Solvent Selection and Recovery: Practical Experience and Reflections in Intermediate Synthesis

In the process of pharmaceutical intermediate process development, if I were to say which step is most easily overlooked in the early stages and most often leads to problems later on, it would definitely be solvent selection.

In many projects, solvents are often treated simply as a “reaction medium” at the beginning:

—If it dissolves the reactants, allows the reaction to proceed, and has been used in the literature, it’s considered acceptable.

However, those who have truly experienced pilot-scale and large-scale production understand that the choice and recovery method of solvents often fundamentally determine whether a project can successfully move towards industrial production.

Based on our experience in actual projects, more than half of the scale-up failures, cost overruns, or compliance issues are rooted in solvent-related problems. These problems are often not due to the reaction itself being unsuccessful, but rather because “the solvent selection was not considered thoroughly enough” in the early stages.

In this article, I want to share some real-world insights on solvent selection and recovery in intermediate synthesis, based on our frontline experience.

Why is Solvent Selection Particularly Important at the Intermediate Stage?

At the active pharmaceutical ingredient (API) stage, the solvent system is usually relatively mature and fixed.

But the intermediate stage is completely different:

• The synthesis route is not yet finalized.
• There are many steps, and the sources of impurities are complex.
• Process changes are relatively frequent.
• It requires both rapid progress and room for future scale-up.

This means that solvent selection at the intermediate stage is actually laying the foundation for process stability for the next three to five years.

We have seen many projects like this:

• Smooth sailing in the laboratory stage
• Concentrated solvent-related problems erupt during pilot-scale and large-scale production
• Ultimately, the route development has to be adjusted or even redone.

Tracing the reasons, many times it’s simply because an “easy-to-use in the lab” solvent was chosen in the early stages.

Solvents that are “Convenient” in the Lab May not be Suitable for Scale-Up

This sounds very realistic, but it’s a lesson many people only learn after making mistakes. In a laboratory setting, the following solvents are very convenient to use:

• DCM (Dichloromethane)
• DMF (N,N-Dimethylformamide)
• NMP (N-Methylpyrrolidone)
• DMSO (Dimethyl sulfoxide)

However, when scaling up to large-scale production, they often present a series of challenges:

• Difficulty in controlling residues
• High recovery costs
• Significant safety and environmental pressures
• Persistent compliance risks

We once handled a project where the key reaction showed excellent selectivity in DMF, and the laboratory data was very promising.  However, once scaled up to kilogram quantities, problems arose:

• DMF has a high boiling point, significantly extending the removal time.
• Intermediate product residual solvent levels repeatedly exceeded limits.
• Vacuum drying time had to be extended for each batch.

Ultimately, the client had to readjust the solvent system at the intermediate stage, delaying the overall project progress by at least two months.

This lesson is clear: in intermediate process development, solvent issues are not just chemical problems, but also engineering problems.

Mature Solvent Selection must be Integrated Throughout the Entire Process

When we conduct route assessments internally, solvent selection is never just about “can this reaction be done,” but rather requires answering at least the following questions:

1️⃣ Can this solvent be reliably recovered in the future?

Is it suitable for conventional reduced-pressure distillation? Does it easily form azeotropes with impurities? Will impurities accumulate after multiple recovery cycles?

If a solvent is theoretically recoverable, but the actual recovery purity is unstable, it is practically unusable in industrial production.

2️⃣ Will it amplify impurity risks?

Some solvents may appear “clean” in the laboratory, but when scaled up, they may:

• Participate in side reactions
• Promote the formation of certain impurities

These risks are particularly fatal at the intermediate stage, as impurities can easily be carried into subsequent steps, causing cascading problems.

3️⃣ Is it compatible with subsequent steps?

If a solvent performs well in the current step, but:

• Must be completely replaced in the next step
• Or leads to difficulties in intermediate crystallization

Then the overall process efficiency will often be significantly reduced.

Solvent Recovery is not a “Nice-to-Have,” but a Critical Component of Cost

In actual production, the proportion of solvent costs in the raw material costs of intermediates is often underestimated. In some projects, our calculations have shown that:

Solvent procurement + processing + losses

can account for more than 30% of the cost per kilogram of intermediate.

Therefore, what’s truly important is not just “whether it can be recycled,” but rather:

Can the recycled solvent be used reliably, safely, and repeatedly?

We have adopted the following strategies in several projects:

• Setting a target for the number of solvent reuse cycles during the process development phase
• Establishing separate impurity trend monitoring for recycled solvents
• Clearly defining which steps allow the use of recycled solvents and which require fresh solvents

These strategies rarely appear in academic papers, but they significantly impact the commercial viability of projects.

From a Compliance Perspective, Solvent Selection Must Be Considered “Upfront”

With the implementation of guidelines such as ICH Q3C, Q3A/Q3B, regulatory agencies are paying significantly more attention to solvent issues.

Now, when we assist clients in preparing submission documents, we are frequently asked:

• Why was this solvent chosen at the intermediate stage?
• Have lower-risk alternatives been evaluated?
• How is cross-contamination from recycled solvents controlled?

This reflects a trend: solvent selection is no longer simply an internal technical decision, but has become a key area of ​​auditing and inquiry.

Final Thoughts

A mature intermediate process team will not treat solvents as mere “background.”

Instead, they will clearly determine:

• Which solvents are suitable for rapid advancement
• Which are suitable for stable production
• Which are convenient to use but have high long-term costs

In intermediate synthesis, solvent selection and recycling are not just part of environmental requirements or cost control, but a core process decision that runs through R&D, scale-up, compliance, and the supply chain.

If you are currently working on an intermediate project, or are repeatedly adjusting for scale-up, cost, or process stability issues, you might want to reconsider:

Were the solvents chosen initially truly well-considered for the final production?

Looking for a reliable partner in solvent selection and recovery for intermediate synthesis?

We support pharma and biotech companies with process-validated solvent strategies, recovery feasibility assessment, and scalable intermediate manufacturing.

👉 Talk to our technical team to discuss your process requirements.

Email: sunqian0123@gamil.com
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