For decades, spray drying has relied on a small set of “gold-standard” solvents. If you wanted high solubility, fast evaporation, and robust processing, mixtures containing dichloromethane (DCM) or methanol were the obvious choice. They worked reliably and predictably.
Today, the regulatory and toxicological landscape is changing. Solvents that were once considered acceptable during manufacturing are now being re-evaluated. And when a solvent moves closer to a critical carcinogenic classification, the consequences for drug development are immediate.
This is why solvent selection in spray drying is becoming an urgent challenge in amorphous solid dispersion (ASD) manufacturing.
The Spray-Drying Solvent Problem
In spray drying, solvents are chosen because they solve several physical problems at the same time:
- They dissolve both API and polymer at high concentrations
- They evaporate rapidly during atomization
- They enable high throughput and good particle formation
DCM checks all these boxes. It has a low boiling point, high volatility, and excellent solubilization power for many poorly soluble APIs and polymers.
But it has two critical drawbacks: it is hard to replace and toxic.
Methanol is also toxic, but its acceptable residual limits are still relatively high (3,000 ppm), which is achievable with standard secondary drying strategies. DCM is different: its acceptable limits are already much lower (600 ppm), and if classifications tighten further, single-digit ppm targets become realistic.
These low limits are particularly problematic because DCM is difficult to remove from amorphous matrices. It has a relatively large hydrodynamic radius and interacts strongly with many ASD systems, which slows diffusion and leads to solvent trapping in the solid dispersion.
Reducing residual DCM from around 50,000 ppm to 600 ppm may already require aggressive conditions and one to two days of secondary drying. Pushing further, from 600 ppm to 10 ppm, is a completely different regime, where drying times can increase from days to weeks. It blocks equipment, delays development timelines, increases energy consumption, and raises the risk of crystallization or degradation under harsh conditions. In other words: regulatory limits turn into process limits.
Why “Just Switching the Solvent” Isn’t That Simple
When DCM becomes a problem, the instinct is to swap it for a “safer” solvent and move on. In practice, this rarely works because the solvent isn’t just a carrier. It controls the entire pathway from feed solution to solid particle.
A new solvent changes what dissolves, what stays mixed, and what happens inside the droplet while it dries. A blend that looks perfectly homogeneous in the feed can demix within milliseconds once the fast-evaporating component leaves first. And the final powder can trap residual solvent very differently depending on how strongly that solvent interacts with the ASD matrix.
Most formulation teams rely on a small number of standard solvent systems. They have deep experience with those systems, but very little beyond them. Take water: For poorly water-soluble APIs, water is the strongest anti-solvent imaginable. And it is associated with crystallization risk, humidity sensitivity, and stability problems. So most teams exclude it by reflex. It’s understandable but incomplete.
In carefully designed solvent mixtures, small amounts of water can dramatically enhance solubility. Water forms strong hydrogen-bonding networks that can stabilize APIs and polymers in solution when combined with an appropriate lead solvent. The key is ratio and context.
Water may be problematic during storage, but during manufacturing it can be a powerful co-solvent. It is non-toxic, non-flammable, non-explosive, and regulator-friendly. When used in controlled amounts, it can unlock solubility regimes that would otherwise require far more hazardous solvents.
So the real question isn’t “What’s the safer replacement for DCM?”
It’s: Which solvent system stays soluble, stays mixed, stays spray-dryable along the full evaporation trajectory, and is non-toxic? It’s a formulation design question.
In Silico Screening of Safer Solvent Systems
This is where a predictive, physics-based approach is very helpful.
At amofor, we use thermodynamic modeling to screen and design alternative solvent systems to avoid extensive experimental trial-and-error work, implemented through our PC-SAFT-based SOLCALC software. The goal is to find a solvent system that remains viable across the entire spray-drying workflow.
Step 1: Broad Solvent Screening
We start with a curated database of roughly 60–70 solvents that are suitable for pharmaceutical spray drying. These solvents cover a wide range of polarities, hydrogen-bonding capabilities, and volatilities. The database combines literature data with experimentally validated big data collections comprising over 2,500 solubility points across 150 APIs (small molecules).
Using PC-SAFT-based modeling, we predict the solubility of the API and relevant polymers in these pure solvents and rank them by solubilization potential. This immediately narrows the search space to the most promising candidates.
Step 2: Binary and Ternary Solvent Mixtures
Pure solvents are rarely sufficient. The real leverage lies in solvent mixtures. We systematically explore binary and, if needed, ternary solvent systems. The key questions are:
- Does the mixture show a solubility maximum?
- At which composition is solubility highest?
- How sensitive is solubility to small composition changes?
This step often reveals non-intuitive results. Adding a second or third solvent can dramatically increase solubility, even if that solvent alone is a poor solvent for the API. Here, more environmentally friendly components, such as water or low-molecular alcohols, can become powerful enablers.
Step 3: From Solubility to Spray-Drying Reality
High solubility is necessary, but it is not sufficient. That is why using the same physical modeling framework, we evaluate how candidate solvent systems behave during and after drying, including:
- Evaporation behavior and composition shifts during drying
- Risk of demixing inside the particle
- Residual solvent accumulation and removability
- Effects on wet glass transition temperature and plasticization
- Humidity sensitivity and implications for shelf life
These properties are tightly interconnected. A solvent system that improves solubility but significantly lowers the wet Tg may increase crystallization risk. A solvent that evaporates more slowly may improve homogeneity but complicate residual solvent removal.
By integrating all of these factors, we identify solvent systems that are not only less toxic, but stable, manufacturable, and regulatorily robust. Greener solvents are only an improvement if the final formulation remains viable as a solid drug product.
Practical Takeaways for ASD Formulators
For formulation teams, this means:
- Solvent choice must move upstream in development
- Secondary drying cannot be the only mitigation strategy
- Dependency on a single “gold-standard” solvent is a hidden risk
- Predict-first screening can save months of experimental rework
Those who address it proactively will gain flexibility. Those who wait may find that their proven process no longer fits within acceptable limits.
At amofor, we help formulation teams navigate this transition with mechanistic understanding and clear solvent indications.
Contact our experts and schedule a free demo to see how your formulation team can adopt this method!
