Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions

The overall crystallization rates and mean relaxation times of amorphous nifedipine and phenobarbital in the presence of poly(vinylpyrrolidone) (PVP) were determined at various temperatures to gain further insight into the effect of molecular mobility on the crystallization rates of amorphous drugs and the possibility of predicting stability from their molecular mobility. Nifedipine-PVP (9:1 w/w) and phenobarbital-PVP (95:5 w/w) solid dispersions were prepared by melting and rapidly cooling mixtures of each drug and PVP. The amount of amorphous nifedipine remaining in the solid dispersion was calculated from the heat of crystallization,which was obtained by differential scanning calorimetry. The amount of amorphous phenobarbital remaining in the solid dispersion was estimated from the change in the heat capacity at its glass transition temperature (T(g)). The time required for the amount of amorphous drug remaining to fall to 90% (t(90)) was calculated from the profile of time versus the amount of amorphous drug remaining. The t(90) values for the solid dispersions studied were 100-1000 times longer than those of pure amorphous drugs when compared at the same temperature. Enthalpy relaxation of the amorphous drugs in the solid dispersions was reduced compared with that in the pure amorphous drugs, indicating that the molecular mobility of the amorphous drugs is reduced in the presence of PVP. The temperature dependence of mean relaxation time (tau) for the nifedipine-PVP solid dispersion was calculated using the Adam-Gibbs-Vogel equation. Parameters D and T(0) in this equation were estimated from the heating rate dependence of T(g). Similar temperature dependence was observed for t(90) and tau values of the solid dispersion, indicating that the information on the temperature dependence of the molecular mobility, along with the crystallization data obtained at around the T(g), are useful for estimating the t(90) of overall crystallization at temperatures below T(g) in the presence of excipients.     

Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib

The effectiveness of different polymers, alone or in combination, in inhibiting the crystallization of celecoxib (CEX) from amorphous solid dispersions (ASDs) exposed to different temperatures and relative humidities was evaluated. It was found that polyvinylpyrrolidone (PVP) and PVP-vinyl acetate formed stronger or more extensive hydrogen bonding with CEX than cellulose-based polymers. This, combined with their better effectiveness in raising the glass transition temperature (T_g) of the dispersions, provided better physical stabilization of amorphous CEX against crystallization in the absence of moisture when compared with dispersions formed with cellulose derivatives. In ternary dispersions containing 2 polymers, the physical stability was minimally impaired by the presence of a cellulose-based polymer when the major polymer present was PVP. On exposure to moisture, stability of the CEX ASDs was strongly affected by both the dispersion hygroscopicity and the strength of the intermolecular interactions. Binary and ternary ASDs containing PVP appeared to undergo partial amorphous–amorphous phase separation when exposed 94% relative humidity, followed by crystallization, whereas other binary ASDs crystallized directly without amorphous–amorphous phase separation.     

Stability and Solubility of Celecoxib-PVP Amorphous Dispersions: A Molecular Perspective

PURPOSE: The purpose of the current study is to evaluate the solubility advantage offered by celecoxib (CEL) amorphous systems and to characterize and correlate the physical and thermodynamic properties of CEL and its amorphous molecular dispersions containing poly(vinylpyrrolidone) (PVP). METHODS: The measurement of crystalline content, glass transition temperatures, and enthalpy relaxation was performed using differential scanning calorimetry. Solubility and dissolutions studies were conducted at 37 degrees C to elucidate release mechanisms. Further, the amorphous systems were characterized by polarized light microscopy and X-ray powder diffraction studies. RESULTS: The PVP content has a prominent effect on the stability and solubility profiles of amorphous systems. A dispersion of 20% w/w PVP with CEL resulted in a maxima in terms of solubility enhancement and lowering of relaxation enthalpy. The release of drug from amorphous molecular dispersions was found to be drug-dependent and independent of the carrier. CONCLUSIONS: The solubility enhancement and enthalpy relaxation studies with respect to PVP concentration helped in a better prediction of role of carrier and optimization of concentration in the use of solid dispersions or amorphous systems. The drug release mechanism is drug-controlled rather than carrier-controlled.     

Inhibition of albendazole crystallization in poly(vinylpyrrolidone) solid molecular dispersions

The main aim of the study was to investigate the mechanisms of the stabilizing effect of poly(vinylpyrrolidone) (PVP) on amorphous albendazole (ABZ). Solid dispersions of ABZ with PVP polymers and with a copolymer containing poly(vinylacetate) (PVP/VA) were prepared using the solvent casting method. The effects of PVP molecular weight, composition and content on the crystallization of ABZ from the amorphous state were investigated using differential scanning calorimetry. Stability of the amorphous drug with respect to isothermal crystallization was studied at different polymer concentrations and storage temperatures. Solid dispersions were found to be X-ray amorphous and exhibited a single glass transition temperature (Tg). Onset of crystallization and extent of inhibition increased with concentration and molecular weight of the homopolymer. In spite of its having a higher molecular weight, replacement of about 40% of vinylpyrrolidone monomers with vinylacetate groups (as in the copolymer) resulted in reduced inhibition of crystallization. ABZ crystallized from the amorphous state in the absence of polymer even when stored below the Tg. The solvent casting method greatly reduced the requirement for polymer to achieve X-ray amorphous solid dispersions. Such dispersions exhibited a significant increase in induction time and reduction in the rate of crystallization at polymer concentrations as low as 5% and at temperatures as high as 70 degrees C. Factors other than mobility, such as drug-polymer hydrogen bonding' were also found to be involved in crystallization inhibition.     

Differences in crystallization rate of nitrendipine enantiomers in amorphous solid dispersions with HPMC and HPMCP

To clarify the contribution of drug-polymer interaction to the physical stability of amorphous solid dispersions, we studied the crystallization rates of nitrendipine (NTR) enantiomers with identical physicochemical properties in the presence of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP) and polyvinylpyrrolidone (PVP). The overall crystallization rate at 60°C and the nucleation rate at 50-70°C of (+)-NTR were lower than those of (-)-NTR in the presence of 10-20% HPMC or HPMCP. In contrast, similar crystallization profiles were observed for the NTR enantiomers in solid dispersions containing PVP. The similar glass transition temperatures for solid dispersions of (-)-NTR and (+)-NTR suggested that the molecular mobility of the amorphous matrix did not differ between the enantiomers. These results indicate that the interaction between the NTR enantiomers and HPMC or HPMCP is stereoselective, and that differences in the stereoselective interaction create differences in physical stability between (-)-NTR and (+)-NTR at 50-70°C. However, no difference in physical stability between the enantiomers was obvious at 40°C. Loss of the difference in physical stability between the NTR enantiomers suggests that the stereoselective interaction between NTR and the polymers may not contribute significantly to the physical stabilization of amorphous NTR at 40°C.     

Role of molecular interaction in stability of celecoxib-PVP amorphous systems

Stabilization of an amorphous solid against devitrification can be achieved using additives that interact specifically with the parent molecule, and restrain it from rearranging into a crystal lattice. The amorphous form of celecoxib (CEL) was stabilized by poly(vinylpyrrolidone) (PVP), both in the solid state and during dissolution. A comprehensive characterization of CEL-PVP binary amorphous systems by thermal, spectroscopic, and computer simulation techniques provided greater insight into the molecular interaction between the two species. PVP antiplasticized the amorphous CEL, thus raising its glass transition temperature (T(g)) and restricting the molecular mobility. The T(g)()mix values for CEL-PVP binary amorphous systems of varying composition showed positive deviation from those predicted through the Gordon-Taylor/ Kelley-Bueche equation, thus indicating a molecular interaction between CEL and PVP. This was further substantiated by shifts observed in DSC melting endotherms of CEL, and FTIR bands for C=O stretching vibrations in PVP for CEL-PVP binary amorphous systems. Computer simulation showed stronger H-bonds between amido protons of CEL and carbonyl O of a monomeric unit of PVP, compared to those observed in pure amorphous CEL. These molecular interactions between CEL and PVP supported the stabilizing action of PVP for the amorphous form of CEL.     

Crystallization of Amorphous Solid Dispersions of Resveratrol during Preparation and Storage—Impact of Different Polymers

The objective of this study was to investigate intermolecular interactions between resveratrol and polymers in amorphous blends and to study the potential correlations between compound–polymer interactions, manufacturability, and stability of the amorphous system to crystallization during storage. Polymers included two grades of poly (vinylpyrrolidone) (PVP), Eudragit E100 (E100), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose acetate butyrate, and poly (acrylic acid) (PAA). Amorphous blends (“solid dispersions”) were prepared by dissolving both resveratrol and polymer in a solvent followed by rotary evaporation. Crystallinity was evaluated using X‐ray powder diffraction and was studied as a function of time. Mid‐infrared (IR) spectroscopy was used to investigate resveratrol–polymer interactions. Polymer influence on the crystallization behavior of resveratrol varied and could be correlated to the polymer structure, whereby polymers with good hydrogen bond acceptor groups performed better as crystallization inhibitors. Resveratrol–polymer hydrogen bonding interactions could be inferred from the IR spectra. Somewhat surprisingly, E100 and resveratrol showed evidence of an acid–base reaction, in addition to intermolecular hydrogen bonding interactions. PVP K29/32 appeared to form stronger hydrogen bond interactions with resveratrol relative to HPMC, HPMCAS, and PAA, consistent with acceptor group chemistry. Long‐term stability of the systems against crystallization suggested that stability is linked to the type and strength of intermolecular interactions present. whereby resveratrol blended with E100 and PVP K29/32 showed the greatest stability to crystallization. In conclusion, amorphous resveratrol is unstable and difficult to form, requiring the assistance of a polymeric crystallization inhibitor to facilitate the formation of an amorphous solid dispersion. Polymers effective at inhibiting crystallization were identified, and it is rationalized that their effectiveness is based on the type and strength of their intermolecular interactions with resveratrol.     

Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine

The ability of various polymers to inhibit the crystallization of amorphous felodipine was studied in amorphous molecular dispersions. Spin-coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose (HPMC) were prepared and used for measurement of the nucleation rate and to probe drug-polymer intermolecular interactions. Bulk solid dispersions were prepared by a solvent evaporation method and characterized using thermal analysis. It was found that each polymer was able to significantly decrease the nucleation rate of amorphous felodipine even at low concentrations (3-25% w/w). Each polymer was found to affect the nucleation rate to a similar extent at an equivalent weight fraction. For HPMC and HPMCAS, thermal analysis indicated that the glass transition temperature (T(g)) of the solid dispersions were not significantly different from that of felodipine alone, whereas an increase in T(g) was observed for the PVP containing solid dispersions. Infrared spectroscopic studies indicated that hydrogen bonding interactions were formed between felodipine and each of the polymers. These interactions were stronger between felodipine and PVP than for the other polymers. It was speculated that, at the concentrations employed, the polymers reduce the nucleation rate through increasing the kinetic barrier to nucleation.     

Amorphous Drug–Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Challenging Case of Lumefantrine-PAA

Lumefantrine (LMF), a high-mobility and easy-to-crystallize WHO drug for treating malaria, can form an amorphous salt with poly(acrylic acid) (PAA) that is remarkably stable against crystallization at high humidity and temperature and has fast dissolution rate. The amorphous salt up to 75% drug loading was synthesized under a mild slurry condition easily implemented in basic facilities for global health. Salt formation was confirmed by IR spectroscopy and the much elevated glass transition temperature. At 50% drug loading, the amorphous salt resists crystallization for at least 18 months under the highly stressful condition of 40 °C and 75% RH. In contrast, the dispersion containing neutral LMF in PVP fully crystallized in 4 d and the dispersion in HPMCAS, a weak polyelectrolyte of lower charge density than PAA, crystallized by 50% in 7 d. The amorphous salt at 50% drug loading showed much faster dissolution than crystalline LMF: In SGF, the area under the curve (AUC) was 30 times larger within the gastric emptying time (4 h); in FaSSIF, the enhancement was even larger – by 200 times. Nanodroplets were detected during the dissolution in SGF, possibly accounting for the apparent enhancement of dissolution rate. The LMF-PAA example as a challenging case, along with the previously reported clofazimine-PAA, demonstrates the general utility of amorphous drug–polymer salts to achieve high stability under tropical conditions and enhanced dissolution and bioavailability.     

Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and (1)H NMR relaxation times

Isothermal crystallization of amorphous nifedipine, phenobarbital, and flopropione was studied at temperatures above and below their glass transition temperatures (T(g)). A sharp decrease in the crystallization rate with decreasing temperature was observed for phenobarbital and flopropione, such that no crystallization was observed at temperatures 20-30 degrees C lower than their T(g) within ordinary experimental time periods. In contrast, the crystallization rate of nifedipine decreased moderately with decreasing temperature, and considerable crystallization was observed at 40 degrees C below its T(g) within 4 months. The molecular mobility of these amorphous drugs was assessed by enthalpy relaxation and (1)H-NMR relaxation measurements. The enthalpy relaxation time of nifedipine was smaller than that of phenobarbital or flopropinone at the same T - T(g) values, suggesting higher molecular mobility of nifedipine. The spin-lattice relaxation time in the rotating frame (T(1rho)) decreased markedly at temperature above T(g). The slope of the Arrhenius type plot of the T(1rho) for nifedipine protons changed at about 10 degrees C below the T(g), whereas the slope for phenobarbital protons became discontinuous at about 10 degrees C above the T(g). Even at temperatures below its T(g), the spin-spin relaxation process of nifedipine could be described by the sum of its Gaussian relaxation, which is characteristic of solid protons, and its Lorentzian relaxation, which is characteristic of protons with higher mobility. In contrast, no Lorentzian relaxation was observed for phenobarbital or flopropione at temperatures below their T(g). These results also suggest that nifedipine has higher molecular mobility than phenobarbital and flopropione at temperatures below T(g). The faster crystallization of nifedipine than that of phenobarbital or flopropione observed at temperatures below its T(g) may be partly ascribed to its higher molecular mobility at these temperatures.     

A Comparison of the Physical Stability of Amorphous Felodipine and Nifedipine Systems

Purpose The objective of this study was to investigate thermodynamic and kinetic factors contributing to differences in the isothermal nucleation rates of two structurally related calcium channel blockers, nifedipine and felodipine, both alone and in the presence of poly(vinylpyrrolidone) (PVP).Materials and Methods Thin films of amorphous systems were cast onto glass slides and the nucleation rate was determined using optical microscopy. Enthalpy, entropy, and free energy of crystallization of the pure compounds were measured using differential scanning calorimetery (DSC). Molecular mobility and glass transition temperature of each amorphous system were characterized using DSC and hydrogen bonding patterns were analyzed with infrared spectroscopy. The composition dependence of the thermodynamic activity of the amorphous drug in the presence of the polymer was estimated using Flory‐Huggins lattice theory.Results Nifedipine crystallized more readily than felodipine from the metastable amorphous form both alone and in the presence of PVP despite having a similar glass transition temperature and molecular mobility. Nifedipine was found to have a larger enthalpic driving force for crystallization and a lower activation energy for nucleation.Conclusions The properties of the metastable form alone did not explain the greater propensity for nifedipine crystallization. When considering the physical stability of amorphous systems, it is important to also consider the properties of the crystalline counterpart.     

Physical stability and enthalpy relaxation of drug-hydroxypropyl methylcellulose phthalate solvent change co-precipitates

The poorly water-soluble drug GWX was co-precipitated with hydroxypropyl methylcellulose phthalate (HPMCP) using a solvent change method. The two co-precipitate formulations made, with drug-HPMCP ratios of 2:8 and 5:5, were analysed using modulated temperature differential scanning calorimetry. They were found to consist of completely amorphous solid solution and a mixture of amorphous solid solution, crystalline drug and amorphous drug, respectively. Stability with respect to crystallization of the two co-precipitates and pure amorphous drug made by quench cooling was compared by storing preparations at 25 degrees C and 40 degrees C, under vacuum over P(2)O(5), and at 75% relative humidity (r.h.). Humidity (75% r.h. compared with dry) had a larger influence on crystallization of the amorphous drug than temperature (25 degrees C compared with 40 degrees C). The solid solution phase in co-precipitates had a relatively higher stability than amorphous drug alone, with respect to crystallization, in presence of the plasticizer water, and crystalline drug. These findings were partly explained by evidence of decreased molecular mobility in the amorphous solid solution with respect to amorphous drug alone, using enthalpy relaxation measurements. At an ageing temperature of 65 degrees C, the calculated half-life for enthalpy relaxation of the 2:8 drug-HPMCP ratio coprecipitate was about 6 orders of magnitude greater than that of amorphous drug alone, indicating a large difference in relative molecular mobility.     

Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers.

Water associated with amorphous polymers is known to affect their chemical and physical properties. The purpose of this study was to investigate the nature of water-polymer interactions for some polymers of pharmaceutical interest. Using Raman spectroscopy, polymer-water hydrogen bond interactions were probed for two molecular weight grades of poly(vinylpyrrolidone), namely PVP K90 and PVP K12, and also for poly(vinylacetate) and poly(vinyl pyrrolidone-co-vinyl acetate). Water vapor absorption isotherms were obtained for the polymers, and the effect of the absorbed water on the glass transition temperature was determined. A knowledge of the water content and physical state of the polymer was used to aid interpretation of Raman spectral changes. The strength of the hydrogen bond formed with water was found to depend on the chemistry of the polymer, with the pyrrolidone group interacting more strongly than the acetate group. However, minor differences were also observed between the degree of interaction of water and polymer for PVP K12 and PVP K90 at some water contents. This result is attributed to differences in the structural relaxation changes accompanying plasticization by water for the two molecular weight grades. Using principal components analysis of the spectral data, it was also possible to differentiate between samples in the rubbery state and samples in the glassy state. In conclusion, water sorbed into polymers causes changes in the polymer Raman spectra not only because of hydrogen bonding, but also as a result of the plasticizing effect of water on polymer mobility.     

Correlation between molecular mobility and crystal growth of amorphous phenobarbital and phenobarbital with polyvinylpyrrolidone and L-proline

The aim of the present study is to determine if the correlation between molecular mobility and crystallization growth rates exists over a broad temperature range from temperatures below the glass transition (T(g)) to temperatures above the glass transition. Phenobarbital and solid dispersions of phenobarbital with PVP and L-proline were studied in this research. Relaxation times below and above the T(g) were measured. Crystallization was followed in a hot-stage microscope and crystal growth rates were measured by observing radial growth of a single crystal. Arrhenius type temperature dependences were found both in relaxation times and crystal growth rates over studied temperature ranges, in all cases studied except in the case of pure phenobarbital, where a change of slope was observed for the crystal growth rate for the temperature range below T(g). For all cases, molecular mobility was correlated with crystal growth rate, for the temperature range studied, with a coupling coefficient of 0.38 for phenobarbital, and 0.23 and 0.28 for solid dispersions with PVP and proline respectively. By establishing the coupling between molecular mobility and crystal growth rate, predictive models can be created to estimate the stability of amorphous materials both, for pure form as well as for solid dispersions.     

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     

Ability of Different Polymers to Inhibit the Crystallization of Amorphous Felodipine in the Presence of Moisture

Purpose To investigate the ability of various polymers to inhibit the crystallization of amorphous felodipine from amorphous molecular dispersions in the presence of absorbed moisture. Methods Spin coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose (HPMC) were exposed to different storage relative humidities and nucleation rates were measured using polarized light microscopy. Solid dispersions were further characterized using differential scanning calorimetry, infrared spectroscopy and gravimetric measurement of water vapor sorption. Results It was found that the polymer additive reduced nucleation rates whereas absorbed water enhanced the nucleation rate as anticipated. When both polymer and water were present, nucleation rates were reduced relative to those of the pure amorphous drug stored at the same relative humidity, despite the fact that the polymer containing systems absorbed more water. Differences between the stabilizing abilities of the various polymers were observed and these were explained by the variations in the moisture contents of the solid dispersions caused by the different hygroscopicities of the component polymers. No correlations could be drawn between nucleation rates and the glass transition temperature (T _g) of the system. PVP containing solid dispersions appeared to undergo molecular level changes on exposure to moisture which may be indicative of phase separation. Conclusions In conclusion, it was found that for a given storage relative humidity, although the addition of a polymer increases the moisture content of the system relative to that of the pure amorphous drug, the crystallization tendency was still reduced.     

A study of amorphous molecular dispersions of indomethacin and its sodium salt.

Amorphous solid dispersions of indomethacin (IMC) and sodium indomethacin (NaIMC) over a range of compositions were prepared by physically mixing amorphous IMC and amorphous NaIMC, as well as by coprecipitation from methanol solution. Measurement of glass transition temperatures, T(g), for the physical mixtures revealed two values indicating, as expected, phase separation. In contrast, all samples of coprecipitated materials exhibited one value of T(g), which was greater than that predicted for ideal miscibility in the formation of a molecular dispersion. Such nonideality suggests a stronger acid-salt interaction in the amorphous state than that between acid-acid and salt-salt. FTIR spectroscopic analysis provides evidence for interactions between NaIMC and IMC through a combination of hydrogen bonding and ion-dipole interactions between the carboxylic group of the acid and the carboxylate anion of the salt. The inhibition of isothermal crystallization of IMC by NaIMC only when in molecular dispersion is believed to result from the interaction between the acid and the salt, which prevents the formation of hydrogen-bonded carboxylic acid dimers for IMC, required for the formation of crystal nuclei and crystallization.     

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.     

Enthalpy Relaxation in Binary Amorphous Mixtures Containing Sucrose

Purpose. To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. Methods. Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVP/VA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. Results. Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran PVP > PVP/VA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (H) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). Conclusions. The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a T_g that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below T_g, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.     

Stability prediction of amorphous benzodiazepines by calculation of the mean relaxation time constant using the Williams-Watts decay function.

The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam was studied using differential scanning calorimetry for ageing temperatures which were below the glass transition temperature, and ageing times up to 16 h. Experimental determination of the relaxation enthalpy and the heat capacity change, both accompanying the glass transition, enabled us to calculate the extent of relaxation of the amorphous drugs at specific ageing conditions. Fitting of the relaxation function to the Williams-Watts two parameter decay function led to calculation of the mean relaxation time constant tau and the molecular relaxation time distribution parameter beta. The mean relaxation time constants for the three drugs increased from approximately ten h at the glass transition temperature with more than eight orders of magnitude at 66 K below the glass transition temperature. It was found that the benzodiazepines exhibited significant molecular mobility until approximately 50 K below the glass transition temperature; below this temperature molecular mobility becomes unimportant with respect to the shelf life stability. Hence the presented procedure provides the formulation scientist with a tool to set storage conditions for amorphous drugs and glassy pharmaceutical products.