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.     

Molecular Motions in Sucrose-PVP and Sucrose-Sorbitol Dispersions—II. Implications of Annealing on Secondary Relaxations

Purpose

To determine the effect of annealing on the two secondary relaxations in amorphous sucrose and in sucrose solid dispersions.

Methods

Sucrose was co-lyophilized with either PVP or sorbitol, annealed for different time periods and analyzed by dielectric spectroscopy.

Results

In an earlier investigation, we had documented the effect of PVP and sorbitol on the primary and the two secondary relaxations in amorphous sucrose solid dispersions (1). Here we investigated the effect of annealing on local motions, both in amorphous sucrose and in the dispersions. The average relaxation time of the local motion (irrespective of origin) in sucrose, decreased upon annealing. However, the heterogeneity in relaxation time distribution as well as the dielectric strength decreased only for β₁- (the slower relaxation) but not for β₂-relaxations. The effect of annealing on β₂-relaxation times was neutralized by sorbitol while PVP negated the effect of annealing on both β₁- and β₂-relaxations.

Conclusions

An increase in local mobility of sucrose brought about by annealing could be negated with an additive.     

Coupling Between Chemical Reactivity and Structural Relaxation in Pharmaceutical Glasses

Purpose To test the hypothesis that the molecular motions associated with chemical degradation in glassy amorphous systems are governed by the molecular motions associated with structural relaxation. The extent to which a chemical process is linked to the motions associated with structural relaxation will depend on the nature of the chemical process and molecular motion requirements (e.g., translation of a complete molecule, rotational diffusion of a chemical functional group). In this study the chemical degradation and molecular mobility were measured in model systems to assess the degree of coupling between chemical reactivity and structural relaxation. The model systems included pure amorphous cephalosporin drugs, and amorphous molecular mixtures containing a chemically labile drug and an additive expected to moderate molecular mobility.Methods Amorphous drugs and mixtures with additives were prepared by lyophilization from aqueous solution. The physical properties of the model systems were characterized using optical microscopy and differential scanning calorimetry. The chemical degradation of the drugs alone and in mixtures with additives was measured using high-performance liquid chromatography (HPLC). Molecular mobility was measured using isothermal microcalorimetry to measure enthalpy changes associated with structural relaxation below T _g.Results A weak correlation between the rates of degradation and structural relaxation times in pure amorphous cephalosporins suggests that reactivity in these systems is coupled to molecular motions in the glassy state. However, when sucrose was added to one of the cephalosporin drugs stability improved even though this addition reduced T _g and the relaxation time constant, , suggesting that there was no correlation between reactivity and structural relaxation in the cephalosporin mixtures. In contrast, the rate of ethacrynate sodium dimer formation in mixtures was more strongly coupled to the relaxation time constant, .Conclusions These studies suggest that the extent to which chemical degradation is coupled to structural relaxation in glasses motions is determined by how closely the motions of the rate controlling step in chemical degradation are associated with structural relaxation. Moderate coupling between the rate of dimer formation for ethacrynate sodium in mixtures with sucrose, trehalose and PVP and structural relaxation constants suggests that chemical changes that require more significant molecular motion, and includes at least some translational diffusion, are more strongly coupled to the molecular motions associated with structural relaxation. The observation that sucrose stabilizes cefoxitin sodium even though it lowers T _g and reduces the relaxation time constant, is perhaps a result of the importance of other kinds of molecular motions in determining the chemical reactivity in glasses.     

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 Relationship Between Protein Aggregation and Molecular Mobility Below the Glass Transition Temperature of Lyophilized Formulations Containing a Monoclonal Antibody

Purpose. To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. Methods. The temperature dependence of relaxation time constant, , was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, , in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. Results. For both sucrose and trehalose formulations, the variation in with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited <2% aggregation at t values <10, where t is the time of storage. Conclusions. Since the relaxation times for sucrose and trehalose formulations at 5°C are on the order of 10⁸ and 10⁶ hrs, it is likely that both formulations would undergo very little (<2%) aggregation in a practical time scale under refrigerated conditions.     

Time-Dependence of Molecular Mobility during Structural Relaxation and its Impact on Organic Amorphous Solids: An Investigation Based on a Calorimetric Approach

Purpose To develop a calorimetry-based model for estimating the time-dependence of molecular mobility during the isothermal relaxation of amorphous organic compounds below their glass transition temperature (T _g).Methods The time-dependent enthalpy relaxation times of amorphous sorbitol, indomethacin, trehalose and sucrose were estimated based on the nonlinear Adam‐Gibbs equation. Fragility was determined from the scanning rate dependence of T _g. Time evolution of the fictive temperature was determined from T _g, the heat capacity of the amorphous and crystalline forms, and from the enthalpy relaxation data.Results Relaxation time changes significantly upon annealing for all compounds studied. The magnitude of the increase in relaxation time does not depend on any one parameter but on four parameters: T _g, fragility, and the crystal–liquid and glass–liquid heat capacity differences. The obtained mobility data for indomethacin and sucrose, both stored at T _g−16 K, correlated much better with their different crystallization tendencies than did the Kohlrausch‐Williams‐Watts (KWW) equation.Conclusions The observed changes in relaxation time help explain and address the limitations of the KWW approach. Due consideration of the time-dependence of molecular mobility upon storage is a key element for improving the understanding necessary for stabilizing amorphous formulations.     

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.     

Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions

Purpose. To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy. Methods. Solid dispersions of PVP and indomethacin were prepared using a solvent evaporation technique and IR and FT-Raman spectra were obtained. Results. A comparison of the carbonyl stretching region of indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of indomethacin is not as dimers. Addition of PVP to amorphous indomethacin increased the intensity of the infrared band assigned to non-hydrogen bonded carbonyl. Con-comitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a solution of indomethacin in methylpyrrolidone at the same weight percent. Conclusions. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystallisation kinetics by preventing the self association of indomethacin molecules. The similarity of results for solid dispersions and solutions emphasises the 'solution' nature of this binary amorphous state.     

The Effect of Low Concentrations of Molecularly Dispersed Poly(Vinylpyrrolidone) on Indomethacin Crystallization from the Amorphous State

Purpose. To investigate the effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) (PVP) on indomethacin (IMC) crystallization from the amorphous state using particle size effects to identify possible mechanisms of crystallization inhibition. Methods. Different particle sizes of amorphous IMC and 1, 2, and 5% PVP were stored dry at 30°C for 84 days. PXRD was used to calculate the rate and extent of crystallization and the polymorph formed. Results. Crystallization from amorphous IMC and IMC/PVP molecular dispersions yielded the polymorph of IMC. Crystallization rates were reduced at larger particle size and in the presence of 1, 2, and 5%PVP. Crystallization did not reach completion in some IMC/PVP samples, with the quantity of uncrystallized amorphous phase proportional to particle size. Conclusions. Low concentrations of molecularly dispersed PVP affected IMC crystallization from the amorphous state. Formation of -IMC at rates dependent on particle size indicated that surface nucleation predominated in both the absence and presence of PVP. Excellent correlation was seen between the extent of crystallization and simulated depths of crystal penetration, supporting the hypothesis that increasing local PVP concentration inhibits crystal growth from surface nuclei into the amorphous particle.     

Comparative Investigation by Two Analytical Approaches of Enthalpy Relaxation for Glassy Glucose,Sucrose, Maltose,and Trehalose

No HeadingPurpose. In an effort to understand the stability of glassy sugars such as glucose, sucrose, maltose, and trehalose, the molecular mobility below the glass transition temperature (T_g) was investigated by an enthalpy relaxation measurement with differential scanning calorimetry (DSC).Methods. The glassy sample was aged over several days at (T_g – 10) K to (T_g – 30) K, before a DSC heating scan was taken. The relaxed enthalpy (H_relax) was estimated from the endothermic peak area. The enthalpy relaxation time was analyzed from the time course of H_relax using two different approaches; Kohlrausch-Williams-Watts (KWW) and extended Adam-Gibbs (exAG).Results. ^KWW, which is defined as the mean average enthalpy relaxation time in a distribution, and ^eff₀ and ^eff, which correspond to the enthalpy relaxation time of the initial minimum and final maximum cooperative rearrangement region, were estimated by KWW and exAG, respectively. And three activation energies for enthalpy relaxation were calculated from the Arrhenius plot.Conclusions. Although these Es originated from different theoretical backgrounds, almost the same trend was observed for a comparison of the values of the four sugars. The finding that the Es of glassy trehalose were the largest among the four sugars may support the reason that glassy trehalose is an effective stabilizer.     

Dependence of the Molecular Mobility and Protein Stability of Freeze-Dried γ-Globulin Formulations on the Molecular Weight of Dextran

Purpose. The effect of the molecular weight of dextran on the molecular mobility and protein stability of freeze-dried serum -globulin (BGG) formulations was studied. The stabilizing effect of higher molecular weight dextran is discussed in relation to the molecular mobility of the formulations. Methods. The molecular mobility of freeze-dried BGG formulations containing dextrans of various molecular weights was determined based on the free induction decay of dextran and water protons measured by proton NMR. The protein stability of the formulations was determined at temperatures ranging from 20 to 70°C by size exclusion chromatography. Results. Changes in the molecular mobility of freeze-dried formulations that occurred at temperatures below the glass transition temperature could be detected as the molecular mobility-changing temperature (T_mc), at which dextran protons started to exhibit a Lorentzian relaxation decay due to higher mobility in addition to a Gaussian relaxation decay. T_mc increased as the molecular weight of dextran increased. The proportion of dextran protons which exhibited the higher mobility relaxation process (P_hm) at temperatures above T_mc decreased as the molecular weight of dextran increased. Protein stability was closely related to molecular mobility. The temperature dependence of the denaturation rate changed at around T_mc, and denaturation in the microscopically liquidized state decreased as P_hm decreased with increasing molecular weight of dextran. Conclusions. The effect of the molecular weight of dextran on the protein stability of freeze-dried BGG formulations could be explained in terms of the parameters obtained by ¹H-NMR such as T_mc and P_hm. These parameters appear to be useful in preformulation and stability prediction of freeze-dried formulations.     

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

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

Effect of Sucrose/Raffinose Mass Ratios on the Stability of Co-Lyophilized Protein During Storage Above the Tg

Purpose. To examine the potential of raffinose as an excipient in stabilizing protein and to study the effect of sucrose/raffinose mass ratios on the stability of co-lyophilized protein and amorphous solids during storage at an elevated temperature. Methods. Glucose-6-phosphate dehydrogenase (G6PDH) was co-lyophilized with sucrose and raffinose mixed at different mass ratios. The activity of dried G6PDH was monitored during storage at 44°C. Thermal properties of sucrose/raffinose matrices were determined by differential scanning calorimetry (DSC). Results. Mass ratios of sucrose to raffinose did not affect the recovery of G6PDH activity after freeze-drying, but significantly affected the stability of freeze-dried G6PDH during storage. The sucrose-alone formulation offered the best enzyme stabilization during storage. With increasing fraction of raffinose, the G6PDH stability decreased, sugar crystallization inhibited, and crystal-melting temperature increased. Conclusions. Despite the higher T_g of the formulations with higher fraction of raffinose, they provided less protection for G6PDH than did sucrose alone during storage. Our data do not support the prediction from recent thermophysical studies that raffinose should be superior to sucrose and trehalose as a potential excipient or stabilizer.     

Molecular Mobility in Mixtures of Absorbed Water and Solid Poly(vinylpyrrolidone)

Poly(vinylpyrrolidone) (PVP) was used as model system to examine molecular mobility in mixtures of absorbed water with solid amorphous polymers. Water vapor absorption isotherms were determined, along with diffusion and proton NMR relaxation measurements of absorbed water. Concurrently, measurements of glass transition temperatures (T _g) and carbon-13 NMR relaxation times for PVP were determined as a function of water content. Two water contents were used as reference points: W _m, obtained from the fit of water absorption isotherms to the BET equation, corresponding to the first shoulder in the sigmoid isotherm; and W _g, the amount of water necessary to depress T _g to the isotherm temperature. Translational diffusion coefficients of water, along with proton T ₁ relaxation time constants, show that both the translational and the rotational mobility of the water is hindered by the presence of the solid polymer and that the absorbed water is most likely represented by two or more populations of water with different modes or time scales of motion. The presence of "tightly bound or immobilized water at levels corresponding to W _m, however, is unlikely, since water molecules maintain a high degree of mobility, even at the lowest levels of water. Above W _g, water shows an increase in mobility with increasing water content, but it is always less mobile than bulk water. With increasing water content, carbon-13 T ₁ relaxation time constants for PVP, measured under the same conditions as above, indicate a major increase in the molecular mobility of carbon atoms associated with the pyrrolidone side chains.     

Water sorption behavior of lyophilized protein–sugar systems and implications for solid-state interactions

This study examines the water sorption behavior of proteins co-lyophilized with sugar/polyol excipients. Gravimetric sorption analysis (GSA) was used to measure water sorption of the lyophilized mixtures and these data allowed for calculation of the water monolayer (M₀). Lyophilized protein–mannitol mixtures behaved as predicted from the data for the pure components. Mannitol was shown to crystallize upon lyophilization. For protein co-lyophilized with sucrose or trehalose, which remain amorphous upon lyophilization, M₀ tended to be lower than that expected based on contributions of the pure protein and sugar. This negative deviation supports the view that amorphous sugars and pharmaceutical proteins interact in the solid state in such a way as to reduce the availability of water-binding sites. At high relative humidities (rh), sucrose and trehalose were susceptible to moisture-induced crystallization. When co-lyophilized protein was present, the GSA data revealed that this crystallization required a higher rh, or did not occur. For the temperature-induced (non-isothermal) sucrose crystallization, which was studied by differential scanning calorimetry, it was found that the temperature of crystallization tended to increase with an increasing amount of protein. The tendency to crystallize rose in the presence of elevated moisture, whether or not protein was present, likely due to the ability of water to plasticize the solid phase.     

Effects of Sucrose and Trehalose on the Preservation of the Native Structure of Spray-Dried Lysozyme

Purpose. To investigate the effects of sucrose, trehalose, sucrose/dextran mixtures, and sucrose/trehalose mixtures on the preservation of the native structure of spray-dried lysozyme in the solid state. Methods. The intensity of the -helical band and the melting enthalpies (H_m ) of spray-dried lysozyme in the dried form and in aqueous solution were obtained using second derivative FTIR and differential scanning calorimetry (DSC) respectively. Results. The intensity of the -helical band and the H m of spray-dried lysozyme obtained were linearly correlated and both suggest that the stabilization of lysozyme in the dried form was excipient concentration-dependent with a close to maximum stabilization being conferred by sucrose or trehalose at a mass ratio 1–2 (sugar:enzyme). Sucrose appeared to be more effective than trehalose on a weight by weight basis whilst stabilizing effects of dextran/sucrose or trehalose/sucrose mixtures were found to be additive. Conclusion. Dehydration during spray drying was considered the main stress to the denaturation of lysozyme. A major effect of the sugars in protecting lysozyme against dehydration was attributable to hydrogen bonding between the sugar and protein molecules, which lead to an increase in the change in the negative value of the free energy between native and denatured states.     

The Effect of Water Plasticization on the Molecular Mobility and Crystallization Tendency of Amorphous Disaccharides

Purpose

To study how water plasticization affects the molecular mobility and crystallization tendency of freeze-dried trehalose, sucrose, melibiose and cellobiose.

Methods

Freeze-dried disaccharides were subjected to different relative humidity atmospheres and their physical stabilities were evaluated. Lyophilizate water sorption tendencies and glass transition temperatures were modeled using Brunauer-Emmett-Teller (BET) and Gordon-Taylor (GT) equations, respectively. Sucrose and cellobiose crystallization tendencies were compared by using the concept of reduced crystallization temperature (RCT), and the molecular mobilities of trehalose and melibiose were compared by measuring their T₁H relaxation time constants.

Results

Based on the BET and GT models, water sorption tendency and the resulting plasticizing effect were different in sucrose when compared to the other disaccharides. Trehalose and melibiose exhibited generally slower crystallization rates when compared to sucrose and cellobiose. Amorphous melibiose was shown to be particularly stable within the studied water content range, which may have partly been caused by its relatively slow molecular mobility.

Conclusions

Slow amorphous-to-crystalline transition rate is known to be important for lyoprotecting excipients when formulating a robust drug product. The physical stabilities of amorphous trehalose and melibiose even with relatively high water contents might make their use advantageous in this respect compared to sucrose and cellobiose.     

Molecular Mobility of Protein in Lyophilized Formulations Linked to the Molecular Mobility of Polymer Excipients,as Determined by High Resolution 13C Solid-State NMR

Purpose. The mobility of protein molecules in lyophilized protein formulations was compared with that of excipient molecules based on the spin-lattice relaxation time (T₁) of each molecule determined by high resolution ¹³C solid-state NMR. The relationship between molecular mobility and protein stability is discussed. Methods. Protein aggregation of lyophilized bovine serum --globulin (BGG) formulation containing dextran was measured by size exclusion chromatography. The T₁ of the BGG carbonyl carbon and dextran methin carbon in the formulation was determined by high resolution ¹³C NMR, and subsequently used to calculate the correlation time (_C) of each carbon. The spin-spin relaxation time (T₂) of BGG and dextran protons was measured by pulsed NMR spectrometry, and the critical temperature of appearance of Lorentzian relaxation due to liquid BGG and dextran protons (T_mc) was determined. Results. The _C of dextran methin carbon in BGG-dextran formulations exhibited a linear temperature dependence according to the Adam-Gibbs-Vogel equation at lower temperatures, and a nonlinear temperature dependence described by the Vogel-Tamman-Fulcher equation at higher temperatures. The temperature at which molecular motion of dextran changed was consistent with the T_mc. The _C of BGG carbonyl carbon exhibited a similar temperature dependence to the _C of the dextran methin carbon and substantially decreased at temperatures above T_mc in the presence of dextran. The temperature dependence of BGG aggregation could be described by the Williams-Landel-Ferry equation even at temperatures 20°C lower than T_mc. Conclusions. High resolution ¹³C solid-state NMR indicated that the molecular motion of BGG was enhanced above T_mc in association with the increased global segmental motion of dextran molecules.     

Prediction of Onset of Crystallization in Amorphous Pharmaceutical Systems: Phenobarbital,Nifedipine/PVP,and Phenobarbital/PVP

The aim of this work is to determine if a stability testing protocol based on the correlations between crystallization onset and relaxation time above the glass transition temperature (T_g) can be used to predict the crystallization onsets in amorphous pharmaceutical systems well below their T_g. This procedure assumes that the coupling between crystallization onset and molecular mobility is the same above and below T_g. The stability testing protocol has been applied to phenobarbital, phenobarbital/polyvinylpyrrolidone (PVP) (95/5, w/w), and nifedipine/PVP (95/5, w/w). Crystallization onsets have been detected by polarized light microscopy examination of amorphous films; molecular mobility has been determined by dielectric relaxation spectroscopy above T_g and by both isothermal calorimetry and modulated differential scanning calorimetry below T_g. We find that small amounts of PVP significantly retard re-crystallization. This dramatic effect of PVP is not related to mobility, so this approach applies, at best, to extrapolation of high temperature data on a given formulation to low temperatures. Variation in molecular mobility at these concentrations of PVP is not the dominant factor in determining variation in propensity for re-crystallization from glassy systems; we suggest surface interactions between PVP and nuclei and/or small crystals slowing growth control variation in crystallization kinetics between formulations. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3887-3900, 2010     

Physical stability of redispersible dry emulsions containing amorphous sucrose.

The objective of the present study was to estimate the stability of redispersible dry emulsions containing amorphous sucrose. Dry emulsions were prepared by spray drying liquid o/w-emulsions in a laboratory spray dryer. The effect of hydroxypropyl methylcellulose (HPMC) on the glass transition temperature T(g) of spray dried sucrose-HPMC mixtures, relative to the T(g) of amorphous sucrose, was investigated. For the sucrose-HPMC mixtures the values of T(g) followed the ideal Gordon-Taylor equation up to 30% HPMC. For dry emulsions containing 40% HPMC, 30% lipid and 30% sucrose, the T(g) was increased by 12 degrees C relative to the T(g) of amorphous sucrose. The stability of the dry emulsions was investigated by a conventional stability study and by an enthalpy relaxation study. The measured enthalpy recovery of amorphous sucrose below T(g) was used to calculate molecular relaxation time parameters based on the Williams-Watts equation. The molecular mobility of amorphous sucrose at temperatures 50 degrees C below T(g) was low and negligible with respect to the shelf life stability. It was concluded that the dry emulsions are physically stable with respect to the lifetime of a pharmaceutical product when stored in dry condition and at temperatures up to 28 degrees C.