Initial Supersaturation Research Articles

Supersaturated polymeric micelles for oral cyclosporine A delivery

Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81–3.53 (p<0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6±24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption.

Modeling nucleation and growth of bubbles during foaming of molten aluminum with high initial gas supersaturation

An idealized nucleation and growth based model was used to predict bubble size distribution in liquid aluminum foam, based on the assumption that the entire quantity of hydrogen added as TiH2 was retained in solution initially. The model considered simultaneous nucleation and growth of bubbles in the first stage, and pure bubble growth in the second stage. Bubble nucleation was found to be feasible only heterogeneously within narrow crevices in non wetting substrates. Effects of initial gas supersaturation on total expansion, final bubble size distribution, total number of bubbles, and average bubble size were investigated. Model predictions of foam characteristics were compared with experimental observations on foams prepared by dissociating TiH2 foaming agent in liquid aluminium, and good match between the two was found with respect to average cell size and total number of bubbles. Differences between model predictions and experimental observations, especially in the nature of bubble size distribution, and limitations of the model were explained.

Propagation of Biochirality: Crossovers and Nonclassical Crystallization Kinetics of Aspartic Acid in Water

All experimental procedures discussed could be treated as a screening tool for probing the existence of molecular association among the chiral molecules and the solvent system. The molecular association phases of a racemic conglomerate solution (CS) and a racemic compound solution (RCS), and the templating effect of aspartic acid solid surface were observed to minimize the chance of redissolving racemic conglomerate and racemic compound aspartic acid in water and reforming an RCS in crossovers experiments. Only 1 %wt% of l-aspartic acid was adequate enough to induce a transformation from a racemic compound aspartic acid to a racemic conglomerate aspartic acid. This would make the propagation of biochirality more feasible and sound. However, tetrapeptide, (l-aspartic acid)4 , failed to induce enantioseparation as templates purely by crystallization. Nonclassical crystallization theory was needed to take into account the existence of a CS. Fundamental parameters of the crystallization kinetics such as the induction time, interfacial energy, Gibbs energetic barrier, nucleation rate, and critical size of stable nuclei of: (i) racemic compound aspartic acid, (ii) racemic compound aspartic acid seeded with 1 %wt% l-aspartic acid, (iii) racemic conglomerate aspartic acid, and (iv) l-aspartic acid were evaluated and compared with different initial supersaturation ratios. Morphological studies of crystals grown from the crystallization kinetics were also carried out.

Nonstoichiometric Polyelectrolyte Complexes Versus Polyanions as Templates on CaCO3-Based Composite Synthesis

The characteristics of calcium carbonate microparticles formed in supersaturated aqueous solutions, in the presence of some strong/weak anionic polymers or with nonstoichiometric polyelectrolyte complexes with negative charges in excess (NPEC-n), have been investigated under different relative inorganic/polymer ratios, tuned by initial solution supersaturation and polymer concentration. For this purpose two polyanions which contain the carboxylic and sulfonic ionic groups, poly(2-acrylamido-2-methylpropanesulfonic acid-co-acrylic acid) and chondroitin-4-sulfate, were used. NPEC-n dispersions prepared with the same polyanions and chitosan as a polycation were also used as templates for calcium carbonate crystallization. Scanning electron microscopy was used to provide the particle morphologies and flow particle image analysis to evidence their mean sizes and sphericities. The polymer presence in the composite particles was evidenced by X-ray photoelectron spectroscopy, particle charge densities, and zeta p...

Kinetics of segregation processes in solutions: Saddle point versus ridge crossing of the thermodynamic potential barrier

Based on the solution of a set of kinetic equations describing nucleation and growth in solutions, the most probable path of evolution of the cluster ensemble in nucleation and growth processes is specified as a function of the initial supersaturation. The classical Gibbs' approach is employed for the description of the thermodynamic properties of the system (utilizing the capillarity approximation). As an alternative, the classical method is replaced by the generalized Gibbs' approach. It is shown that signification deviations from the saddle point of the trajectory of cluster evolution are found only if the generalized Gibbs' approach is employed, allowing one to account for and to determine the changes of the cluster state as a function of supersaturation and cluster size. In addition, the origin for the deviation of the most probable path of evolution (from the path via the saddle point of the thermodynamic potential surface) is specified.

Soft impingement in diffusion-controlled growth of binary alloys: moving boundary effect in one-dimensional system

The impact of soft impingement on the kinetics of diffusion-controlled growth of binary alloys is investigated. An analytical approach is developed which takes into account the process of island growth, that is the time dependence of the position of the nucleus/parent phase interface. The concentration profile, the growth law, and the kinetics of the fraction of transformed phase are computed and compared with those attained for point islands. At odd with the point island approach the local kinetics of growth depends on initial supersaturation. On the other hand, the whole transformation kinetics is in good agreement with that of the point island model with an Avrami exponent close to the theoretical value n = 0.5. The concentration profile is well described by a polynomial function in the whole spatial domain, with an exception for the initial stage of the phase separation. The effect of the spatial distribution of the nuclei on the kinetics is also studied in the model case of hard-core correlation among nuclei.

Precipitation of Mg-carbonates at elevated temperature and partial pressure of CO2

In this paper, we present an experimental study on the precipitation of magnesium carbonates (Mg-carbonates) from a solution containing magnesium chloride and sodium carbonate and in the presence of supercritical carbon dioxide. We performed homogeneous (unseeded) batch precipitation experiments at 100bar of CO2 and at 90°C, 120°C, and 150°C. The system was monitored with online temperature and pressure sensors and an online Raman spectroscopy probe. We investigated the effect of temperature and solution composition, i.e., supersaturation ratio, pH, speciation, ionic strength, and water activity on the mechanism and the kinetics of the precipitation of Mg-carbonates. Raman spectroscopy measurements allowed us to follow the temporal evolution of the solution and suspension composition and showed two Mg-carbonates can form under the investigated conditions, i.e., magnesite and hydromagnesite. The precipitation of these two phases occurred between pH 5.5 and 6.5 and was influenced by temperature, supersaturation ratio with respect to magnesite (SM) and hydromagnesite (SH), and the initial concentration of magnesium.At all investigated temperatures, we observed direct precipitation of magnesite while at 120°C and 150°C also simultaneous precipitation of magnesite and hydromagnesite followed by the transformation of the latter into the former. Under highly supersaturated conditions with respect to magnesite, SM as large as 20, magnesite nucleated rapidly when the system was also supersaturated with respect to hydromagnesite, SH as large as 1.5; whereas no nuclei formed within 20h, otherwise. The analysis of the data collected at 120°C and at 150°C highlighted that the change in the type of mechanism was associated with the initial supersaturation ratios and the initial concentration of magnesium in solution. At 120°C, the transformation process lasted for 2h, slowing down the formation of magnesite, despite of the large SM; whereas at 150°C, the transformation process was only 5min long, without affecting magnesite precipitation.

Magnetically induced phase condensation in an aqueous dispersion of magnetic nanogels

The applicability of aqueous magnetic colloids depends on their colloidal stability under the influence of various factors like external magnetic field and temperature. The magnetically induced phase condensation of magnetic colloids leads to the formation of spindle-like condensed phase drops of highly packed magnetic colloidal particles. The condensed phase drops are aligned parallel to the external magnetic field and may grow up to several microns thickness and tens or even hundreds of microns length. Thus, the magnetically induced phase condensation could be an advantage in magnetic separation applications, whereas in magnetic drug targeting applications it could lead to blood vessel clogging as well as to a significant decrease of the specific surface. We present the results of an experimental study regarding the influence of the external magnetic field and temperature on the magnetically induced phase condensation in an aqueous dispersion of pNIPA magnetic nanogels. A theoretical model was developed for the analysis of the data from forward light scattering experiments. It was found that the volume weight of the condensed phase increases with passing time, with increasing field intensity and temperature decrease. Using the proposed model, the magnetic field intensity dependence of the initial supersaturation of the sample was calculated.

Fabrication of superhydrophobic surfaces via CaCO3 mineralization mediated by poly(glutamic acid)

Surfaces with micrometer and nanometer sized hierarchical structures were fabricated by an one-step in situ additive controlled CaCO3 mineralization method. After chemical modification, the surfaces with various morphologies showed superhydrophobicity in different states, which could be easily adjusted by the initial supersaturation of the mineralization solution (concentration of calcium ion and poly(glutamic acid)). Generally, the “lotus state” surface which was covered by a thick layer of tetrahedron-shaped CaCO3 particles to exhibit a contact angle (CA) of 157±1° and a very low contact angle hysteresis (CAH) (roll-off angle=1°) was produced under high supersaturation. On the other hands, the petal-like surface with flower-shaped calcite spherulites was obtained in a relative low supersaturation, which showed both high CA (156±2°) and CAH (180°) in a “Cassie impregnating wetting state”.

Homogeneous Nucleation-Growth Dynamics Induced by Single Laser Pulse in Supersaturated Solutions

Our original approach consists of observing the dynamics of homogeneous crystal growth throughout the volume of highly supersaturated solutions. The crystal growth is induced at room temperature by a powerful single nanosecond laser pulse and is observed using a synchronized time-resolved optical detection. The supersaturated solution readily transforms after the pulse into a homogeneous gel-like slurry consisting of nanometric crystals. From the analysis of the signals via a kinetic model, we derive the elementary accretion rate constant, the nuclei concentration, and its dependence upon the initial supersaturation concentration. This approach could permit a quantitative study of the homogeneous phase transition dynamics for various other systems.

Polydisperse aerosol condensation with heat and mass conservation II: Fluid dynamic couplings for an embedded aerosol zone

Aerosol condensational growth in a fluid field, including water vapor depletion and latent heat of condensation, is studied by a newly developed model coupling aerosol condensation with fluid dynamics. This model couples the fluid dynamics (via ANSYS FLUENT) and a time-dependent model [1] developed for nonsteady state, nonisothermal conditions. Mass and heat are effectively conserved throughout the computational domain with changes driven by aerosol condensation and evaporation. In turn, these changes promote fluid movement and its evolution. Communications between the air parcel, inside which the aerosol particles are introduced, and the outside environment are allowed by means of mass and heat transfer. Comparison between results of models with and without computational fluid dynamics (CFD) shows that the fluid movement due to aerosol condensation can have significant impact on the aerosol growth. By comparing the growth of both monodisperse and polydisperse (NH4)2SO4 particles of different number densities at various initial supersaturation conditions, particle number concentrations are shown to have great impact on the aerosol condensational growth with mass and heat exchange between the inside and outside of the air parcel.

Assessment of a Five-Layer Laminate Technique to Measure the Saturation Solubility of Drug in Pressure-Sensitive Adhesive Film

A five-layer laminate technique is used to determine the saturation solubility of a drug in a thin polymer film, c(p)(s), of pressure-sensitive adhesive (PSA) used to prepare transdermal patches. A drug-loaded donor polymer film is attached via a separating membrane to an initially drug-free acceptor polymer film. Diffusion of drug occurs into the acceptor up to saturation solubility equilibrium. This systematic study of the technique using the drug tamsulosin and the PSA Duro Tak 87-4098 was a kinetic analysis of the diffusion process. It was found that the technique gives an equilibrium value for c(p)(s) in a PSA polymer film in the presence of crystalline phase of the drug in the donor. A highly permeable Perthese-separating membrane caused overshoot in the acceptor, most likely induced by initial supersaturation of the donor. Change to a less-permeable ethylene-vinyl-acetate-separating membrane avoided overshoot, but gave a prolonged time, >300 days, to equilibrium. Preloading the acceptor accelerated the equilibration process to approximately 50 days with the Perthese. Suitable experimental conditions are identified that, if performed correctly, allow the technique to give an equilibrium value for c(p)(s).

Nucleation on active centers in confined volumes

Kinetic equations describing nucleation on active centers are solved numerically to determine the number of supercritical nuclei, nucleation rate, and the number density of nuclei for formation both of droplets from vapor and also crystalline phase from vapor, solution, and melt. Our approach follows standard nucleation model, when the exhaustion of active centers is taken into account via the boundary condition, and thus no additional equation (expressing exhaustion of active centers) is needed. Moreover, we have included into our model lowering of supersaturation of a mother phase as a consequence of the phase transition process within a confined volume. It is shown that the standard model of nucleation on active centers (Avrami approach) gives faster exhaustion of active centers as compared with our model in all systems under consideration. Nucleation rate (in difference to standard approach based on Avrami model) is equal to the time derivative of the total number of nuclei and reaches some maximum with time. At lower nucleation barrier (corresponding to higher initial supersaturation or lower wetting angle of nucleus on the surface of active center) the exhaustion of active centers is faster. Decrease in supersaturation of the mother phase is faster at higher number of active centers.

Spontaneous Crystalline-to-Amorphous Phase Transformation of Organic or Medicinal Compounds in the Presence of Porous Media, Part 3: Effect of Moisture

Amorphization of crystalline compounds using mesoporous media is a promising technique to improve the solubility and drug release of poorly-soluble compounds. The objective of this paper is to understand the effect of moisture on the capacity and performance of vapor-phase mediated amorphization. Mesoporous silicon dioxide (SiO(2)) and crystalline naphthalene were used as the model system. The effect of moisture on the amorphization capacity of naphthalene was determined using adsorption chambers with various levels of relative humidity. Enthalpy and capacity of water vapor adsorption on SiO(2) were measured using isothermal microcalorimetry and thermogravimetry. Moisture not only suppressed the amorphization capacity of naphthalene, but reversed an already-amorphized formulation as well. On the other hand, through the same competitive interaction, improved drug release and enhanced solubility were obtained. The initial supersaturation was followed by an entropy-driven crystallization. In addition, moisture-induced siloxane bond fracture was found at normal processing conditions, which led to the changes in silica surface chemistry. However, the implication in amorphization has not reached a definitive conclusion. Humidity during processing and storage must be carefully controlled for this type of amorphous formulation. Further investigation is needed to better understand the moisture-induced changes of silica.

Determination of the Crystal Growth Rate of Paracetamol As a Function of Solvent Composition

Growth kinetics, growth mechanisms, and the effect of solvent composition for the antisolvent crystallization of paracetamol in methanol–water mixtures have been determined by means of isothermal seeded batch experiments at constant solvent composition. A numerical model incorporating the population balance equation based on antisolvent free solubility was fitted to the desupersaturation data, and growth rate parameters are evaluated. An attenuated total reflectance–Fourier transform infrared (ATR-FTIR) probe was employed to measure online solute concentration and focused beam reflectance measurement (FBRM) was utilized to ensure negligible nucleation occurred. The model is validated by the final particle size distributions (PSDs) and online solute concentration measurements. Crystal growth rate was found to decrease with increasing water mass fractions up to a mass fraction of 0.68 where an increase is observed. A method has been introduced linking the effect of solvent composition with the growth mechanism and the growth rates. Utilizing the growth mechanism it has been postulated that a combination of the solubility gradient, viscosity, selective adsorption, and surface roughening are responsible for the reduction in growth rates with solvent composition. Furthermore, the effects of seed mass, size and initial supersaturation on the crystal growth rates were investigated to demonstrate the efficacy of the model at predicting these various phenomena.

The influence of crystallization conditions on the onset of dendritic growth of calcium carbonate

AbstractUnderstanding the crystallization of calcium carbonate is relevant in numerous fields like biomineralization, geology and industrial applications where calcium carbonate forms. In order to enhance the knowledge about the formation of calcium carbonate with focus on the vaterite polymorph, in this work calcium carbonate has been crystallized in aqueous solutions at temperatures from 5 °C to 90 °C. Special attention has been directed to higher temperatures for which the effect of the initial supersaturation on the resulting crystal morphologies and the onset of dendritic growth have been studied. In analogy to snow crystal formation, it has been found that in a certain temperature range hexagonal plate‐like crystals form at low supersaturation whereas dendritic patterns start to appear at higher supersaturation. The symmetrical branches characteristic for dendritic growth get less pronounced as the temperature is decreased. The results reported here related to the interdependence between supersaturation, crystal morphology and growth mechanisms, can be used in future works to predict particle formation and to design crystal architectures. (© 2012 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Polydisperse aerosol condensation with heat and mass conservation: I. Model description with applications to homogeneous systems

A computational solution of the coupled heat and mass transport equations for aerosols, which may be either single component or multicomponent, in a finite volume is developed under nonsteady state and nonisothermal conditions. It is capable of computing the temperature and vapor density profile around the droplets. Both mass and heat are conserved effectively in the volume, which enables this computational model to describe time-dependent, competitive, aerosol condensation and evaporation. Calculations for pure water particles and sodium nitrate particles in the presence of water vapor are performed. By comparing the particle growth for different number densities at various initial supersaturation conditions, both the initial saturations and particle number concentrations are shown to have great impact on the aerosol condensational growth. Detailed discussions on the change of bulk temperature, bulk relative humidity (RH), total surface area and volume are given.

Heterogeneous nucleation and growth mechanism on hydrophilic and hydrophobic surface

Heterogeneous nucleation and nucleation period of calcium carbonate on the mica and the highly oriented pyrolytic graphite (HOPG) substrate have been investigated. Calcium carbonate was prepared by the reaction of calcium nitrate solution with sodium carbonate solution. In the reaction crystallization of calcium carbonate, calcite and vaterite were nucleated on the both substrates. We counted the number of crystalline calcium carbonate on the substrates obtained from various initial supersaturations of calcium carbonate. The number of crystals on the mica surface was much higher than on the HOPG surface. Additionally, the number of crystals on the mica was greatly affected by changing of initial supersaturation. In order to explain the difference between the mica and the HOPG surface, a possible model for the nucleation period of calcium carbonate has been discussed. The surface crystallization on the mica and the HOPG could be described by considering the supersaturation in the bulk solution and in the vicinity of substrate, separately.

Crystallization of Mefenamic Acid from Dimethylformamide Microemulsions: Obtaining Thermodynamic Control through 3D Nanoconfinement

Recently we showed how crystallization in microemulsions could lead directly to the most stable polymorph, thereby leapfrogging Ostwald’s rule of stages. Here we consider in more details the crystallization of mefenamic acid from dimethylformamide microemulsions. Crystallization of mefenamic acid from bulk DMF has previously been shown to produce only the metastable Form II irrespective of the supersaturation or temperature. In contrast, we show that stable Form I can be produced from DMF microemulsions provided the lowest supersaturations that can achieve crystallization are used; these correspond to initial supersaturations that are significantly higher than those commonly used in bulk solution crystallizations, owing to the large decrease in supersaturation that occurs when a nuclei grows in a 3D-nanoconfined droplet. Increasing the supersaturation above the minimum required for crystallization leads to increasing proportions of metastable Form II crystals. In compositions crystallizing a mixture of Form I and Form II crystals, the Form I crystals can nevertheless be obtained exclusively by slowly heating the microemulsions.

Interactions of salicylic acid derivatives with calcite crystals

Investigation of basic interactions between the active pharmaceutical compounds and calcium carbonates is of great importance because of the possibility to use the carbonates as a mineral carrier in drug delivery systems. In this study the mode and extent of interactions of salicylic acid and its amino acid derivates, chosen as pharmaceutically relevant model compounds, with calcite crystals are described. Therefore, the crystal growth kinetics of well defined rhombohedral calcite seed crystals in the systems containing salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil- l-aspartic acid (N-Sal-Asp) or N-salicyloil- l-glutamic acid (N-Sal-Glu), were investigated. The precipitation systems were of relatively low initial supersaturation and of apparently neutral pH. The data on the crystal growth rate reductions in the presence of the applied salicylate molecules were analyzed by means of Cabrera & Vermileya’s, and Kubota & Mullin’s models of interactions of the dissolved additives and crystal surfaces. The crystal growth kinetic experiments were additionally supported with the appropriate electrokinetic, spectroscopic and adsorption measurements. The Langmuir adsorption constants were determined and they were found to be in a good correlation with values obtained from crystal growth kinetic analyses. The results indicated that salicylate molecules preferentially adsorb along the steps on the growing calcite surfaces. The values of average spacing between the adjacent salicylate adsorption active sites and the average distance between the neighboring adsorbed salicylate molecules were also estimated.