Primary Nucleation Mechanism Research Articles

Early stage aggregation of a coarse-grained model of polyglutamine.

In this paper, we study the early stages of aggregation of a model of polyglutamine (polyQ) for different repeat lengths (number of glutamine amino acid groups in the chain). In particular, we use the Large-scale Atomic/Molecular Massively Parallel Simulator to study a generic coarse-grained model proposed by Bereau and Deserno. We focus on the primary nucleation mechanism involved and find that our results for the initial self-assembly process are consistent with the two-dimensional classical nucleation theory of Kashchiev and Auer. More specifically, we find that with decreasing supersaturation, the oligomer fibril (protofibril) transforms from a one-dimensional β sheet to two-, three-, and higher layer β sheets as the critical nucleus size increases. We also show that the results are consistent with several predictions of their theory, including the dependence of the critical nucleus size on the supersaturation. Our results for the time dependence of the mass aggregation are in reasonable agreement with an approximate analytical solution of the filament theory by Knowles and collaborators that corresponds to an additional secondary nucleation arising from filament fragmentation. Finally, we study the dependence of the critical nucleus size on the repeat length of polyQ. We find that for the larger length polyglutamine chain that we study, the critical nucleus is a monomer, in agreement with experiment and in contrast to the case for the smaller chain, for which the smallest critical nucleus size is four.

Concentration dependent switch in the kinetic pathway of lysozyme fibrillation: Spectroscopic and microscopic analysis

Formation of amyloid fibrils is found to be a general tendency of many proteins. Investigating the kinetic mechanisms and structural features of the intermediates and the final fibrillar state is essential to understand their role in amyloid diseases. Lysozyme, a notable model protein for amyloidogenic studies, readily formed fibrils in vitro at neutral pH in the presence of urea. It, however, showed two different kinetic pathways under varying urea concentrations when probed with thioflavin T (ThT) fluorescence. In 2M urea, lysozyme followed a nucleation-dependent fibril formation pathway which was not altered by varying the protein concentration from 2mg/ml to 8mg/ml. In 4M urea, the protein exhibited concentration dependent change in the mechanism. At lower protein concentrations, lysozyme formed fibrils without any detectable nuclei (nucleation-independent polymerization pathway). When the concentration of the protein was increased above 3mg/ml, the protein followed nucleation-dependent polymerization pathway as observed in the case of 2M urea condition. This was further verified using microscopic images of the fibrils. The kinetic parameters such as lag time, elongation rate, and fibrillation half-time, which were derived from ThT fluorescence changes, showed linear dependency against the initial protein concentration suggested that under the nucleation-dependent pathway conditions, the protein followed primary-nucleation mechanism without any significant secondary nucleation events. The results also suggested that the differences in the initial protein conformation might alter the mechanism of fibrillation; however, at the higher protein concentrations lysozyme shifted to nucleation-dependent pathway.

Determination of Nucleation and Growth Mechanisms of the B Polymorph of L‐Histidine by Induction Time Measurement

AbstractThe nucleation and growth mechanisms of the B polymorph of L‐histidine (L‐his) in a water‐ethanol system were determined based on induction time measurements. The induction times were experimentally determined at different supersaturations and correlated using the models of mononuclear and polynuclear mechanisms. The primary nucleation mechanism of the B polymorph of L‐his was identified as a polynuclear mechanism and the growth mechanism was found to be a two‐dimensional nucleation‐mediated growth. These mechanisms of the B polymorph of L‐his will be used to characterize the polymorphic transformations and the overall crystallization rate of L‐his.

Abnormal flow behavior and necklace microstructure of powder metallurgy superalloys with previous particle boundaries (PPBs)

Powder metallurgy (P/M) has been introduced as an innovative process to manufacture high performance components with fine, homogenous and segregation-free microstructure. Unfortunately, previous particle boundary (PPB) precipitated during the powder metallurgy process. Since undesirable PPB is detrimental to mechanical properties, hot extrusion or/and isothermal forging are needed. In present research, isothermal compression tests were conducted on P/M FGH4096 superalloys with typical PPBs. Abnormal flow behavior during high-speed deformation has been quantitatively investigated. Caused by the competition mechanism between work-hardening and dynamic-softening, abnormal flow behaves typical four stages (viz., work-hardening, stable, softening and steady). Microstructure observation for hardening or/and softening mechanism has been investigated. Meanwhile, necklace microstructure was observed by scanning electron microscope, and the grain fraction analysis was performed by using electron backscatter diffraction. Transmission electron microscopy was used for characterizing the boundary structure. Necklace microstructural mechanism for processing P/M superalloys has been developed, and the dynamic recrystallization model has also been conducted. Bulge–corrugation model is the primary nucleation mechanism for P/M superalloys with PPBs. When PPB is entirely covered with new grains, necklace microstructure has formed. Bulge–corrugation mechanism can repeatedly take place in the following necklace DRX.

Nucleation and morphology of sodium metaborate dihydrate from NaOH solution

Szaibelyite ore is an important boron mineral used for producing boron compounds. Sodium metaborate dihydrate can be prepared through leaching of the szaibelyite ore in NaOH solution and the leaching liquor mainly consists of NaBO2 and NaOH. In this work, the induction time for sodium metaborate dihydrate crystallized in NaOH solution from 30 to 50°C was systematically investigated. The primary nucleation and growth mechanism were determined on the basis of the induction time measurements. The crystals of various morphologies under different crystallization conditions were obtained: the rod-like crystals preferred to form at low temperature, while the plate-like crystals formed at high temperature; when the crystallization temperature was 30°C, the flat rod-like crystals formed at low supersaturation, while the slim rod-like crystals formed at high supersaturation. Finally, the growth mechanism of the sodium metaborate dihydrate was identified with various models and the 2D nucleation-mediated model gave satisfactory fitting results.

Ice formation on nitric acid‐coated dust particles: Laboratory and modeling studies

AbstractChanges in the ice nucleation characteristics of atmospherically relevant mineral dust particles caused by a coating of nitric acid are not well understood. Further, the atmospheric implications of dust coatings on ice‐cloud properties under different assumptions of primary ice nucleation mechanisms are unknown. We investigated the ice nucleation ability of Arizona Test Dust, illite, K‐feldspar, and quartz as a function of temperature (−25°C to −30°C) and relative humidity with respect to water (75% to 110%). The particles (bare or nitric acid coated) were size selected at 250 nm, and the fraction of particles nucleating ice at various temperature and saturation conditions was determined. All of the dust species nucleated ice at subsaturated conditions, although the coated particles (except quartz) showed a reduction in their ice nucleation ability relative to bare particles. However, at supersaturated conditions, bare and coated particles had nearly equivalent ice nucleation characteristics. The results of a single‐column model showed that simulated ice crystal number concentrations are mostly dependent upon the coated particle fraction, primary ice nucleation mechanisms, and competition among ice nucleation mechanisms to nucleate ice. In general, coatings were observed to modify ice‐cloud properties, and the complexity of ice‐cloud and mixed‐phase‐cloud evolution when different primary ice nucleation mechanisms compete for fixed water vapor budgets was supported.

Determination of Metastable Zone Widths and the Primary Nucleation and Growth Mechanisms for the Crystallization of Disodium Guanosine 5′-Monophosphate from a Water–Ethanol System

Metastable zone widths (MSZWs) and induction times (tind’s) were measured by turbidity techniques during the antisolvent crystallization of disodium guanosine 5′-monophosphate (5′-GMPNa2). Measured MSZWs can be affected by numerous process parameters, including temperature, the agitation rate, and the antisolvent addition rate. An exponential equation was used to correlate the supersolubility and solubility data for different conditions, and to afford predictions of the MSZW values. Values of tind at different temperatures and mole fractions of water were assessed to determine the primary nucleation and growth mechanisms of 5′-GMPNa2 crystals in the water–ethanol system. The measured tind’s were then correlated using mononuclear and polynuclear mechanistic models. The fitting results identified the primary nucleation mechanism for 5′-GMPNa2 as polynuclear, which relates tind and the supersaturation for various growth mechanisms. The growth mechanism of 5′-GMPNa2 was found to be diffusion-controlled at all experimental temperatures.

Nucleation of ammonium aluminum sulfate dodecahydrate from unseeded aqueous solution

The metastable zone width (MSZW) and the induction times for the cooling crystallization of ammonium aluminum sulfate dodecahydrate from unseeded aqueous solution were measured using focused beam reflectance measurement (FBRM). Dependence of MSZW on cooling rate and saturation temperature and dependence of the induction time on supersaturation and temperature were systematically investigated. Classical 3D nucleation based approach of Sangwal was employed to correlate MSZW with cooling rate. Linear plots of (T⁎/ΔTmax)2 versus lnR gave values of the parameters F1, F, and Z. According to the classical theory, the primary nucleation mechanism was identified and the interfacial energy was calculated.

Determination of Primary Nucleation Mechanisms of α-Synuclein Amyloid Aggregation

Protein conformational diseases represent a class of pathologies in which specific peptides or proteins form aberrant self-assemblies that constitute the hallmark of several neurodegenerative diseases. Specifically, the formation of intra-neuronal inclusions of the protein α-synuclein (αSyn) is associated with the pathogenesis of Parkinson's disease (PD).A great interest is in the early stages of αSyn aggregation, for which soluble monomeric proteins are converted into fibrillar nanostructures. It has been shown that at these stages many parallel and competing pathways take contemporaneously place and it is currently very difficult to address on these mechanisms by using standard techniques of molecular investigations. In order to overcome the limitations of standard approaches, we employed ensemble-averaged kinetic studies coupled with microdloplet technology in order to characterize the primary nucleation early stages of αSyn amyloid formation and therefore to elucidate the fundamental mechanisms underlying this phenomenon. Testing different aggregation conditions, we have been able to understand that the primary nucleation mechanism underlying αSyn aggregation is not homogeneous, whereas it is catalysed by different factors, including air/water surface interactions.The full characterization of all the processes involved in the aggregation mechanism of αSyn will be fundamental for devising new and innovative therapeutic strategies against PD. Indeed, based on our analysis, we expect that it will be possible to design and screen pharmacological compounds able to selectively inhibit the nucleation steps that trigger either the overall of the process or specifically the formation of the toxic aggregated species.

Actinides oxalate precipitation in emulsion modeling: From the drop scale to the industrial process

An original process of actinides coprecipitation based on pulsed flow column is studied. The novelty of this process lies in the confinement of the aqueous reagents in separated droplets, dispersed in an inert organic phase (W/O emulsion). Precipitation occurs inside drops when they coalesce. Besides the implementation of well-known technologies of the nuclear industry, this precipitation in emulsion process is particularly convenient for the control of supersaturation, and ensures the sticky precipitates’ confinement within drops, thereby limiting the fouling risk and its adverse consequences on productivity and safety.A thorough understanding of the precipitation mechanisms and their interactions with the hydrodynamic conditions prevailing around and inside the drops is essential for the process optimization. In this context, numerical simulations were conducted, accompanying experiments, to study the process sensitivity. Different levels were considered in the modeling task, going from the emulsion behavior inside the column, to the reagents mixing and precipitation within the drops.Regarding the drop scale, on which we focus in this paper, preliminary static and dynamic observations revealed a stage of mixing of the reagents, followed by a progressive concentration of particles at the drop center leading to their agglomeration. In the modeling three configurations of the reagents’ mixing were therefore considered relatively to the Hill vortices experimentally noticed. CFD simulations allowed calculating possible mean supersaturation profiles in the drop. Two simplified models were proposed to simulate the precipitation inside the drops. Based on the population balance modeling framework, they consider primary nucleation and growth mechanisms and take into consideration either instantaneous or progressive mixing of the reagents. These simplified models were validated with CFD+PBM simulations. Based on the drop scale simulations, process modeling has been discussed.

Nucleation mechanisms of dynamic recrystallization in Inconel 625 superalloy deformed with different strain rates

The effects of strain rates on the hot working characteristics and nucleation mechanisms of dynamic recrystallization (DRX) were studied by optical microscopy and electron backscatter diffraction (EBSD) technique. Hot compression tests were conducted using a Gleeble-1500 simulator at a true strain of 0.7 in the temperature range of 1000 to 1150 °C and strain rate range of 0.01 to 10.00 s−1. It is found that the size and volume fraction of the DRX grains in hot-deformed Inconel 625 superalloy firstly decrease and then increase with increasing strain rate. Meanwhile, the nucleation mechanism of DRX is closely related to the deformation strain rate due to the deformation thermal effect. The discontinuous DRX (DDRX) with bulging of original grain boundaries is the primary nucleation mechanism of DRX, while the continuous DRX (CDRX) with progressive subgrain rotation acts as a secondary nucleation mechanism. The twinning formation can activate the nucleation of DRX. The effects of bulging of original grain boundaries and twinning formation are firstly gradually weakened and then strengthened with the increasing strain rate due to the deformation thermal effect. On the contrary, the effect of subgrain rotation is firstly gradually strengthened and then weakened with the increasing strain rate.

Early stages of nucleation and growth in melt crystallized polyethylene

Time-resolved synchrotron small angle X-ray scattering (SAXS) was used to investigate the early stages of crystallization in melt crystallized polyethylene. Classic Gibbs nucleation or density fluctuation theory can be used to describe the primary nucleation mechanism. At 110 °C, no signal of crystallization can be detected by SAXS for 30 min. When it is lower than 110 °C, the low q scattering intensity (0.008 < q < 0.03 Å−1) begins to upturn, and the primary nucleation process starts. The measured fractal dimension of the critical nuclei is in the vicinity of 3 which is close to the prediction of classic Gibbs nucleation theory. The growth rate of density fluctuations R(q) at different scattering vector q for different temperatures was obtained by analyzing the increase of scattering intensities. The results show that the growth rate of density fluctuation gets much bigger with the decrease of the isothermal crystallization temperature, but there is no signal of spinodal decomposition mechanism, in which there should be a linear relationship between R(q)/q2 and q2.

Quality-by-Design: An Integrated Process Analytical Technology Approach to Determine the Nucleation and Growth Mechanisms During a Dynamic Pharmaceutical Coprecipitation Process

The objective of this study was to demonstrate the feasibility of using an integrated process analytical technology (PAT) approach to determine nucleation and growth mechanisms of a dynamic naproxen (drug)-Eudragit L100 (polymer) coprecipitation process. The influence of several thermodynamically important formulation and process variables (drug/polymer ratio, alcohol, and water usages) on coprecipitation process characteristics was investigated via real-time in situ focused beam reflectance measurement (FBRM) monitoring and near real-time particle vision microscopy measurement. The final products were characterized by near-infrared (NIR) spectroscopy and NIR chemical imaging microscopy. The coprecipitation nucleation induction time (t(ind) ) was measured by both FBRM trend statistics and process trajectory method, respectively. Furthermore, nucleation kinetics was evaluated based on t(ind) measurement and corresponding supersaturation ratio (S) estimated. It was found that plots of ln(t(ind) ) versus (ln(2) S)(-1) consist of two linear segments and are consistent with classical primary nucleation mechanisms. Apparently, the coprecipitation process is governed by heterogeneous primary nucleation mechanism at low S (14 ≤ S ≤ 503) and by homogeneous primary nucleation mechanism at high S (1216 ≤ S ≤ 3649). Off-line characterizations collectively supported this statement. Therefore, it demonstrated that integration real-time PAT process monitoring with first-principles modeling and off-line product characterization could enhance understanding to coprecipitation process dynamics and nucleation/growth mechanisms, which is impossible via off-line techniques alone.

Primary nucleation of alpha-lactose monohydrate: The effect of supersaturation and temperature

Temperature and supersaturation are defined by classical nucleation theory as the key variables determining the rate of nucleation. These two variables were investigated, using turbidity to measure the induction time for the primary nucleation of alpha-lactose monohydrate. Absolute alpha-lactose supersaturations ranging from 8 to 32 (g per 100 g water) were investigated at temperatures of 25 °C, 40 °C, 50 °C and 60 °C. Using the results, the homogeneous and heterogeneous primary nucleation mechanisms were considered individually. When expressed as absolute supersaturation, temperature had an insignificant effect on the primary nucleation rate and the point at which homogeneous nucleation became the dominant mechanism. Classical nucleation theory can be used to show that at high supersaturation the temperature effect becomes negligible. This explains why conflicting observations on the effect of temperature on the nucleation rate of alpha-lactose monohydrate are given in the literature.

Determining the primary nucleation and growth mechanism of cloxacillin sodium in methanol–butyl acetate system

The primary nucleation and growth mechanism of cloxacillin sodium in methanol–butyl acetate system are determined on the basis of induction time measurements. The induction time of cloxacillin sodium is experimentally determined by the laser scattering method at different supersaturations and temperatures. The measured induction times are then treated using the models of mononuclear and polynuclear mechanisms. It is discovered that the primary nucleation mechanism of cloxacillin sodium is identified as polynuclear mechanism, which relates the induction time and the supersaturation for various growth mechanisms. On the basis of these analyses, the growth mechanism of cloxacillin sodium is two-dimensional nucleation-mediated growth at 285 K, and changes into spiral growth with increasing temperature (at 291 and 297 K).

SGGP 2007 - Understanding and Modelling of Crystallization Mechanisms by In-Situ Analytical Technologies Monitoring

The batch cooling crystallization of an industrial active pharmaceutical ingredient that exhibits a needle-like habit was investigated. A model of the time variations of key physical properties of particles (crystal size distribution CSD and specific area) was designed using an approach based on the simple population balance equation. The experiments were monitored thanks to three in-situ process analytical sensors (Mid-IR spectroscopy, in-situ microscopy and laser backscattering). Primary and secondary surface nucleation mechanisms as well as growth of the main crystal dimension (length) were described resulting in a six parameter model. The model roughly represents the effects of different cooling strategies on the supersaturation profile, the CSD and the specific area of the final particles. First, a very weak primary nucleation occurs leading to an initial population of a few large crystals. A second population of crystals is generated afterwards through secondary nucleation mechanisms. The particles issued from the second burst of nucleation largely dominate (in mass and in number) the final overall population. Second, two important features of the crystallization process are outlined, which are commonly observed during the industrial crystallization of APIs (Active Pharm. Ing.) in impure mother liquors.

Microstructure-properties relationship in two Al-Mg-Si alloys through a combination of extrusion and aging

Aluminum alloys containing magnesium and silicon as the major solutes are strengthened by precipitation of the metastable precursors (β″) of the equilibrium β (Mg2Si) phase. In this study, dynamic aging of two Al-Mg-Si alloys—the 6061 (Al-1.34% Mg2Si) and 6069 (Al-2.25% Mg2Si) alloys—was conducted through equal channel angular extrusion (ECAE). Equal channel angular extrusion-assisted dynamic aging provides the potential for improving mechanical properties. The aging time scale is reduced from ∼1,000 min. for conventional static peak aging to ∼10 min. by using ECAE-assisted dynamic aging. Compared to the significant strengthening effect in static aging treatment, a notable further increase in ultimate tensile strength is achieved by dynamic aging: over 40 MPa for the 6061 alloy and 100 MPa for the 6069 alloy. Microstructures of both aged alloys were characterized using transmission electron microscopy; dislocation-assisted precipitation was observed to be the primary precipitate nucleation and growth mechanism during the dynamic aging process. It is concluded that ECAE-assisted dynamic aging is controllable and efficient in executing aging treatment that could result in superior mechanical properties of Al-Mg-Si alloys.

A systematic comparison of static and dynamic ageing of two Al–Mg–Si alloys

Abstract Aluminium alloys containing Mg and Si as the major solutes are strengthened by precipitation of the metastable precursors (β″) of the equilibrium β (Mg2Si) phase. In this study, both static and dynamic ageing of two Al–Mg–Si alloys—the 6061 (Al–1.34% Mg2Si) and 6069 (Al–2.25% Mg2Si) alloys—were aged at 170 °C and compared to evaluate the potential for improving the mechanical properties. Dynamic ageing was conducted through the procedure of equal channel angular extrusion (ECAE). It is shown that the ageing time scale is reduced from ∼1000 min for conventional static peak-ageing to ∼10 min by using ECAE-aided dynamic ageing. Compared to the significant strengthening effect in static peak-ageing treatment, a notable further increase in ultimate tensile strength (UTS) is achieved by dynamic ageing: over 40 MPa for the 6061 alloy and 100 MPa for the 6069 alloy. Ductility of dynamically aged alloys is found to be comparable to that of the statically peak-aged samples. Microstructures of both statically and dynamically aged alloys were characterised using transmission electron microscopy; dislocation-assisted precipitation was observed to be the primary precipitate nucleation and growth mechanism during dynamic ageing process. It is concluded that dynamic ageing using ECAE is efficient in executing ageing treatment that results in superior mechanical properties of the Al–Mg–Si alloys.

Nucleation and morphology of barium carbonate crystals in a semi-batch crystallizer

A double-jet feed, semi-batch crystallization system was used to explore the nucleation kinetics, growth kinetics and morphology of barium carbonate crystals under a constant pH value. The nucleation rate and the growth rate can be determined successfully by the initial rate method. The results showed that heterogeneous nucleation is dominant in the primary nucleation mechanism, and the effect of specific power input on the nucleation rate is obvious. The results also showed that the pH and initial concentration of the solution play an important role on the morphology of barium carbonate crystals. The crystal forms are floc, candy-like, olivary with end dendrite, olivary-like and needle-like, depending on the operating conditions. At high to moderate concentrations the floc precipitates are the major products in the pH range of 9.0–10.0. At moderate to low concentrations the candy-like and olivary with end dendrite crystals become the major products. At low concentrations and low pH values the crystal forms are olivary-like and needle-like precipitates. However, the results showed that the crystal forms of barium carbonate are concerned with the nucleation rates. On the other hand, the investigations showed that the well-sharp crystal forms follow the surface-integration growth mechanism and the dendrite crystals obey the diffusion growth mechanism.

Investigation of the unseeded nucleation of gibbsite, Al(OH) 3, from synthetic bayer liquors

This paper presents the novel application of multi-angle laser light scattering (MALLS) together with transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and In-lens field emission scanning electron microscopy (IFESEM) for studying the unseeded nucleation of gibbsite from synthetic Bayer liquor (sodium aluminate). The effects of supersaturation in the absence or presence of a known inhibitor (sodium gluconate) were examined. In each series of experiments, both homogeneous and heterogeneous primary nucleation mechanisms were observed. For the unpoisoned liquor used in this work the nucleation appeared to be homogeneous for supersaturation ratios greater than 2.51±0.07 and heterogeneous for lower values. From the induction period measurements, the interfacial tension at 60°C was determined to be 45±6 mJ m −2, and used to predict the critical nucleus size of 1.2±0.1 nm. This was then compared to the measured particle sizes from samples examined by TEM (10–40 nm) and IFESEM (∼50 nm). A crystallite size was determined by XRD to be 22±6 nm. The presence of sodium gluconate inhibitor extended the region over which homogeneous nucleation is dominant, but did not affect the measured value of the interfacial tension and hence the critical nucleus size. This is consistent with the poison inhibiting processes on the solid phase and not the solution phase.