Process development in medicinal chemistry and chemical synthesis refers to the transition from discovery-phase chemistry (where compounds are made on a milligram to gram scale for biological evaluation) to scalable, robust, safe, and cost-effective synthetic routes suitable for preclinical, clinical, and eventually commercial production.

1. Medicinal Chemistry Context

  • Goal: Generate diverse analogs for SAR (structure–activity relationship) studies.

  • Scale: Milligram to gram.

  • Focus: Speed, novelty, flexibility, and structural diversity.

  • Approach: Tolerate low yields or expensive reagents, since speed to data is more important.

  • Typical Characteristics:

    • Multistep linear syntheses.

    • Limited purification strategies (e.g., chromatography, preparative HPLC).

    • Minimal emphasis on scalability, safety, or cost.

3. Bridging the Two

Medicinal chemistry routes are often unsuitable for scale-up, so our process chemists redesign routes:

  • Replace exotic reagents with safer, readily available ones.

  • Redesign protecting-group strategies or avoid them.

  • Develop catalytic (metal, biocatalytic, photochemical) alternatives.

  • Ensure crystallinity and polymorph control for regulatory approval.

  • Perform cost-of-goods (CoG) analysis.

4.Key Activities in Process Development

  1. Route Scouting & Evaluation

    • Assess multiple synthetic options for scalability.

  2. Reaction Optimization

    • Yield, selectivity, solvent choice, reagent economy.

  3. Safety & Environmental Assessment

    • Thermochemical screening, solvent/reagent hazard analysis, waste minimization.

  4. Purification & Isolation

    • Crystallization, salt formation, polymorph screening.

  5. Scale-Up Trials

    • From lab (10–100 g) → kilo lab → pilot plant → commercial scale.

  6. Regulatory Compliance

    • ICH guidelines for impurities, API specifications, cGMP considerations.

2. Process Chemistry / Development Chemistry

  • Goal: Deliver practical, safe, and scalable synthetic routes.

  • Scale: 100 g → kilograms → tons.

  • Focus: Safety, cost, robustness, reproducibility, regulatory compliance.

  • Approach: Optimize synthetic efficiency and product quality.

  • Typical Characteristics:

    • Route scouting: finding shorter, convergent pathways.

    • Step economy and green chemistry (solvent replacement, atom economy).

    • Robust purification (crystallization instead of chromatography).

    • Control of impurities (genotoxic, isomeric, polymorphic).

    • Process analytical technology (PAT) for real-time monitoring.

    • Risk assessments: thermal stability, hazardous reagents, scalability issues.