Our Thermodynamic Spray Dryer Modeling – Your Digital Microscope In Spray Drying

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Spray drying is a leading technique for manufacturing amorphous solid dispersions (ASDs). At its core lies atomization: you dissolve an active pharmaceutical ingredient (API) and polymers in a solvent mixture, feed this solution into a spray dryer, and collect the resulting powder. But anyone who’s run a spray drying campaign knows that it’s an extremely complex and challenging process. Each parameter – temperature, flow rate, solvent composition – must be carefully tuned to achieve desired product stability and efficacy.

At amofor, we bring a holistic perspective to this complexity. Our approach? A digital twin powered by the PC-SAFT thermodynamic model. Imagine a digital microscope that lets you see how molecules (API, polymer, solvents) interact in real-time during the spray dryer process. This blog is about how we use PC-SAFT to tackle the challenges in spray drying processes – and why it matters for your next drug development project.

Spray Drying Challenges

Most spray drying setups, especially at CDMOs or pharmaceutical companies, rely on rigid, fixed parameters. They often apply the same temperatures, mass flows, and operating windows to virtually every API–polymer system, regardless of their unique characteristics. This “one-size-fits-all” approach ignores the unique chemical and physical properties of each formulation.

Here’s where things get tricky. Example solvent mixtures in spray drying: When solvent mixtures begin to evaporate, conditions can shift rapidly. One solvent will evaporate faster than another, altering the composition of the droplet and changing the interactions between the API and polymer in milliseconds. The result? Potential demixing within the particles, although the ASD matrix would be completely miscible. You may also end up with particles retaining undesirable levels of residual solvents, rendering the batch unsuitable for use.

Avoiding these problems requires a deeper understanding of the process – one that takes into account the interplay between engineering parameters and molecular-level interactions. This is what our PC-SAFT-powered SOLCALC software enables.

How PC-SAFT Solves Spray Drying Challenges

PC-SAFT serves as both an interaction model and a robust equation of state, capable of simulating vapor pressures, fugacities, and evaporation tendencies under various pressures and temperatures – particularly for complex mixtures. This means it not only lets you explore how molecules interact in real-time but also predicts how they’ll behave under different conditions. Specifically, with PC-SAFT, you can:

  • Model intermolecular interactions: Capture key molecular forces such as hydrogen bonding, van der Waals forces and polar interactions, which guide how molecules attract or repel each other.
  • Simulate phase changes dynamically: Solvents don’t simply vanish; they evaporate at different rates, altering droplet composition in real-time.
  • Predict Metastable States: ASDs are deliberately kept in a metastable state -thermodynamically inclined to crystallize but prevented from doing so by high energetic barriers. PC-SAFT models this behavior, helping you avoid risks like crystallization or phase separation.

In other words, PC-SAFT doesn’t just tell you where your system ends up – it shows you how it gets there and why it gets there. This comprehensive scientific understanding is critical for ASDs, where even small deviations can lead to costly failures.

Our Workflow: Tailor-Made Spray Dryer Design

Instead of relying on trial-and-error runs, we can run virtual design of experiments (DoE) to identify the optimal spray drying conditions. These simulations are tailor-made for specific API–polymer combinations, solvent mixtures, and equipment designs. How does it work?

  1. We start with minimal training data – just a few solubility points for the API in select solvents are enough. No chemical structures are needed!
  1. Within a day, we can parameterize the API’s interaction profile in PC-SAFT.
  2. We screen solvent mixtures to ensure perfect homogenous mixing with the ASD material and simulate how changes in parameters like inlet temperature or mass flow rates affect critical quality attributes (residual solvent levels, glass transition, and crystallization risks).
  3. Want minimal solvent residue? Higher throughput? Lower risk of sticking? We identify which parameters best achieve your targets.

This method eliminates guesswork and ensures every experiment is purpose-driven and informed by robust simulations.

Scaling From Lab-Stage To Late-Stage Manufacturing

Scaling up spray drying from a small lab setup to full-scale production introduces new challenges. Equipment size, mass flows, temperatures, recycling streams, and residence times can all affect outcomes. With PC-SAFT, we predict how these variables will impact outlet temperatures, crystallization risks, and powder properties – before you commit to large, costly trials.

For instance, by simulating how equipment scale impacts droplet behavior, we can fine-tune process parameters to maintain consistent powder quality across scales and provide solutions to mitigate risks during scale-up.

Over the past few years, we’ve applied this approach already to multiple client projects, from early phase 1 to advanced phase 3 clinical projects, each involving unique API-polymer-solvent combinations. These projects have consistently demonstrated fewer crystallization issues, less sticky residue, and reduced cleanup efforts, meeting regulatory requirements. Clients have also reported faster development timelines and significant cost savings.

Ready To Do Less To Achieve More?

Spray drying doesn’t have to be a black box. With PC-SAFT and our digital twin approach, we turn complexity into clarity, helping you achieve faster, smarter, and more cost-effective drug development.

Ready to see the difference? Contact Dr. Christian Lübbert today and take the guesswork out of spray drying.

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