Atomic-level structure of an amorphous solid dispersion
9 affiliations
- 1Institut des Sciences et Ingénierie Chimiques
- 2École Polytechnique Fédérale de Lausanne (EPFL
- 3National Centre for Computational Design and Discovery of Novel Materials MARVEL
- 4Sustainable Innovation & Transformational Excellence, Pharmaceutical Technology & Development, Operations
- 5AstraZeneca
- 6Predictive Science, Digital and Automation, Pharmaceutical Sciences
- 7R&D, AstraZeneca
- 8Global Product Development, Pharmaceutical Technology & Development, Operations
- 9Early Product Development and Manufacturing, Pharmaceutical Sciences
Abstract
Amorphous materials play a pivotal role across condensed-matter physics, materials science, and pharmaceuticals, for example enabling increased dissolution rates and higher in-vivo exposure for poorly bioavailable molecules. In particular, amorphous solid dispersions (ASDs), disordered multi-component mixtures of an active ingredient within a polymer matrix, are widely used to trap molecules in metastable high-energy states. However, because these systems lack longrange order, directly observing their atomic-level spatial arrangements has remained an outstanding challenge, rendering their long-term physical stability unpredictable and leaving formulation science reliant on empirical screening. Here we report the first complete three-dimensional, atomic-level structure elucidation of an amorphous solid dispersion. By combining solid-state NMR crystallography with machine-learning-accelerated quantum chemical calculations, we determine the structural ensemble of the drug AZD5462 within a copovidone matrix. We show that the polymer drives a total reconfiguration of the hydrogen-bonding network, substituting self-association with API–polymer interactions and fundamentally altering the local conformational energy landscape by raising the kinetic barriers to rearrangement. The structure explains why the formulation remains physically stable for over two years, whereas the pure amorphous drug recrystallizes within hours. These findings establish a rigorous structural framework for disordered multi-component materials, paving the way for the rational, structure-directed design of amorphous matter.
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BibTeX
@misc{holmes2026atomiclevel,
title = {{Atomic-level structure of an amorphous solid dispersion}},
author = {Jacob B. Holmes and Daria Torodii and Tommaso Casalini and Ruben Rodriguez-Madrid and Sten O. Nilsson Lill and Anna Svensk Ankarberg and Okky Dwichandra Putra and Staffan Schantz and Lyndon Emsley},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010694/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010694/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Atomic-level structure of an amorphous solid dispersion
AU - Jacob B. Holmes
AU - Daria Torodii
AU - Tommaso Casalini
AU - Ruben Rodriguez-Madrid
AU - Sten O. Nilsson Lill
AU - Anna Svensk Ankarberg
AU - Okky Dwichandra Putra
AU - Staffan Schantz
AU - Lyndon Emsley
PY - 2026
DA - 2026/10/20
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010694/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010694/v1
AB - Amorphous materials play a pivotal role across condensed-matter physics, materials science, and pharmaceuticals, for example enabling increased dissolution rates and higher in-vivo exposure for poorly bioavailable molecules. In particular, amorphous solid dispersions (ASDs), disordered multi-component mixtures of an active ingredient within a polymer matrix, are widely used to trap molecules in metastable high-energy states. However, because these systems lack longrange order, directly observing their atomic-level spatial arrangements has remained an outstanding challenge, rendering their long-term physical stability unpredictable and leaving formulation science reliant on empirical screening. Here we report the first complete three-dimensional, atomic-level structure elucidation of an amorphous solid dispersion. By combining solid-state NMR crystallography with machine-learning-accelerated quantum chemical calculations, we determine the structural ensemble of the drug AZD5462 within a copovidone matrix. We show that the polymer drives a total reconfiguration of the hydrogen-bonding network, substituting self-association with API–polymer interactions and fundamentally altering the local conformational energy landscape by raising the kinetic barriers to rearrangement. The structure explains why the formulation remains physically stable for over two years, whereas the pure amorphous drug recrystallizes within hours. These findings establish a rigorous structural framework for disordered multi-component materials, paving the way for the rational, structure-directed design of amorphous matter.
ER -