Investigating the Interaction Pattern and Structural Elements of a Drug-Polymer Complex at the Molecular Level

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Amorphous solid dispersions (ASDs) enhance drug solubility and stability.
• Understanding drug-polymer interactions is key for ASD formulation.
• Molecular mechanisms of drug-polymer association in ASDs remain unclear.

Purpose of the Study:

• To elucidate the molecular interactions between clofazimine (CLF) and hypromellose phthalate (HPMCP) in ASDs.
• To investigate the impact of these interactions on drug loading and physical stability.
• To propose a structural model for the CLF-HPMCP drug-polymer complex.

Main Methods:

• Preparation of ASDs using the solvent evaporation method.
• Spectroscopic analysis (UV/vis, 1H NMR) in chloroform.
• Advanced NMR techniques (NOESY, DOSY) for interaction and mobility studies.
• Quantum chemistry calculations for structural validation.

Main Results:

• HPMCP as a carrier yielded high CLF loading (63% w/w) and a color change indicating strong association.
• Spectroscopic data confirmed protonation of CLF and ion pair formation with HPMCP.
• NOESY and DOSY revealed significant drug-polymer association and influenced CLF molecular mobility.
• Quantum chemistry supported the ion-pair binding model between protonated CLF and HPMCP carboxylate.

Conclusions:

• Protonated CLF binds to HPMCP via an ion pair, driven by carboxylate interaction.
• A molecular model of the CLF-HPMCP complex was proposed.
• Understanding drug-polymer interactions at a molecular level is crucial for rational ASD design.