Process Chemistry Research Development & Scale-up Synthesis

Critical to the drug discovery and development process, synthetic chemistry and scale-up synthesis are essential to the successful execution of any small molecule program. Charles River has been delivering scale-up and process chemistry services to drug developers for over 20 years, with a strong track record of success. Our experienced process chemistry services team regularly support medicinal chemistry programs in the supply of key late-stage building blocks at scales that enable rapid SAR development, in addition to supplying larger amounts of active pharmaceutical ingredients (API) that allow for more extensive in vivo characterization studies, including preclinical non-GLP safety toxicology.

Process Chemistry Services

Our Process Research and Development chemists work with dedicated purpose-built reactor rigs, to develop safe scalable processes that can efficiently enable large-scale synthesis. Our scale-up chemistry team has extensive experience taking synthetic sequences from medicinal chemistry programs that have previously only produced mgs of material, going on to design and optimize synthetic sequences that have delivered kgs. Drawing upon a wide range of synthetic expertise and technologies, our chemists are also supported in their synthesis planning with access to SciFindern, which includes full retrosynthetic analysis powered by CAS and ChemPlanner®, helping to increase the likelihood of a “right first time” approach to synthetic chemistry execution.

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Discovery chemists guide key decisions by considering factors such as client intellectual property (IP) generation, compound stability for in vivo studies, solubility and other poor property issues, weak exposure in an animal, and off-target selectivity.
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Scale-Up Chemistry and Synthesis

Our chemical scale-up group can support all classical small molecule chemistries, prosecuting large-scale synthesis in house at scales that can deliver up to 2 kg API in a single batch. Our maximum scale of operation sees us working with 20 L jacketed reactor systems, capable of operating in the -40 °C to +150 °C temperature range. For highly sensitive chemistries requiring -78 °C cryogenics, we can support single batch processing at up to 10 L scale. Our scale-up synthesis and process chemistry services are available under either FTE or FFS business models, subject to research phase, client needs, and project requirements.

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Key Process Chemistry Services Capabilities

  • Optimization and, as necessary, redesign of synthetic routes (PR&D), to ensure reproducible and robust synthesis that consistently delivers quality in scale-up synthesis
  • Scaled-up isolation and purification, including possible development of chromatography-free routes, with strong emphasis on process control and crystallization to attain the specified standards of purity with control of any side products
  • Solid form characterization and development, building a robust understanding and control of batch-to-batch crystalline variability, ensures materials delivered in vivo consistently deliver the expected solubility, absorption, and exposure levels
  • Isolation and characterization of side products, to help understand process liability and build in key points of hold and control
  • Detailed risk assessments and reviews, including (where appropriate) generation of early calorimetric data to help de-risk large-scale manufacture.
  • Provision of full technical transfer documentation and support, ensuring efficient transfer of the developed chemistry to facilitate third-party cGMP manufacture
  • Management of other specialist CROs & CDMOs in the further development and supply of materials suitable to enter GLP studies and beyond.

Process & Scale-up Chemistry Equipment

  • Radleys reactor ready pilot system, 5-10-20 L jacketed vessels
  • Huber Unistat 405 heater/chiller (-40 °C to +150 °C)
  • 5-20 L flange-flask reaction glassware
  • High-capacity Interchim Puriflash® 4100 & 4125
  • Buchi R220 Pro (20 L)
  • Mettler Toledo EasyMax 402, (100/400 mL) including calorimetry probe

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Frequently Asked Questions (FAQs) About Scale-Up Chemistry and Process Chemistry Services

  • What size of scale-up chemistry can you support?

    We have dedicated jacketed reactor rigs up to 20 L scale, which typically allows us to work in the 500 g - 1.5 kg batch scale, subject to solubility and required reaction volumes. During process optimization, these parameters are typically assessed and optimized to maximize processing efficiency and scale-up synthesis batch up costs.

  • Are you able to fully support the preclinical development of a small molecule candidate?

    We are able to fully manage the onward development of preclinical candidates, including all aspects of scale-up chemistry, pharmaceutical development, and safety assessment. Under our One Step program, we can manage the journey from candidate to clinic-ready, with in-house process research and scale-up chemistry, combined with tailored pharmaceutical sciences development (materials sciences and formulation). We work through managed partners for manufacture of cGxP materials, which will fund GLP safety toxicology and generate the data required for IND/CTA. To date, more than 100 preclinical candidates worked on by Charles River scientists have reached the clinic, with over a third achieving proof-of-concept and beyond.

  • Why is it necessary to carry out polymorph (solid form) screening at this early stage of preclinical development?

    Batch-to-batch variance of solid form can have a major impact on the observed solubility, dissolution rates, and pharmacokinetics of APIs. When entering development, it is critical that every batch of material prepared consistently delivers the absorption and exposure characteristics expected, so that when moving through PK, PK/PD, dose escalation, maximum theoretical dose (MTD) DRF, and finally through 28-day repeat dosing, all studies achieve their targeted goals.

    Learn more about Polymorph Screening

  • What are the typical timelines for a small molecule scale up project?

    Whilst no two programs are alike, typical small molecule development projects, with a nominal 5-6 step synthesis, often take between 3-5 months in development to ensure that the route and process developed is both robust and safe to scale. This would take you from g scale medicinal chemistry to kg scale development, ready to support IND studies. Synthetic complexity in the candidate will almost certainly influence achievable timelines, however our team will be able to provide more detailed assessment and guidance once chemistry has been shared. Talk to our chemistry services team to receive a personalized estimate.