Investigating and Comparing the Applicability of the R3m Molecular Descriptor and Solubility Parameter Estimation...

Evaluation of different amorphous solid dispersion carrier matrices is enabled by active pharmaceutical ingredient (API) structure-based predictions. This study compares the utility of Hansen Solubility Parameters with the R3m molecular descriptor for identifying dispersion polymers based on the structure of the drug molecule. Twelve API-polymer combinations (4 APIs and 3 interrelated polymers) were used to test each approach. Co-solidified mixtures containing 75% API were prepared by melt-quenching. Phase behavior was evaluated and classified using differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and hot stage microscopy. Observations of dispersion behavior were compared to predictions made using the Hansen Solubility Parameter and R3m. The solubility parameter approach misclassified the dispersion behavior of 1 API-polymer combination and also did not produce definite predictions in 3 out of 12 of the API-polymer combinations. In contrast, R3m classifications of dispersion behavior were correct in all but two cases, with one misclassification and one ambiguous prediction. The solubility parameters best classify dispersion behavior when specific drug-polymer intermolecular interactions are present, but may be less useful otherwise. Ultimately, these two methods are most effectively used together, as they are based on distinct features of the same molecular structure.