Predictive Design of Polymer-Based Amorphous Solid Dispersion

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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).