(654e) Design and Validation of a Droplet Based Microfluidic System to Study Non-Photochemical Laser Induced Nucleation

Crystallization is one of the most widely used separation/purification techniques for production of crystals with desired product quality in chemical industry, especially for pharmaceutical and fine chemical sectors. Despite its widespread use, controlling key properties such as crystal size distribution, purity, morphology and polymorphic outcome remains a significant challenge with immense implications on product quality and its performance¹. In an effort to improve our control over aforementioned crystal properties, a plethora of methods have been proposed including Non-Photochemical Laser Induced Nucleation (NPLIN). NPLIN is a physiochemical phenomenon in which a nanosecond laser pulse induces instantaneous crystallization in solutions of low supersaturation which would otherwise take many weeks to nucleate². The term ‘non- photochemical’ implies that the operated wavelength and laser pulse intensity do not induce a photochemical reaction as the solute and the solvent has no absorption bands at the incident wavelength³. So far, NPLIN was investigated through irradiating a supersaturated solution in millilitre size vial and later counting the crystallized vials by visual inspection. For each repetition, a new sample vial is manually placed on the beam path and this procedure is repeated at least 80 to 100 times for statistically accurate measurements. This manual procedure is laborious, time-consuming and limits the number of experimental conditions studied for the assessment of kinetic parameters⁴. Microfluidics represents an alternative to acquire automated and statistically reliable data. Thus we design, develop and validate a droplet based microfluidic platform to quantify the influence of NPLIN on nucleation kinetics in potassium chloride from solution.

Experiments

The microfluidic NPLIN experiments were carried out using a droplet based microfluidic device as shown in Figure 1. The device is divided into four main zones: mixing, droplet generation, laser exposure and crystal observation zones. Dispersed phase containing KCl undersaturated aqueous solution (Sigma Aldrich – CAS: 7447-40-7) is initially mixed and further its droplets are generated in a temperature-controlled environment at 35^oC using silicone oil (Sigma Aldrich – CAS: 63148-62-9) as the continuous phase in a coaxial manner using two precision syringe pumps (NE-1002X). At the exit of the temperature-controlled environment, KCl droplets cool down to room temperature at 24^oC and become supersaturated. The droplets then enter the laser exposure zone coupled with two near-infrared (NIR) sensors. IR sensors detect the interfaces between two liquid⁵ and measures droplet velocity and length. The droplets were then exposed to a continuous train of 10 Hz laser pulses (9-14 pulses per droplet) with an unfocused laser beam of 1.35 mm diameter using Nd-YAG laser device (Continuum Powerlite DLS 8000) at different laser wavelengths (1064, 532 nm) to investigate the effects of laser wavelength on the nucleation probability. After the droplets pass the laser exposure location, they are allowed to nucleate and grow for some time in the crystal observation zone and were finally imaged at the end of the capillary using a camera. Experiments were performed using KCl supersaturations of 1.05 and 1.10 without and with four different laser intensities (10, 25, 50, 100 MW/cm²). The nucleation probabilities were than calculated from the videos taken at the end of the capillary using manual image analysis and automatic image analysis.

Results & Discussion

Figure 2(A) and 2(B) shows the normalized nucleation probabilities for the control cooling and irradiation experiments for two different supersaturations (1.05 and 1.1) respectively at fixed time 55.3±4.5 seconds i.e. P(t=55.3±4.5 s). The experiments were performed at different laser intensities (MW/cm²) for all wavelengths. The normalized nucleation probability obtained in cooling experiments is displayed as black lines for both the supersaturations in both the figures. From the graphical trends of Figure 2(A) for S = 1.05 droplets, the nucleation probability observed was lower as compared to its cooling experiments upon irradiation with 10 MW/cm² laser intensity for all wavelengths. Except for 1064 nm laser light, laser irradiation at 532 nm with 25 MW/cm² resulted in comparable nucleation probability values to its controlled cooling experiments. Overall, for the S = 1.05 droplets, laser irradiation at all wavelengths is only proven to be effective at higher (≥ 50 MW/cm²) laser intensities for giving relatively higher nucleation probability values as compared to cooling experiments. In contrast for S = 1.1 droplets, the laser irradiation was found to be effective at laser intensities ≥ 25 MW/cm² giving higher nucleation probabilities as compared to its reference cooling experiments. It can clearly be seen that at all wavelengths the nucleation probabilities follow similar trends with overlapping error bars, suggesting that these values are comparable. From these trends, it can be commented that there is no wavelength effect observed on nucleation probabilities determined.

Although supersaturation is strictly a nucleation affecting factor and not a NPLIN affecting factor, its variation still caries through in the nucleation probabilities observed within the laser irradiation experiments. Interestingly enough, besides it expected effect of resulting in a higher nucleation probability, for S = 1.10 cooled and irradiated droplets vs S = 1.05 cooled and irradiated droplets, other effects can also be observed within the data. For S = 1.10 droplets, irradiation at 25 MW/cm² with 1064 and 532 nm light was already seen to be beneficial for inducing nucleation. Whereas at S = 1.05, irradiation at these intensities offered comparable or significantly lower nucleation probabilities in comparison to its controlled cooling experiments. The significant lower nucleation probability upon irradiation of S = 1.05 droplets with laser intensities of 10 MW/cm² is not seen in S = 1.10 droplets. We think this might be due to some supersaturation dependent effect, possibly being explained by a supersaturation dependent laser intensity threshold needed to offer improved nucleation probabilities.

Conclusion

We developed and validated a microfluidic setup to address the lack of large data sets in NPLIN experiments focussing on nucleation kinetics. Results of the laser irradiation experiments performed on aqueous KCl droplets at different laser intensities indicated that increasing the supersaturation increases the nucleation probability. However, no wavelength effect was observed on the nucleation probabilities determined at the operated laser intensities.

References

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