High-throughput encapsulated nanodroplet screening for accelerated co-crystal discovery

Area of Science:

• Materials Science
• Crystallography
• Pharmaceutical Science

Background:

• Co-crystals are vital in pharmaceuticals for enhancing active pharmaceutical ingredient properties.
• Discovering co-crystals is challenging due to complex experimental requirements and resource intensity.

Purpose of the Study:

• To introduce a high-throughput (HTP) nanoscale co-crystallization method, Encapsulated Nanodroplet Crystallisation (ENaCt).
• To demonstrate ENaCt's efficiency in rapidly screening co-crystallization space and discovering novel co-crystal structures.

Main Methods:

• Utilized ENaCt for HTP screening of binary, ternary, and quaternary co-crystal combinations.
• Explored solvent, encapsulating oil, and stoichiometry variations in nanoscale droplets.
• Determined co-crystal structures using single crystal X-ray diffraction (SCXRD).

Main Results:

• Successfully screened 18 binary co-crystal combinations and discovered 10 novel binary co-crystals.
• Identified ternary and quaternary higher-order co-crystals (HOCs).
• In total, 54 co-crystal structures were elucidated, including 17 novel binary, 8 novel ternary, and 4 novel quaternary co-crystals.

Conclusions:

• ENaCt is a powerful and efficient tool for discovering small molecule co-crystals.
• The parallelized HTP nanoscale workflow significantly accelerates co-crystal research.
• ENaCt facilitates rapid access to diverse co-crystal forms, including complex higher-order structures.