Predictive Design of Polymer-Based Amorphous Solid Dispersion

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

Amorphous solid dispersions comprising drug dissolved in polymers are known to enhance the dissolution performance and bioavailability of poorly water soluble drug. The exploitation of these approaches in marketed products has however been limited because of the inherent instability of the amorphous form, leading to physical instability and recrystallisation of the active ingredient rendering the product inactive. Thus, designing stable dispersed systems is a major challenge in the development of polymer based amorphous molecular dispersions. The aim of this project is to develop and test approaches for applying pair distribution function (PDF) analysis to reveal local short-range structure, and assess the ability to predict stable, metastable or unstable formulations. Specifically the project will develop tools that provide insight into structure-process-property interactions towards more predictive design of amorphous materials and formulated systems through control of short range packing within known solubility ranges. In addition, the project will provide experimental data to contribute to the development of advanced group contribution methods for drug-polymer solubility prediction.
The aim of this project is to develop and test approaches for applying pair distribution function (PDF) analysis to reveal local short-range structure, and assess the ability to predict stable, metastable or unstable formulations. Specifically the project will develop tools that provide insight into structure-process-property interactions towards more predictive design of amorphous materials and formulated systems through control of short range packing within known solubility ranges. In addition, the project will provide experimental data to contribute to the development of advanced group contribution methods for drug-polymer solubility prediction.
- The project will involve preparation of amorphous materials utilising melt-quench, lyophilisation and spray drying and exploit a suite of physical analysis methods in addition to x-ray scattering for PDF generation.
- PDF analysis will be with combined with other techniques available in the CMAC National Facility including DSC, dissolution, nano-CT, imaging spectroscopies, AFM and ToF-SIMS to provide an unprecedented insight into the homogeneity, structure, physical composition and performance of molecular dispersions. Multivariate data analysis will be utilised to identify early changes in phase composition marking the onset of instability.
- Solubility and phase composition data determined from these well characterised systems will then contribute directly to the development and testing of solubility predictions utilising the novel gSAFT framework being developed by collaborators at Imperial College (C. Adjiman).

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509760/1 01/10/2016 30/09/2021
2030991 Studentship EP/N509760/1 01/10/2017 31/03/2021 Ecaterina Bordos
 
Description Development of a novel empirical methodology to assess the saturated solubility of active pharmaceutical ingredients (API) in polymeric matrices directly during hot melt extrusion (HME). This is a process analytical technology (PAT) - based methodology that uses a low-frequency Raman tool to monitor the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolves within the polymeric matrix. Overall, this approach has demonstrated a novel capability to provide real-time API-polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Collaboration with University of Leeds and Diamond Light Source facilities has led to the application of synchrotron phase-contrast tomography (Sync-PC-µCT) to investigate the inner structure of binary ASDs produced by HME. Sync-PC-µCT provided unprecedented insight into the phase distribution homogeneity and distinguished between crystalline and amorphous API regions, polymer-rich regions, impurities and the porous fraction. By correlating to fundamental API-polymer solubility data, these results provide further insight into the dynamics of the drug solubilisation process within the polymeric matrix and ASD stability.
Exploitation Route The methodology developed for API-polymer solubility determination has the potential to determine the viable HME operational space for a targeted manufacture of stable amorphous solid dispersion systems. As such, it can applied to different API-polymer systems and implemented in a real industrial pharmaceutical scenario for process and formulation optimisation.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.6b00763