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

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

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

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

Molecular Mobility and Fragility in Indomethacin: A Thermally Stimulated Depolarization Current Study

Purpose. To show that thermally stimulated depolarization currents (TSDC), which is a dielectric experimental technique relatively unknown in the pharmaceutical scientists community, is a powerful technique to study molecular mobility in pharmaceutical solids, below their glass transition temperature (T_g). Indomethacin (T_g = 42°C) is used as a model compound. Methods. TSDC is used to isolate the individual modes of motion present in indomethacin, in the temperature range between –165°C and +60°C. From the experimental output of the TSDC experiments, the kinetic parameters associated with the different relaxational modes of motion were obtained, which allowed a detailed characterization of the distribution of relaxation times of the complex relaxations observed in indomethacin. Results. Two different relaxational processes were detected and characterized: the glass transition relaxation, or -process, and a sub-T_g relaxation, or secondary process. The lower temperature secondary process presents a very low intensity, a very low activation energy, and a very low degree of cooperativity. The fragility index (Angell's scale) of indomethacin obtained from TSDC data is m = 64, which can be compared with other values reported in the literature and obtained from other experimental techniques. Conclusions. TSDC data indicate that indomethacin is a relatively strong glass former (fragility similar to glycerol but lower than sorbitol, trehalose, and sucrose). The high-resolution power of the TSDC technique is illustrated by the fact that it detected and characterized the secondary relaxation in indomethacin, which was not possible by other techniques.     

The Activation Energy at T g and the Fragility Index of Indomethacin,Predicted from the Influence of the Heating Rate on the Temperature Position and on the Intensity of Thermally Stimulated Depolarization Current Peak

Purpose. The purpose of this study was to estimate the activation energy at the glass transition temperature (and the fragility index) of amorphous indomethacin from the influence of heating rate on the features of the relaxation peaks obtained by thermally stimulated depolarization currents (TSDC) and to compare the obtained results with those obtained by other procedures based on TSDC data. Methods. The glass transition temperature region of amorphous indomethacin was characterized at different heating rates by TSDC in a way similar to that used to determine the kinetics of the glass transition relaxation by differential scanning calorimetry. The features of a thermal sampled TSDC peak, namely the temperature location and the intensity, depend on the heating rate. Results. The activation energy for structural relaxation (directly related to glass fragility) was estimated from the heating rate dependence of the TSDC peak location, T _m, and of the maximum intensity of the TSDC peak, I(T _m). Conclusions. The methods for determining the activation energy for structural relaxation and fragility of indomethacin from TSDC data obtained with different heating rates were compared with other procedures previously proposed. TSDC, which is not a very familiar technique in the community of pharmaceutical scientists, proved to be a very convenient technique to study molecular mobility and to determine the fragility index in glass-forming systems. The value of 60 appears as a reasonable value of the fragility index of indomethacin.     

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.     

An Evaluation of the Use of Modulated Temperature DSC as a Means of Assessing the Relaxation Behaviour of Amorphous Lactose

Purpose. To evaluate the use of Modulated Temperature DSC(MTDSC) as a means of assessing the relaxation behaviour ofamorphous lactose via measurement of the heat capacity, glasstransition (Tg) and relaxation endotherm. Methods. Samples of amorphous lactose were prepared by freezedrying. MTDSC was conducted using a TA Instruments 2920 MDSCusing a heating rate of 2°C/minute, a modulation amplitude of ±0.3°Cand a period of 60 seconds. Samples were cycled by heating to 140°Cand cooling to a range of annealing temperatures between 80°C and100°C, followed by reheating through the Tg region. Systems werethen recooled to allow for correction of the Tg shift effect. Results. MTDSC enabled separation of the glass transition from therelaxation endotherm, thereby facilitating calculation of the relaxationtime as a function of temperature. The relative merits of using MTDSCfor the assessment of relaxation processes are discussed. In addition,the use of the fictive temperature rather than the experimentally derivedTg is outlined. Conclusions. MTDSC allows assessment of the glass transitiontemperature, the magnitude of the relaxation endotherm and the valueof the heat capacity, thus facilitating calculation of relaxation times.Limitations identified with the approach include the slow scanningspeed, the need for careful choice of experimental parameters and theTg shift effect.     

Direct Observation of the Enthalpy Relaxation and the Recovery Processes of Maltose-Based Amorphous Formulation by Isothermal Microcalorimetry

Purpose. The applicability of isothermal microcalorimetry (IMC) for evaluating enthalpy relaxation and recovery processes of amorphous material was assessed. Methods. A maltose-based formulation was prepared by freeze-dry method. Differential scanning calorimetry (DSC) was used to investigate its glass transition and relaxation behaviors. IMC was applied to quantitatively analyze the relaxation and the recovery processes. The IMC data were analyzed using a derivative of the Kohlrausch-Williams-Watts equation. Results. The glass transition temperature of the formulation and its fictive temperature stored at 15°C for 1 year were 62 and 32°C, respectively. DSC study showed that annealing below the fictive temperature increased the enthalpy recovery, but it was decreased by annealing at higher temperatures. IMC enabled direct observation of the heat flow during both the relaxation and the recovery processes. The decay constant for the recovery process (recovery time) was much smaller and less sensitive to the temperature than that for the relaxation process (relaxation time). Conclusions. IMC was successfully used to obtain quantitative information on both relaxation and recovery processes of amorphous material. The relaxation parameters obtained by this method could explain the thermodynamic behavior of the formulation.     

Characterisation of the Glass Transition of an Amorphous Drug Using Modulated DSC

Purpose. The use of modulated differential scanning calorimetry (MDSC) as a novel means of characterising the glass transition of amorphous drugs has been investigated, using the protease inhibitor saquinavir as a model compound. In particular, the effects of measuring variables (temperature cycling, scanning period, heating mode) have been examined. Methods. Saquinavir samples of known moisture content were examined using a TA Instruments 2920 MDSC at a heating rate of 2°C/min and an amplitude of ± 0.159°C with a period of 30 seconds. These conditions were used to examine the effects of cycling between - 50°C and 150°C. A range of periods between 20 and 50 seconds were then studied. Isothermal measurements were carried out between 85°C and 120°C using an amplitude of ± 0.159°C with a period of 30 seconds. Results. MDSC showed the glass transition of saquinavir (0.98 ± 0.05%w/w moisture content) in isolation from the relaxation endotherm to give an apparent glass transition temperature of 107.0° C ± 0.4C. Subsequent temperature cycling gave reproducible glass transition temperatures of approximately 105°C for both cooling and heating cycles. The enthalpic relaxation peak observed in the initial heating cycle had an additional contribution from a Tg 'shift' effect brought about by the difference in response to the glass transition of the total and reversing heat flow signals. Isothermal studies yield a glass transition at 105.9°C ± 0.1°C. Conclusions. MDSC has been shown to be capable of separating the glass transition of saquinavir from the relaxation endotherm, thereby facilitating measurement of this parameter without the need for temperature cycling. However, the Tg 'shift' effect and the number of modulations through the transition should be taken into account to avoid drawing erroneous conclusions from the experimental data. MDSC has been shown to be an effective method of characterising the glass transition of an amorphous drug, allowing the separate characterisation of the Tg and endothermic relaxation in the first heating cycle.     

A Pragmatic Test of a Simple Calorimetric Method for Determining the Fragility of Some Amorphous Pharmaceutical Materials

Purpose. To evaluate a simple calorimetric method for estimating the fragility of amorphous pharmaceutical materials from the width of the glass transition region. Methods. The glass transition temperature regions of eleven amorphous pharmaceutical materials were characterized at six different heating and cooling rates by differential scanning calorimetry (DSC). Results. Activation energies for structural relaxation (which are directly related to glass fragility) were estimated from the scan rate dependence of the glass transition temperature, and correlations between the glass transition widths and the activation energies were examined. The expected correlations were observed, and the exact nature of the relationship varied according to the type of material under consideration. Conclusions. The proposed method of determining the fragility of amorphous materials from the results of simple DSC experiments has some utility, although "calibration of the method for each type of materials is necessary. Further work is required to establish the nature of the relationships for a broad range of amorphous pharmaceutical materials.     

Phase Behavior of Binary and Ternary Amorphous Mixtures Containing Indomethacin, Citric Acid, and PVP

Purpose. To better understand the nature of drug-excipient interactions we have studied the phase behavior of amorphous binary and ternary mixtures of citric acid, indomethacin and PVP, as model systems. Methods. We have prepared amorphous mixtures by co-melting or coprecipitation from solvents, and have measured glass transition temperatures with differential scanning calorimetry. Results. Citric acid and indomethacin in the amorphous state are miscible up to 0.25 weight fraction of citric acid, equivalent to about 2 moles of citric acid and 3 moles of indomethacin. Phase separation, as reflected by two Tg values, occurs without crystallization leading to a saturated citric acid-indomethacin amorphous phase and one essentially containing only citric acid. PVP-citric acid and PVP-indomethacin form non-ideal miscible systems at all compositions. A ternary system containing 0.3 weight fraction of PVP produces a completely miscible system at all citric acid-indomethacin compositions. The use of 0.2 weight fraction of PVP, however, only produces miscibility up to a weight fraction of 0.4 citric acid relative to indomethacin. The two phases above this point appear to contain citric acid in PVP and citric acid in indomethacin, respectively. Conclusions. Two components of an amorphous solid mixture containing citric acid and indomethacin with limited solid state miscibility can be solublized as an amorphous solid phase by the addition of moderate levels of PVP.     

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.     

Molecular Mobility in Raffinose in the Crystalline Pentahydrate Form and in the Amorphous Anhydrous Form

Purpose The aims of the study are to characterize the slow molecular mobility in solid raffinose in the crystalline pentahydrate form, as well as in the anhydrous amorphous form (T_g = 109°C at 5°C/min), and to analyze the differences and the similarities of the molecular motions in both forms.Methods Thermally stimulated depolarization current (TSDC) is used to isolate the individual modes of motion present in raffinose, in the temperature range between −165 and +60°C. From the experimental output of the TSDC experiments, the kinetic parameters associated with the different relaxational modes of motion were obtained, which allowed a detailed characterization of the distribution of relaxation times of the complex relaxations observed in raffinose. The features of the glass transition relaxation in raffinose were characterized by differential scanning calorimetry (DSC).Results A complex mobility was found in the crystalline form of raffinose. From the analysis of the TSDC data, we conclude that these molecular motions are local and noncooperative. A sub-T_g relaxation, or secondary process, was also detected and analyzed by TSDC in the amorphous phase. It has low activation energy and low degree of cooperativity. The glass transition was studied by DSC. The fragility index (Angell’s scale) of raffinose obtained from DSC data is m = 148.Conclusions TSDC proved to be an adequate technique to study the molecular mobility in the crystalline pentahydrate form of raffinose. In the amorphous form, on the other hand, the secondary relaxation was analyzed by TSDC, but the study of the glass transition relaxation was not possible by this experimental technique as a consequence of conductivity problems. The DSC study of the glass transition indicates that raffinose is an extremely fragile glass former.     

Determination of the Viscosity of an Amorphous Drug Using Thermomechanical Analysis (TMA)

Purpose. To evaluate thermomechanical analysis (TMA) as a technique for determining the viscosity of amorphous pharmaceutical materials. This property of amorphous drugs and excipients is related to their average rate of molecular mobility and thus to their physical and chemical stability. Methods. Indomethacin was selected as a model amorphous drug whose viscosity has previously been reported in the literature. A Seiko TMA 120C thermomechanical analyzer was utilized in isothermal penetration mode to determine the viscosity of the amorphous drug over the maximum possible range of temperatures. Results. Using a cylindrical penetration geometry it was possible to accurately determine the viscosity of amorphous indomethacin samples by TMA over the temperature range from 35 to 75°C. The results were consistent with those reported in the literature using a controlled strain rheometer over the range 44–75°C. The limiting lower experimental temperature for the TMA technique was extended to significantly below the calorimetric glass transition temperature (T_g 42°C), thus allowing a direct experimental determination of the viscosity at T_g to be made. Conclusions. Thermomechanical analysis can be used to accurately determine the viscosity of amorphous pharmaceutical materials at temperatures near and above their calorimetric glass transition temperatures.     

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.     

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.     

Structural and Dynamic Properties of Crystalline and Amorphous Phases in Raffinose-Water Mixtures

Purpose. To obtain an improved characterisation of the raffinose-water solid-solid and solid-liquid state diagram, and to study the thermophysical behaviour of the solid amorphous phase. This information is expected to shed light on the potential of rafTinose as a pharmaceutical excipient, for stabilising labile preparations at high temperatures. Methods. X-ray diffraction, scanning electron microscopy, polarised-light microscopy, differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA) were applied to study raffinose pentahydrate and its behaviour during progressive dehydration. Results. Isothermal dehydration of raffinose pentahydrate led to its gradual amorphisation, but also to minor changes in the diffractograms, suggesting the probability of lower stable hydrates. Their existence was confirmed by DSC. Anhydrous raffinose was found to be completely amorphous, and this was supported by the gradual disappearance of birefringence during dehydration. In contrast, electron micrographs, taken during the dehydration process, exhibited no changes in the original ultrastructural crystal morphology. The widths of the glass-to-fluid transitions and the absolute specific heats of crystalline and amorphous phases in the vitreous and fluid states were used to estimate some structural and relaxation characteristics of amorphous raffinose-water mixtures. Conclusions. Raffinose forms the most 'fragile' glass of those pharmaceutical excipients for which data are available. In its thermomechanical properties, it is superior to trehalose and should therefore be effective as a long-term stabiliser for dried biopharmaceutical preparations at temperatures up to 65°C.     

Effect of Glass Transition Temperature on the Stability of Lyophilized Formulations Containing a Chimeric Therapeutic Monoclonal Antibody

Purpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, T_g, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Results. Sucrose formulation (T_g ~ 59°C) when stored at 60°C was found to undergo significant aggregation, while the trehalose formulation (T_g ~ 80°C) was stable at 60°C. The instability observed with sucrose formulation at 60°C can be attributed to its T_g (~59°C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the T_gs of the formulations containing sucrose or trehalose, but to different degrees. Conclusions. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40°C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60°C) where one formulation is in the glassy state while the other is near or above its T_g.     

Crystallization Behavior of Mannitol in Frozen Aqueous Solutions

Purpose. To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions. Methods. Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions. Results. Rapid cooling (20°C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10°C and 5°C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32°C and -25°C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of 100 mM, the buffer salts significantly inhibited mannitol crystallization. Conclusions. The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.     

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.     

Transport of Fentanyl Through Pig Buccal and Esophageal Epithelia <Emphasis Type="Italic">in Vitro</Emphasis>. Influence of Concentration and Vehicle pH

Purpose To validate pig esophageal epithelium as a model for the permeability barrier of the buccal mucosa, the transport of fentanyl across the two tissues was compared in vivo.Methods The epithelia were separated by immersing the excised mucosae into an isotonic saline solution at 60–65°C. Fentanyl was delivered as the citrate salt at a concentration of 1 or 2 mg/mL buffered at one of four pH values (between 6.0 and 7.4).Results Across both barriers, drug transport increased proportionally with concentration as expected. However, drug flux was not linearly related to the unionized fraction of the drug; indeed, fentanyl delivery was significant even when 98.5% of the drug was in the ionized form.Conclusions Buccal and esophageal fluxes were very similar under all conditions suggesting that the esophageal epithelium is a representative tool for buccal transport studies in vitro.