Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*)

Anasuya Sahoo; Raj Suryanarayanan; Ronald A. Siegel

doi:10.1021/acs.molpharmaceut.0c00576

Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*)

Anasuya Sahoo, Raj Suryanarayanan, Ronald A. Siegel

Pharmaceutics

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8 Scopus citations

Abstract

Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C∗ is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C∗ in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔH_f), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔH_f/ΔH_f,C=0= f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼T_g+ 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C∗ in selecting polymer concentrations when formulating drugs as ASDs.

Original language	English (US)
Pages (from-to)	4401-4406
Number of pages	6
Journal	Molecular pharmaceutics
Volume	17
Issue number	11
DOIs	https://doi.org/10.1021/acs.molpharmaceut.0c00576
State	Published - Nov 2 2020

Bibliographical note

Funding Information:
This work was supported by Industrial Partners for Research in Interfacial and Materials Engineering (IPRIME), an academic-industrial consortium at the University of Minnesota (UMN). The authors thank Prof. Christopher Macosko, Chemical Engineering and Material Science Department, UMN, for access to the microcompounder to prepare the ASDs by hot-melt extrusion, and the rheometer for viscosity measurements. Additionally, we thank Prof. Timothy Lodge, Chemistry Department UMN, for access to the high-temperature light scattering system for hydrodynamic radius measurement. We thank Prof. Christopher Ellison Chemical Engineering and Material Science Department, UMN, for access to GPC for molecular weight measurements. We thank Mr. Myles Brostrom 3M Corporation, for assistance in XRD measurements. Portions of this work were carried out in the Characterization Facility, UMN, which receives partial support from NSF through the MRSEC program.

Publisher Copyright:
© 2020 American Chemical Society. All rights reserved.

Keywords

)
amorphous solid dispersions (ASD)
crystallization
enthalpy of fusion
melt quenching
overlap concentration (C

PubMed: MeSH publication types

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

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title = "Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*)",

abstract = "Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a {"}sphere of influence{"} of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C∗ is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C∗ in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0= f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg+ 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C∗ in selecting polymer concentrations when formulating drugs as ASDs.",

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author = "Anasuya Sahoo and Raj Suryanarayanan and Siegel, {Ronald A.}",

note = "Funding Information: This work was supported by Industrial Partners for Research in Interfacial and Materials Engineering (IPRIME), an academic-industrial consortium at the University of Minnesota (UMN). The authors thank Prof. Christopher Macosko, Chemical Engineering and Material Science Department, UMN, for access to the microcompounder to prepare the ASDs by hot-melt extrusion, and the rheometer for viscosity measurements. Additionally, we thank Prof. Timothy Lodge, Chemistry Department UMN, for access to the high-temperature light scattering system for hydrodynamic radius measurement. We thank Prof. Christopher Ellison Chemical Engineering and Material Science Department, UMN, for access to GPC for molecular weight measurements. We thank Mr. Myles Brostrom 3M Corporation, for assistance in XRD measurements. Portions of this work were carried out in the Characterization Facility, UMN, which receives partial support from NSF through the MRSEC program. Publisher Copyright: {\textcopyright} 2020 American Chemical Society. All rights reserved.",

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month = nov,

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doi = "10.1021/acs.molpharmaceut.0c00576",

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AU - Sahoo, Anasuya

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N1 - Funding Information: This work was supported by Industrial Partners for Research in Interfacial and Materials Engineering (IPRIME), an academic-industrial consortium at the University of Minnesota (UMN). The authors thank Prof. Christopher Macosko, Chemical Engineering and Material Science Department, UMN, for access to the microcompounder to prepare the ASDs by hot-melt extrusion, and the rheometer for viscosity measurements. Additionally, we thank Prof. Timothy Lodge, Chemistry Department UMN, for access to the high-temperature light scattering system for hydrodynamic radius measurement. We thank Prof. Christopher Ellison Chemical Engineering and Material Science Department, UMN, for access to GPC for molecular weight measurements. We thank Mr. Myles Brostrom 3M Corporation, for assistance in XRD measurements. Portions of this work were carried out in the Characterization Facility, UMN, which receives partial support from NSF through the MRSEC program. Publisher Copyright: © 2020 American Chemical Society. All rights reserved.

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AB - Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C∗ is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C∗ in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0= f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg+ 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C∗ in selecting polymer concentrations when formulating drugs as ASDs.

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Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*)

Abstract

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Keywords

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