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Modelling phase separation in amorphous solid dispersions.
Acta Biomater 2019; 94:410-424AB

Abstract

Much work has been devoted to analysing thermodynamic models for solid dispersions with a view to identifying regions in the phase diagram where amorphous phase separation or drug recrystallization can occur. However, detailed partial differential equation non-equilibrium models that track the evolution of solid dispersions in time and space are lacking. Hence theoretical predictions for the timescale over which phase separation occurs in a solid dispersion are not available. In this paper, we address some of these deficiencies by (i) constructing a general multicomponent diffusion model for a dissolving solid dispersion; (ii) specializing the model to a binary drug/polymer system in storage; (iii) deriving an effective concentration dependent drug diffusion coefficient for the binary system, thereby obtaining a theoretical prediction for the timescale over which phase separation occurs; (iv) calculating the phase diagram for the Felodipine/HPMCAS system; and (iv) presenting a detailed numerical investigation of the Felodipine/HPMCAS system assuming a Flory-Huggins activity coefficient. The numerical simulations exhibit numerous interesting phenomena, such as the formation of polymer droplets and strings, Ostwald ripening/coarsening, phase inversion, and droplet-to-string transitions. A numerical simulation of the fabrication process for a solid dispersion in a hot melt extruder was also presented. STATEMENT OF

SIGNIFICANCE:

Solid dispersions are products that contain mixtures of drug and other materials e.g. polymer. These are liable to separate-out over time - a phenomenon known as phase separation. This means that it is possible the product differs both compositionally and structurally between the time of manufacture and the time it is taken by the patient, leading to poor bioavailability and so ultimately the shelf-life of the product has to be reduced. Theoretical predictions for the timescale over which phase separation occurs are not currently available. Also lacking are detailed partial differential equation non-equilibrium models that track the evolution of solid dispersions in time and space. This study addresses these issues, before presenting a detailed investigation of a particular drug-polymer system.

Authors+Show Affiliations

School of Mathematics, NUI Galway, University Road, Galway, Ireland. Electronic address: martin.meere@nuigalway.ie.Istituto per le Applicazioni del Calcolo, CNR, Rome, Italy.Division of Biomedical Engineering, University of Glasgow, Glasgow G12 8QQ, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31238110

Citation

Meere, Martin, et al. "Modelling Phase Separation in Amorphous Solid Dispersions." Acta Biomaterialia, vol. 94, 2019, pp. 410-424.
Meere M, Pontrelli G, McGinty S. Modelling phase separation in amorphous solid dispersions. Acta Biomater. 2019;94:410-424.
Meere, M., Pontrelli, G., & McGinty, S. (2019). Modelling phase separation in amorphous solid dispersions. Acta Biomaterialia, 94, pp. 410-424. doi:10.1016/j.actbio.2019.06.009.
Meere M, Pontrelli G, McGinty S. Modelling Phase Separation in Amorphous Solid Dispersions. Acta Biomater. 2019;94:410-424. PubMed PMID: 31238110.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modelling phase separation in amorphous solid dispersions. AU - Meere,Martin, AU - Pontrelli,Giuseppe, AU - McGinty,Sean, Y1 - 2019/06/22/ PY - 2019/02/13/received PY - 2019/05/10/revised PY - 2019/06/07/accepted PY - 2019/6/27/pubmed PY - 2019/6/27/medline PY - 2019/6/26/entrez KW - Amorphous solid dispersion KW - Drug diffusion KW - Mathematical model KW - Phase separation SP - 410 EP - 424 JF - Acta biomaterialia JO - Acta Biomater VL - 94 N2 - Much work has been devoted to analysing thermodynamic models for solid dispersions with a view to identifying regions in the phase diagram where amorphous phase separation or drug recrystallization can occur. However, detailed partial differential equation non-equilibrium models that track the evolution of solid dispersions in time and space are lacking. Hence theoretical predictions for the timescale over which phase separation occurs in a solid dispersion are not available. In this paper, we address some of these deficiencies by (i) constructing a general multicomponent diffusion model for a dissolving solid dispersion; (ii) specializing the model to a binary drug/polymer system in storage; (iii) deriving an effective concentration dependent drug diffusion coefficient for the binary system, thereby obtaining a theoretical prediction for the timescale over which phase separation occurs; (iv) calculating the phase diagram for the Felodipine/HPMCAS system; and (iv) presenting a detailed numerical investigation of the Felodipine/HPMCAS system assuming a Flory-Huggins activity coefficient. The numerical simulations exhibit numerous interesting phenomena, such as the formation of polymer droplets and strings, Ostwald ripening/coarsening, phase inversion, and droplet-to-string transitions. A numerical simulation of the fabrication process for a solid dispersion in a hot melt extruder was also presented. STATEMENT OF SIGNIFICANCE: Solid dispersions are products that contain mixtures of drug and other materials e.g. polymer. These are liable to separate-out over time - a phenomenon known as phase separation. This means that it is possible the product differs both compositionally and structurally between the time of manufacture and the time it is taken by the patient, leading to poor bioavailability and so ultimately the shelf-life of the product has to be reduced. Theoretical predictions for the timescale over which phase separation occurs are not currently available. Also lacking are detailed partial differential equation non-equilibrium models that track the evolution of solid dispersions in time and space. This study addresses these issues, before presenting a detailed investigation of a particular drug-polymer system. SN - 1878-7568 UR - https://www.unboundmedicine.com/medline/citation/31238110/Modelling_phase_separation_in_amorphous_solid_dispersions L2 - https://linkinghub.elsevier.com/retrieve/pii/S1742-7061(19)30419-2 DB - PRIME DP - Unbound Medicine ER -