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Phase Identification and Discovery of an Elusive Polymorph of Drug-Polymer Inclusion Complex Using Automated 3D
Molly Lightowler1, Shuting Li2, Xiao Ou2
1Department of Materials and Environmental Chemistry, Stockholm University, Stockholm, SE-106 91, Sweden.
Angewandte Chemie (International Ed. in English)
|February 21, 2024
Summary
Automated 3D electron diffraction (3D ED) rapidly identified six griseofulvin (GSF) crystal phases, including new inclusion complexes. This method enables direct structure determination of complex, beam-sensitive pharmaceutical compounds, crucial for drug development.
Area of Science:
- Crystallography
- Materials Science
- Pharmaceutical Science
Background:
- 3D electron diffraction (3D ED) is a powerful technique for crystal structure determination.
- Identifying different solid forms (polymorphs) of active pharmaceutical ingredients is critical for drug efficacy and development.
- Complex crystallization products often contain multiple phases, making characterization challenging.
Purpose of the Study:
- To implement an automated, low-dose 3D ED protocol for identifying and determining the structures of multiple phases in a griseofulvin (GSF) crystallization product.
- To demonstrate the capability of automated 3D ED for rapid and accurate phase identification and structure determination of beam-sensitive materials.
- To investigate the relationship between crystal structure and stability for GSF inclusion complexes.
Main Methods:
- Development and application of an automated, low-dose 3D ED protocol.
- Batch data collection using commercial software for over 230 datasets.
- Automated data processing and analysis for unit cell determination and phase identification.
- Direct structure determination of identified phases using 3D ED.
Main Results:
- Successfully identified six phases from a GSF melt-crystallization product, including known forms (III, I), a known inclusion complex (GSF-PEG IC-I), and minor phases (II, V, and a new GSF-PEG IC-II).
- Accurate unit cell parameters enabled direct phase identification.
- Direct structure determination of all six phases was achieved using 3D ED.
- The stability of GSF-PEG inclusion complex polymorphs was correlated with their crystal structures.
Conclusions:
- Automated 3D ED provides a powerful tool for accurate phase identification and direct structure determination of complex, beam-sensitive crystallization products.
- This technique significantly aids in solid form screening, a crucial aspect of pharmaceutical development.
- The study highlights the potential of low-dose, automated 3D ED for efficient characterization in drug discovery and development.
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