Nucleation Induction Time Research Articles

The combination of hydroxypropylmethylcellulose acetate succinate and L-lysine into ternary amorphous solid dispersions of quercetin to enhance its dissolution

The purpose of this study was to enhance quercetin (Que) dissolution by preparing its ternary amorphous solid dispersions. The ternary amorphous solid dispersions were prepared by solvent evaporation method using hydroxypropylmethylcellulose acetate succinate (HPMCAS) and L-lysine (lys) as the carriers. The effect of the combination of polymer and amino acid on nucleation inhibition was evaluated by the nucleation induction time. Supersaturation tests were used to investigate the ability of maintaining Que supersaturation of the combination of polymer and lys. The dissolution results showed that the dissolution effect of ternary solid dispersions was better than binary solid dispersions. Stronger crystallization inhibition didn't lead to better dissolution effect and the dissolution of the prepared amorphous solid dispersions of Que was carrier-controlled. Lys modified the dissolution microenvironment of the solid dispersions, which made drug dissolution in the optimal pH environment, and effectively improved drug dissolution. Polymer/lys can be one of the most potential carriers for preparing amorphous solid dispersions of Que.

Interaction of Polymers with Enzalutamide Nanodroplets-Impact on Droplet Properties and Induction Times.

Amorphous solid dispersions (ASDs), which consist of a drug dispersed in a polymeric matrix, are increasingly being applied to improve the in vivo performance of poorly water-soluble drugs delivered orally. The polymer is a critical component, playing several roles including facilitating drug release from the ASD, as well as delaying crystallization from the supersaturated solution generated upon dissolution. Certain ASD formulations dissolve to produce amorphous drug-rich nanodroplets. The interaction of the polymer with these nanodroplets is poorly understood but is thought to be important for inhibiting crystallization in these systems. In this study, the impact of ionic polymers on the crystallization kinetics of enzalutamide from supersaturated solutions containing different amounts of amorphous nanodroplets was evaluated by determination of nucleation induction times. The amount of the polymer associated with the drug nanodroplets was also determined. When comparing two polymers, hydroxypropylmethyl cellulose acetate succinate (HPMCAS) and Eudragit E PO, it was found that the crystallization tendency and physical properties of the drug nanodroplets varied in the presence of these two polymers. Both polymers distributed between the aqueous phase and the drug-rich nanodroplets. A greater amount of Eudragit E PO was associated with the drug-rich nanodroplets. Despite this, Eudragit E PO was a less-effective crystallization inhibitor than HPMCAS in systems containing nanodroplets. In conclusion, in supersaturated solutions containing amorphous nanodroplets, the extent of association of a polymer with the drug nanodroplet does not solely predict crystallization inhibition.

Crystallization kinetics in a 5BaO·8SiO2 glass

The accuracy of a Differential Thermal Analysis (DTA) technique for predicting the temperature range of significant nucleation is examined in a 5BaO·8SiO2 glass based on iterative numerical calculations. The diffusion coefficient is calculated from the measured induction time and the crystal growth velocity. The Classical Theory of Nucleation and the Diffuse Interface Theory were used to model crystal nucleation and growth. However, in both theories, two different diffusion coefficients were required for the calculated crystallization peaks to match the measured DTA data. The development of small nuclei near the critical size during nucleation was calculated using the diffusion coefficient from the measured induction time for nucleation. The growth of nuclei much larger than the critical size was determined by the diffusion coefficient from the measured growth velocity. The difference could reflect a complicated nucleation process in which the primary nucleating phase is not the 5BaO·8SiO2 crystal.

Continuous and controllable synthesis of MnO2/PPy composites with core–shell structures for supercapacitors

A slug-based microreactor system was constructed to integrate the redox reaction between KMnO4 and MnSO4 with the chemical oxidative polymerization of pyrrole for the preparation of MnO2/PPy composite with a typical core–shell structure. MnO2 was formed as the core while PPy acted as the shell. The size distribution variation of MnO2 particles was elaborated by the crystallization theory and the comparison between the micromixing time and the nucleation induction time. It was found that the morphology of the MnO2/PPy composite was significantly affected by the molar ratio among KMnO4, MnSO4 and pyrrole and the residence time due to the competition between the pyrrole polymerization and the MnO2 crystallization. A probable mechanism for the formation of the PPy/MnO2 composite was proposed. The electrochemical performance of the MnO2/PPy composite with core–shell was better than that of MnO2. The enhanced performance demonstrated the synergistic effect between MnO2 and PPy for the fabrication of the core–shell structure. This work developed the design of particles with core–shell structures from the droplet-based microreactor to the slug-based microreactor with a relatively higher flux. The size of the prepared material decreased from microscale in the droplet-based microreactor to nanoscale in this slug-based microreactor. Such a novel strategy can be applied for efficiently preparing functional materials with controllable structures and properties.

Toward a bio-based hybrid inhibition of gas hydrate and corrosion for flow assurance

The development of a hybrid inhibition of corrosion and gas hydrate formation in offshore oil and gas fields is the main object of this study. Sunflower oil was used as an inexpensive and environmentally friendly resource for synthesizing a dual function inhibitor to prevail incompatibility difficulty between anti-hydrate and anti-corrosion reagents. The results of hydrate inhibition experiments revealed that phosphorylated waterborne polyurea/urethane (Ph-WPUU) can significantly reduce the average onset temperature and delay the induction time of hydrate nucleation compared to pure water. Besides, the constant value of torque at the 100 and 60% water-cuts with decane phase and foam-like methane-propane hydrate formed in the presence of Ph-WPUU occurred. This may indicate mitigation of hydrate particles agglomeration. On the other hand, the Ph-WPUU showed corrosion inhibition efficiency around 96% at 700 ppm concentration. Moreover, the quantum chemical study revealed that the presence of the triglyceride group of sunflower oil in the Ph-WPUU structure plays an effective role as an active site to interact with the carbon steel surface. These results indicate that the application of Ph-WPUU provides a bio-based strategy to develop and design single polymer molecules that exhibit both hydrate and corrosion inhibition, and this approach refers to the terms of green chemistry.

Secondary Nucleation Kinetics of AIBN Crystallisation in Methanol: Online Imaging-Based Measurement and Modelling

The secondary nucleation process of 2,2-azobisisobutyronitrile (AIBN) seeded crystallisation in methanol in a stirred tank reactor was studied at varying initial supersaturation levels, temperatures, crystal seed numbers, and stirrer speeds. The average secondary nucleation rate, induction time, and agglomeration ratio were measured using on-line microscopic imaging. The initial supersaturation level, temperature, and stirrer speed were found to be positively correlated with the secondary nucleation rate. A small change in the crystal seed number, i.e., 1-20, did not substantially affect the secondary nucleation rate throughout the secondary nucleation process. An increase in the initial supersaturation level and crystal seed number decreased the induction time, and an increase in the strength of agitation promoted the initiation of secondary nucleation at a stirring rate greater than 250 revolutions per minute (rpm). Temperature exerted a complex effect on the induction time. Regarding the agglomeration ratio, the initial supersaturation level positively correlated with the agglomeration ratio, while the stirrer speed negatively correlated with this parameter. Finally, based on the measured data, the average secondary nucleation rate, induction time, and final crystal suspension density were correlated. This study provides guidance for the control of supersaturation, induction time, stirring, and other factors in the crystal seed addition process in AIBN crystallisation.

Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40°C/75% RH) for 6months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Cross‐nucleation of polybutene‐1 Form II on Form I seeds with different morphology

Polybutene-1 (PB-1) trigonal Form I crystals with different morphologies, namely spherulitic, hedritic, and fibrous, were used as seeds to quantitatively study the cross-nucleation kinetics of the tetragonal Form II. Interestingly, a large difference in the cross-nucleation ability of the various Form I seeds was observed. The Form I fiber exhibits the fastest cross-nucleation, followed by the hedrite and eventually by the spherulite. The nucleation induction time was quantified from the evolution of the transmitted light intensity via polarized optical microscopy. The data were tested against different nucleation models, revealing that the rate-determining step for nucleation is the growth of the nucleus to attain the critical dimension, rather than the formation of the first crystalline layer in contact with the substrate. In addition, for spherulitic seeds, a meaningful dependence of cross-nucleation induction time on Form I lamellar thickness was found, with the kinetics being faster for higher original seed's crystallization temperatures. The results were interpreted assuming a free energy barrier for cross-nucleation which is a function of the mismatch between the daughter and the parent polymorphs' lamellar dimensions. This aspect, together with the calculated low values of interfacial free energy difference parameter for nucleation, suggests the possible existence of an epitaxial relationships between cross-nucleating PB-1 Form II and Form I.

Aluminum-Based Promotion of Nucleation of Carbon Dioxide Hydrates.

Gas hydrate formation has several applications in CO2 sequestration, flow assurance, and desalination. Nucleation of hydrates is constrained by very high induction (wait) times, which necessitates the use of complex nucleation promotion techniques to form hydrates. Presently, we report the discovery of a simple, passive nucleation promotion technique, wherein an aluminum surface significantly accelerates nucleation of CO2hydrates. Statistically meaningful measurements of induction times for CO2 hydrate nucleation were undertaken using water droplets as individual microsystems for hydrate formation. The influence of various metal surfaces, droplet size, CO2 dissolution time, and the presence of salts in water on nucleation kinetics was characterized. Interestingly, we observe nucleation initiation only on aluminum surfaces, the influence of which cannot be replicated by salts of aluminum. We discover that the aluminum-water interface is responsible for nucleation promotion. We hypothesize that hydrogen bubbles generated at the aluminum-water interface are responsible for nucleation promotion.

Modeling nonisothermal crystallization in a BaO∙2SiO2 glass

AbstractThe accuracy of a differential thermal analysis (DTA) technique for predicting the temperature range of significant nucleation is examined in a BaO∙2SiO2 glass by iterative numerical calculations. The numerical model takes account of time‐dependent nucleation, finite particle size, size‐dependent crystal growth rates, and surface crystallization. The calculations were made using the classical and, for the first time, the diffuse interface theories of nucleation. The results of the calculations are in agreement with experimental measurements, demonstrating the validity of the DTA technique. They show that this is independent of the DTA scan rate used and that surface crystallization has a negligible effect for the glass particle sizes studied. A breakdown of the Stokes‐Einstein relation between viscosity and the diffusion coefficient is demonstrated for low temperatures, near the maximum nucleation rate. However, it is shown that accurate values for the diffusion coefficient can be obtained from the induction time for nucleation and the growth velocity in this temperature range.

Determination of Metastable Zone Width and Nucleation Induction Period of Palm Oil and its Olein/Stearin in Melting Layer Crystallization

AbstractMeasurement methods of metastable zone width (MZW) and nucleation induction time for melting layer crystallization of palm oil (PO) and its olein/stearin (POL/PST) were established, and the effects of cooling rate (corresponding to various supercoolings) on MZWs and induction time for melting layer crystallization of PO, POL, and PST were determined. The results indicated that the MZW coherently rose with increasing cooling rates with respect to PO and POL, while it declined with higher cooling rates for PST. The induction period results demonstrated that the nucleation induction periods of PO, PST, and POL decreased with increasing supercoolings, and the lag time for nucleation negatively correlated to the melting point of oils at the same supercooling. These data could offer significant instruction in designing and controlling the melting layer crystallization process for palm oil.

Influence of solvent on crystal nucleation of benzocaine

The influence of the solvent in nucleation of benzocaine FII was explored by measuring nucleation induction times, probing solvent–solute interactions with spectroscopy and modelling the strength of solvent–solute intermolecular interactions using DFT.

L-ascorbyl palmitate modify the crystallization behavior of palm oil: Mechanism and application

L-ascorbyl palmitate (L-AP) is a potential fat crystallization modifier, formed by the ester bond of ascorbic acid and palmitic acid. The effects of L-AP on the crystallization behavior of palm oil (PO) and its application in bread were systematically investigated. L-AP addition led to higher crystallization rate and lower induction time of nucleation with the increasing concentration from 1% to 5%. L-AP slightly affected the growth mechanism of PO, and they all showed the instantaneous nucleation and linear growth. Meanwhile, in presence of L-AP, a desirable β′ polymorphism and lower thickness of the nanoscale crystals were observed in the PO. Higher fractal dimension (Db) and smaller average particle size (D) were acquired by analyzing the polarized light microscope (PLM) pictures, which represented more ordered organization of the crystal lattice due to the interactions between triglycerides and L-AP. Furthermore, the specific volume increased and the baking decreased after adding L-AP according to the baking analysis. Bread made of PO with L-AP was satisfactory, showing higher cell density, smaller cell average area and lower hardness. In summary, L-AP had great potential to be a highly effective fat crystallization modifier and increased the compatibility of PO to be severed as the formulations of baking fat in the food industry.

Chemically reactive membrane crystallisation reactor for CO2–NH3 absorption and ammonium bicarbonate crystallisation: Kinetics of heterogeneous crystal growth

The feasibility of gas-liquid hollow fibre membrane contactors for the chemical absorption of carbon dioxide (CO2) into ammonia (NH3), coupled with the crystallisation of ammonium bicarbonate has been demonstrated. In this study, the mechanism of chemically facilitated heterogeneous membrane crystallisation is described, and the solution chemistry required to initiate nucleation elucidated. Induction time for nucleation was dependent on the rate of CO2 absorption, as this governed solution bicarbonate concentration. However, for low NH3 solution concentrations, a reduction in pH was observed with progressive CO2 absorption which shifted equilibria toward ammonium and carbonic acid, inhibiting both absorption and nucleation. An excess of free NH3 buffered pH suitably to balance equilibria to the onset of supersaturation, which ensured sufficient bicarbonate availability to initiate nucleation. Following induction at a supersaturation level of 1.7 (3.3 M NH3), an increase in crystal population density and crystal size was observed at progressive levels of supersaturation which contradicts the trend ordinarily observed for homogeneous nucleation in classical crystallisation technology, and demonstrates the role of the membrane as a physical substrate for heterogeneous nucleation during chemically reactive crystallisation. Both nucleation rate and crystal growth rate increased with increasing levels of supersaturation. This can be ascribed to the relatively low chemical driving force imposed by the shift in equilibrium toward ammonium which suppressed solution reactivity, together with the role of the membrane in promoting counter-current diffusion of CO2 and NH3 into the concentration boundary layer developed at the membrane wall, which permitted replenishment of reactants at the site of nucleation, and is a unique facet specific to this method of membrane facilitated crystallisation. Free ammonia concentration was shown to govern nucleation rate where a limiting NH3 concentration was identified above which crystallisation induced membrane scaling was observed. Provided the chemically reactive membrane crystallisation reactor was operated below this threshold, a consistent (size and number) and reproducible crystallised reaction product was collected downstream of the membrane, which evidenced that sustained membrane operation should be achievable with minimum reactive maintenance intervention.

Impact of Monomeric versus Micellar Surfactant and Surfactant–Polymer Interactions on Nucleation–Induction Times of Atazanavir from Supersaturated Solutions

Supersaturating formulations such as amorphous solid dispersions (ASDs) can lead to solution concentrations much higher than the crystalline solubility achieving enhanced oral bioavailability of poorly aqueous soluble compounds. However, they can potentially crystallize with a loss of their solubility advantage. Various polymers have been extensively used to delay crystallization. Increasingly, surfactants are being incorporated into ASDs to improve processing and dissolution performance. While the effect of polymers has been widely studied, the impact of surfactants on crystallization has not yet been explored to the same extent. In this work, the effect of a commonly used surfactant, sodium dodecyl sulfate (SDS) on the nucleation induction time (NIT) of a model compound, atazanavir (ATZ) was studied. NITs of supersaturated solutions with the same supersaturation ratio (SR) were measured in the presence of various SDS concentrations, ranging from well below the critical micelle concentration (CMC) to wel...

Molecular Self-assembly in Solution and the Nucleation Pathway: the Case of p-Nitrobenzoic Acid

The homogeneous nucleation during fast cooling crystallization and the heterogeneous nucleation during the solution-mediated polymorphic transformation (SMPT) of p-nitrobenzoic acid (PNBA) were investigated to elucidate the connection between the molecular self-assembly and the nucleation process. Process analytical technology (PAT) tools, such as attenuated total reflection-Fourier-transform infrared (ATR-FTIR) spectroscopy were successfully applied to highlight the existence of solution-phase dimers and monomers. The combination of solubility measurements, measured nucleation induction time, polymorphic outcome and transformation, and computational chemistry was used to demonstrate the connection among solvation, molecular self-assembly in solution, and the nucleation pathway of PNBA. The orders of solubility and nucleation rates in different solvents were found to be consistent with those of solute–solvent binding energies. The dimerization of PNBA molecules in hydrogen-bonded dimers and stacked dimers through π–π interactions seem similar in all four solvents investigated in this study, which indicates that the desolvation of PNBA is the key step during the overall nucleation pathway.

Time-dependent nucleation rate measurements in BaO⋅2SiO2 and 5BaO⋅8SiO2 glasses

The two-step heat treatment method is used to measure the steady state crystal nucleation rate and induction time as a function of temperature in BaO⋅2SiO2 and 5BaO⋅8SiO2 glasses. For both glasses, the temperature for maximum nucleation rate and the temperature range for significant nucleation agree well with previous estimates from differential thermal analysis studies. The data are analyzed with a new iterative method to obtain the interfacial free energy and critical work of cluster formation as a function of temperature. For temperatures below the temperature at which steady-state nucleation rate is a maximum, the critical work of cluster formation is shown to strongly deviate from expectations of the classical theory of nucleation.

Effects of modified metal surface on the formation of methane hydrate

In this study, the influence of modified metal surface on the induction time, gas consumption, hydrate growth rate and water conversion to hydrate was investigated. Results demonstrated that the metal surface reduced the induction time by 60% and decreased the stochasticity of hydrate nucleation by 72% at 5.0 MPa in 100 ppm sodium dodecyl sulfate solution. The promotion effect was more significant at 4.1 MPa that the induction time was shorten from 600 min to 142 min. Both the induction time and stochasticity of nucleation decreased with the decreasing hole sizes of metal surface. It also demonstrated that the metal surface increased the gas-liquid interfacial curvature, which decreased the energy barriers for gaseous methane molecules transferring into liquid phase. As a result, the metal surface facilitated the dissolution of methane and increased the kinetics of hydrate growth and water conversion to hydrate. Moreover, the water conversion increased with the height of metal surface in 3 mol% tetrahydrofuran solution due to the capillary force caused by the hydrophilicity of metal surface, while it hindered the migration of water molecules as the metal surface was coated with hydrophobic paraffin, which resulted in few hydrate growth on the upper metal surface and the decrease of water conversion to hydrate.

Influence of rare earth oxides on kinetics and reaction mechanisms in CMAS silicate melts

Dissolution of different rare earth oxides RE2O3 and cyclosilicate Ca3RE2(Si3O9)2 was studied at 1200 °C in a pseudo-ternary CAS melt. This investigation is relevant to CMAS resistant thermal barrier coatings (TBC) used in aircraft engines. CMAS is a generic term for the molten siliceous deposits resulting from the ingestion of mineral particles with the intake air. The aim was to assess the influence of the rare earth on the reaction kinetics, solubility limits and underlying phase equilibria in a model CAS melt. RE2O3 (RE = Nd, Sm, Gd, Dy and Yb) were selected to span a wide range of trivalent lanthanide sesquioxides and Lewis basicities. Powders dispersed in CAS glass-beads were reacted at 1200 °C and quenched after several durations. All the RE2O3 led to the formation of metastable apatite, and then to stabilization of cyclosilicate in CAS. Disilicate Yb2Si2O7 was also obtained in Yb2O3 bead-sample during early-stage of interaction. However, RE2O3 oxide basicity has a direct influence on silicates (apatite, disilicate and cyclosilicate) solubility limits in CAS, on RE-apatite crystal growth as well as on induction time for RE-cyclosilicate nucleation. The results are discussed in the light of crystal chemistry, thermodynamic considerations and RE cation field strength (Z/r²) which is alternative to define oxide basicity.

Impact of Surfactant and Surfactant-Polymer Interaction on Desupersaturation of Clotrimazole

The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium > vitamin E TPGS > sodium dodecyl sulfate > Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.