Polymer Type Impacts Amorphous Solubility and Drug-Rich Phase Colloidal Stability: A Mechanistic Study Using Nuclear Magnetic Resonance Spectroscopy

Ueda, Keisuke; Taylor, Lynne S.

doi:10.1021/acs.molpharmaceut.0c00061

Cited by 47 publications

(92 citation statements)

References 59 publications

(113 reference statements)

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“…Interestingly, the more noticeable downfield shifts were seen in the niclosamide-PVP sample. According to Ueda et al (2020), peak broadening is related to mobility suppression [35]. This means that, contrary to our previous dissolution observations, PVP interacts more strongly with niclosamide than with PVP-VA in solution.…”

Section: Solution Nmr Showed the Relevance Of The 2-pyrrolidinone Group For Niclosamide's Stabilization After Dissolutioncontrasting

confidence: 91%

Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study

Jara

Warnken

2021

Pharmaceutics

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We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved a more than two-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, Biopharmaceutics Classification System (BCS) class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP–VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using differential scanning calorimetry (DSC), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), Fourier-transform infrared (FTIR), and dynamic light scattering (DLS). The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a four-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

show abstract

Section: Solution Nmr Showed the Relevance Of The 2-pyrrolidinone Group For Niclosamide's Stabilization After Dissolutioncontrasting

confidence: 91%

Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study

Jara

Warnken

2021

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…According to Ueda et al (2020), peak broadening is related to mobility suppression [34]. This means that, contrary to our previous dissolution observations, PVP interacts more strongly with niclosamide than with PVP-VA in solution.…”

Section: Solution Nmr Showed the Relevance Of The 2-pyrrolidinone Group For Niclosamide's Stabilization After Dissolutioncontrasting

confidence: 91%

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Jara

Warnken

2020

Preprint

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We developed an amorphous solid dispersion (ASD) of the poorly water soluble molecule niclosamide that achieved more than a 2 fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60 fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, BCS class II, and a poor glass former with low bioavailability in vivo. Hot melt extrusion is a high throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer polyvinylpyrrolidone vinyl acetate (PVPVA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and DLS. The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side by side diffusion test, these nanoparticles produced a 4 fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

show abstract

“…Interestingly, the more noticeable downfield shifts were seen in the niclosamide-PVP sample. According to Ueda et al (2020), peak broadening is related to mobility suppression [34]. This means that, contrary to our previous dissolution observations, PVP interacts more strongly with niclosamide than with PVP-VA in solution.…”

Section: Solution Nmr Showed the Relevance Of The 2-pyrrolidinone Group For Niclosamide's Stabilization After Dissolutioncontrasting

confidence: 91%

Amorphous Solid Dispersions and the Confounding Effect of Nanoparticles in in Vitro Dissolution and in Vivo Testing: Niclosamide as a Case Study

Williams¹,

Warnken²,

Jara³

2020

Preprint

View full text Add to dashboard Cite

We developed an amorphous solid dispersion (ASD) of the poorly water-soluble molecule niclosamide that achieved more than a 2-fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60-fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, BCS class II, and a poor glass former with low bioavailability in vivo. Hot-melt extrusion is a high-throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer polyvinylpyrrolidone–vinyl acetate (PVP–VA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and DLS. The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side-by-side diffusion test, these nanoparticles produced a 4-fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

show abstract

Polymer Type Impacts Amorphous Solubility and Drug-Rich Phase Colloidal Stability: A Mechanistic Study Using Nuclear Magnetic Resonance Spectroscopy

Cited by 47 publications

References 59 publications

Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study

Amorphous Solid Dispersions and the Contribution of Nanoparticles to In Vitro Dissolution and In Vivo Testing: Niclosamide as a Case Study

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

Amorphous Solid Dispersions and the Confounding Effect of Nanoparticles in in Vitro Dissolution and in Vivo Testing: Niclosamide as a Case Study

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