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Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers

[Image: see text] Enteric polymers are widely used in amorphous solid dispersion (ASD) formulations. The aim of the current study was to explore ASD failure mechanisms across a wide range of pH conditions that mimic in vivo gastric compartment variations where enteric polymers such as hydroxypropyl...

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Autores principales: Nguyen, Hanh Thuy, Van Duong, Tu, Taylor, Lynne S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997068/
https://www.ncbi.nlm.nih.gov/pubmed/36730186
http://dx.doi.org/10.1021/acs.molpharmaceut.2c00895
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author Nguyen, Hanh Thuy
Van Duong, Tu
Taylor, Lynne S.
author_facet Nguyen, Hanh Thuy
Van Duong, Tu
Taylor, Lynne S.
author_sort Nguyen, Hanh Thuy
collection PubMed
description [Image: see text] Enteric polymers are widely used in amorphous solid dispersion (ASD) formulations. The aim of the current study was to explore ASD failure mechanisms across a wide range of pH conditions that mimic in vivo gastric compartment variations where enteric polymers such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are largely insoluble. Delamanid (DLM), a weakly basic drug used to treat tuberculosis, was selected as the model compound. Both DLM free base and the edisylate salt were formulated with HPMCP, while DLM edisylate ASDs were also prepared with different grades of HPMCAS. Two-stage release testing was conducted with the gastric stage pH varied between pH 1.6 and 5.0, prior to transfer to intestinal conditions of pH 6.5. ASD particles were collected following suspension in the gastric compartment and evaluated using X-ray powder diffraction and scanning electron microscopy. Additional samples were also evaluated with polarized light microscopy. In general, ASDs with HPMCP showed improved overall release for all testing conditions, relative to ASDs with HPMCAS. ASDs with the edisylate salt likewise outperformed those with DLM free base. Impaired release for certain formulations at intestinal pH conditions was attributed to surface drug crystallization that initiated during suspension in the gastric compartment where the polymer is insoluble; crystallization appeared more extensive for HPMCAS ASDs. These findings suggest that gastric pH variations should be evaluated for ASD formulations containing weakly basic drugs and enteric polymers.
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spelling pubmed-99970682023-03-10 Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers Nguyen, Hanh Thuy Van Duong, Tu Taylor, Lynne S. Mol Pharm [Image: see text] Enteric polymers are widely used in amorphous solid dispersion (ASD) formulations. The aim of the current study was to explore ASD failure mechanisms across a wide range of pH conditions that mimic in vivo gastric compartment variations where enteric polymers such as hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are largely insoluble. Delamanid (DLM), a weakly basic drug used to treat tuberculosis, was selected as the model compound. Both DLM free base and the edisylate salt were formulated with HPMCP, while DLM edisylate ASDs were also prepared with different grades of HPMCAS. Two-stage release testing was conducted with the gastric stage pH varied between pH 1.6 and 5.0, prior to transfer to intestinal conditions of pH 6.5. ASD particles were collected following suspension in the gastric compartment and evaluated using X-ray powder diffraction and scanning electron microscopy. Additional samples were also evaluated with polarized light microscopy. In general, ASDs with HPMCP showed improved overall release for all testing conditions, relative to ASDs with HPMCAS. ASDs with the edisylate salt likewise outperformed those with DLM free base. Impaired release for certain formulations at intestinal pH conditions was attributed to surface drug crystallization that initiated during suspension in the gastric compartment where the polymer is insoluble; crystallization appeared more extensive for HPMCAS ASDs. These findings suggest that gastric pH variations should be evaluated for ASD formulations containing weakly basic drugs and enteric polymers. American Chemical Society 2023-02-02 /pmc/articles/PMC9997068/ /pubmed/36730186 http://dx.doi.org/10.1021/acs.molpharmaceut.2c00895 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Nguyen, Hanh Thuy
Van Duong, Tu
Taylor, Lynne S.
Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title_full Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title_fullStr Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title_full_unstemmed Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title_short Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers
title_sort impact of gastric ph variations on the release of amorphous solid dispersion formulations containing a weakly basic drug and enteric polymers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997068/
https://www.ncbi.nlm.nih.gov/pubmed/36730186
http://dx.doi.org/10.1021/acs.molpharmaceut.2c00895
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