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Tailoring poly(2-oxazoline)s for drug delivery: predicting API compatibility via COSMO-RS.
Alžběta Zemánková1, Alex Mathers1, Fatima Hassouna2
1Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
International Journal of Pharmaceutics
|February 16, 2026
Summary
The Conductor-like Screening Model for Real Solvents (COSMO-RS) accurately predicts naproxen solubility in poly(2-oxazoline)s (POx). Realistic polymer models improve predictions, aiding early formulation screening of drug excipients.
Area of Science:
- Computational chemistry and materials science.
- Drug formulation and excipient screening.
Background:
- Accurate prediction of drug solubility in polymers is crucial for pharmaceutical formulation.
- Poly(2-oxazoline)s (POx) are a class of polymers with potential as drug excipients.
- The Conductor-like Screening Model for Real Solvents (COSMO-RS) is a computational tool for predicting physical properties.
Purpose of the Study:
- To evaluate the predictive capability of COSMO-RS for naproxen (NAP) solubility in three different poly(2-oxazoline)s (POx).
- To assess the influence of POx side-chain structure on naproxen solubility predictions.
- To compare the accuracy of different polymer model representations within COSMO-RS.
Main Methods:
- Solid-liquid equilibrium (SLE) data for NAP-POx systems were experimentally determined using differential scanning calorimetry (DSC) and a step-wise dissolution method.
- COSMO-RS simulations were performed using two models: a CH3-capped COSKF trimer and a more realistic CH3/OH-terminated pentamer.
- Sigma-profile analysis was employed for qualitative assessment of polarity and interactions.
Main Results:
- Pentamer-based COSMO-RS calculations provided more accurate thermodynamic descriptions and correctly predicted the experimental compatibility ranking: poly(2-ethyl-2-oxazoline) (PEtOx) > poly(2-n-butyl-2-oxazoline) (PBuOx) > poly(2-phenyl-2-oxazoline) (PPhOx).
- The model accurately accounted for PBuOx's crystallinity loss in NAP-rich mixtures.
- Absolute average deviations were lower for pentamer models (4.3–11.9 wt%) compared to trimer models (8.3–19.5 wt%), indicating improved accuracy.
Conclusions:
- COSMO-RS, particularly with realistic polymer models like pentamers, is effective for predicting naproxen solubility in POx excipients.
- The study demonstrates the utility of COSMO-RS in differentiating between closely related POx excipients during early-stage formulation development.
- Computational screening using COSMO-RS can guide the selection of appropriate excipients for drug formulations.
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