The crystalline landscape of a drug substance can significantly impact its development in terms of time, cost, and complexity. While we generally recommend progressing with the most stable crystalline form of your drug substance, identifying that form is not always straightforward.
This is where our deep understanding of thermodynamics and the analytical tools used in Form and Formulation come into play, helping to reduce risks to your project.
Our interest extends beyond anhydrous polymorphs; we also explore hydrates and solvates. Although solvates are rarely suitable for development, hydrates might be the most appropriate form for further advancement.
Designing A Polymorph Screen
Polymorph screening, which aims to identify as many crystal forms as possible, starts with a suitable base material. Commonly, this is amorphous material prepared by lyophilization, spray drying, or melt quench cooling. While there are alternatives, these methods are routinely performed in our laboratories.
We then employ a diverse range of solvents and experimental conditions to generate new crystal forms. The experimental design encompasses all conditions the material might encounter, either deliberately or accidentally, during scale-up and manufacture. This includes:
Primary analysis of solids is conducted using XRPD, with novel forms further characterised using the tools within Form and Formulation to understand their solid form nature. This includes:
- XRPD to confirm novelty of crystal form.
- TGA to assess hydration / solvation
- DSC for thermal profile, e.g. melting point and enthalpy of any transitions
- DVS to assess hygroscopicity, hydration formation / dehydration.
- Multinuclear NMR to confirm chemical integrity and solvent
The nomination of the most suitable form for further development is based on a variety of criteria. Once complete, the material undergoes further characterisation to de-risk the project, including stability studies, solubility, and dissolution profiles. This selected form then feeds into our formulation studies.