Phase Appropriate Crystallization Process Development

Our dedicated group of crystallization experts has a legacy of success in particle engineering and technology transfer. Experienced scientists and engineers offer a fit-for-purpose approach to crystallization processes adapted for each stage of pharmaceutical development. We take a quality by design approach to crystallization process development, aiming for the consistent preparation of batches with the desired purity, crystal form and particle properties. We enable reproducible and streamlined downstream processes, including filtration, drying, transfer and storage of the bulk drug substance, as well as critical performance attributes for drug product formulation and manufacturing.

Design of Crystallization Process

Solid form understanding and preliminary solubility data must be gathered to identify possible crystallization techniques and solvent systems for the design of a scalable process. Standard solution crystallization techniques include cooling, antisolvent addition, pH swing, reaction and evaporation. We collect metastable zone width information in systems of interest to determine suitable seeding conditions and control strategy. Online and offline monitoring during crystallization may also provide valuable insight into nucleation and growth of the crystals as well as the polymorphic form. Our scientists have access to specialized equipment for crystallization process development, including controlled laboratory reactors from 50 mL to 2 L, equipment for solubility and metastable zone width determination and in situ or at-line monitoring of crystal form, supersaturation, nucleation, particle size and morphology.

Process Analytical Technology and Quality by Design

Our scientists have access to process analytical technology equipment to allow development and optimization of crystallization using a quality by design approach:

  • Solubility determination capability
    • Crystal16™
    • Solvent addition
    • Gravimetric
    • Equilibrium solubility with analysis of supernatant by UV-vis, HPLC or UPLC
  • Controlled laboratory reactors from 50 mL to 2 L scale
    • Mettler Toledo EasyMax™ controlled lab reactors (50–100 mL)
    • Radleys Lara™ (100, 250, 500 mL, 1 L and 2 L)
  • In situ and offline monitoring
    • pH
    • Mettler Toledo Turbidity Trb 8300
    • Kaiser Raman RXN3
    • Image analysis
  • Filtration
    • Vacuum filtration
    • Agitated filter dryer (up to 2 L scale)
    • Centrifuge

Crystallization Optimization

We can design, optimize or troubleshoot your crystallization process for product purity, recovery or solids separation and isolation. Our experts provide you with an understanding of your process to reduce operational problems by means of:

  • Polymorph investigations
  • Control and measurement of impurities
  • Kinetics of nucleation and growth
  • Crystal size distribution measurement and modification
  • Habit modification
  • Filtration studies
  • Drying investigations