Physical stability of hydroxypropyl methylcellulose-based amorphous solid dispersions: Experimental and computational study

Anton Iemtsev; Fatima Hassouna; Alex Mathers; Martin Klajmon; Marcela Dendisová; Lenka Malinová; Tereza Školáková; Michal Fulem

doi:10.1016/j.ijpharm.2020.119845

Physical stability of hydroxypropyl methylcellulose-based amorphous solid dispersions: Experimental and computational study

Int J Pharm. 2020 Nov 15:589:119845. doi: 10.1016/j.ijpharm.2020.119845. Epub 2020 Sep 12.

Authors

Anton Iemtsev¹, Fatima Hassouna², Alex Mathers³, Martin Klajmon³, Marcela Dendisová³, Lenka Malinová⁴, Tereza Školáková⁵, Michal Fulem⁶

Affiliations

¹ Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic; Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
² Department of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic. Electronic address: hassounf@vscht.cz.
³ Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
⁴ Department of Polymers, University of Chemistry and Technology, Prague, Technická 3, 166 28 Prague 6, Czech Republic.
⁵ Department of Organic Technology, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
⁶ Department of Physical Chemistry, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic. Electronic address: fulemm@vscht.cz.

PMID: 32931845
DOI: 10.1016/j.ijpharm.2020.119845

Abstract

The preparation of an amorphous solid dispersion (ASD) is a promising strategy for improving the poor oral bioavailability of many active pharmaceutical ingredients (APIs). However, poor predictability of ASD long-term physical stability remains a prevalent problem. The purpose of this study was to evaluate and compare the predictive performance of selected models concerning solid-liquid equilibrium (SLE) curve and glass-transition temperature (T_g) line modeling of ibuprofen (IBU) in cellulosic polymers (i.e., hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS)). For SLE curve modeling, an empiricalanalyticalapproach(Kyeremateng et al., 2014)and the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) equation of state (EOS) were chosen. Due to the unavailability of PC-SAFT parameters for both polymers, an approximation procedure for parametrization was applied. The Gordon-Taylor equation and Kwei equation were considered for T_g line determination. The impact of various computational set-ups (e.g., model parametrization or extrapolation length) on IBU solubility prediction at storage conditions was thoroughly investigated, assessed and confronted with the results from an 18-month physical stability study. IBU developed stable 20 wt% API content ASDs with both HPMC and HPMCAS.The extrapolation behavior and subsequent ASD thermodynamic stability prediction at storage conditions deduced from the aforementioned models weresignificantly different. Overall, the PC-SAFT EOS predicted higher IBU solubility in both polymers and, thus, a lower recrystallization tendency when compared to the empirical analytical approach. At higherIBU concentrations, liquid-liquid demixing inIBU-polymer systems was predicted by the PC-SAFT EOS, which was in qualitative disagreement with experimental observation.

Keywords: Amorphous solid dispersion; Hot-melt extrusion; PC-SAFT; Phase diagram; Physical stability; Solid-liquid equilibrium.

MeSH terms

Chemistry, Pharmaceutical*
Drug Stability
Excipients*
Hypromellose Derivatives
Methylcellulose
Solubility

Substances

Excipients
Hypromellose Derivatives
Methylcellulose