CRYSTALLIZATION

CRYSTALLIZATION AND PARTICLE ENGINEERING PLATFORM

Apeloa CDMO has integrated its resources and capabilities in solid chemistry into a Crystallization and Particle Engineering Platform (CPEP). This platform is led by experienced crystallization scientists, equipped with advanced analytical instruments and state-of-the-art development facilities across different scales. Apeloa CDMO can serve its customers better with competencies in solid-form screening and preliminary assessment, particle characterization, crystallization development and optimization, and particle micronization.

CRYSTALLIZATION TECHNOLOGY LEADERS

A small-molecule API may have tens of solid forms, each with its own unique crystal structure and therapeutic effectiveness. It is necessary to find and evaluate as many solid forms as possible for the purpose of optimal therapeutic effects and proprietary protection.

A solid form has many different attributes including particle size, crystal habit, particle morphology, purity, surface roughness, and chemistry. Having the right combinations of these attributes can lead to satisfactory processing and bioavailability. Some of these attributes must be manipulated to achieve the desired outcome via crystallization and particle engineering. This requires adequate evaluation and balancing of five particle formation mechanisms:

  1. nucleation
  2. crystal growth
  3. agglomeration
  4. breakage
  5. dissolution at different operating conditions

The third challenge is scale-up issues. Even with geometric similarity, the spatial distribution of concentration, temperature, and kinetic dissipation rate in stirred tanks varies drastically across different scales, which affects crystallization and particle engineering processes. Furthermore, commercial crystallizers often differ in construction material, geometry, and impeller design from those for development. These differences may exacerbate scale-up issues.

Apeloa CDMO and CPEP would like to partner with customers to tackle these challenges with their experiences and capabilities in solid state chemistry.

CRYSTALLIZATION EXPERTS

White multistory building with blue stripe on tree lined pharmaceutical campus specializing in crystallization.

RECOGNIZED CRYSTALLIZATION EXPERTS

Apeloa CDMO has built its scientific expertise by bringing on leading scientists and engineers to support the company’s expanding service offering.  With its growth in demand and technical benefits of crystallization and particle sizing technologies, Apeloa CDMO has expanded its faculties, equipment, and analytical instruments to become a market leader in crystallization services.

MOLECULE LIFE CYCLE SERVICES

Laboratory scientist in white lab coat viewing crystallization sample inside benchtop UV inspection box.

CRYSTALLIZATION SERVICES ACROSS THE LIFE CYCLE OF SMALL-MOLECULE DRUGS

Apeloa CDMO aspires to be a one-stop service center where customers can entrust their drug candidates at various development stages, whether it is solid form screening, characterization and evaluation, fit-for-purpose, or systematic crystallization development.

Our services include:

  • Early-stage solid form screening, including salt, co-crystal, polymorph, solvate, hydrate
  • Characterization of powders using microscope, PXRD, TGA, DSC, DVS, HPLC
  • Conversion between different solid forms
  • Chemical stability assessment of solids
  • Dissolution studies
  • Fit-for-purpose crystallization development
  • Systematic crystallization development from gram to kilogram scale
  • DoE and robustness study
  • Crystallization optimization for control of crystal size, polymorph, purity, crystal habit, solvent residue, occurrence of oiling out (LLPS)
  • Chiral resolution via crystallization

MICRONIZATION

A pile of white powder that has undergone powder size process at Apeloa CDMO in its crystallization group.

PARTICLE MICRONIZATION DEVELOPMENT

Micronized or even nano-sized particles are needed in many dosage formulations. Micron-sized particles of some APIs can be directly generated via fast precipitation in anti-solvents. However, the success of direct precipitation relies on the solubility profile and crystallization kinetics of the APIs. In comparison, milling is more often employed to reduce the particle size of many APIs. With extensive in-house milling capabilities, Apeloa’s CDMO team can develop micronization processes to deliver the desired particle size.

  • Hammer Mill: similar to “pin-milling”, it is a mechanical milling process that can reduce particle size to 50-100 µ
  • Jet milling: a dry milling process, resulting in particle sizes as low as 1-10 µ
  • High-shear wet milling: reducing particle size in a slurry to around 20 µ
  • Wet bead milling: producing sub-micron particles, depending on the size of beads in the mill.
  • Spray drying: used to dry slurries from wet milling or generate particles from solutions via fast evaporation of solvents.

PARTICLE CHARACTERIZATION

Apeloa CDMO lab containing more than 10 white HPLC systems on benchtops, operated by two scientists in white lab coats.

ADVANCED PARTICLE CHARACTERIZATION INSTRUMENTATION

Using state-of-the-art analytical instruments, our solid-state chemists are able to characterize a wide range of material properties, including crystal structure, hygroscopicity, particle morphology, particle size, purity, and flowability.  A comprehensive characterization ensures production of high-quality functional materials and enables detection of possible in-process form changes.

PAT

Large suite containing 8 large stainless steel production reactors for manufacturing of APIs and intermediates.

PROCESS ANALYTICAL TECHNOLOGY (PAT)

Crystallization scientists place emphasis on the mechanistic understanding of crystallization and particle engineering, which is the key to development of robust and scalable processes. PAT sensors afford real-time information on solution composition, solids concentration, and polymorphic transformation. Combined with process modelling, the real-time information leads to understanding of various mechanisms at work.

Apeloa CPEP is equipped with the following PAT sensors.

  • Mettler-Toledo PVM (particle vision measurement)
  • Mettler-Toledo FBRM (focused beam reflectance measurement)
  • Mettler-Toledo Probe-based Raman spectroscopy
  • Bruker ANTARIS II FT-NIR analyzer (near infrared spectroscopy)