Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

Nicholas J. Van Zee; Marc A. Hillmyer; Timothy P. Lodge

doi:10.1021/acsabm.0c01173

Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

Nicholas J. Van Zee, Marc A. Hillmyer, Timothy P. Lodge

Chemistry (Twin Cities)

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

4 Scopus citations

Abstract

Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship.

Original language	English (US)
Pages (from-to)	7243-7254
Number of pages	12
Journal	ACS Applied Bio Materials
Volume	3
Issue number	10
DOIs	https://doi.org/10.1021/acsabm.0c01173
State	Published - Oct 19 2020

Bibliographical note

Funding Information:
We acknowledge the financial support of the DuPont Company for this work. We thank Dr. Ziang Li for assistance and providing the PND polymer for the initial studies. We also thank Prof. Theresa M. Reineke, Dr. Anatolii A. Purchel, Dr. Ralm Ricarte, Monica L. Ohnsorg, and Claire Seitzinger for helpful discussions. Parts of this work were performed at DuPont–Northwestern–Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by E.I. DuPont de Nemours & Co., The Dow Chemical Company and Northwestern University. This research was also supported by Sector 12 at APS. APS is a U.S. Department of Energy (DOE) of Science User Facility operated for the DOE Office of Science under Contract No. DE-AC02-06CH11357.

Publisher Copyright:
© 2020 American Chemical Society.

Keywords

amorphous solid dispersions
drug delivery
drug-rich nanoparticles
polymer-drug interactions
solution-state

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10.1021/acsabm.0c01173

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title = "Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles",

abstract = "Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship. ",

keywords = "amorphous solid dispersions, drug delivery, drug-rich nanoparticles, polymer-drug interactions, solution-state",

author = "{Van Zee}, {Nicholas J.} and Hillmyer, {Marc A.} and Lodge, {Timothy P.}",

note = "Funding Information: We acknowledge the financial support of the DuPont Company for this work. We thank Dr. Ziang Li for assistance and providing the PND polymer for the initial studies. We also thank Prof. Theresa M. Reineke, Dr. Anatolii A. Purchel, Dr. Ralm Ricarte, Monica L. Ohnsorg, and Claire Seitzinger for helpful discussions. Parts of this work were performed at DuPont–Northwestern–Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by E.I. DuPont de Nemours & Co., The Dow Chemical Company and Northwestern University. This research was also supported by Sector 12 at APS. APS is a U.S. Department of Energy (DOE) of Science User Facility operated for the DOE Office of Science under Contract No. DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

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month = oct,

day = "19",

doi = "10.1021/acsabm.0c01173",

language = "English (US)",

volume = "3",

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N2 - Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship.

AB - Amorphous solid dispersions (ASDs) of crystallizable drugs and polymer excipients are attractive for enhancing the solubility and bioavailability of hydrophobic drug molecules. In this study, the solution behavior of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PND) and poly(vinylpyrrolidone-co-vinylacetate) (PVPVA), as polymer excipients, and nilutamide (NLT), phenytoin (PHY), and itraconazole (ITN) as model drugs, were monitored by an in vitro dissolution assay, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and polarized optical microscopy (POM). High degrees of drug supersaturation were coincident with the formation of amorphous nanoparticles in each system. The difference in particle size and kinetic stability between PND and PVPVA systems suggest a difference in how the polymers interact with the drug-rich phase. A series of scenarios are proposed based on whether the polymer interacts more strongly with the drug-rich nanoparticles or with water. Understanding the contribution of drug-rich nanoparticles to achievable supersaturation and the effect of polymer excipients on these particles will inform the design of future solid dispersion systems through a better understanding of the polymer/drug solution relationship.

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KW - drug-rich nanoparticles

KW - polymer-drug interactions

KW - solution-state

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SN - 2576-6422

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ER -

Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

Abstract

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