Aggregated Solution Morphology of Poly(acrylic acid)-Poly(styrene) Block Copolymers Improves Drug Supersaturation Maintenance and Caco-2 Cell Membrane Permeation

Anatolii A. Purchel, William S. Boyle, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Amorphous solid dispersions of polymers and drugs have been shown to improve supersaturation maintenance of poorly water-soluble drugs. Herein, amorphous spray-dried dispersions (SDDs) of poly(acrylic acid)-polystyrene (PS-b-PAA) diblock copolymers with differing degrees of polymerization were prepared in aggregated and nonaggregated states with the Biopharmaceutical Classification System Class II drug, probucol (PBC). Specifically, PS90-b-PAA15, PS90-b-PAA80, PS38-b-PAA220, and PS38-b-PAA320 amphiphilic block polymers that covered a compositional range in the area of oral drug delivery were prepared to examine the role of molecular weight and controlled aggregation in promoting drug supersaturation and maintenance. In addition, hydrophilic homopolymers PAA20, PAA96, PAA226, and PAA392 were prepared as controls to evaluate the role of the block copolymer-based SDDs in PBC solubilization. Characterization such as powder X-ray diffraction, scanning electron microscopy, and dissolution tests under nonsink conditions were then performed to evaluate the SDDs. When comparing the block copolymer systems, polymers that were preaggregated into micellular structures prior to spray drying with the drug promoted higher drug solubility and maintenance than when the drug was formulated with molecularly dissolved PS-PAA block polymer. Interestingly, the aggregated PS90-b-PAA80 SDD with 25 wt % PBC achieved 100% burst release and maintained full supersaturation of PBC at pH 6.5 (physiological pH in the small intestine). Dissolution studies conducted at the pH of the stomach (pH = 1.2) show that a minimal amount of drug (∼10 μg/mL) was released, which could be used for protecting drugs from acidic environments (stomach) before reaching the small intestine. To evaluate drug bioavailability, in vitro Caco-2 cell assays were performed, which reveal that PAA-based excipients do not hinder drug permeation across the epithelial membrane and that PS90-b-PAA80 SDD with 25 wt % PBC achieved the highest membrane permeability coefficient. This work demonstrates that block copolymer-based SDDs capable of preaggregating into nanostructures may be a tunable drug-delivery platform that can improve solubility and supersaturation maintenance of Class II pharmaceutics while also not prohibiting bioavailability through model intestinal membranes. Indeed, this concept may be extended to accommodate a myriad of pharmaceutical and excipient structures.

Original languageEnglish (US)
Pages (from-to)4423-4435
Number of pages13
JournalMolecular pharmaceutics
Issue number11
StatePublished - Nov 4 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 American Chemical Society.


  • block copolymers
  • caco-2 cell assay
  • oral drug delivery
  • poly(acrylic acid)
  • solid dispersion

MRSEC Support

  • Shared

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.


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