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Multiple linear regression modelling to predict the stability of polymer-drug solid dispersions: comparison of the effects of polymers and manufacturing methods on solid dispersion stability

Fridgeirsdottir, Gudrun; Harris, Robert; Dryden, Ian L.; Fischer, Peter M.; Roberts, Clive J.

Authors

Gudrun Fridgeirsdottir Gudrun.Fridgeirsdottir@nottingham.ac.uk

Robert Harris rharris@juniperpharma.com

IAN DRYDEN IAN.DRYDEN@NOTTINGHAM.AC.UK
Professor of Statistics

Peter M. Fischer peter.fischer@nottingham.ac.uk



Abstract

Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 °C and 75% relative humidity (RH). Significant differences in times to crystallisation (onset of crystallisation) were observed between both the different polymers and the two processing methods. Stability from zero days to over one year was observed. The extensive experimental dataset obtained from this stability study was used to build multiple linear regression models to correlate physicochemical properties of the active pharmaceutical ingredients (API) with the stability data. The purpose of these models is to indicate which combination of processing method and polymer carrier is most likely to give a stable solid dispersion. Six quantitative mathematical multiple linear regression-based models were produced based on selection of the most influential independent physical and chemical parameters from a set of 33 possible factors, one model for each combination of polymer and processing method, with good predictability of stability. Three general rules are proposed from these models for the formulation development of suitably stable solid dispersions. Namely, increased stability is correlated with increased glass transition temperature (Tg) of solid dispersions, as well as decreased number of H-bond donors and increased molecular flexibility (such as rotatable bonds and ring count) of the drug molecule.

Citation

Fridgeirsdottir, G., Harris, R., Dryden, I. L., Fischer, P. M., & Roberts, C. J. (2018). Multiple linear regression modelling to predict the stability of polymer-drug solid dispersions: comparison of the effects of polymers and manufacturing methods on solid dispersion stability. Molecular Pharmaceutics, 15(5), https://doi.org/10.1021/acs.molpharmaceut.8b00021

Journal Article Type Article
Acceptance Date Mar 13, 2018
Online Publication Date Mar 13, 2018
Publication Date May 30, 2018
Deposit Date Apr 6, 2018
Publicly Available Date Mar 14, 2019
Journal Molecular Pharmaceutics
Print ISSN 1543-8384
Electronic ISSN 1543-8392
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 15
Issue 5
DOI https://doi.org/10.1021/acs.molpharmaceut.8b00021
Keywords solid dispersion, stability, multiple linear regression model, hot melt extrusion, spray-drying, amorphous
Public URL http://eprints.nottingham.ac.uk/id/eprint/50924
Publisher URL https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00021
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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