Technological innovation and application progress of continuous flow technology in the pharmaceutical field

Ⅰ. Core Advantages and Driving Factors of Continuous Flow Technology

Continuous Flow Technology (CFT) realizes the continuous process of the entire chemical reaction through equipment such as microchannel reactors and fixed beds. Its core advantages lie in process intensification and precise control, which is significantly different from the traditional batch production. The Yuanhuai continuous flow microreactor can effectively solve users' pain points:

Enhanced safety: Microreactors have a small liquid holding capacity (typically <100 mL), enabling safe handling of high-risk reactions such as nitrification and diazotization.

Efficiency breakthrough: The mass transfer and heat transfer rates are increased by 10 to 100 times, and the reaction time is shortened from the hour level to the minute level or even the second level

Quality consistency: The push-flow characteristic eliminates the amplification effect, and the yield deviation from the laboratory to industrial production is less than 5%

Green manufacturing: Reduce solvent usage by 30% to 70% and lower carbon emissions by more than 50%

Ⅱ. Classification and Application Scenarios of Key Technologies of Continuous Flow Technology in Pharmaceutical Production

According to the characteristics of the reaction system, continuous flow technology can be classified into the following types:

Gas-liquid reaction system

Application case: Carbonylation reactions involving CO/CO₂, such as the continuous synthesis of paroxetine intermediates (yield 92%, purity >99%)

Technological breakthrough: The Tube-in-Tube (Tube-in-tube) gas loading device achieves efficient gas-liquid mixing

2. Solid-liquid reaction system

Application case: Palladium-catalyzed Suzuki coupling reaction, catalyst life extended to over 500 hours (traditional batch <50 hours)

Innovative design: SiliaCat-DPP-Pd fixed-bed reactor, palladium residue <30 ppb

3. Gas-liquid-solid reaction system

Application case: Continuous hydrogenation reaction system, integrating electrolytic water hydrogen production technology to replace high-pressure hydrogen cylinders

Extended application: Deuterated drug synthesis, precisely introducing deuterium atoms by replacing heavy water

4. Liquid-liquid reaction system

Application case: Synthesis of hydantoin compounds by Bucherer-Bergs reaction, with the yield increased to 95% (70% in the traditional batch reaction)

High-pressure intensification: The reaction time is shortened to 10 minutes under the conditions of 120℃ and 20 bar

5. Multiphase integration system

Innovative model: The SPS-FLOW system developed by Wu Jie's team from the National University of Singapore combines continuous flow and solid-phase synthesis to achieve six-step fully automated production of Prexasertib (with a total yield of 65%).

Derivatization potential: By modularly replacing reaction steps, 23 tetrazole derivatives were synthesized (yields 43%-70%)

Ⅲ. Quality Control and Supervision Framework for Continuous Flow Pharmaceuticals

The core requirements of the ICH Q13 guideline

Batch definition: It allows batch definition by time or material flow rate, flexibly adapting to market demands

Process Analysis Technology (PAT) : Online monitoring of parameters such as pH, temperature, and concentration, with real-time feedback and adjustment

Equipment verification: It is necessary to prove the process stability of continuous operation for more than 100 hours

2. Typical case: Continuous synthesis of tetrazole drugs

Optimization strategy: Optimize the reaction path through thermodynamic calculation to suppress the generation of by-products such as formamidine (increase the yield from <20% to 84%)

Process safety: The continuous use of TMSN3 (highly toxic azide reagent) reduces the risk of exposure

Ⅳ. Technical Challenges and Innovative Solutions

1. Compatibility issues of the reaction system

Bottleneck: Solvent/reagent conflicts in multi-step reactions (such as incompatibility between polar solvents and metal catalysts)

Breakthrough: Modular design for solid-phase synthesis, enabling independent optimization of each step (such as compatibility with LDA-sensitive reagents in Prexasertib synthesis)

2. Equipment blockage and maintenance costs

Innovative materials: The corrosion resistance of the silicon carbide microchannels in the Yuanhuai reactor has been enhanced by 10 times, and its service life exceeds 5 years

Online Cleaning (CIP) : Integrated pulse backflushing system, maintenance cycle extended to 30 days

3. Supervision and standardization lag behind

Countermeasures: Under the FDA's "Quality from Design (QbD)" framework, establish a database of critical quality attributes for continuous production (CQAs)

Industry collaboration: Pfizer, Eli Lilly and other enterprises jointly released the "Continuous Pharmaceutical White Paper" to promote GMP adaptation

Ⅴ. Future Development Trends and Research Directions

1. Intelligent integration: AI-driven self-optimization system for response parameters (such as the closed-loop loop control platform developed by MIT)

2. Green Chemistry Extension: Optical/Electrical continuous flow systems for C-H bond activation reactions (Reducing carbon emissions by 90%)

3. Biopharmaceutical fusion: Continuous encapsulation technology of lipid nanoparticles (LNP) for mRNA vaccines

4. Modular factory: Containerized continuous production units, enabling distributed pharmaceutical manufacturing