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By Application AutoChem Applications Particle Size Distribution Flocculation

Flocculation

Control Particle Size Distribution for Confident Process Development

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What Is Flocculation?

Flocculation is a fundamental process utilized to facilitate the aggregation of small particles in a liquid or solution to form larger clusters, known as flocs.

This process is typically achieved through the addition of specialized chemicals known as flocculants, which serve to promote particle clumping and aid in the collision and attachment of particles. Flocculation is important in many industries and natural systems, allowing for the separation of solids from liquids and the purification of water and other liquids.

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What Is the Difference between Flocculation and Coagulation?

Flocculation and coagulation are two processes that are often used together to remove impurities and contaminants.

Coagulation involves the addition of chemicals, known as coagulants, to water, buffer, or solvents that destabilize the particles and cause them to clump together. This process typically involves the creation of particles referred to as "flocs," but more accurately characterized as aggregates. Aggregates are more easily separated from soluble components (often water) through sedimentation or filtration.

Flocculation takes these smaller aggregates created during coagulation and combines them into even larger aggregates known as "flocs." This process is typically achieved through the addition of flocculants, which are specialized chemicals that promote the agglomeration of particles.

In essence, coagulation is the initial step in particle aggregation, while flocculation is a subsequent step that creates larger and more easily removable agglomerated flocs. Both processes are critical in the removal of impurities and contaminants from water or other soluble sources.

Step 1: Coagulation

A coagulant is an agent that is used to promote the aggregation or clumping together of fine particles suspended in a liquid. Coagulation is a chemical process that involves the addition of a coagulant to neutralize the charge of dispersed particles. Small, sub-micron biological and chemical molecules often carry negative surface charges that hinder aggregation and settling (1a).

Coagulant chemicals can adsorb to the particles and neutralize the negative charges. Neutralization, or sometimes titration to an acidic pH, enables particles to stick together, resulting in the formation of stable and well-suspended sub-micron coagulant particles known as microflocs (1b).

Rapid mixing is required for proper dispersion of coagulant chemicals to promote particle collisions and clump formation (1c). The joined particles are still quite small and not visible to the naked eye.

Step 2: Flocculation

Flocculation increases the size of the still submicron coagulant clumps making them easier to separate. This generally requires gentle mixing and using a high molecular weight polymeric or other ionic flocculants. The flocculant adsorbs the coagulant particles, modifying surface properties and bridging gaps to facilitate flocs formations (2a). By bringing particles into close proximity, the effective range of van der Waals attraction forces is increased, thereby reducing the energy barrier for flocculation. This enables the formation of loosely packed groups of flocs.

Agglomeration, binding, and strengthening of flocs continue until visibly suspended macroflocs form (2b). Sedimentation will occur given the right particle weight, size, and strength of interaction. The large macroflocs are very sensitive to mixing, and, once they are torn apart by strong shear, it is difficult or impossible for them to reform.

Flocculation happens naturally during the formation of snowflakes and subsea sediments but is also deliberately applied in the biotechnology, petroleum, pulp and paper, wastewater, and mining industries.  

Why Is Flocculation Important?

Applications in Industry

Biopharmaceuticals
Whole, high-viability mammalian cells are often easy to filter due to their size and distribution. However, microbial cells from bacterial and yeast systems have much smaller monomeric cell units. The biomass burden of microbial cells or mammalian cells with low viability and small median particulate size can create lots of small cell fragments, which clog filters and slow down filtration rates. Flocculation is used to reduce the overall number of particles while increasing the particle size distribution, thus improving filtration and ensuring an efficient and cost-effective separation of cell material from the supernatant. Flocculation may also be applied if the cell culture produces multiple products and/or by-products that are expressed within different cellular structures or micro-environments of the fermentation matrix. Examples include membrane-bound, intermembrane space, or supernatant expression, as well as products that are adsorbed to polymers or even in a multi-phase-capture such as an emulsion. 

Water and wastewater treatment
Wastewater can contain significant amounts of suspended particulate matter, which often takes a long time to settle. Flocculation water treatment expedites sedimentation and ensures efficient solid/liquid separation. Large volumes of used water can be processed quickly, minimizing environmental impact by reducing the amount of time and space needed for used water storage. 

Pulp and paper
Cellulose fiber is one of the main ingredients in pulp and paper, but it also requires glue, impregnation, and fillers to achieve the required sheet properties for an acceptable paper product. Flocculation is frequently applied during the dewatering process to combine fibers, fillers, and other additives in a way that ensures the solid material separates quickly and can be produced in large quantities. 

Precious metal mining
Product streams often contain a wide range of different metals that need to be separated to obtain a pure product. Selective precipitation of individual metals is usually accompanied by flocculation and sedimentation to ensure quick separation from the remaining liquid.

Particle Size Analysis for Process Optimization

Take Control of Particles

Particles, crystals, and droplets can cause issues for scientists at every stage from research through manufacturing. Offline analytics are vital for quality control, but taking control of particles can only happen when you understand how process parameters influence particle size, shape, and count. 

This paper, Particle Size Analysis for Process Optimization, introduces the limitations of offline analysis for process optimization and provides practical techniques to:

  • Improve fundamental process understanding
  • Attack design problems with comprehensive data
  • Improve safety and productivity with unattended operation

Key Considerations for Efficient Flocculation Processes

Process Parameters and Downstream Performance

Flocculation is an important unit operation that requires development and optimization to run efficiently. Key considerations and process parameters include: 

  1. Flocculant or coagulant type and concentration
  2. Mixing intensity, shear stress, and mixing time
  3. Dosing rate, location, and temperature 
  4. Solids concentration
  5. Particle size and count
  6. Downstream performance analysis:
    • Completeness of flocculation (kinetics)
    • Processing time and efforts for solid removal
    • Liquid phase purity (including measurement of residual flocculant)
    • Filtration capacity and efficiency
    • Filter membrane breakthrough of debris or by-products

Liquids in Flocculation

Flocculants, Buffers, and Surfactants

Flocculant addition
Flocculation is primarily driven by the type and dosage of chemical agents added to initiate coagulation and particle flocculation. Secondary drivers include more traditional physical parameters (e.g., mixing, temperature, etc.). Characterization of liquid flocculant stability, mixing kinetics, homogeneity, and the final concentration is just as important during process characterization as it is during more apparent particle engineering goals (e.g., particle size distribution and counts). Added flocculants or excipients should also be characterized for their impact on flocculation outcome, as well as process kinetics and regulatory implications. 

In-situ ATR-FTIR and Raman spectroscopy are powerful multi-attribute methods that can simultaneously track and quantify multiple flocculants or excipients in real time. Combining this spectroscopic data with information about particle distribution and kinetics can help determine the ideal, and often minimal, amount of flocculant needed, minimizing the burden on downstream removal. Buffers and surfactants can also be accurately characterized and controlled in real time.

Flocculant removal
The decision to include flocculation in a process comes with the significant trade-off of a downstream requirement to completely remove added flocculant, surfactant, or process intermediates. This requirement often results in added process time and additional analytical methods needed to quantify or verify the absence of any added processing excipients. As such, it is advantageous to minimize the amount of flocculant, coagulant, surfactant, or other components added.

When inline methods such as ATR-FTIR spectroscopy or Raman spectroscopy are integrated before and after chromatography, quantitative mass-transfer measurements of the product, flocculant, and excipients can also be determined. This may serve as a potential supplement to offline analytical methods.

Understanding Particle Mechanisms

Flocculation and Breakage

In-situ particle size distribution tools allow scientists to track trends in individual size classes and observe the behavior of particles stirred at a steady state in real time. When the flocculant is added, the number of fines drops significantly and the number of large flocs increases sharply. Eventually, the shear of the stirrer will start to destroy the flocs. Large particle counts will decrease, and small counts will increase again.  

Understanding flocculation particle mechanisms helps to identify the root causes of suboptimal process performance, downstream production challenges, and out-of-specification products. Obtaining detailed, in-situ particle data is the first step to effective process optimization, quality by design (QbD), and efficient manufacturing.

Floc Breakage Kinetics

Mixing Intensity and Shear

Floc Breakage Kinetics

Flocculation requires gentle stirring. As individual floc types have different strengths, it is important to understand what rpm range constitutes gentle for a specific floc system. In-situ particle size distribution tools provide insight into how the small particle size class changes when flocs are created and stirred at different speeds. Fast stirring breaks flocs and the number of fines can increase to nearly the same level as before flocculation. Slow stirring leaves most flocs intact. Images from in-situ particle size analyzers support these findings and show larger flocs at low rpm.

Mixing intensity and shear optimization is a successful strategy to prevent floc breakage. Breaking flocs should be avoided becasue it defeats the purpose of flocculation and increases filtration times. Filtration rates and cake dewatering are fastest at the point of optimal flocculation. Any deviation from this point impacts operations, product quality, and manufacturing costs.

In-situ particle size analyzer shows flocs fully developed and floc breakage becoming predominant process

Mixing Zone Residence Time (MZRT)

The Ideal Window

In a variety of industries, flocculation processes are run in batch or continuous mode with either dynamic or static mixers. One of the key process parameters in both modes is the Mixing Zone Residence Time (MZRT). The point of optimal flocculation is located at 1:38 min after flocculant injection in this case. 

With the use of an in-situ particle size analyzer, this tool shows that flocs have fully developed and floc breakage is about to become the predominant process. We can also see trends in individual size classes, visualize the point of optimal flocculation, and define the MZRT window in which the number of small particles reaches an acceptable minimum.

Operating outside the MZRT window either means that flocs have not yet fully formed or that floc breakage is already compromising floc size and optimal process performance. Both cases are suboptimal because of a high number of free small particles and only the MZRT window ensures the desired product and process performance. The MZRT window is different for each particle/flocculant system and requires adjustment depending on suspension composition, mixing intensity, and flocculant type.

How to Choose the Best Flocculant

How to Choose the Best Flocculant?

Flocculant Screening

Chemical companies continuously develop new and innovative flocculants with improved flocculation performance. However, not every flocculant is suitable for every particle system. Testing and confirming performance within a specific system will ensure the best flocculant is used. Particle size analyzers reveal that:

  • Flocculant A shows a weak flocculation performance and is hardly able to reduce the number of small particles in the system.
  • Flocculant B captures a considerable quantity of small particles. However, flocculation kinetics are slow, and the floc breakage rate is higher than the point of optimal flocculation.
  • Flocculant C shows a good overall performance with quick flocculation kinetics, almost complete capture of fines, and impressive floc stability beyond the point of optimal flocculation.

In-situ particle size analyzers can monitor flocculation performance of different flocculants in real time. This enables scientists and engineers to make fact-based decisions during flocculant selection and flocculation process optimization.

flocculation application support

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flocculation laboratory instruments

Instruments for Flocculation Process Optimization

Featured Application: Continuous Flocculation – Antibody Harvest

Process Feedback and Orthogonal Analytics

Efficient, flexible, and cost-effective methods for continuous cell removal must be developed before a fully continuous and integrated product train can be realized. The authors describe the development and testing of such an integrated continuous and disposable set-up for cell separation by flocculation combined with depth filtration.

ParticleTrack measurements were performed inline, after the addition of 0.0375% pDADMAC, and positioned at the outlet of the tubular reactor (static-mixing). ParticleTrack (FBRM) monitors flocc size, and when overlaid with time-resolved pressure, indicates the approach to filter saturation and trends with pressure events. The various methods and flocculant type evaluated resulted in different outcomes for total drug substance yield, purity, and High Molecular Weight Index (HMWI). These outcomes also showed a correlation to divergent particle size distributions resulting from the chosen flocc type.

This data builds on previous publications showing correlation to other flocculation parameters such as flocc reagent concentration, mixing force or shear, mixing resonance time, temperature, and starting condition and composition of whole cell broth. By using flocculation, the required depth filtration areas were successfully reduced by a factor of 4 compared with a conventional filtration train for which ParticleTrack (FBRM) was well suited to enable continuous antibody harvesting.

Burgstaller, D., Krepper, W., Haas, J., Maszelin, M., Mohoric, J., Pajnic, K., Jungbauer, A., & Satzer, P. (2018b). Continuous cell flocculation for recombinant antibody harvesting. Journal of Chemical Technology & Biotechnology, 93(7), 1881–1890. https://doi.org/10.1002/jctb.5500

Applications

Citations and References

Flocculation in Journal Publications

  • Zhang, C., Zhu, Z., & Liu, R. (2023c). The intrinsic relationship between flocculation effect and apparent viscosity of fresh slurry. Construction and Building Materials, 371, 130769. https://doi.org/10.1016/j.conbuildmat.2023.130769
  • Jokinen, L. (2022). Optimising flocculation and cell separation of fermentation broth with in-situ particle size analysis. Theseus. https://www.theseus.fi/handle/10024/744426
  • Costine, A., Fawell, P. D., Chryss, A., Dahl, S., & Bellwood, J. (2020b). Development of Test Procedures Based on Chaotic Advection for Assessing Polymer Performance in High-Solids Tailings Applications. Processes, 8(6), 731. https://doi.org/10.3390/pr8060731
  • Grabsch, A., Yahyaei, M., & Fawell, P. D. (2020b). Number-sensitive particle size measurements for monitoring flocculation responses to different grinding conditions. Minerals Engineering, 145, 106088. https://doi.org/10.1016/j.mineng.2019.106088
  • Vajihinejad, V., & Soares, J. B. P. (2018). Monitoring polymer flocculation in oil sands tailings: A population balance model approach. Chemical Engineering Journal, 346, 447–457. https://doi.org/10.1016/j.cej.2018.04.039
  • Burgstaller, D., Krepper, W., Haas, J., Maszelin, M., Mohoric, J., Pajnic, K., Jungbauer, A., & Satzer, P. (2018c). Continuous cell flocculation for recombinant antibody harvesting. Journal of Chemical Technology & Biotechnology, 93(7), 1881–1890. https://doi.org/10.1002/jctb.5500
  • Senczuk, A., Petty, K., Thomas, A. L., McNerney, T. M., Moscariello, J., & Yigzaw, Y. (2016b). Evaluation of predictive tools for cell culture clarification performance. Biotechnology and Bioengineering. https://doi.org/10.1002/bit.25819
  • McNerney, T. M., Thomas, A. L., Senczuk, A., Petty, K., Zhao, X., Piper, R., Carvalho, J. G., Hammond, M. D., Sawant, S. G., & Bussiere, J. L. (2015c). PDADMAC flocculation of Chinese hamster ovary cells: enabling a centrifuge-less harvest process for monoclonal antibodies. mAbs, 7(2), 413–428. https://doi.org/10.1080/19420862.2015.1007824
  • Cobbledick, J., Nguyen, A. K., & Latulippe, D. R. (2014). Demonstration of FBRM as process analytical technology tool for dewatering processes via CST correlation. Water Research, 58, 132–140. https://doi.org/10.1016/j.watres.2014.03.068
  • Li, Z. J., Pizzelli, K., Romero, J., Chrostowski, J., Evangelist, G., Hamzik, J., Soice, N., & Cheng, K. W. E. (2013a). Clarification of recombinant proteins from high cell density mammalian cell culture systems using new improved depth filters. Biotechnology and Bioengineering, 110(7), 1964–1972. https://doi.org/10.1002/bit.24848
  • Senaputra, A., Jones, F., Fawell, P. D., & Smith, P. (2014). Focused beam reflectance measurement for monitoring the extent and efficiency of flocculation in mineral systems. Aiche Journal, 60(1), 251–265. https://doi.org/10.1002/aic.14256
  • Govoni, S., & Keiser, B. (2001b). Monitoring Flocculation of Newsprint in the Laboratory and on a Paper Machine. ResearchGate. https://www.researchgate.net/publication/289334218_Monitoring_Flocculation_of_Newsprint_in_the_Laboratory_and_on_a_Paper_Machine
  • Blanco, A., Fuente, E., Alonso, A., & Negro, C. (2010). Optimal use of flocculants on the manufacture of fibre cement materials by the Hatschek process. Construction and Building Materials, 24(2), 158–164. https://doi.org/10.1016/j.conbuildmat.2007.06.017
  • Uncles, R., Bale, A., Stephens, J., Frickers, P., & Harris, C. (2010). Observations of Floc Sizes in a Muddy Estuary. Estuarine Coastal and Shelf Science, 87(2), 186–196. https://doi.org/10.1016/j.ecss.2009.12.018
  • Owen, A., Fawell, P. D., & Swift, J. (2007). The preparation and ageing of acrylamide/acrylate copolymer flocculant solutions. International Journal of Mineral Processing, 84(1–4), 3–14. https://doi.org/10.1016/j.minpro.2007.05.003

FAQs

Frequently Asked Questions on Flocculation

What is the definition of flocculation?

Flocculation is a process by which small particles in a liquid come together to form larger, clumped masses called flocs. This can occur naturally or through the addition of certain chemicals called flocculants. In natural flocculation, small particles in a liquid may come together due to a variety of factors such as gravity, Brownian motion, or electrostatic forces. As these particles collide and stick together, they begin to form larger masses that can eventually settle out of the liquid.

Flocculation can also be induced through the addition of flocculants, which are substances that promote the formation of flocs. These chemicals work by neutralizing the electrical charges on the surface of the particles, causing them to attract each other and form larger clumps. Flocculants are commonly used in wastewater treatment, mining, and other industries where the separation of solids from liquids is necessary. Once the flocs have formed, they can be separated from the liquid through a variety of methods, such as sedimentation, filtration, or centrifugation. The resulting liquid is often much clearer and easier to handle than before flocculation.

What is flocculation in water treatment?

The coagulation-flocculation process is commonly used in wastewater treatment to remove turbidity and bacteria. Flocculation encourages suspended particles to bind together and form large, agglomerate particles known as "flocs." These flocs readily float to the surface or sediment at the bottom, providing an efficient and cost-effective means of speeding their separation.

What is the difference between coagulation and flocculation?

Coagulation and flocculation are two distinct processes that are employed one after the other to overcome the forces that keep the suspended particles stable. The particles' charges are neutralized by coagulation, but they can bind together and grow by flocculation, which makes it easier to remove them from the liquid. Read more on flocculation vs coagulation.

What is a flocculated suspension?

A flocculated suspension refers to a mixture or dispersion of solid particles in a liquid where the particles have come together and formed larger clusters or aggregates called flocs. These flocs are held together by weak physical forces, such as van der Waals forces or bridging between particles, rather than being uniformly distributed throughout the liquid. The formation of flocs in a suspension leads to the settling or separation of the solid particles, making them easier to remove or filter from the liquid phase. Flocculation is commonly employed in various industries, including wastewater treatment, mining, and chemical processing, to facilitate the separation and clarification of suspended solids from liquids.