Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions

Water vapor absorption isotherms were measured for three amorphous hydrophobic drug/poly(vinylpyrrolidone) (PVP) dispersions in the concentration range 10-90% w/w PVP. Experimental isotherms were compared to predicted isotherms calculated using each individual component isotherm multiplied by its weight fraction. Indomethacin (IMC)/PVP, ursodeoxycholic acid (UDCA)/PVP and indapamide (IDP)/PVP amorphous dispersions all exhibited experimental isotherms reduced relative to predicted isotherms indicating that dispersion formation altered the water vapor absorption properties of the individual components. For all three drug/PVP systems, deviation from predicted water uptake was greatest close to the 1:1 drug:PVP monomer composition, indicating that intermolecular interaction in amorphous dispersions affects the water uptake properties of the individual components. Using dry glass transition temperature (T(g)) data, the extent of drug/PVP interaction was shown to be greatest in the IDP/PVP system, which could explain why the largest reduction in water vapor absorption was found in this system. The plasticizing effect of absorbed water varied according to dry dispersion PVP content in all systems and the resulting nonideal changes in free volume, calculated using the Vrentas model, were greatest close to the 1:1 drug:PVP monomer composition. A three-component Flory-Huggins model successfully predicted isotherms for IMC/PVP compositions from 60 to 90% w/w PVP and identified an IMC-PVP interaction parameter chi in the range 1.27-1.49, values that suggest poor homogeneity of mixing in the dry system. These data indicate that amorphous dispersion formation causes both chemical and physical changes in the individual amorphous components that can have a significant effect on their water vapor absorption properties.     

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.     

The relationship between "BET" and "free volume"-derived parameters for water vapor absorption into amorphous solids

Water vapor absorption isotherms for amorphous solids with the same chemical composition but differing in molecular weight (i.e., PVP-90, PVP-30, and PVP-12), and for glucose, trehalose, and two molecular weight grades of dextran were obtained at 30 degrees C and analyzed using the Brunauer-Emmett-Teller (BET) equation to obtain the parameters, W(m) and C(B). Similar analyses were carried out for the same molecule (e.g., glucose or fructose) at -10 and 40 degrees C. Within each chemical group, W(m), the apparent BET-like parameter that is generally referred to as the "monolayer-limit of absorption", changed very little. In contrast, C(B), a measure of the free energy of absorption, significantly increased with increasing molecular weight or decreasing temperature, leading to a shift from a Type III to a Type II isotherm. The shift in isotherm shape correlates directly with the glass transition temperature, T(g), of the dry sample relative to the operating temperature, T (i.e., Type III when T > T(g) and Type II when T < T(g). These results are shown to be consistent with the combined Flory-Huggins solution model and Vrentas structural relaxation model; wherein Type II isotherm behavior, observed for T < T(g), reflects nonideal volumetric contributions to the overall free energy of absorption due to plasticization by water, as described by Vrentas, whereas Type III behavior only reflects the Flory-Huggins solution model. These volumetric free energy changes within each chemical group are shown to be correlated to the values of the "BET" parameter C(B).     

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.     

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

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

Investigation of drug–polymer interaction in solid dispersions by vapour sorption methods

The objective of this study was to investigate the effect of different polymeric carriers in solid dispersions with an active pharmaceutical ingredient (API) on their water vapour sorption equilibria and the influence of the API–polymer interactions on the dissolution rate of the API. X-ray diffraction, scanning electron microscopy (SEM), moisture sorption analysis, infrared (IR) spectroscopy and dissolution tests were performed on various API–polymer systems (Valsartan as API with Soluplus, PVP and Eudragit polymers) after production of amorphous solid dispersions by spray drying. The interactions between the API and polymer molecules caused the water sorption isotherms of solid dispersions to deviate from those of ideal mixtures. The moisture sorption isotherms were lower in comparison with the isotherms of physical mixtures in all combinations with Soluplus and PVP. In contrast, the moisture sorption isotherms of solid dispersions containing Eudragit were significantly higher than the corresponding physical mixtures. The nature of the API–polymer interaction was explained by shifts in the characteristic bands of the IR spectra of the solid dispersions compared to the pure components. A correlation between the dissolution rate and the water sorption properties of the API–polymer systems has been established.     

Characteristics of hydrogen bond formation between sugar and polymer in freeze-dried mixtures under different rehumidification conditions and its impact on the glass transition temperature

The characteristics of hydrogen bond formation between trehalose and polyvinylpyrrolidone (PVP) in amorphous mixtures at different hydration states were quantitatively investigated. Amorphous trehalose-PVP mixtures were prepared by freeze-drying and equilibrated at different relative humidities (RH). Infrared (IR) spectra of the trehalose-PVP mixtures were obtained by Fourier transform IR spectroscopy,(FTIR) and the IR band corresponding to C=O groups of PVP was deconvolved into the component bands responsible for C=O groups that were free and restricted by hydrogen bonds, to estimate the degree of the trehalose-PVP interactions. The FTIR analysis indicated that approximately 80% of the C=O groups of PVP formed hydrogen bonds with trehalose in the presence of more than 3 g of trehalose per gramme of PVP, independent of the RH. IR analysis of the O--H stretching vibration of the sugar demonstrated that the presence of PVP lead to an increase in the free hydroxyl groups of trehalose that did not form hydrogen bonds at RH 0%. On the other hand, the water sorption behavior of the trehalose-PVP mixtures suggested that rehumidification diminished the effect of PVP on increasing the free OH groups. Thus a peculiar relationship may exist between Tg, RH and the composition of the mixture: The presence of PVP increased Tg at RHs 0 and above 23% but decreased Tg at 11%.     

Interaction between water and poly(vinylpyrrolidone) containing polyethylene glycol

Information on the interaction between water and polymers is indispensable for manufacturing solid dispersion of a drug by hot-melt extrusion because this interaction affects various properties of the water-polymer mixtures, such as their viscoelastic properties. In this study, poly(vinylpyrrolidone) K30 (PVP) containing 0%, 10%, and 20% poly(ethylene glycol) 400 (PEG) was used as model amorphous polymers. The interaction of water with these polymers was assessed by the evaluation of the glass transition temperature (Tg), the point on the isotherm corresponding to the weight of sorbed water required to form a complete monolayer on the solid surface (apparent Wm), and the maximal amount of nonfreezing water, which were measured by differential scanning calorimetry and water sorption isotherms. In all of the systems with a water content below a certain water fraction (0.1 for PVP, 0.12 for PVP-PEG 10%, and 0.16 for PVP-PEG 20%), the Tg values were successfully predicted using theoretical equations, whereas the experimental Tg values were higher than predicted for those with a water content above these water fraction levels. In addition, these values of water fraction are similar to the apparent W(m) values determined using the Guggenheim-Anderson-DeBoer (GAB) equation (0.110, 0.117, and 0.147 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively). Nonfreezing water is detected above 0.47, 0.49, and 0.51 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively. Miscibility between water and PVP or PVP-PEG seems to change according to the water content in the system. All parameters increase with the concentration of PEG in the sample. This may be explained by the fact that PEG has a larger number of polymer repeating units, which may therefore interact with water more than PVP.     

A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/polyvinylpyrrolidone

Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 ≤ X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 ≤ X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 ≤ X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (χ) were determined for the two systems (χ = -1.8 for SDM, χ = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co-milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems.     

Application of quartz crystal microbalance to study the impact of pH and ionic strength on protein-silicone oil interactions

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.     

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug–polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T_g) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug–polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity ≥75%. In contrast, the solid dispersions remained miscible on heating. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:169–185, 2010     

Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions

The purpose of the present study was to investigate the effects of molecular weight (MW) of polyvinylpyrrolidone (PVP) on glass transition and crystallization of sucrose. Thus, sucrose was co-lyophilized with 2.5 and 5.0% w/w PVP of different molecular weights, which were characterized using gel permeation chromatography. Freeze drying was carried out for 48 h at a shelf temperature of -40 degrees C and a pressure of about 36 Pa. The samples were then dried in a vacuum oven at 24 degrees C for 12 h before drying for a further 12 h at 40 degrees C. Differential scanning calorimetry (DSC) was employed to measure the glass transition temperature (Tg), dynamic crystallization temperature (Tc) and isothermal crystallization induction time (tc) at 85 degrees C of sucrose. Isothermal water vapour sorption of each sample was also measured at different relative humidities. Tg values of sucrose varied from 48.3+/-0.8 degrees C for freeze-dried (FD) sucrose alone to 58.8+/-0.8 degrees C for the mixture containing 5.0% PVP of nominal MW 300 K. PVP increased sucrose T(g) significantly (ANOVA P<0.05). Although there was no significant difference (P>0.05) in Tg of the mixtures containing 2.5% w/w PVP of different MW, samples with 5.0% PVP of MW 300 K produced a significantly higher (P<0.05) Tg than the other mixtures. All mixtures were shown to possess higher (P<0.01) Tc than FD sucrose alone, which exhibited a T(c) of approximately 85 degrees C. PVP of MW 300 K consistently induced a significantly (P<0.05) higher Tc of sucrose than PVP of smaller MW. Increasing PVP concentration from 2.5 to 5.0% also resulted in a substantial increase in sucrose Tc. Using isothermal water vapour absorption, sucrose tc was found to increase up to over 10 times when it was co-lyophilized with 2.5% PVP, the actual value of tc being dependent upon the MW of the PVP. For example, PVP of MW 300 K resulted in a sucrose tc at 85 degrees C (89.1-95.6 min), which was approximately seven times higher than that of 2.5% PVP of MW 24 or 40 K. A longer tc of sucrose was also observed for mixtures containing PVP of MW 300 K than when sucrose was mixed with PVP of smaller MW. Thus the effect of PVP on sucrose Tg, Tc and tc was found to be dependent upon MW. PVP of higher MW was more efficient in inhibiting sucrose crystallization and by stabilizing glassy structures of the sugar, these polymers may improve the stability of co-lyophilized proteins and peptides.     

Molecular Dynamics Simulation of Amorphous Indomethacin-Poly(Vinylpyrrolidone) Glasses: Solubility and Hydrogen Bonding Interactions

Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T_g) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T_g with IMC–PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC–IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC–PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC–PVP HBs. The difference (6.5 MPa^1/2) between the solubility parameters in amorphous IMC (25.5 MPa^1/2) and PVP (19.0 MPa^1/2) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (< 7 MPa^1/2). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (? 0.61 ± 0.25), which takes into account the IMC–PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline γ-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions. © 2012Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:876–891, 2013     

Sugar-polymer hydrogen bond interactions in lyophilized amorphous mixtures

The objective of this work was to investigate hydrogen bonding interactions between a variety of glass-forming sugars and a model polymer, poly(vinylpyrrolidone) (PVP), in binary amorphous solid solutions, produced by lyophilization. The glass transition temperatures of the sugars and sugar-PVP colyophilized mixtures were assessed using differential scanning calorimetry. The hydrogen bonding interactions between each sugar and PVP were monitored using FT-Raman spectroscopy. Sucrose was found to hydrogen bond to a greater extent with PVP at a particular sugar:polymer ratio than the other disaccharides studied including trehalose and the trisaccharide raffinose. Maltodextrins showed a decreased tendency to hydrogen bond with the polymer compared to the lower molecular weight sugars. The extent of hydrogen bonding was found to correlate inversely with the glass transition temperature of the sugar, with the tendency to hydrogen bond decreasing as the Tg increased. The importance of hydrogen bonding interactions to the thermodynamics of mixing in amorphous solids is discussed.     

Chemical stability of peptides in polymers. 1. Effect of water on peptide deamidation in poly(vinyl alcohol) and poly(vinyl pyrrolidone) matrixes.

This paper examines the effect of water content, water activity, and glass transition temperature (T(g)) on the deamidation of an asparagine-containing hexapeptide (VYPNGA; Asn-hexapeptide) in lyophilized poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) at 50 degrees C. The rate of Asn-hexapeptide deamidation increases with increasing water content or water activity and, hence, decreasing T(g). The rate of deamidation is more sensitive to changes in these parameters in PVA than in PVP. Deamidation is clearly evident in the glassy state in both formulations. In the glassy state, the peptide is more stable in PVA than in PVP formulations but is less stable in the rubbery state. No single variable (water content, water activity, or T(g)) could account for the variation in deamidation rates in PVA and PVP formulations. Deamidation rates were correlated with the degree of plasticization by water (distance of T(g) from the dry intrinsic glass transition temperature); coincident curves for the two polymers were obtained with this correlation. Deamidation in PVA and PVP was closely correlated with the extent of water-induced plasticization experienced by the formulation relative to its glass transition at 50 degrees C, suggesting that the physical state of formulations could be used to predict chemical stability.     

Solid films of blended poly(vinyl alcohol)/poly(vinyl pyrrolidone) for topical S-nitrosoglutathione and nitric oxide release

Nitric oxide (NO) is responsible for biological actions in mammals, ranging from the control of arterial pressure to immunological responses. In this study, S-nitrosoglutathione (GSNO), a spontaneous NO donor, was incorporated in solid films of blended poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) comprising a biomaterial with potential for the local delivery of NO. In dry conditions, the extinction of the absorption bands of GSNO was correlated with the increase of the absorption band of its dimmer, GS-SG, implying NO release through the homolytic cleavage of the S-N bond. Mass spectrometry was used to confirm and to monitor the release of free NO from solid PVA/PVP-GSNO films to the gas phase. Kinetic measurement based on the Griess reaction was used to show that solid PVA/PVP-GSNO films are also capable of releasing both NO and GSNO to aqueous solution trough diffusion. Storage experiments have shown that GSNO is highly stabilized in the dry PVA/PVP matrix. The results indicate that GSNO-containing PVA/PVP films may be used for delivering free NO and/or GSNO topically and controllably.     

Antisolvent Recrystallization Strategy to Screen Appropriate Carriers to Stabilize Filgotinib Amorphous Solid Dispersions

Drugs in amorphous solid dispersions (ASDs) are highly dispersed in hydrophilic polymeric carriers, which also help to restrain recrystallization and stabilize the ASDs. In this study, microscopic observation after antisolvent recrystallization was developed as a rapid screening method to select appropriate polymers for the initial design filgotinib (FTN) ASDs. Using solvent evaporation, FTN ASDs with the polymers were prepared, and accelerated experimentation validated this screening method. Fourier-transform infrared spectroscopy, Raman scattering, and nuclear magnetic resonance revealed hydrogen-bonding formation in the drug-polymer binary system, which was critical for ASDs stabilization. A Flory-Huggins interaction parameter and water sorption isotherms were applied to evaluate the strength of the interaction between FTN and the polymers. The dissolution rate was also significantly improved by ASDs formulation, and the presence of the polymers exerted solubilization effects. These results suggested the efficacy of this screening method as a preliminary tool for polymer selection in ASDs design.     

Solid state properties of pure UC-781 and solid dispersions with polyvinylpyrrolidone (PVP K30)

The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by coevaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be; a = 8.1556(7) A,b = 17.658(2) A and c = 23.609(2) A; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50% w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.     

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.     

Phase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility

PURPOSE: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis. METHODS: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC). RESULTS: Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees C/69% RH. CONCLUSIONS: Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the "extent of molecular miscibility," referred to as "solid solubility," was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the "solid solubility limit" were physically stable even under accelerated stability conditions.