In-line measurement of liquid-liquid phase separation boundaries using a turbidity-sensor-integrated continuous-flow...

Area of Science:

• Chemical Engineering
• Crystallization Science
• Process Analytical Technology

Background:

• Liquid-liquid phase separation (LLPS), or oiling-out, is a critical issue in active pharmaceutical ingredient (API) crystallization.
• LLPS negatively impacts crystallization rate, purity, particle morphology, and size distribution.
• Current methods for determining LLPS boundaries are often time-consuming and complex.

Purpose of the Study:

• To develop a rapid and accurate method for evaluating LLPS boundaries.
• To implement a continuous-flow microfluidic device integrated with a turbidity sensor for LLPS detection.
• To demonstrate the device's effectiveness using a beta-alanine, water, and isopropanol (IPA) mixture.

Main Methods:

• A fully integrated continuous-flow microfluidic device was designed and constructed.
• A custom-designed, in-line turbidity sensor was incorporated into the microfluidic device.
• Streams of beta-alanine solution, water, and IPA were pumped at varying flow rates to induce and detect turbidity changes.
• Optical microscopy was used for visual confirmation of oil droplet formation and disappearance.

Main Results:

• The microfluidic device successfully detected the onset of turbidity, indicating LLPS.
• LLPS boundaries for the beta-alanine mixture were determined in under 30 minutes.
• Visual tracking via optical microscopy confirmed the turbidity measurements.

Conclusions:

• The turbidity-sensor-integrated microfluidic device provides a fast and accurate method for determining LLPS boundaries.
• This approach significantly enhances the efficiency of crystalline material development by enabling rapid LLPS assessment.
• The technology holds potential for optimizing crystallization processes across various industries.