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Updated: Jul 14, 2025
14:55
Atomic Scale Structural Studies of Macromolecular Assemblies by Solid-state Nuclear Magnetic Resonance Spectroscopy
Published on: September 17, 2017
15.5K
Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and
Zhenxuan Chen1, Haichen Nie2,3, Chris J Benmore4
1Analytical Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Molecular Pharmaceutics
|October 6, 2023
Summary
High-resolution structural analysis of amorphous pharmaceuticals like posaconazole is crucial for stability. This study combined X-ray PDFs and ssNMR to reveal molecular packing and interactions in amorphous posaconazole and its solid dispersion.
Area of Science:
- Pharmaceutical sciences
- Materials science
- Analytical chemistry
Background:
- Understanding amorphous pharmaceutical structures is key to predicting physicochemical stability.
- Limited high-resolution analytical tools have hindered detailed structural investigations of amorphous drugs.
- Amorphous solid dispersions are vital for improving drug solubility and bioavailability.
Purpose of the Study:
- To investigate the molecular packing and intermolecular interactions of amorphous posaconazole and its amorphous solid dispersion.
- To demonstrate the synergistic power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) for high-resolution amorphous structure analysis.
- To elucidate the drug-polymer interactions in amorphous solid dispersions.
Main Methods:
- Synchrotron X-ray pair distribution functions (PDFs) were employed to analyze atomic-level structure.
- Solid-state nuclear magnetic resonance (ssNMR) 19F-13C distance measurements provided complementary structural information.
- Empirical Potential Structure Refinement (EPSR) methodology was used to model the amorphous structures.
- Principal Component Analysis (PCA) was applied to integrate PDF and ssNMR data.
Main Results:
- A rigid conformation and short-range intermolecular C-F contacts were identified in amorphous posaconazole.
- ssNMR 19F-13C distance measurements corroborated the findings from X-ray PDF analysis.
- PCA revealed insights into the chemical nature of drug-polymer interactions in the amorphous solid dispersion.
- The study successfully achieved high-resolution structural insights into amorphous systems.
Conclusions:
- The combined use of X-ray PDF and ssNMR, along with advanced modeling, provides a powerful approach for high-resolution structural characterization of amorphous pharmaceuticals.
- Understanding the molecular packing and intermolecular interactions is essential for controlling the physicochemical stability of amorphous drugs and their dispersions.
- This methodology offers a pathway to better comprehend and optimize amorphous solid dispersion formulations.
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