Secondary Nucleation

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform

Allan S Myerson - One of the best experts on this subject based on the ideXlab platform.

  • experimental evaluation of contact Secondary Nucleation mechanisms
    Crystal Growth & Design, 2014
    Co-Authors: Allan S Myerson
    Abstract:

    Contact Secondary Nucleation has vital importance in industrial crystallizers for reactions and purification, and it recently has been linked to contributing to biological homochirality emerged at an abiotic evolutionary stage. Despite years of studies, the mechanism of contact Secondary Nucleation has not been resolved whether contact Secondary nuclei originate from parent crystals via microattrition or from semiordered solute clusters at the interface of parent crystals. This study takes advantage of the unique thermodynamic and kinetic properties of the glycine system that is capable of differentiating the origin of contact Secondary nuclei based on the polymorph of Secondary nuclei obtained. It is demonstrated using two different experimental designs that contact Secondary nuclei could originate both from the semiordered solute molecules at the interface layer of existing crystals and from parent crystals themselves via the mechanism of microattrition depending on the magnitude of the contact force. W...

  • contact Secondary Nucleation as a means of creating seeds for continuous tubular crystallizers
    Crystal Growth & Design, 2013
    Co-Authors: Shin Yee Wong, Allan S Myerson
    Abstract:

    The control of crystal size of any crystallization process is especially important in the pharmaceutical industry where small sizes are often desired. Seeding is often used as a method of controlling crystal size and suppressing primary Nucleation in batch processes. The continuous mixed suspension mixed product removal crystallizers are self-seeded; however, crystal attrition and contact Secondary Nucleation due to crystal interaction with the impeller influence the crystal size. In this study, a nuclei generation device (nucleator) employing contact Secondary Nucleation is described. The nucleator consists of a “crossed” flow tube with four openings. Two of the openings are the inlet of supersaturated solution and the outlet of crystal slurry, respectively. The other two openings are for contact Nucleation, where the parent crystal comes into contact with a platform under an applied stress. The rate of Nucleation and the size of the crystals generated can be controlled by supersaturation (S = c/cs) and ...

Patrick J. Frawley - One of the best experts on this subject based on the ideXlab platform.

  • Secondary Nucleation of Sodium Chlorate: The Role of Initial Breeding
    Crystal Growth & Design, 2020
    Co-Authors: René R.e. Steendam, Patrick J. Frawley
    Abstract:

    Secondary Nucleation is the key mechanism behind the creation of new crystals in industrial crystallization processes. Sodium chlorate has widely been used throughout literature as a model compound to study Secondary Nucleation due to its ability to crystallize as a chiral solid which makes it feasible to determine whether new crystals have originated from solution or from a seed crystal. Despite its widespread use, a significant level of ambiguity regarding sodium chlorate still exists including inconsistent solubility data, nontransferrable results between batch and continuous experiments and inconclusive theories about whether Secondary Nucleation of sodium chlorate is possible through fluid shear. In the present work, the inconsistencies around sodium chlorate are resolved using novel continuous shear-induced Secondary Nucleation experiments involving stationary seed crystals. First, accurate solubility data of sodium chlorate in water was determined using a laser method and compared with literature d...

  • Secondary Nucleation from Nuclei Breeding and Its Quantitative Link with Fluid Shear Stress in Mixing: A Potential Approach for Precise Scale-up in Industrial Crystallization
    Organic Process Research & Development, 2020
    Co-Authors: Mustafa Yousuf, Patrick J. Frawley
    Abstract:

    The development of robust process scale-up involves a clear understanding of mixing hydrodynamics in crystallization. In the present work, particle imaging velocimetry (PIV) was used to determine the fluid turbulent shear stress (TSS) as a function of scale-up involving cooling crystallization experiments at different agitation rates. At a given scale, with increased agitation rate from 300 to 370 rpm, the Secondary Nucleation threshold (SNT) and product mean particle size were observed to decrease due to increased TSS. In nuclei breeding, the nucleated crystals at the seed surface are readily sheared off by the increased fluid shear stress. This catalytic process enhanced the rate of Secondary Nucleation, and hence a decrease in SNT. The SNT and mean particle size increased with scale size due to a decrease in average turbulent dissipation rate which resulted from a decrease in TSS. Secondary Nucleation due to nuclei breeding was found to have a quantitative link with TSS. This resulted in a constant SNT...

  • Experimental Evaluation of Fluid Shear Stress Impact on Secondary Nucleation in a Solution Crystallization of Paracetamol
    Crystal Growth & Design, 2018
    Co-Authors: Mustafa Yousuf, Patrick J. Frawley
    Abstract:

    Cooling crystallization experiments were performed at 300 and 370 rpm over a range of saturation temperatures for the measurements of the metastable zone width (MSZW) using a large seed of paracetamol crystal in propan-2-ol solution. Particle imaging velocimetry (PIV) was used to quantify the fluid shear stress at each agitation rate employed, which was found to be 0.07 and 0.11 N/m2 respectively. A decrease in MSZW and growth only zone (GNZ) was observed with increasing shear stress, and the Secondary Nucleation threshold (SNT) was determined with a relative supersaturation ratio (Sr) of 1.17 at 0.07 N/m2 and 1.08 at 0.11 N/m2. Focused beam reflectance measurement (FBRM) displayed an increase in particle counts as Nucleation progressed, with total counts increased by 25% at a higher fluid shear as more nuclei were being sheared off from the seed surface. Crystal nuclei breeding is proposed as a mechanism of Secondary Nucleation, where the surface of a seed crystal served as a Nucleation site for the pre-...

  • the effects of supersaturation temperature agitation and seed surface area on the Secondary Nucleation of paracetamol in ethanol solutions
    Chemical Engineering Science, 2012
    Co-Authors: Patrick J. Frawley, Niall A. Mitchell, Clifford T Ociardha, Kieran W Hutton
    Abstract:

    This work details the estimation of the Secondary Nucleation kinetics of paracetamol in ethanol solutions for cooling crystallisation processes, by means of isothermal under-seeded batch experiments. A numerical model, incorporating the population balance equation and the method of moments has been developed to describe the seeding process for a typical cooling crystallisation process, accounting for the primary and Secondary Nucleation and subsequent crystal growth. Primary Nucleation and growth kinetics have been previously evaluated from induction time experiments and isothermal seeded batch experiments, respectively, allowing the Secondary Nucleation rate to be evaluated for a wide range of experimental conditions. The experimental technique involved the utilisation of two in-situ Process Analytical Techniques (PAT), a Focused Beam Reflectance Measurement (FBRM®) utilised to qualitatively indicate the occurrence of Secondary Nucleation and an Attenuated Total Reflectance — Fourier Transform Infrared (ATR-FTIR) probe employed for the online monitoring of solute concentration. Initial Particle Size Distributions (PSD) were used in conjunction with desupersaturation profiles to determine the Secondary Nucleation rate as a function of supersaturation, temperature and crystal surface area. Furthermore, the effects of agitation rate on the Secondary Nucleation rate were also investigated. Experimental data were compared to the model simulation, with the accuracy of the estimated Secondary Nucleation kinetics validated by means of the final product PSD and solute concentration.

  • The effects of supersaturation, temperature, agitation and seed surface area on Secondary Nucleation
    2012
    Co-Authors: Patrick J. Frawley, Niall A. Mitchell, Clifford T. Ó’ciardhá, Kieran W Hutton
    Abstract:

    This work details the estimation of the Secondary Nucleation kinetics of paracetamol in ethanol solutions for cooling crystallisation processes, by means of isothermal under-seeded batch experiments. A numerical model, incorporating the population balance equation and the method of moments, has been developed to describe the seeding process for a typical cooling crystallisation process, accounting for the primary and Secondary Nucleation and subsequent crystal growth. Primary Nucleation and growth kinetics have been previously evaluated from induction time experiments, and isothermal seeded batch experiments, respectively, allowing the Secondary Nucleation rate to be evaluated for a wide range of experimental conditions. The experimental technique involved the utilisation of two in-situ Process Analytical Techniques (PAT), with an Focused Beam Reflectance Measurement (FBRM) utilised to qualitatively indicate the occurrence of Secondary Nucleation and an Attenuated Total Reflectance Fourier Transform Infrared (ATRFTIR) probe employed for the online monitoring of solute concentration. Initial Particle Size Distributions (PSD) were used in conjunction with desupersaturation profiles to determine the Secondary Nucleation rate as a function of supersaturation, temperature and crystal surface area. Furthermore, the effects of agitation rate on the Secondary Nucleation rate were also investigated. Experimental parameters were compared to the model simulation, with the accuracy of the estimated Secondary Nucleation kinetics validated by means of the final product PSD and solute concentration.

Sara Linse - One of the best experts on this subject based on the ideXlab platform.

  • Secondary Nucleation and elongation occur at different sites on Alzheimer’s amyloid-β aggregates
    Science Advances, 2019
    Co-Authors: Tom Scheidt, Samuel I A Cohen, Sara Linse, Urszula Łapińska, Janet R. Kumita, Daniel R. Whiten, David Klenerman, Mark R. Wilson, Michele Vendruscolo, Christopher M. Dobson
    Abstract:

    The aggregates of the Aβ peptide associated with Alzheimer’s disease are able to both grow in size as well as generate, through Secondary Nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: the Brichos domain, which suppresses specifically Secondary Nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Aβ fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

  • Secondary Nucleation and elongation occur at different sites on alzheimer s amyloid β aggregates
    Science Advances, 2019
    Co-Authors: Tom Scheidt, Samuel I A Cohen, Sara Linse, Janet R. Kumita, Daniel R. Whiten, David Klenerman, Mark R. Wilson, Urszula łapinska, Michele Vendruscolo
    Abstract:

    The aggregates of the Aβ peptide associated with Alzheimer’s disease are able to both grow in size as well as generate, through Secondary Nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: the Brichos domain, which suppresses specifically Secondary Nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Aβ fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

  • Secondary Nucleation in amyloid formation
    Chemical Communications, 2018
    Co-Authors: Mattias Tornquist, Thomas C T Michaels, Kalyani Sanagavarapu, Xiaoting Yang, Georg Meisl, Samuel I A Cohen, Tuomas P J Knowles, Sara Linse
    Abstract:

    Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as Secondary Nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent Secondary Nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding Secondary Nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent Secondary Nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of Secondary Nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by Secondary Nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent Secondary Nucleation in amyloid formation.

  • monomer dependent Secondary Nucleation in amyloid formation
    Biophysical Reviews, 2017
    Co-Authors: Sara Linse
    Abstract:

    Secondary Nucleation of monomers on the surface of an already existing aggregate that is formed from the same kind of monomers may lead to autocatalytic amplification of a self-assembly process. Such monomer-dependent Secondary Nucleation occurs during the crystallization of small molecules or proteins and self-assembled materials, as well as in protein self-assembly into fibrous structures. Indications of Secondary Nucleation may come from analyses of kinetic experiments starting from pure monomers or monomers supplemented with a low concentration of pre-formed aggregates (seeds). More firm evidence requires additional experiments, for example those employing isotope labels to distinguish new aggregates arising from the monomer from those resulting from fragmentation of the seed. In cases of amyloid formation, Secondary Nucleation leads to the formation of toxic oligomers, and inhibitors of Secondary Nucleation may serve as starting points for therapeutic developments. Secondary Nucleation displays a high degree of structural specificity and may be enhanced by mutations or screening of electrostatic repulsion.

  • Secondary Nucleation of monomers on fibril surface dominates α synuclein aggregation and provides autocatalytic amyloid amplification
    Quarterly Reviews of Biophysics, 2017
    Co-Authors: Ricardo Gaspar, Georg Meisl, Tuomas P J Knowles, Alexander K Buell, Laurence Young, Clemens F Kaminski, Emma Sparr, Sara Linse
    Abstract:

    Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a Secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be Nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the Secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify Secondary Nucleation of monomers on the fibril surface as the dominant Secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for Secondary Nucleation and this may have important implications in the spreading of PD. (Less)

Tuomas P J Knowles - One of the best experts on this subject based on the ideXlab platform.

  • Secondary Nucleation in amyloid formation
    Chemical Communications, 2018
    Co-Authors: Mattias Tornquist, Thomas C T Michaels, Kalyani Sanagavarapu, Xiaoting Yang, Georg Meisl, Samuel I A Cohen, Tuomas P J Knowles, Sara Linse
    Abstract:

    Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as Secondary Nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent Secondary Nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding Secondary Nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent Secondary Nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of Secondary Nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by Secondary Nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent Secondary Nucleation in amyloid formation.

  • Secondary Nucleation of monomers on fibril surface dominates α synuclein aggregation and provides autocatalytic amyloid amplification
    Quarterly Reviews of Biophysics, 2017
    Co-Authors: Ricardo Gaspar, Georg Meisl, Tuomas P J Knowles, Alexander K Buell, Laurence Young, Clemens F Kaminski, Emma Sparr, Sara Linse
    Abstract:

    Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a Secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be Nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the Secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify Secondary Nucleation of monomers on the fibril surface as the dominant Secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for Secondary Nucleation and this may have important implications in the spreading of PD. (Less)

  • dynamics of protein aggregation and oligomer formation governed by Secondary Nucleation
    Journal of Chemical Physics, 2015
    Co-Authors: Thomas C T Michaels, Hamish W Lazell, Paolo Arosio, Tuomas P J Knowles
    Abstract:

    The formation of aggregates in many protein systems can be significantly accelerated by Secondary Nucleation, a process where existing assemblies catalyse the Nucleation of new species. In particular, Secondary Nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including molecular species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the physical size of protein filaments plays a key role in determining their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of Secondary Nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that Secondary Nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an analytical treatment of the master equation describing the growth kinetics of linear protein structures proliferating through Secondary Nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability of analytical solutions for the full filament distribution allows us to identify the key physical parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through Secondary Nucleation and discuss the implications of our work for understanding the factors that promote or curtail the production of these species with a potentially high deleterious biological activity.

  • proliferation of amyloid β42 aggregates occurs through a Secondary Nucleation mechanism
    Proceedings of the National Academy of Sciences of the United States of America, 2013
    Co-Authors: Samuel I A Cohen, Sara Linse, Michele Vendruscolo, Christopher M. Dobson, Leila M Luheshi, Erik Hellstrand, Duncan A White, Luke Rajah, Daniel E Otzen, Tuomas P J Knowles
    Abstract:

    The generation of toxic oligomers during the aggregation of the amyloid-β (Aβ) peptide Aβ42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer’s disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed Secondary Nucleation reaction, rather than through a classical mechanism of homogeneous primary Nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer’s disease. These results reveal that the aggregation of Aβ42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the Aβ aggregation cascade and suggest that perturbation of the Secondary Nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic Aβ42 oligomers.

Xuzhong Gong - One of the best experts on this subject based on the ideXlab platform.

  • synergetic effect of Secondary Nucleation and growth on the lithium carbonate particle size in the gas liquid reactive crystallization of licl nh3 h2o co2
    Particuology, 2020
    Co-Authors: Menghua Tian, Zhi Wang, Xuzhong Gong
    Abstract:

    Abstract In this study, the gas‒liquid reactive crystallization of LiCl–NH3·H2O–CO2 was adopted to produce Li2CO3. The weakly alkaline nature of NH3·H2O in the absence of any recarbonation process resulted in a unimodal and easily controllable particle size distribution (PSD) of the obtained Li2CO3. The reaction temperature significantly influenced both the Li2CO3 particle size and PSD. By increasing the temperature from 25 to 60 °C, the volume weighted mean particle size increased from 50.5 to 100.5 μm, respectively. The Li2CO3 Secondary Nucleation rate and growth rate were obtained by focused beam reflectance measurements and a laser particle size analyzer, respectively. The Secondary Nucleation rate of Li2CO3 reduced as a function of temperature, whereas the growth rate increased. In addition to improving the surface energy of the crystals to enhance the growth process, higher temperatures also reduced the supersolubility of Li2CO3, which also plays a role to decrease the Secondary Nucleation rate. At a constant temperature, supersaturation affects the Li2CO3 particle size through the synergistic effect of Secondary Nucleation and growth. Hence, with improved supersaturation, the mean particle size of Li2CO3 decreased. The results provide a meaningful way to evaluate the crystallization process and to regulate the particle size.

  • Synergetic effect of Secondary Nucleation and growth on the lithium carbonate particle size in the gas–liquid reactive crystallization of LiCl–NH3·H2O–CO2
    Particuology, 2019
    Co-Authors: Menghua Tian, Zhi Wang, Xuzhong Gong
    Abstract:

    Abstract In this study, the gas‒liquid reactive crystallization of LiCl–NH3·H2O–CO2 was adopted to produce Li2CO3. The weakly alkaline nature of NH3·H2O in the absence of any recarbonation process resulted in a unimodal and easily controllable particle size distribution (PSD) of the obtained Li2CO3. The reaction temperature significantly influenced both the Li2CO3 particle size and PSD. By increasing the temperature from 25 to 60 °C, the volume weighted mean particle size increased from 50.5 to 100.5 μm, respectively. The Li2CO3 Secondary Nucleation rate and growth rate were obtained by focused beam reflectance measurements and a laser particle size analyzer, respectively. The Secondary Nucleation rate of Li2CO3 reduced as a function of temperature, whereas the growth rate increased. In addition to improving the surface energy of the crystals to enhance the growth process, higher temperatures also reduced the supersolubility of Li2CO3, which also plays a role to decrease the Secondary Nucleation rate. At a constant temperature, supersaturation affects the Li2CO3 particle size through the synergistic effect of Secondary Nucleation and growth. Hence, with improved supersaturation, the mean particle size of Li2CO3 decreased. The results provide a meaningful way to evaluate the crystallization process and to regulate the particle size.