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 language | English (US) |
|---|---|
| Pages (from-to) | 246-256 |
| Number of pages | 11 |
| Journal | Molecular pharmaceutics |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 4 2021 |
Bibliographical note
Funding Information:This work was supported by the William and Mildred Peters endowment fund (to R.S.), an NSF-GOALI grant NSF-CMMI-1662039 (to R.S.), an NIH grant GM120600 (to B.D.), and a NSF grant NSF-ACI-1339649 (to B.D.). Supercomputer calculations were performed on Comet at the San Diego Supercomputing Center (support through an NSF/XSEDE grant TG-MCB070039N to B.D.) and on Lonestar-5 at the Texas Advanced Computing Center (supported through a UT grant TG457201 to B.D.). ITC experiments were performed using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. K.K.A.E. acknowledges the Bighley Graduate Student Fellowship. We thank Beckman Coulter, Indianapolis for the use of an Optima AUC instrument and for supporting this research financially. We thank Amy Henrickson for performing the CBZ/HPMCAS experiments at the Canadian Center for Hydrodynamics (University of Lethbridge, Alberta, Canada) with support from the Canada Foundation for Innovation (CFI-37589 to B.D.) and the Canada 150 Research Chairs program (C150-2017-00015 to B.D.). We also thank Dr. Courtney Aldrich for granting access to the ITC-200 microcalorimeter and Akash Bhattacharya and Amy Henrickson for their help with experimental runs.
Publisher Copyright:
© 2020 American Chemical Society.
Keywords
- amorphous solid dispersions
- dissolution
- drug
- polymer interactions
- sedimentation velocity analytical ultracentrifugation