Nuclear Magnetic Resonance for the Characterisation of Hot-Melt Extruded Pharmaceutical Amorphous Solid Dispersions
type: CreativeWork
description: Low aqueous solubility of active pharmaceutical ingredients (APIs) presents one of the greatest and most frequent challenges to formulation scientists. An estimated 75% of pharmaceutical compounds under development suffer from poor solubility. The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble APIs. Hot-melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical industry. HME involves the combination of an API and a polymer, which are heated and intensively mixed to yield a homogeneous product. Despite the growth in the application of HME to drug development, there are still substantial gaps in our understanding regarding the dynamics of drug dissolution and dispersion in viscous polymers as well as physical stability (phase separation and API recrystallization). Computational models have been built in order to predict optimal processing conditions (e.g. temperature, residence time, drug loading), but they are limited by the lack of supporting data for key mass transport parameters. A key omission is the lack of experimental data on the API diffusion coefficient at conditions relevant to HME. This dissertation reports the first measurements of API diffusion in pharmaceutical polymer melts at temperatures relevant to the HME process, by means of high-temperature PFG NMR. These measurements were performed in the absence of any solvents, for a range of drug loadings, temperatures, polymer systems and drug species. The mechanism of the diffusion process and its relationship to viscosity was explored with the Stokes-Einstein and Arrhenius models. Viscosity plots obtained from the rheology experiments uncovered the possibility of HME processing at significantly lower temperatures to reduce the risk of thermal degradation. Additional characterisation of extrudates prepared 30◦C below the drug’s melting point conclud…
abstract: Low aqueous solubility of active pharmaceutical ingredients (APIs) presents one of the greatest and most frequent challenges to formulation scientists. An estimated 75% of pharmaceutical compounds under development suffer from poor solubility. The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble APIs. Hot-melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical industry. HME involves the combination of an API and a polymer, which are heated and intensively mixed to yield a homogeneous product. Despite the growth in the application of HME to drug development, there are still substantial gaps in our understanding regarding the dynamics of drug dissolution and dispersion in viscous polymers as well as physical stability (phase separation and API recrystallization). Computational models have been built in order to predict optimal processing conditions (e.g. temperature, residence time, drug loading), but they are limited by the lack of supporting data for key mass transport parameters. A key omission is the lack of experimental data on the API diffusion coefficient at conditions relevant to HME. This dissertation reports the first measurements of API diffusion in pharmaceutical polymer melts at temperatures relevant to the HME process, by means of high-temperature PFG NMR. These measurements were performed in the absence of any solvents, for a range of drug loadings, temperatures, polymer systems and drug species. The mechanism of the diffusion process and its relationship to viscosity was explored with the Stokes-Einstein and Arrhenius models. Viscosity plots obtained from the rheology experiments uncovered the possibility of HME processing at significantly lower temperatures to reduce the risk of thermal degradation. Additional characterisation of extrudates prepared 30◦C below the drug’s melting point conclud…
author: Pisa Chen, Elena
language: eng
keywords: NMR, High-temperature NMR, Diffusion, Drug-polymer
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/1675cf20-cbd6-4faf-b561-1d371e033317/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-03-01
date modified: 2026-07-22T22:24:28Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.75624