Hydramotion’s ReactaVisc was deployed with AstraZeneca to resolve critical gaps in understanding the rheology of a caffeine crystallisation system. The study demonstrates how real-time viscosity measurement exposes reaction kinetics, stabilises process development, and strengthens the pathway from lab trials to plant-scale operation.
Crystallisation Process Overview
Crystallisation is a core operation in pharmaceutical synthesis, where product quality is defined by polymorph, particle size distribution, and solid-phase structure. Achieving these outcomes requires precise control of nucleation and growth under tightly constrained thermal and mechanical conditions. Rheology is often the earliest and most sensitive indicator of how a crystallising system is behaving, yet it is also one of the least monitored parameters in practice.
AstraZeneca set out to characterise crystallisation behaviour in a controlled laboratory environment using caffeine as the model compound. Caffeine exhibits polymorphism, forms hydrates, and shows complex nucleation and growth kinetics, making it an appropriate stand-in for more industrially sensitive APIs.
The ReactaVisc real-time reaction viscometer was deployed alongside a particle size analyser to gain a deeper understanding of the reaction. The probe-based nature of the viscometer means direct insertion into the reactor flask to track the reaction in real time.
Challenges with Offline Measurement
1. Limited Visibility Into Early-Stage Structure Formation
Conventional lab viscometers only offer point-in-time measurements and struggle to track the rapid, nonlinear viscosity changes that occur as solids begin to form. This lack of resolution leaves critical reaction events effectively invisible.
2. Equipment-Dependent Behaviour
Crystallising systems are highly sensitive to geometry, mixing, heat transfer, and residence time. Without real-time rheological data, distinguishing intrinsic reaction kinetics from equipment effects is difficult.
3. Scale-Up Uncertainty
Small-scale crystallisation trials often fail to predict plant behaviour because key rheological markers such as onset of structure, peak viscosity, and yield-stress development are not captured.
Solution: Deploying ReactaVisc for Real-Time Viscosity
The ReactaVisc reaction vessel viscometer is a high-performance, research-grade instrument for the continuous on-line measurement of fluid viscosity in laboratory or pilot-scale process assemblies. The ReactaVisc maintains accuracy under all reaction conditions and is designed to fit easily among the often overcrowded array of devices on these vessels. It can also be easily adjusted to suit varying fluid depths using Hydramotion’s special HydraGland™ vessel adaptor.
| RV3 Dimensions | RV3 Reaction Vessel Mounting Example |
High accuracy and repeatability is achieved mainly through the use of high stability materials and sensory techniques which exclusively measure true shear viscosity whilst avoiding secondary effects caused by temperature, flow, solid particles or bubbles.
All ReactaViscs have an integral thermometer to simultaneously keep track of both viscosity and temperature, and by eliminating thermal effects, temperature corrected viscosity will help reveal true viscous changes taking place in the liquid.
There are no moving parts, seals or bearings and consequently routine maintenance is not required. The instrument can be mounted in any vessel of suitable dimensions fitted with an appropriate connector or adaptor.
AstraZeneca integrated Hydramotion’s ReactaVisc directly into the crystallisation vessel alongside a particle-size probe. This provided simultaneous visibility into:
- Continuous viscosity evolution throughout nucleation, growth, and aggregation
- Emergence of solid structures that normally remain undetected
- Coupling between particle formation and bulk rheology
- Reaction kinetic signatures not resolvable using offline tools
The probe’s sensitivity allowed the team to see viscosity rise in direct correspondence with early crystal formation - a clear indicator of structure development.
The researchers also found they were able to determine the peak viscosity and correlate it with the product's yield stress.
Key Findings
1. ReactaVisc Captures the True Onset of Crystallisation
As the solid phase began to form, viscosity increased sharply. ReactaVisc resolved these transitions in real time, making it possible to observe the crystallisation mechanism rather than infer it after the fact.
2. Real-Time Diagnosis of Rheological Instabilities
Researchers identified several reaction conditions that produced undesirable rheology shifts. With live viscosity data, they adjusted parameters during the experiment instead of waiting for batch results.
3. Peak Viscosity Correlates With Yield Stress
The team linked the maximum viscosity point to the system’s yield stress - a reliable marker for endpoint structure and batch-to-batch consistency.
4. Rheology + Particle Size = Complete Process Picture
Pairing ReactaVisc with particle-size data created a unified view of structural and mechanical evolution, strengthening the kinetic model.
Impact on Scale-Up
Real-time viscosity tracking allowed AstraZeneca to identify scale-critical behaviours:
- Onset and rate of structure formation
- Maximum shear resistance regions
- Transition points that drive downstream filtration, drying, and handling
These insights were translated into a scale-up framework, reducing uncertainty when moving from lab vessels to pilot and plant equipment. The study demonstrated that viscosity is not just a descriptive parameter, it is a control-relevant signal that strengthens process understanding and reduces development risk.
Whitepaper published by Frans L. Muller, AstraZeneca available here:
On the rheological behaviour of batch crystallisations
Or download pdf below: