Real-Time Monitoring of Nanoparticle Growth During Crystallization and Synthesis through Spatially Resolved Dynamic Light Scattering

Various processes to create nanoparticles exist within different industries such as pharma, cosmetics, inks, coatings, chemicals, food and more. Commonly applied ‘bottom-up’ approaches in which nanoparticles are synthesized, crystallized or precipitated lack a real-time monitoring tool to follow initial stages of particle growth. Although some particle size monitoring tools are available for larger above micron size particles, the submicron area remains a challenge to monitor in real time. Since kinetics of ‘bottom-up’ approaches are important for understanding and control of these processes, there is a general desire to monitor the initial stages of particle growth as early as possible.

Spatially Resolved Dynamic Light Scattering (SR-DLS), a relatively new technology for inline, online and at-line nanoparticle size monitoring, was developed and introduced by InProcess-LSP in 2019. SR-DLS is capable of measuring nanoparticle size in real time in the submicron region in flowing and undiluted nanosuspensions. In addition, high measurement frequencies of 5 to 10 seconds allow monitoring of relatively fast changing processes as well, and provide a full ‘picture’ of the particle growth process of interest.

Technical Background: Spatially Resolved Dynamic Light Scattering is based on low coherence interferometry of backscattered broadband light (multiple wavelengths instead of a single wavelength laser). Similar to conventional DLS, intensity fluctuations due to Brownian motion of nanoparticles are recorded and translated to diffusion rate and particle size. In addition to conventional DLS intensity fluctuations are obtained simultaneously as a function of depth in the sample up to about 3mm. Depth resolved data enables the effective and automatic filtering of single and multiple scattered light which results in a significantly wider accessible turbidity range compared to conventional DLS. As a result, many nanosuspensions up to relative high concentrations or turbidity can be measured without dilution. The spatially resolved data also allows to measure and correct for flow. Additional movement of particles due to flow is filtered out to obtain the Brownian motion component only for particle size characterization. Measurements are performed non-invasively in samples as such or directly in the process through any glass interface such as a vial, a flow cell or a specific flask or container type.

Crystallization

The initial stage of crystallization includes nucleation which relates to the transition from an (oversaturated) liquid phase to the solid phase. After nucleation, particles start to growth and new particles will be formed in parallel by ongoing nucleation. As a result of the increasing solid concentration the driving force to nucleate due to super saturation will decrease and particle growth will become the dominant mechanism. In Figure 1 the particle size distributions measured by SR-DLS are shown for an ibuprofen crystallization process in a glass vial (based on the addition of anti-solvent).

Real time particle size distribution information at different time points, during the antisolvent crystallization of Ibuprofen.

Figure 1. Real time particle size distribution information at different time points, during the antisolvent crystallization of Ibuprofen. Image Credit: InProcess-LSP 

After 1 and 5 minutes the PSD fit shows a small fraction of around 10 nm particles most likely corresponding to the formation of new particles in the nucleation stage. The fraction of small particles disappear in time and particles of a few 100 nm start growing in time.

Additional studies with ibuprofen in 2-propanol were executed to monitor the effect of anti-solvent (in this case water) ratio and presence of surfactant (tween 80). In Figure 2 some examples of the monitored crystallization process in real time are shown. The real-time data shows a direct effect of different solvent/anti-solvent ratios to particle size (the more anti-solvent, the smaller the particles). The effect of the surfactant is also significant, particle size increases much faster without surfactant which is most likely due to the formation of aggregates.

Real time information about the growth of particles during the antisolvent crystallization of ibuprofen from a 2-propanol solution using different amounts of water (with or without Tween 80) as anti-solvent.

Figure 2. Real time information about the growth of particles during the antisolvent crystallization of ibuprofen from a 2-propanol solution using different amounts of water (with or without Tween 80) as anti-solvent. Image Credit: InProcess-LSP 

Shown data was all recorded in a static glass vial mode. Since no sample handling is required and measurements are performed non-invasively through the glass wall of the vial, this type of crystallization studies can be executed conveniently at low volumes in a rather simple manner. 

Synthesis

Particle growth of titanium dioxide particles was monitored online in real time by SR-DLS. A different setup compared to the crystallization example was applied to show applicability of SR-DLS to measure flowing suspensions as well. An online loop connected to a micro-flowcell sampling module of a NanoFlowSizer with a small peristaltic pump circulated the reaction mixture continuously, and particle size measurements were recorded every 10 seconds. A number of experiments were recorded in real time for which the amount of added KCl in the reaction mixture was varied to obtain differently sized particles.

A) Real time monitoring of nanoparticle size during titanium oxide synthesis by SR-DLS via online loop; B) Online real time particle size information of synthesized TiO2 particles for different KCl concentrations.

Figure 3. A) Real time monitoring of nanoparticle size during titanium oxide synthesis by SR-DLS via online loop; B) Online real time particle size information of synthesized TiO2 particles for different KCl concentrations. Image Credit: InProcess-LSP 

The SR-DLS technology is able to measure over a wide turbidity range which allows continuous and real-time measurements up to relatively high concentrations of even highly scattering materials (like titanium dioxide).

Particle Growth Versus Aggregation

In the previous examples, SR-DLS showed to be suitable for real-time monitoring of particle growth processes. However, particle size data as such does not distinguish between ‘real’ particle growth and particle aggregation. Besides particle size information, backscatter intensity as recorded by SR-DLS is obtained simultaneously for each particle size measurement and is directly related to the concentration (in principle turbidity) of the suspension. In case of particle growth the concentration increases, while the concentration remains unchanged in case of aggregation. Both mechanisms may be identified based on backscatter intensity data.

SR-DLS particle size and backscatter intensity of silica particle growth (Stöber) and aggregation.

Figure 4. SR-DLS particle size and backscatter intensity of silica particle growth (Stöber) and aggregation. Image Credit: InProcess-LSP 

In Figure 4 two processes involving the formation of silica particles show increasing particle size in time. One of the processes is based on actual particle growth (Stöber synthesis) and one of the processes is based on aggregation only by adding salt to 100nm silica particles. The backscatter intensity corresponding to the particle growth (Stöber) data shows a close relation with the expected increase in turbidity (based on Raleigh scattering) for a situation in which particles only grow (with constant number density). The obtained backscatter intensity of the silica suspension with added salt shows a nearly constant backscatter intensity indicating no significant change in concentration and therefore indicating aggregation. 

Conclusions

Spatially Resolved Dynamic Light Scattering offers new opportunities to monitor growth of nanoparticles in real time. The fast data acquisition allows monitoring of particle size and particle size distribution every 5 to 10 seconds. Due to the ability to measure over a wide turbidity range in static and flowing suspensions, different measurement configurations can be applied to monitor particle size formation during crystallization or synthesis. Combination of the simultaneously obtained backscatter intensity with particle size information allows distinguishing between particle growth and particle aggregation.  

This information has been sourced, reviewed and adapted from materials provided by InProcess-LSP.

For more information on this source, please visit InProcess-LSP.

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