Lactose Inline Crystallization – from Lab to Industry

Ultrasonic-assisted crystallization is an efficient technique for enhancing solid formation under continuous flow conditions. Below we present you a study that focuses on the inline crystallization of lactose from a lactose/water/isopropanol ternary system, utilizing the Hielscher UP200St-TD-FlowCell sonication chamber. The application of ultrasound yielded significant improvements in system stability, crystal morphology, and runtime continuity. Here, you can find the optimized experimental protocol, key performance outcomes, and the route to industrial scale-up.

Process Intensification: Lactose Crystallization using Sonication

Crystallization is essential in the pharmaceutical and food industries for purification and particle engineering. However, traditional batch processes suffer from limitations in reproducibility and fouling, particularly during scale-up. Continuous crystallization under ultrasonic conditions offers a compelling alternative by enhancing nucleation rates, improving size distribution, and mitigating fouling-related challenges.

In their study, Zettl and colleagues (2020) use a model hydrophilic system — lactose monohydrate in a water/isopropanol mixture — to investigate the operational benefits of the Hielscher UP200St-TD-FlowCell in a continuous crystallization configuration.

Materials and Methods – Ultrasonic Lactose Crystallization on Bench-top

Materials

• Solute: α-Lactose monohydrate
• Solvent system: Deionized water and isopropanol in a ternary phase ratio optimized for lactose supersaturation
• Sonicator: UP200St-TD equipped with the flow-through sonication cell (TD-FlowCell)

Equipment Configuration
The UP200St-TD-FlowCell was configured in a closed-loop continuous crystallization circuit. A peristaltic pump circulated the supersaturated lactose solution through the sonication chamber, where ultrasound is imparted energy into the system. Inline temperature control ensured thermal stability during prolonged operation.

Ultrasonic lactose crystallization in continuous mode
(Study and image: ©Zettl et al., 2020)

Lactose Solubility
The saturation concentration of lactose, which is a disaccharide composed of glucose and galactose, in water at room temperature (commonly defined as 20–25 °C) is approx. 18.9 wt% at 25°C.
Lactose solubility increases with temperature, but not linearly. At 50°C, it rises to approx. 31 wt%, and at 70°C, it is approx. 45 wt%.

Protocol for Continuous Lactose Crystallization

Objective: Minimize system fouling and maximize runtime under continuous sonication.

Step-by-Step Protocol:

1. Preparation of Feed Solution
   • Dissolve α-lactose monohydrate in deionized water at 50°C to obtain a saturated solution.
   • For the aqueous lactose suspension, add 233 g of a-lactose per 1000 g of water
   • Stir the mixture until the material is fully dissolved.
   • Afterward, let the solution cool down to 25°C in order to obtain a saturated solution.
2. System Setup
   • Prime the flow circuit with the feed solution.
   • Set the flow rate to 60 mL/min (optimal for residence time of ~30 seconds in the ultrasonic chamber).
   • The feed suspension and the antisolvent are fed via two feeding ports into the process chamber of the ultrasonic flow cell.
   • Set the flow rate of 27g/ min of 15 wt % lactose suspension. Induce precipitation by adding 27g/min of pre-cooled isopropanol (12°C), resulting in a total mass flow rate of 54g/min. (The mass flow rate of 54g/min corresponds to a volume flow rate to 60 mL/min)
   • Initiate sonication at 100% amplitude. Maintain operating temperature between 25–30°C.
3. Crystallization Phase
   • Maintain continuous sonication without interruption. Hielscher sonicators are built for 24/7 operation.
   • Collect crystallized lactose from a downstream filter module every 60 minutes.
4. Post-Process Characterization
   • Analyze crystal morphology via SEM.
   • Quantify crystal size distribution using laser diffraction (D50 target: 80–100 µm).
   • Determine purity via HPLC (lactose monohydrate >98%).

Composition of Lactose Suspensions with Suspended Solid Mass Fraction in the Feed (w s,f), Suspended Solid Mass Fraction in the Product (w s,p), Dissolved Solid Mass Fraction in the Product (w d,p), Water Mass Fraction in the Product (w H2O,p), Isopropanol Mass Fraction in the Product (w IA,p), and Ethanol Mass Fraction in the Product (w EtOH,p) used in the study by Zettl et al., 2020.

Results and Benefits of Ultrasonic Lactose Crystallization

• Agglomeration Mitigation:
  Inline ultrasonication effectively suppressed crystal agglomeration, yielding well-separated, prismatic lactose crystals.
• Foam Reduction:
  Notably, ultrasound reduced surface foam formation — a common issue in antisolvent crystallizations involving alcohols — thereby improving volumetric throughput.
• Clogging Prevention:
  No fouling or clogging was observed during extended operation, confirming the role of acoustic cavitation in maintaining clean surfaces and preventing solid deposition within the flow cell.
• Continuous Runtime:
  The process can maintained in continuous operation, with crystal quality remaining consistent across time points.

Ultrasonic lactose crystallization: Lactose crystallized under different conditions: ultrasonic energy input, added carrageenan or whey (WPC) influences lactose crystal size
study and picture: © Sanchez-García et al., 2018.

Scale-up of Ultrasonic Lactose Crystallization

Hielscher inline sonicators, engineered in Germany to the highest industrial standards, offer a robust solution for continuous crystallization of lactose and other solids from supersaturated solutions. Designed for pharma-grade applications, these systems support precise control over nucleation and crystal growth, ensuring reproducible particle size distributions and process consistency. With linear scalability from lab to production scale, Hielscher ultrasonic reactors enable seamless process transfer, minimizing development time and cost. Coupled with comprehensive technical consulting, these sonicators provide tailored solutions that integrate easily into cGMP-compliant crystallization workflows—making them ideal for the pharmaceutical, biotech, and food industries.

The table below gives you an indication of the approximate processing capacity of our ultrasonicators:

Design, Manufacturing and Consulting – Quality Made in Germany

Hielscher ultrasonicators are well-known for their highest quality and design standards. Robustness and easy operation allow the smooth integration of our ultrasonicators into industrial facilities. Rough conditions and demanding environments are easily handled by Hielscher ultrasonicators.

Hielscher Ultrasonics is an ISO certified company and put special emphasis on high-performance ultrasonicators featuring state-of-the-art technology and user-friendliness. Of course, Hielscher ultrasonicators are CE compliant and meet the requirements of UL, CSA and RoHs.