Quartz crystal microbalance

Tracking sub milisecond viscosity dynamics in biopharmaceuticals

news background
Prof. Diethelm Johannsmann

Prof. Diethelm Johannsmann

TU Clausthal, Germany

View Publication
Case studyProduct: MLA-3

Summary

Challenge: Researchers at TU Clausthal needed to measure rapid changes in the viscosity of protein solutions driven by electrochemical stimuli. Standard Quartz Crystal Microbalance (QCM) techniques involving frequency sweeps were too slow to capture these millisecond-scale kinetics.

Solution: The team utilized the MLA-3 to implement a "Fast Mode" measurement. By monitoring a single frequency rather than sweeping, the setup achieved a time resolution of 100 µs.

Outcome: The experiment successfully resolved the kinetics of pH-driven viscosity changes in Bovine Serum Albumin (BSA), determining a characteristic response time of roughly 7 milliseconds—dynamics previously invisible to slower measurement techniques.
Figure 1

A typical quarz crystal used for quartz crystal microbalance.

Tracking sub milisecond viscosity dynamics in biopharmaceuticals

Context: The Viscosity of Pharmaceuticals
In the development of pharmaceuticals, particularly high-concentration protein solutions like Bovine Serum Albumin (BSA), viscosity is a critical parameter. High viscosity can complicate manufacturing and injection, often caused by protein-protein interactions (PPIs).

To study these interactions, researchers use Electrochemical Quartz Crystal Microbalance (EQCM). While typically used to measure mass deposition, EQCM can also analyze the viscoelasticity of the bulk liquid near the sensor surface. However, analyzing how quickly these properties change in response to electrical stimuli requires exceptional speed.

The Challenge: Speed vs. Precision
Standard electrochemistry relies heavily on transient measurements to avoid convection effects. However, conventional impedance analysis for QCM is limited by the physics of the resonator.

  • Frequency Sweeps: A typical impedance sweep takes roughly 1 second to avoid "ringing" artifacts, which is far too slow for millisecond-scale kinetics.
  • Ring-down: While faster, ring-down methods require averaging that typically limits data acquisition to fractions of a second.

The research team at TU Clausthal aimed to observe millisecond-scale viscosity changes triggered by switching the electrode potential, requiring a data acquisition rate significantly higher than standard commercial instruments could provide.

The Solution: "Fast Mode" with MLA-3
To overcome the speed limit, the researchers employed the MLA-3 from Intermodulation Products to implement a specific "Fast Mode".

Instead of sweeping across a frequency band, the MLA-3 was configured to monitor the electrical admittance at a single fixed frequency near the resonance peak.

  • High-Speed Acquisition: This approach allowed the instrument to acquire frequency readings at a rate of 10,000 Hz (one point every 100 µs).

  • Noise Reduction: While high-speed measurements inherently increase noise, the stability of the MLA-3 allowed for extensive averaging. By accumulating data over repetitive cycles (up to 12 hours), the team reduced the root-mean-square noise to approximately 30 mHz, comparable to slow, high-precision impedance analysis.

The Outcome: Resolving 7ms Kinetics
The study focused on BSA solutions where the pH was modulated electrically. By switching the electrode potential, the researchers induced local pH changes, which in turn altered the solution's viscosity.

Using the MLA-3 in Fast Mode, the team successfully plotted the kinetics of the viscosity change (Δη′). The data revealed that the solution viscosity follows the pH change with a characteristic response time (τ) of 7.1 ± 1 ms.

This proved that the MLA-3 could resolve kinetic processes faster than the diffusion time of ions in the double layer, confirming that the viscosity changes were due to intrinsic protein dynamics rather than simple adsorption artifacts.

Back to Quartz crystal microbalance