Microstructural Insights into Solid Dispersions: A Combined Small-Angle Neutron Scattering and Molecular Dynamics...

Solid dispersion is a widely adopted formulation strategy to enhance the solubility of water-insoluble drugs. However, the molecular-level structural determinants of stability and dissolution behavior remain poorly understood. This study integrates Small-Angle Neutron Scattering (SANS) technology with coarse-grained molecular dynamics (CGMD) simulations to investigate the effects of preparation methods (melting vs solvent evaporation) and drug loadings (10%, 15%, 25%) on the microstructure and crystallinity of PXM-PEG solid dispersions. Deuterated PEG (d-PEG) is used in the SANS to enhance the scattering intensity in samples. The findings revealed that the lamellar thickness decreased significantly from 173.01 Å (pure d-PEG) to 44.12 Å (25% drug loading, melting method), while the d-spacing reduced from 71.13 to 36.65 Å, indicating a substantial disruption of the crystalline structure. Conversely, samples prepared by solvent evaporation maintained larger d-spacing (up to 93.27 Å at 10% drug loading) and more stable layer stacking (Nlayers ∼5.6), demonstrating higher structural order. The results indicate that the preparation method significantly influences the structural characteristics of the solid dispersions. The melting method yielded a higher amorphous content at low drug loadings, which is expected to improve drug solubility and bioavailability. In contrast, the solvent evaporation method tended to produce solid dispersions with higher crystallinity and uniform structures at higher drug loadings. SANS results indicated that samples prepared by the melting method exhibited higher disorder in the high-q region, while those prepared by the solvent evaporation method showed greater crystallinity. The CGMD simulations further elucidated the dynamic aggregation and structural formation of the drug and polymer molecules during the preparation process. In the melting simulations, drug and polymer molecules gradually aggregated into dense clusters, while in the solvent evaporation simulations, the aggregates grew larger and more asymmetrical as the solvent evaporated, ultimately forming ordered structures. The combined results from SANS and molecular dynamics simulations indicated the "sandwich-like" structure of PXM-PEG solid dispersions. The outcomes of this innovative approach have the potential to advance the development of solid dispersion formulations, enhance research and development efficiency, and pave the way for the industrial production of solid dispersions.