradation. We conclude that a mechanistic understanding of the impact of water on the stability of amorphous pharmaceuticals would require systematic studies of water distribution and clustering, while such investigations are lacking.

The importance of individual protein molecule dynamics in developing and assessing solid state protein preparations.

Processing protein solutions into the solid state is a common approach for generating stable amorphous protein mixtures that are suitable for long-term storage. Great care is typically given to protecting the protein native structure during the various drying steps that render it into the amorphous solid state. However, many studies illustrate that chemical and physical degradations still occur in spite of this amorphous material having good glassy properties and it being stored at temperatures below its glass transition temperature (Tg). Because of these persistent issues and recent biophysical studies that have refined the debate ascribing meaning to the molecular dynamical transition temperature and Tg of protein molecules, we provide an updated discussion on the impact of assessing and managing localized, individual protein molecule nondiffusive motions in the context of proteins being prepared into bulk amorphous mixtures. Our aim is to bridge the pharmaceutical studies addressing bulk amorphous preparations and their glassy behavior, with the biophysical studies historically focused on the nondiffusive internal protein dynamics and a protein's activity, along with their combined efforts in assessing the impact of solvent hydrogen-bonding networks on local stability. We also provide recommendations for future research efforts in solid-state formulation approaches.

Impact of sertraline salt form on the oxidative stability in powder blends.

Oxidation of active pharmaceutical ingredients is a common chemical degradation process occurring in solid dosage forms. The aim of this study was to investigate the tendency of various sertraline salts to oxidize in powder blends containing a basic additive. A different extent of conversion of each salt to the free base was observed to occur in the presence of the basic additive, consistent with their respective pHmax values. Sertraline was found to undergo oxidation as the unioinized form, in both solution and powder blends that incorporated an oxidizing agent. In contrast, the ionized form of sertraline remained stable in both cases. Three sertraline salts undergoing a significant extent of conversion from salt to free form in the presence of tribasic sodium phosphate were found to oxidize extensively while sertraline benzoate which had a considerably lower extent of free base formation was more resistant to oxidation. The oxidative degradants were produced through oxidation at the amine functional group of sertraline which is where sertraline is ionized as the salt form. The link between oxidation tendency and the ionization state of sertraline in powder mixtures has thus been demonstrated in this study.

Glassy dynamics of sorbitol solutions at terahertz frequencies.

The absorption spectra of D-sorbitol and a range of its concentrated aqueous solutions were studied by terahertz spectroscopy over the temperature interval of 80 K < T < 310 K. It is shown that the slow-down of molecules at around the glass transition temperature, Tg, dramatically influences the thermal dependence of the absorption at terahertz frequencies. Furthermore, two different absorption regimes are revealed below Tg: at temperatures well below Tg, the absorption resembles the coupling of terahertz radiation to the vibrational density of states (VDOS); above these temperatures, between 160 K and Tg, in the sample of pure sorbitol and the sample of a solution of 70 wt% sorbitol in water, another type of absorption is observed at terahertz frequencies. Several possibilities of the physical origin of this absorption are discussed and based on the experimental data this process is tentatively assigned to the Johari-Goldstein ß-relaxation processes shifting to lower frequencies at temperatures below Tg leaving behind a spectrum largely dominated by losses into the VDOS.

Chemical stability of amorphous materials: specific and general media effects in the role of water in the degradation of freeze-dried zoniporide.

The objective of the present work was to determine whether hydrolysis in a model lyophile was influenced by general media effects with water-changing properties of the medium or via a specific mechanism of water as a reactant. Four formulations of zoniporide and sucrose (1:10) were prepared with variable amounts of sorbitol [0%-25% (w/v) of total solids). These formulations were then equilibrated at 6% and 11% relative humidity using saturated salt solutions. The lyophile cakes were analyzed by differential scanning calorimetery (DSC), (isothermal microcalorimetry (IMC), solid- state nuclear magnetic resonance (ssNMR) spectroscopy, and ultraviolet-visible diffuse reflectance (DFR) spectroscopy. DSC and IMC were used to assess the global molecular mobility. ssNMR relaxation times were measured to access local mobility. The DFR was used to determine the solid-state acidity expressed as the Hammett acidity function. Stability of samples was evaluated at 40°C by monitoring potency and purity by high-performance liquid chromatography (HPLC). Results were interpreted in terms of the various roles of water: media effect, plasticization, polarity, and reactant. The kinetics of hydrolysis was observed to be correlated with either/both specific "chemical" effects, that is, water reactant as well as media effect, specifically global molecular mobility of the matrix. Increase in reaction rate with increase in water content is not linear and is a weaker dependence than in some hydrolytic reactions in organic solvents. A moderate amount of an inert plasticizer, sorbitol, conferred additional stabilization, possibly by restricting the amplitude and frequency of fast motions that are on a small length scale.

Pronounced microheterogeneity in a sorbitol-water mixture observed through variable temperature neutron scattering.

In this study, the structure of concentrated d-sorbitol-water mixtures is studied by wide- and small-angle neutron scattering (WANS and SANS) as a function of temperature. The mixtures are prepared using both deuterated and regular sorbitol and water at a molar fraction of sorbitol of 0.19 (equivalent to 70% by weight of regular sorbitol in water). Retention of an amorphous structure (i.e., absence of crystallinity) is confirmed for this system over the entire temperature range, 100-298 K. The glass transition temperature, Tg, is found from differential scanning calorimetry to be approximately 200 K. WANS data are analyzed using empirical potential structure refinement, to obtain the site-site radial distribution functions (RDFs) and coordination numbers. This analysis reveals the presence of nanoscaled water clusters surrounded by (and interacting with) sorbitol molecules. The water clusters appear more structured compared to bulk water and, especially at the lowest temperatures, resemble the structure of low-density amorphous ice (LDA). Upon cooling to 100 K the peaks in the water RDFs become markedly sharper, with increased coordination number, indicating enhanced local (nanometer-scale) ordering, with changes taking place both above and well below the Tg. On the mesoscopic (submicrometer) scale, although there are no changes between 298 and 213 K, cooling the sample to 100 K results in a significant increase in the SANS signal, which is indicative of pronounced inhomogeneities. This increase in the scattering is partly reversed during heating, although some hysteresis is observed. Furthermore, a power law analysis of the SANS data indicates the existence of domains with well-defined interfaces on the submicrometer length scale, probably as a result of the appearance and growth of microscopic voids in the glassy matrix. Because of the unusual combination of small and wide scattering data used here, the present results provide new physical insight into the structure of aqueous glasses over a broad temperature and length scale, leading to an improved understanding of the mechanisms of temperature- and water-induced (de)stabilization of various systems, including proteins, pharmaceuticals, and biological objects.

Crystalline, liquid crystalline, and isotropic phases of sodium deoxycholate in water.

Sodium deoxycholate (NaDC) is an important example of bile salts, representing systems with complex phase behavior involving both crystalline and mesophase structures. In this study, properties of NaDC-water mixtures were evaluated as a function of composition and temperature via X-ray diffraction with synchrotron (sXRD) and laboratory radiation sources, water sorption, polarized light, hot-stage microscopy, and freezing-point osmometry. Several phases were detected depending on the composition and temperature, including isotropic solution phase, liquid crystalline (LC) phase, crystalline hydrate, and ice. The LC phase was identified as hexagonal structure by sXRD, with up to 14 high-order reflections detected. The crystalline phase was found to be nonstoichiometric hydrate, based on XRD and water sorption data. The phase diagram of NaDC-water system has been refined based on both results of this study and other reports in literature.

Investigation of design space for freeze-drying: use of modeling for primary drying segment of a freeze-drying cycle.

In this work, we explore the idea of using mathematical models to build design space for the primary drying portion of freeze-drying process. We start by defining design space for freeze-drying, followed by defining critical quality attributes and critical process parameters. Then using mathematical model, we build an insilico design space. Input parameters to the model (heat transfer coefficient and mass transfer resistance) were obtained from separate experimental runs. Two lyophilization runs are conducted to verify the model predictions. This confirmation of the model predictions with experimental results added to the confidence in the insilico design space. This simple step-by-step approach allowed us to minimize the number of experimental runs (preliminary runs to calculate heat transfer coefficient and mass transfer resistance plus two additional experimental runs to verify model predictions) required to define the design space. The established design space can then be used to understand the influence of critical process parameters on the critical quality attributes for all future cycles.

Investigation of PEG crystallization in frozen and freeze-dried PEGylated recombinant human growth hormone-sucrose systems: implications on storage stability.

The objectives of the current study were to investigate (i) the phase behavior of a PEGylated recombinant human growth hormone (PEG-rhGH, ∼60 kDa) during freeze-drying and (ii) its storage stability. The phase transitions during freeze-thawing of an aqueous solution containing PEG-rhGH and sucrose were characterized by differential scanning calorimetry. Finally, PEG-rhGH and sucrose formulations containing low, medium, and high polyethylene glycol (PEG) to sucrose ratios were freeze-dried in dual-chamber syringes and stored at 4°C and 25°C. Chemical decomposition (methionine oxidation and deamidation) and irreversible aggregation were characterized by size-exclusion and ion-exchange chromatography, and tryptic mapping. PEG crystallization was facilitated when it was covalently linked with rhGH. When the solutions were frozen, phase separation into PEG-rich and sucrose-rich phases facilitated PEG crystallization and the freeze-dried cake contained crystalline PEG. Annealing caused PEG crystallization and when coupled with higher drying temperatures, the primary drying time decreased by up to 51%. When the freeze-dried cakes were stored at 4°C, while there was no change in the purity of the PEG-rhGH monomer, deamidation was highest in the formulations with the lowest PEG to sucrose ratio. When stored at 25°C, this composition also showed the most pronounced decrease in monomer purity, the highest level of aggregation, and deamidation. Furthermore, an increase in PEG crystallinity during storage was accompanied by a decrease in PEG-rhGH stability. Interestingly, during storage, there was no change in PEG crystallinity in formulations with medium and high PEG to sucrose ratios. Although PEG crystallization during freeze-drying did not cause protein degradation, crystallization during storage might have influenced protein stability.

Investigation of PEG crystallization in frozen PEG-sucrose-water solutions: II. Characterization of the equilibrium behavior during freeze-thawing.

Our objective was to characterize, by DSC and XRD, the equilibrium thermal behavior of frozen aqueous solutions containing polyethylene glycol (PEG) and sucrose. Aqueous solutions of (i) PEG (2.5-50% w/w), (ii) sucrose (10% w/v) with different concentrations of PEG (1-20% w/v), and (iii) PEG (2% or 10% w/v) with different concentrations of sucrose (2-20% w/v), were cooled to -70 ° C at 5 ° C/min and heated to 25 ° C at 2 ° C/min in a DSC. Annealing was performed for 2 or 6 h at temperatures, ranging from -50 to -20 ° C. Experiments under similar conditions, on select compositions, were also performed in a powder X-ray diffractometer. Two endotherms, observed during heating of a frozen PEG solution (10% w/v), were attributed to PEG-ice eutectic melting and ice melting, and were confirmed by XRD. At higher PEG concentrations (≥ 37.5% w/w), only the endotherm attributed to the PEG-ice eutectic melting was observed. Inclusion of sucrose decreased both PEG-ice melting and ice melting temperatures. In unannealed systems with a fixed sucrose concentration (10% w/v), the PEG-ice melting event was not observed at PEG concentration ≤ 5% w/v. Annealing for 2-6 h facilitated PEG crystallization. In unannealed systems with a fixed PEG concentration (10% w/v), an increase in the sucrose concentration increased the devitrification but decreased the PEG-ice melting temperature. The PEG-ice melting temperatures obtained by DSC and XRD were in good agreement. In ternary systems at a fixed PEG to sucrose ratio, the T' g as well as the PEG-ice melting temperature were unaffected by the total solute concentration. XRD confirmed the absence of a PEG-sucrose-ice ternary eutectic. When the PEG to sucrose ratio was systematically varied, the PEG-ice and ice melting temperatures decreased with an increase in the sucrose concentration. However, at a fixed PEG to sucrose ratio, the PEG-ice melting temperature, was unaffected by the total solute concentration.

Biopolymer mediated trehalose uptake for enhanced erythrocyte cryosurvival.

A biopolymer has been shown to facilitate efficient delivery of trehalose, a bioprotectant normally impermeable to the phospholipid bilayer, into ovine erythrocytes. Cellular uptake of trehalose was found to be dependent on polymer pendant amino acid type and degree of grafting, polymer concentration, pH, external trehalose concentration, incubation temperature and time. Optimization of these parameters yielded an intracellular trehalose concentration of 123 +/- 16 mM and concomitant improvement of erythrocyte cryosurvival of up to 20.4 +/- 5.6%. Intracellular trehalose was shown to impart cellular osmoprotection up to an external osmolarity of 230 mOsm and increased osmotic sensitivity above this threshold. Biopolymer mediated membrane permeability was shown to be rapidly and completely reversible via washing with phosphate buffered saline.

Occurrence of glass transitions in long-chain phosphatidylcholine mesophases.

Several phosphatidylcholine (PC) species were studied by differential scanning calorimetry at different levels of hydration. A glass transition was observed in both lamellar gel and nonlamellar phases, with the glass transition temperature, T(g), decreasing as water content was increased. The structure of the lipid mesophase has a major impact on T(g), with the lamellar gel phase having a higher T(g) than that of nonlamellar phases of the same lipid. While the headgroup has a noticeable influence on the T(g), changing the chain length, on the other hand, has less of an impact. The values of the calorimteric T(g) were compared with other measures of molecular mobility in the PC species at comparable water contents reported in the literature. Observation of a T(g) in different phosphatidylethanolamines (PE), as previously reported, and PC species in this study suggests that a glass transition can be expected to be a common feature of biological membranes and phospholipid bilayer preparations, such as liposomes.

Investigation of PEG crystallization in frozen PEG-sucrose-water solutions. I. Characterization of the nonequilibrium behavior during freeze-thawing.

Our objective was to characterize the nonequilibrium thermal behavior of frozen aqueous solutions containing PEG and sucrose. Aqueous solutions of (i) sucrose (10%, w/v) with different concentrations of PEG (1-20%, w/v), and (ii) PEG (10%, w/v) with different concentrations of sucrose (2-20%, w/v), were cooled to -70 degrees C at 5 degrees C/min and heated to 25 degrees C at 2 degrees C/min in a differential scanning calorimeter. Annealing was performed at temperatures ranging from -50 to -20 degrees C for 2 or 6 h. Similar experiments were also performed in the low-temperature stage of a powder X-ray diffractometer. A limited number of additional DSC experiments were performed wherein the samples were cooled to -100 degrees C. In unannealed systems with a fixed sucrose concentration (10%, w/v), the T'g decreased from -35 to -48 degrees C when PEG concentration was increased from 1% to 20% (w/v). On annealing at -25 degrees C, PEG crystallized. This was evident from the increase in T'g and the appearance of a secondary melting endotherm in the DSC. Low-temperature XRD provided direct evidence of PEG crystallization. Annealing at temperatures

Synchrotron X-ray diffraction investigation of the anomalous behavior of ice during freezing of aqueous systems.

Simple aqueous systems, i.e., phosphate-glycine buffers and pure water, were studied at subambient temperatures by X-ray difractometry using a high-intensity synchrotron radiation source at the Advanced Photon Source of Argonne National Laboratory. Complex X-ray diffraction (XRD) patterns, with two or more poorly resolved peaks in place of each of the four diagnostic peaks of hexagonal ice, 100, 002, 101, and 102, referred as "splitting", were observed in the majority of cases. The splitting of up to 0.05 A (d-spacing) was detected for 100, 002, and 101 peaks, whereas 102 peak was less affected. Deformation of the lattice of hexagonal ice, probably due to local stress created on the ice/ice or ice/container interface during water-to-ice transformation, is proposed as a possible mechanism for the observed splitting of XRD peaks. Using molecular modeling, it was estimated that the observed shifts in the peak positions are equivalent to applying a hydrostatic pressure of 2-3 kbars. The splitting can be used to quantify stresses during freezing, which could improve our understanding of the role of water-to-ice transformation on the destabilization of proteins and other biological systems.

Phase transitions in frozen systems and during freeze-drying: quantification using synchrotron X-ray diffractometry.

PURPOSE: (1) To develop a synchrotron X-ray diffraction (SXRD) method to monitor phase transitions during the entire freeze-drying cycle. Aqueous sodium phosphate buffered glycine solutions with initial glycine to buffer molar ratios of 1:3 (17:50 mM), 1:1 (50 mM) and 3:1 were utilized as model systems. (2) To investigate the effect of initial solute concentration on the crystallization of glycine and phosphate buffer salt during lyophilization. METHODS: Phosphate buffered glycine solutions were placed in a custom-designed sample cell for freeze-drying. The sample cell, covered with a stainless steel dome with a beryllium window, was placed on a stage capable of controlled cooling and vacuum drying. The samples were cooled to -50 degrees C and annealed at -20 degrees C. They underwent primary drying at -25 degrees C under vacuum until ice sublimation was complete and secondary drying from 0 to 25 degrees C. At different stages of the freeze-drying cycle, the samples were periodically exposed to synchrotron X-ray radiation. An image plate detector was used to obtain time-resolved two-dimensional SXRD patterns. The ice, beta-glycine and DHPD phases were identified based on their unique X-ray peaks. RESULTS: When the solutions were cooled and annealed, ice formation was followed by crystallization of disodium hydrogen phosphate dodecahydrate (DHPD). In the primary drying stage, a significant increase in DHPD crystallization followed by incomplete dehydration to amorphous disodium hydrogen phosphate was evident. Complete dehydration of DHPD occurred during secondary drying. Glycine crystallization was inhibited throughout freeze-drying when the initial buffer concentration (1:3 glycine to buffer) was higher than that of glycine. CONCLUSION: A high-intensity X-ray diffraction method was developed to monitor the phase transitions during the entire freeze-drying cycle. The high sensitivity of SXRD allowed us to monitor all the crystalline phases simultaneously. While DHPD crystallizes in frozen solution, it dehydrates incompletely during primary drying and completely during secondary drying. The impact of initial solute concentration on the phase composition during the entire freeze-drying cycle was quantified.

The glass transition and sub-T(g)-relaxation in pharmaceutical powders and dried proteins by thermally stimulated current.

The main goal of the study was to evaluate the applicability of thermally stimulated current (TSC) as a measure of molecular mobility in dried globular proteins. Three proteins, porcine somatotropin, bovine serum albumin, and immunoglobulin, as well as materials with a strong calorimetric glass transition (T(g)), that is, indomethacin and poly(vinypyrrolidone) (PVP), were studied by both TSC and differential scanning calorimetry (DSC). Protein/sugar colyophilized mixtures were also studied by DSC, to estimate calorimetric T(g) for proteins using extrapolation procedure. In the majority of cases, TSC detected relaxation events that were not observed by DSC. For example, a sub-T(g) TSC event (beta-relaxation) was observed for PVP at approximately 120 degrees C, which was not detected by the DSC. Similarly, DSC did not detect events in any of the three proteins below the thermal denaturation temperature whereas a dipole relaxation was detected by TSC in the range of 90-140 degrees C depending on the protein studied. The TSC signal in proteins was tentatively assigned as localized mobility of protein segments, which is different from a large-scale cooperative motions usually associated with calorimetric T(g). TSC is a promising method to study the molecular mobility in proteins and other materials with weak calorimetric T(g).

Comparative rates of freeze-drying for lactose and sucrose solutions as measured by photographic recording, product temperature, and heat flux transducer.

Sublimation from lactose and sucrose solutions has been monitored by temperature measurement, visual observation, heat flux sensing and manometric measurements. Estimates of energy transfer rates to the subliming mass made from visual observations and heat flux measurements are in broad agreement, demonstrating for the first time that heat flux sensors can be used to monitor the progress of lyophilization in individual vials with low sample volumes. Furthermore, it is shown that under identical lyophilization conditions the initial rate of drying for lactose solutions is low with little water sublimation for up to 150 minutes, which contrasts markedly with the much faster initial rate of drying for sucrose solutions. Measurement of the initial heat flux between shelf and vial indicated a lower flux to a 10% lactose solution than to a 10% sucrose solution.

Correlation between chemical reactivity and the Hammett acidity function in amorphous solids using inversion of sucrose as a model reaction.

The goal was to evaluate the effects of acidity, expressed as the Hammett acidity function, on chemical reactivity in freeze-dried materials (lyophiles). Dextran-sucrose-citrate and polyvinyl pyrrolidone (PVP)-sucrose-citrate aqueous solutions, adjusted to pH values of 2.6, 2.8, and 3.0 were freeze dried, and characterized by X-ray powder diffractometry, DSC, isothermal microcalorimetry, and Karl Fischer titrimetry. Lyophiles were also prepared from identical solutions but containing bromophenol blue (BB). Diffuse reflectance-visible spectroscopy was used to measure the extent of BB protonation from which the Hammett acidity functions were determined. The stability studies were performed at 60 degrees C. All the freeze-dried samples were observed to be X-ray amorphous with <0.15% w/w water content. The T(g) of dextran lyophiles were approximately 20 degrees C higher than that of PVP lyophiles whereas enthalpy relaxation rates at 60 degrees C were similar. The Hammett acidity functions were significantly lower (i.e., higher acidity) for dextran systems (<2.2-2.6) when compared with PVP systems (3.3-3.9). The rate of sucrose inversion was significantly (an order of magnitude) higher in dextran lyophiles. This study showed that in amorphous matrices with comparable water content and structural relaxation times, chemical reactivity could be significantly different depending on the matrix "acidity".