Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement

Lindsay M. Johnson; Ziang Li; Andrew J. LaBelle; Frank S. Bates; Timothy P. Lodge; Marc A. Hillmyer

doi:10.1021/acs.macromol.6b02474

Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement

Lindsay M. Johnson, Ziang Li, Andrew J. LaBelle, Frank S. Bates, Timothy P. Lodge, Marc A. Hillmyer

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Solubility-enhancing amorphous solid dispersions are used in the oral delivery of hydrophobic, crystallizable drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations and limit crystallization of the dissolved drug over extended times. We prepared poly(N-isopropylacrylamide)-based excipients of varying molar mass and with various end group identities, and examined their ability to improve the aqueous solubility of the Biopharmaceutical Class System Class II drug, phenytoin. Solid dispersions of these excipients and phenytoin were prepared at 10 wt % drug loading. Performance depended largely on the tendency of the polymer excipient to form micellar aggregates in aqueous buffer. We present several systems that achieved significant improvement of phenytoin solubility, with no indication of drug crystallization over 6 h. This is among the highest enhancement factors seen for phenytoin to date, and the success of these systems is ascribed to the added stability of these “self-micellizing” solid dispersions.

Original language	English (US)
Pages (from-to)	1102-1112
Number of pages	11
Journal	Macromolecules
Volume	50
Issue number	3
DOIs	https://doi.org/10.1021/acs.macromol.6b02474
State	Published - Feb 14 2017

Bibliographical note

Funding Information:
This work was financially supported by The Dow Chemical Company through Agreement 224249AT with the University of Minnesota. We gratefully acknowledge helpful discussions with, in alphabetical order, Dr. Steven J. Guillaudeu, Dr. Jodi Mecca, Dr. William Porter III, Dr. Robert L. Schmitt, and Dr. Timothy Young at the Dow Chemical Company. Parts of this work were carried out in the College of Science & Engineering Characterization Facility, which has received capital equipment funding from the NSF through the UMN MRSEC program under Award Number DMR-1420013. Andrew LaBelle was supported through an Undergraduate Research Opportunities Program (UROP) grant that was awarded by the University of Minnesota.

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© 2017 American Chemical Society.

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abstract = "Solubility-enhancing amorphous solid dispersions are used in the oral delivery of hydrophobic, crystallizable drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations and limit crystallization of the dissolved drug over extended times. We prepared poly(N-isopropylacrylamide)-based excipients of varying molar mass and with various end group identities, and examined their ability to improve the aqueous solubility of the Biopharmaceutical Class System Class II drug, phenytoin. Solid dispersions of these excipients and phenytoin were prepared at 10 wt % drug loading. Performance depended largely on the tendency of the polymer excipient to form micellar aggregates in aqueous buffer. We present several systems that achieved significant improvement of phenytoin solubility, with no indication of drug crystallization over 6 h. This is among the highest enhancement factors seen for phenytoin to date, and the success of these systems is ascribed to the added stability of these “self-micellizing” solid dispersions.",

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note = "Funding Information: This work was financially supported by The Dow Chemical Company through Agreement 224249AT with the University of Minnesota. We gratefully acknowledge helpful discussions with, in alphabetical order, Dr. Steven J. Guillaudeu, Dr. Jodi Mecca, Dr. William Porter III, Dr. Robert L. Schmitt, and Dr. Timothy Young at the Dow Chemical Company. Parts of this work were carried out in the College of Science & Engineering Characterization Facility, which has received capital equipment funding from the NSF through the UMN MRSEC program under Award Number DMR-1420013. Andrew LaBelle was supported through an Undergraduate Research Opportunities Program (UROP) grant that was awarded by the University of Minnesota. Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",

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N2 - Solubility-enhancing amorphous solid dispersions are used in the oral delivery of hydrophobic, crystallizable drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations and limit crystallization of the dissolved drug over extended times. We prepared poly(N-isopropylacrylamide)-based excipients of varying molar mass and with various end group identities, and examined their ability to improve the aqueous solubility of the Biopharmaceutical Class System Class II drug, phenytoin. Solid dispersions of these excipients and phenytoin were prepared at 10 wt % drug loading. Performance depended largely on the tendency of the polymer excipient to form micellar aggregates in aqueous buffer. We present several systems that achieved significant improvement of phenytoin solubility, with no indication of drug crystallization over 6 h. This is among the highest enhancement factors seen for phenytoin to date, and the success of these systems is ascribed to the added stability of these “self-micellizing” solid dispersions.

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Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement

Abstract

Bibliographical note

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MRSEC IRG-3: Hierarchical Multifunctional Macromolecular Materials

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Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement

Abstract

Bibliographical note

MRSEC Support

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MRSEC IRG-3: Hierarchical Multifunctional Macromolecular Materials

University of Minnesota MRSEC (DMR-1420013)

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