Supersaturated System Research Articles

Binary polymeric blends to microencapsulate nitroflurbiprofen: Physicochemical and in silico studies

Nitroflurbiprofen, NFP, a practically insoluble liquid drug, was microencapsulated in hydrophilic micromatrices made of poly( N-vinylpyrrolidone) (PVP), or polyaminomethacrylate (PAMA), or binary blends of polymers thereof. The PAMA/PVP miscibility was assessed both in the solid state (DSC and ATF-FTIR spectroscopy) and in solution by viscometric measurements. The in vitro NFP release test was carried out in over saturation condition to discriminate the increase of NFP apparent solubility (supersaturation degree, SD). Drug/polymer/polymer/water interactions were studied in silico by molecular dynamic (MD) simulations. PAMA and PVP resulted miscible only in aqueous solution. The release of NFP from microparticles occurred according to a non-monotonic pattern due to the formation of instable supersaturated systems and the drug separation in the dissolution medium. After 5 min, the SD was at least 3. The use of PVP/PAMA micromatrices reduced the instability of the supersaturated solutions. MD simulations evidenced that water molecules play a key role in the PAMA/PVP compatibilization process and in stabilization of NFP supersaturated systems by means of H-bond. The docking analyses here find a novel and successful application to predict the different ability of a drug to interact with polymeric blends in solution.

Corrosion Properties of Supersaturated Magnesium Alloy Systems

The range of applications for magnesium alloys is still limited due to their relatively poor corrosion behavior. In recent years, various new magnesium alloys were developed, some of them with improved corrosion properties, thus opening new fields of application. However, the number of alloying elements for the use in conventional cast processes is limited due to their interaction with liquid magnesium, other alloying elements or large differences in the melting temperatures. The possibilities for grain refinement by post-processing are also restricted. PVD techniques can help to produce supersaturated precipitation free and microcrystalline magnesium layers. Using ion beam and magnetron sputtering, binary or ternary Mg-Al, Mg-Ti and Mg-Sn alloy systems as well as standard alloys (AM50, AZ91 and AE42) were deposited on silicon and on magnesium substrates. The effect of the microstructure on the corrosion properties was studied by comparing as cast material and PVD coatings using potentiodynamic polarization, linear polarization resistance, and electrochemical impedance techniques.

Stabilization of solid dispersions of nimodipine and polyethylene glycol 2000

Previous investigations revealed that solid dispersions consisting of 20% (m/m) nimodipine and 80% (m/m) polyethylene glycol 2000 prepared by the melting method, represent supersaturated solid solutions of nimodipine recrystallizing upon storage at +25 °C. The objective of this study was the improvement of the storage stability by preventing recrystallization. The first approach in order to prevent recrystallization was the development of thermodynamically stable solid solutions by using solvents aiming to enhance the solubility of nimodipine in the carrier material. As potential solubility enhancing additives, polyethylene glycol 300, poly(ethylene/propylene glycol) copolymer, polypropylene glycol 1020, propylene glycol, glycerol and ethyl acetate were evaluated. The second approach enhancing storage stability was the addition of recrystallization inhibitors to supersaturated solid solutions, thereby delaying the transformation of the metastable supersaturated system to the thermodynamically stable state. Macrogol cetostearyl ether, macrogol glycerol monostearate, polysorbate 60, cetostearyl alcohol, glycerol monostearate and sodium lauryl sulphate as well as hydroxypropylcellulose, butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmethacrylat-copolymer, polyacrylic acid, polyvinyl alcohol and povidone K17 were included in the study. It could be shown that povidone K17 effectively prevents recrystallization in solid solutions containing 20% (m/m) of nimodipine during storage at +25 °C over silica gel thereby ensuring a substantial increase in the dissolution rate and degree of supersaturation in water. On the contrary, stabilization by solubility enhancement was only successful at drug loadings not exceeding 1% (m/m) using polyethylene glycol 300 as solubility enhancing additive.

Modeling temperature dependence of honey viscosity and of related supersaturated model carbohydrate systems

The viscosities of a unifloral honey and supersaturated sugar solutions were measured between −5 and 70 °C. All systems exhibited Newtonian behavior with reducing viscosity as increasing temperature. Four models (Arrhenius, VTF, WLF and Power Law) were investigated to describe the temperature dependence of viscosity. Among the different ways of using the WLF model, the method of reduced variables was the most suitable way to calculate coefficients. Oppositely, the WLF with “universal coefficients” badly predicted the temperature dependence of viscosity. When the calculated and experimental points were plotted as a function of ( T − T g), WLF (with coefficients calculated by the reduced variables method), VTF and power law models fitted the experimental data in a better trend than the Arrhenius equation. Also, the extrapolation of fitted curves into the glass transition region, showed that the Arrhenius model predicts the lowest viscosity values, while the WLF model (with coefficients calculated by the reduced model method) predicts the highest viscosity values in that region. VTF and Power Law models provided curves with intermediate solutions between Arrhenius and WLF model.

Permeation Enhancement of Ketoprofen Using a Supersaturated System with Antinucleant Polymers

Permeation enhancement of ketoprofen (KP) from supersaturated systems and the effects of antinucleant polymers on both stability and permeation of supersaturated KP were investigated using silicone membrane as a skin model. The supersaturation was prepared by the cosolvent technique with water and propylene glycol (PG). Saturated solubility of KP in water/PG cosolvent increased markedly with an increase in PG percentage. The time-profiles of the cumulative amount of released KP from supersaturated solutions through the membrane increased linearly, and this KP flux had a significant correlation with the degree of saturation (DS) in 80 : 20, 60 : 40, 50 : 50, and 40 : 60 (v/v) water/PG cosolvent systems. The influence of 1% solutions of antinucleant polymers, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and sodium carboxymethylcellulose (SCMC) on the DS and the stability of supersaturated KP was examined in 60 : 40 (v/v) water/PG cosolvent. The remaining DS for 24 h after mixing the solvents increased in the presence of HPMC and SCMC but not PVP. In the presence of SCMC, the physical stability of supersaturated KP was higher, however, the KP flux was lower than that in the control and in the presence of the other polymers. In conclusion, the supersaturation system can be applied to achieve higher transmembrane permeation of KP, and appropriate antinucleant polymers such as HPMC can optimize the physical stability and permeability of KP.

Internally consistent approach for modeling solid-state aggregation. I. Atomistic calculations of vacancy clustering in silicon

A computational framework is presented for describing the nucleation and growth of vacancy clusters in crystalline silicon. The overall approach is based on a parametrically consistent comparison between two representations of the process in order to provide a systematic method for probing the details of atomic mechanisms responsible for aggregation. In this paper, the atomistic component of the overall framework is presented. First, a detailed set of targeted atomistic simulations are described that characterize fully the thermodynamic and transport properties of vacancy clusters over a wide range of sizes. It is shown that cluster diffusion is surprisingly favorable because of the availability of multiple, almost degenerate configurations. A single large-scale parallel molecular dynamics simulation is then used to compute directly the evolution of the vacancy cluster size distribution in a supersaturated system initially containing 1000 uniformly distributed vacancies in a host lattice of 216 000 Si atoms at 1600 K. The results of this simulation are interpreted in the context of mean-field scaling theory based on the observed power-law evolution of the size distribution moments. It is shown that the molecular dynamics results for aggregation of vacancy clusters, particularly the evolution of the average cluster size, can be very well represented by a highly simplified mean-field model. A direct comparison to a detailed continuum model is made in a subsequent article.

Formation and stabilisation of triclosan colloidal suspensions using supersaturated systems

The aim of this paper is to prepare and stabilise, in situ, colloidal microsuspensions of triclosan using the polymer, hydroxypropyl methylcellulose (HPMC). The suspensions were prepared from supersaturated solutions of triclosan. The cosolvent technique was used to create supersaturation. Propylene glycol and water were used as the cosolvents. The triclosan particles had a large needle-shaped morphology, when grown in the absence of the polymer. Moreover, the particles grew rapidly to sizes greater than 5 μm over a period of 7 h. When HPMC was added, the particle sizes were in the range 90–250 nm depending on the amount of polymer present in the solutions. The stability of the solutions was evaluated over a period of 40 days during which the particle sizes did not vary. The results were consistent with the mechanism proposed by Raghavan et al. [Int. J. Pharm. 212 (2001b) 213].

Skin Penetration Enhancement by the Synergistic Effect of Supersaturated Dissolution and Chemical Enhancers.

A lipophilic drug, 17-β-estradiol (E2), and two enhancers, Isopropyl Myristate (IPM) and Glycerol Monooleate (GO), were dissolved in an acrylic pressure sensitive adhesive (DUROTAK® 87-2516, DTM) to manufacture a supersaturated dissolution matrix transdermal delivery system. The analysis of variance (α = 0.05) on the in vitro experimental data showed that the cumulative amount of E2 penetrated from 2–6% E2 (w/w) DTM with 20%(w/w) IPM was not statistically different. When 16% (w/w) crystal inhibitor, polyvinylpyrrolidone (PVP, average M.W. ca. 10, 000), was mixed in DTM, the in vitro cumulative penetration amount of E2 increased proportionally to the concentration of E2 up to 6% (w/w). The cumulative penetration amount of E2 obtained from 4% E2 (w/w) DTM with 20% IPM (w/w) and 16% PVP (w/w) reached 70.0 μg/cm2 at 24 h, and was about 12-fold higher than that from 1% E2 (w/w) DTM. CCD micrograph and X-ray diffraction analysis demonstrated that the enhancers accelerated the crystallization process, but PVP delayed or inhibited this process and maintained the degree of saturation (DS) of E2 in an extended period. The synergistic enhancement can be attributed to the E2 supersaturated dissolution maintained by crystallization inhibitor and alter the solubility and/or diffusion coefficient of E2 in stratum corneum by the chemical enhancers.

An investigation of magnetic field effects on the dissolution of lysozyme crystal and related phenomena.

It is now widely known that a magnetic field, either homogeneous or inhomogeneous, depresses the growth process of protein crystals. In this report, the dissolution process of tetragonal lysozyme crystals is also confirmed to be depressed by a homogeneous magnetic field (inhomogeneity <1.5%). The dissolution process was monitored using a Mach-Zehnder interferometer. The results showed that the concentration change during the dissolution process was slowed in a magnetic field compared with that in the absence of a magnetic field. It was concluded that the diffusion coefficient of the lysozyme molecules in the solution was decreased by the magnetic field. The decrease in the diffusion coefficient may contribute to the slowed growth process. The changes in the spatial concentration distribution under a vertical temperature gradient before crystallization in the absence of a magnetic field was also studied. The concentration in the lower, colder part of the cell increased, while it decreased in the upper, hotter part, a similar phenomenon to that discovered by previous investigators in an isothermal supersaturated solution system. Aggregated domain formation is proposed to explain the concentration redistribution before crystal growth and a suspended crystal model is proposed to explain the decrease of diffusivity in a magnetic field.

Test of the applicability of Kulmala's analytical expression for the mass flux of growing droplets in highly supersaturated systems: growth of homogeneously nucleated water droplets

The formation of aerosols proceeds through nucleation, growth and ageing stages. The understanding of nucleation and droplet growth is essential for handling the more complex atmospheric condensation processes. Following the approach of Fuchs and Sutugin, Fladerer and Strey reported in a previous paper, calculations of theoretical growth curves are performed. Calculated growth curves and experimental data on homogeneously nucleated droplets were shown to agree quantitatively. The analytical mass flux expression derived earlier by Kulmala, which implicitly includes the heat flux to the droplet due to the latent heat of condensation, yields growth curves similar to those obtained according to Fuchs and Sutugin for the extreme conditions of homogeneous nucleation (small initial droplet radii, high supersaturations). We show in this note that Kulmala's formula is applicable to all growth regimes and to initial conditions of high supersaturation, for which it was not expected to work properly.

Permeation enhancement of a highly lipophilic drug using supersaturated systems

Permeation enhancement of a highly lipophilic drug using supersaturated systems

Permeation enhancement of a highly lipophilic drug using supersaturated systems

The potential of supersaturation as a method for enhancing the membrane permeation of highly lipophilic compounds has been investigated using, as a model system, the transport of a lavendustin derivative (LAP, log Ko/w = 5) through silicone membrane. Propylene glycol–water mixtures, which permitted the formulation of LAP at different levels of saturation, were prepared and tested for stability prior to conducting membrane permeation studies. The transport of LAP across silicone membrane from donor solutions containing the drug at different degrees of saturation (DS = 1–5) was evaluated by two independent experimental methods: (i) using attenuated total-reflectance Fourier transform infrared spectroscopy (ATR–FTIR) and (ii) using standard vertical diffusion cells followed by quantification with high-performance liquid chromatography (HPLC). Both methods demonstrated a linear relationship between the DS of the applied solution and the flux through the membrane, yielding similar values for the diffusion coefficients of LAP [diffusion cells, D = 1.75 ( ± 0.16) × 10−7 cm2 s−1 and ATR-FTIR, D = 1.42 ( ± 0.26) × 10−7 cm2 s−1). In addition to the characterization of LAP permeation, ATR-FTIR spectroscopy enabled an examination of solvent transport across the membrane. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:607–616, 2001

Manufacturing routes for metallic foams

The study of metallic foams has become attractive to researchers interested in both scientific and industrial applications. In this paper, various methods for making such foams are presented and discussed. Some techniques start from specially prepared molten metals with adjusted viscosities. Such melts can be foamed by injecting gases or by adding gas-releasing blowing agents which cause the formation of bubbles during their in-situ decomposition. Another method is to prepare supersaturated metal-gas systems under high pressure and initiate bubble formation by pressure and temperature control. Finally, metallic foams can be made by mixing metal powders with a blowing agent, compacting the mix, and then foaming the compact by melting. The various foaming processes, the foam-stabilizing mechanisms, and some known problems with the various methods are addressed in this article. In addition, some possible applications for metallic foams are presented.

Partial replacement of bile salts causes marked changes of cholesterol crystallization in supersaturated model bile systems

Partial replacement of bile salts causes marked changes of cholesterol crystallization in supersaturated model bile systems

Partial replacement of bile salts causes marked changes of cholesterol crystallization in supersaturated model bile systems

Cholesterol crystallization is a key step in gallstone formation and is influenced by numerous factors. Human bile contains various bile salts having different hydrophobicity and micelle-forming capacities, but the importance of lipid composition to bile metastability remains unclear. This study investigated the effect of bile salts on cholesterol crystallization in model bile (MB) systems. Supersaturated MB systems were prepared with an identical composition on a molar basis (taurocholate/phosphatidylcholine/cholesterol, 152 mM:38 mM: 24 mM), except for partial replacement of taurocholate (10, 20, and 30%) with various taurine-conjugated bile salts. Cholesterol crystallization was quantitatively estimated by spectrophotometrically measuring crystal-related turbidity and morphologically scanned by video-enhanced microscopy. After partial replacement of taurocholate with hydrophobic bile salts, cholesterol crystallization increased dose-dependently without changing the size of vesicles or crystal morphology and the rank order of crystallization was deoxycholate>chenodeoxycholate>cholate (control MB). All of the hydrophilic bile salts (ursodeoxycholate, ursocholate and beta-muricholate) inhibited cholesterol precipitation by forming a stable liquid-crystal phase, and there were no significant differences among the hydrophilic bile-salt species. Cholesterol crystallization was markedly altered by partial replacement of bile salts with a different hydrophobicity. Thus minimal changes in bile-salt composition may dramatically alter bile lipid metastability.

Influence of the Interfacial Properties on the Microstructural Development and Properties of Silicon Nitride Ceramics

ABSTRACTThe influence of the sintering additive system on the grain growth anisotropy of silicon nitride has been studied in the two supersaturated oxynitride glass systems M-Si-Al-O-N (where M = Yb, Gd, Nd, La, and Y) and M-Si-Mg-O-N (where M = Lu, Sm, La, Sc and Y). The glasses contained a low volume fraction of grains and offer the possibility to study grain growth without impingement. Both systems show an increase of the aspect ratio with an increasing cation radius of the rare earth elements. The aspect ratios for the Sc- and Y-based glasses are higher than expected from the ionic radius.Analytical transmission electron microscopy of the bulk glass and grain boundary film between flocculated particles reveals a difference in chemical composition. The larger rare earth cations are enriched in the film and the smaller ones are depleted compared to the bulk composition. The enrichment of the larger cations can be considered as an adsorption layer which reduces the growth rate of the prism planes. Glass systems with smaller cations (Yb, Gd) reveal a pronounced growth of the prism planes and sialon is formed in the outer region of the grains. The interfacial strength which determines the fracture toughness increases with a decreasing cation radius, but the effect is mainly attributed to the sialon formation rather than by the cation itself.

Computer Simulation of Crystallization from Solution

The early stages of crystallization are not fully understood, a particularly challenging problem being crystallization from solution. The processes involved at an atomic level remain elusive to experiment. Furthermore, crystallization from solution has been thought to be inaccessible by atomistic computer simulations. This study demonstrates that crystallization from solution can in fact be simulated using the method of molecular dynamics for a model solute/solvent system consisting of atomic species characterized by the Lennard-Jones potential function. The model has been applied to look at the effects of varying supersaturation and of inclusion of a simple inhibitor in the system. The behavior of the model is in accord with experiment. In general, increasing supersaturation causes earlier onset of crystallization. Crystallization in highly supersaturated systems involves liquid−liquid phase separation followed by nucleation in the solute phase. The nucleation event in such systems does not appear to be influenced by the solvent. Inclusion of inhibitors retards the onset. Additionally, extensive solute clustering is observed. The crystallization model and variations on it, as well as step by step extension to realistic systems, should enable further testing and development of theory of crystal nucleation and growth and provide insights of technological importance.

Thermoreversible Gelation of Organic Liquids by Arylcyclohexanol Derivatives: a Structural Study

Physical organogels of a 4-tert-butyl-1-arylcyclohexanol derivative (BACOl) are investigated. The small-angle scattering (SAS) technique (neutrons and X-rays) demonstrates that gel networks result from the entanglement of long, solidlike, and rigid fibers. The related cross-sections are shown to be circular (r ≈ 38 ± 2 Å) with a density comparable to that of the crystalline state and are rather monodisperse. Upon a concentration increase, the fibers merge into crystalline-like heterogeneities (junction zones) which are randomly dispersed in the mesh. The kinetics of BACOl molecular aggregation, during which physical gelation occurs, is studied by SAS, and the typical kinetical times of the supersaturated system are evaluated. Anisotropic scatterings reveal orientational effects in the gel which are sensitive to the solvent type. Electron microscopy (SEM) confirms the fibrillar random texture of the xerogels while it demonstrates that the phase-separated solids from metastable gels present oriented microdomains of bundles of fibers. The calorimetry and scattering techniques indicate that colloids in BACOl gels exhibit complex solvent-dependent mesomorphic relationships involving the basic BACOl bimolecular units (d ≈14.2 Å).

Partial replacement of bile salts causes drastic alteration in bile metastability in supersaturated model bile systems: Relation to bile salt micelle-forming capacity

Partial replacement of bile salts causes drastic alteration in bile metastability in supersaturated model bile systems: Relation to bile salt micelle-forming capacity

Evaluation of the nucleation and coarsening kinetic behavior of the secondary hardening carbide of Fe-HCo-10Ni-1Mo-0.16C steel at two chromium levels, using an analytical and modeling approach: Part II

The effect of 1 % Cr addition on the resistivity during preaging and peak aging of an AF1410 based steel was examined by analytical and modeling approaches. The increased kinetics of aging resulting from a chromium addition, due to a variety of complex microstructural changes,was analyzed by Avrami-Mehl and Wert-Zener formulations, which were modified so that the exponent was a function of time. Using a eneralized Avrami equation, it was shown that the nucleation rate, N(t), at short aging times was large but became a rapidly declining function as N(t) approaches zero in a supersaturated system. A mathematical solution, using AF1410 steel carbide growth data at 510 °C, confirmed reported experimental evidence of second-stage carbide nucleation at 1 to 2 h.