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Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions
June 9, 2025
Condensation: Taming Hydrazine
- Reaction: An α-cyano ketone reacts with hydrazine to form a pyrazole ring.
- Innovation: A microreactor enabled precise dosing of hydrazine, cutting excess from 3× to 1.1× and slashing exposure risks .
Nucleophilic Aromatic Substitution (SNAr)
- Challenge: A high-temperature reaction requiring careful solvent exchange.
- Solution: An automated rotary evaporator switched solvents mid-process, enabling seamless integration with downstream steps .
Crystallization & Salt Formation
- Continuous Crystallization: Two mixed-suspension vessels replaced batch crystallization, improving purity and yield (89.6% overall) .
- Final Step: Boc deprotection and lactate salt formation yielded the monohydrate crystal form required for clinical use .
Table 2: Key Metrics of the Continuous Process
| Step | Yield (%) | Purity (%) |
|---|---|---|
| Pyrazole Formation | 95 | 99.5 |
| SNAr Reaction | 92 | 98.8 |
| Crystallization | 96 | 99.9 |
| Overall | 89.6 | >99.5 |
| Reference |
Why This Matters: Beyond Prexasertib
The success of this project has broader implications:
Safety: Operators avoided direct contact with hydrazine and genotoxic intermediates .
Regulatory Compliance: Real-time Process Analytical Technology (PAT) ensured CGMP compliance, with 24/7 quality monitoring .
Scalability: The entire process ran in standard lab fume hoods, proving that large-scale production doesn’t require massive infrastructure .
Table 3: Advantages of Continuous-Flow CGMP
| Advantage | Impact |
|---|---|
| Reduced Waste | 70% less solvent usage |
| Faster Time-to-Market | Weeks instead of months for scale-up |
| Flexibility | Easily adaptable to other APIs |
| Reference |
The Future of Pharmaceutical Manufacturing
The prexasertib project is a milestone in the shift toward continuous manufacturing. Companies like Pfizer and Novartis are already adopting similar systems for drugs like aliskiren and sildenafil. With advancements in automation and AI, future factories could produce personalized therapies on demand, slashing costs and environmental footprints .
Conclusion: A New Era of Drug Development
The kilogram-scale synthesis of prexasertib under continuous-flow CGMP conditions isn’t just a technical achievement—it’s a blueprint for the future. By merging chemistry, engineering, and smart monitoring, this approach addresses the critical challenges of modern drug development: safety, scalability, and sustainability. As the industry embraces these methods, patients stand to benefit from faster access to life-saving therapies.
References
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Sharma, U. K. & Van der Eycken, E. V. Flow Chemistry for Heterocycles (Springer, 2018).
Angius, G. et al. Oncotarget 8, 111026–111040 (2020).
Alcazar, J. et al. Flow Chemistry in Drug Discovery (Wiley, 2021).
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Johnson, M. D. et al. React. Design & Control (Springer, 2021).