When Unsuspected Crystallinity Ruins Biological Testing in Early Discovery: A Case Study.

Area of Science:

• Pharmaceutical Sciences
• Medicinal Chemistry
• Drug Discovery and Development

Background:

• Solid-state properties like crystallinity significantly influence drug solubility and pharmacokinetics.
• The pharmaceutical industry routinely considers solid-state form during drug development.
• Early-stage drug discovery, especially in academia, often overlooks the impact of solid-state structure.

Purpose of the Study:

• To highlight the critical importance of considering solid-state properties early in drug discovery.
• To present a case study of a false negative result due to unexpected drug crystallinity.
• To investigate the discrepancy in biological testing between crystalline and amorphous forms of a drug candidate.

Main Methods:

• Comparative analysis of crystalline and amorphous batches of a tyrosine kinase inhibitor.
• Assessment of solubility differences between the two solid-state forms.
• Biological testing to evaluate the impact of crystallinity on drug efficacy.

Main Results:

• The crystalline form of the tyrosine kinase inhibitor exhibited lower solubility compared to its amorphous counterpart.
• This solubility difference led to a false negative outcome in biological testing for the crystalline sample.
• Experimentation confirmed crystallinity as the origin of the observed discrepancy.

Conclusions:

• Unexpected drug crystallinity can lead to erroneous conclusions in early biological assessments.
• Early consideration of solid-state properties is crucial for accurate drug discovery and development.
• Integrating solid-state characterization early can prevent costly late-stage failures.