Characterizing Drug-Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation

Kweku K. Amponsah-Efah, Borries Demeler, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

We present a new approach for characterizing drug-polymer interactions in aqueous media, using sedimentation velocity analytical ultracentrifugation (AUC). We investigated the potential interaction of ketoconazole (KTZ), a poorly water-soluble drug, with polyacrylic acid (PAA) and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) in aqueous buffers. The effect of the polymer on the sedimentation coefficient of the drug was the observable metric. The drug alone, when subjected to AUC, exhibited a very narrow sedimentation peak at 0.2 Svedberg (S), in agreement with the expectation for a monomeric drug with a molar mass < 1000 Dalton. Conversely, the neat polymers showed broad profiles with higher sedimentation coefficients, reflecting their larger more heterogeneous size distributions. The sedimentation profiles of the drug-polymer mixtures were expectedly different from the profile of the neat drug. With KTZ-Soluplus, a complete shift to faster sedimentation times (indicative of an interaction) was observed, while with KTZ-PAA, a split peak indicated the existence of the drug in both free and interacting states. The sedimentation profile of carbamazepine, a second model drug, in the presence of hydroxypropyl methyl cellulose acetate succinate (HPMCAS, another polymer) revealed multiple "populations"of drug-polymer species, very similar to the sedimentation profile of neat HPMCAS. The interactions probed by AUC were compared with the results from isothermal titration calorimetry. In vitro dissolution tests performed on amorphous solid dispersions prepared with the same drug-polymer pairs suggested that the interactions may play a role in prolonging drug supersaturation. The results show the possibility of characterizing drug-polymer interactions in aqueous solution with high hydrodynamic resolution, addressing a major challenge frequently encountered in the mechanistic investigations of the dissolution behavior of amorphous solid dispersions.

Original languageEnglish (US)
Pages (from-to)246-256
Number of pages11
JournalMolecular Pharmaceutics
Volume18
Issue number1
DOIs
StatePublished - Jan 4 2021
Externally publishedYes

Keywords

  • amorphous solid dispersions
  • dissolution
  • drug
  • polymer interactions
  • sedimentation velocity analytical ultracentrifugation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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