LCTR pharmaceutical applications in crystallisation and amorphous solid processing

Introduction

The Continuous Manufacturing and Advanced Crystallisation (CMAC) Centre has utilised Laminar Continuous Taylor Reactor (LCTR) technology across several confidential projects to deliver both crystalline and amorphous particles that meet and often exceed the desired particle attributes for active pharmaceutical ingredients (APIs).

Background

CMAC Centre's Role

The CMAC Centre uses a Quality by Digital Design (QbDD) approach to develop models for digitally enhanced design space. Their ability to translate research into applied workflows helps integrate new technologies into the industry, delivering significant impact and value.

LCTR Technology

LCTR technology uses Taylor flow to control mixing, heat transfer, and residence time distribution, resulting in high-purity material production and efficient continuous processes. This technology reduces reaction time, improves productivity, and lowers CO2 emissions compared to traditional reactors.

Importance of Amorphous Materials in Pharmaceuticals

UK research on amorphous materials in pharmaceuticals focuses on improving drug solubility and bioavailability, addressing challenges in crystallization and stability. Projects like CMAC's Digital Design and Manufacture of Amorphous Pharmaceuticals (DDMAP) aim to develop predictive models and advanced processing techniques to enhance the efficiency and effectiveness of drug development

• Crystallization Challenges: avoiding crystallinity in the product is key to performance attributes
• Higher Solubility: amorphous materials dissolve faster and have higher solubility than crystalline forms, crucial for larger, less bioavailable drug molecules.
• Growing Market: increasing number of pharmaceuticals are marketed as amorphous forms (e.g., Zafirlukast, Cefuroxime Axetil, Quinapril Hydrochloride, Nelfinavir Mesylate).

Collaboration and Benefits

CMAC Tier 2 membership provides access to advanced research facilities, collaborative research opportunities, and specialized training sessions. Members also benefit from privileged access to research data and insights, enhancing their knowledge and industry connections.

LCTR is a well-established technology in fine chemicals and battery production, showcasing a proven pathway to scale-up from grams to tonnes. The aim of the collaboration is to replicate and translate these benefits within pharmaceutical synthesis and processes, using lactose as an exemplar compound, generating models that predict conditions for future processes, avoiding inefficient traditional trial-and-error approaches.

Project Summaries

CMAC has used the LCTR on a range of confidential live pharmaceutical compounds in development to investigate the unique properties of the LCTR and the benefits it can deliver. Below are summaries of selected projects:

• Project B:
  • Type of Process: Continuous formation of pure amorphous API
  • Technical Challenge: No crystallinity, processability downstream, yield, sustainable/green process
  • Outcome: Improved FFC vs existing process, high yields, span less than 1.5, reproducible between batches
  • Benefits: Filtration time reduced fivefold, FFC improvement from cohesive (2-4) to free-flowing (7-9)
• Project C:
  • Type of Process: Continuous formation of pure amorphous API
  • Technical Challenge: Proof of ability to scale-down process
  • Outcome: Particle attributes and yields matched
  • Benefits: Proven ability to scale-up and down (scale-down factor of 3)
• Project D:
  • Type of Process: Amorphous solid dispersion
  • Technical Challenge: Improved flow ability, reproducibility, downstream process ability
• • Outcome: Consistent product with improved flow ability, particle size, and span
  • Benefits: Improvement in FFC, filtration, and drying time

Conclusion

The CMAC team found the LCTR system easy to use, quick to set up, and capable of reaching a steady state in a short time. The control of shear and mixing regimes allows for precise control of particle attributes. The LCTR's excellent mixing and constant shear enable precise control of particle formation and growth across a range of compounds. This case study highlights the significant advancements and benefits achieved through the use of the LCTR in pharmaceutical development.