Co-crystal Concept Image

Scalable Co-Crystals

The production of co-crystals is an increasing area of interest for the pharmaceutical industry given they can help to overcome the troublesome properties of many Active Pharmaceutical Ingredients (APIs). In addition to providing an opportunity for improved solubility, stability and bioavailability, co-crystals also offer the potential for synergistic delivery of more than one API to the same site of action (e.g. in the lungs).

A co-crystal is defined as a multi-component crystalline complex, consisting of two or more solid components in a stoichiometric ratio. The constituents are held together in a crystal lattice by non-covalent interactions (e.g. hydrogen bonding and van der Waals forces). They are solids at room temperature and marry the fields of crystal engineering with pharmaceutical sciences. This provides drug developers with the opportunity to effectively customise the physical and material properties of the substance to meet their target product profile (TPP).

To date, the main challenge associated with conventional co-crystallisation technologies is not the clinical and pharmacological benefits that they offer, but the ability to scale the techniques from the laboratory bench top to a commercial manufacturing level. Crystec mSAS® supercritical fluid (SCF) technology provides an attractive, single-step alternative which can be readily transferred from laboratory (200ml) to manufacturing scale (2L).

Crystec mSAS® Case Study

This following case study is on a rheumatoid arthritis drug (a tyrosine kinase inhibitor), conventional technology was unable to reproducibly form a 1:1 co-crystal (API plus co-former). As such, the aim of this project was to generate the 1:1 co-crystal using Crystec’s mSAS® technology and ensure reproducibility.

Product Development

Developing the product involved:

  • • A feasibility study to determine if the API was compatible with the mSAS® process.
  • • Testing the solubility of the API in supercritical carbon dioxide (scCO2) and evaluating the effect of mSAS® processing parameters on API particle size.
  • • A processability assessment for the 1:1 molar ratio API:co-former co-crystal.
  • • Evaluating the effect of thermodynamic and kinetic variables on the formation of the co-crystal within a mSAS® environment.
  • • Evaluating the effect of different processing solvent systems on co-crystal product formation.
  • • Analytical confirmation that the 1:1 co-crystal has been generated using Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Proton Nuclear Magnetic Resonance spectroscopy (1H NMR).
  • • Analysis of the product to determine particle size and morphology, by Sympatec Helios and Scanning Electron Microscope (SEM) imaging respectively.
  • • Robustness testing to ensure that 1:1 co-crystal formation was reproducible

Product Analysis and Performance

mSAS® technology successfully generated a 1:1 molar ratio pure co-crystal of the API and co-former. This was confirmed by DSC, PXRD an 1HMR analysis. The mSAS® process was reproducible and the TPP was achieved.

Co-Crystal - Differential Scanning Calorimetry DSC Analysis 1

DSC traces of 1:1 (API:co-former) ratio co-crystals showing a single melt for the co-crystal. Two traces are displayed, relating to two separate batches, demonstrating batch to batch reproducibility.

Co-Crystal - Differential Scanning Calorimetry DSC Analysis 2

DSC traces of the API alone and the co-former alone. This clearly shows that the melt of the co-crystal differs from the melt of the API and the excipient.