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Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation

[Image: see text] Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomet...

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Autores principales: Hugo Silva, Mariana, Kumar, Ajay, Hodnett, Benjamin K., Tajber, Lidia, Holm, René, Hudson, Sarah P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542716/
https://www.ncbi.nlm.nih.gov/pubmed/36217420
http://dx.doi.org/10.1021/acs.cgd.2c00678
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author Hugo Silva, Mariana
Kumar, Ajay
Hodnett, Benjamin K.
Tajber, Lidia
Holm, René
Hudson, Sarah P.
author_facet Hugo Silva, Mariana
Kumar, Ajay
Hodnett, Benjamin K.
Tajber, Lidia
Holm, René
Hudson, Sarah P.
author_sort Hugo Silva, Mariana
collection PubMed
description [Image: see text] Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomethacin while achieving the desired particle size distribution is described. It was proven that when a metastable form of indomethacin was initially nucleated, the rate of its transformation to the stable form was influenced by the presence of excipients and seeds (17.10 ± 0.20 μm), decreasing from 48 to 4 h. The final particle size (D50) of the indomethacin suspension produced without seeding was 7.33 ± 0.38 μm, and with seeding, it was 5.61 ± 0.14 μm. Additionally, it was shown that the particle size distribution of the seeds and the time point of seed addition were critical to obtain the desired solid-state form and that excipients played a crucial role during nucleation and polymorphic transformation. This alternative, energy-efficient bottom-up method for the production of drug suspensions with a reduced risk of contamination from milling equipment and fewer processing steps may prove to be comparable in terms of stability and particle size distribution to current industrially accepted top-down approaches.
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spelling pubmed-95427162022-10-08 Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation Hugo Silva, Mariana Kumar, Ajay Hodnett, Benjamin K. Tajber, Lidia Holm, René Hudson, Sarah P. Cryst Growth Des [Image: see text] Long-acting injectables are a unique drug formulation strategy, providing a slow and sustained release of active pharmaceutical ingredients (APIs). In this study, a novel approach that combines liquid antisolvent precipitation with seeding to obtain a stable form of the API indomethacin while achieving the desired particle size distribution is described. It was proven that when a metastable form of indomethacin was initially nucleated, the rate of its transformation to the stable form was influenced by the presence of excipients and seeds (17.10 ± 0.20 μm), decreasing from 48 to 4 h. The final particle size (D50) of the indomethacin suspension produced without seeding was 7.33 ± 0.38 μm, and with seeding, it was 5.61 ± 0.14 μm. Additionally, it was shown that the particle size distribution of the seeds and the time point of seed addition were critical to obtain the desired solid-state form and that excipients played a crucial role during nucleation and polymorphic transformation. This alternative, energy-efficient bottom-up method for the production of drug suspensions with a reduced risk of contamination from milling equipment and fewer processing steps may prove to be comparable in terms of stability and particle size distribution to current industrially accepted top-down approaches. American Chemical Society 2022-09-09 2022-10-05 /pmc/articles/PMC9542716/ /pubmed/36217420 http://dx.doi.org/10.1021/acs.cgd.2c00678 Text en © 2022 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 Hugo Silva, Mariana
Kumar, Ajay
Hodnett, Benjamin K.
Tajber, Lidia
Holm, René
Hudson, Sarah P.
Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title_full Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title_fullStr Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title_full_unstemmed Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title_short Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation
title_sort impact of excipients and seeding on the solid-state form transformation of indomethacin during liquid antisolvent precipitation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9542716/
https://www.ncbi.nlm.nih.gov/pubmed/36217420
http://dx.doi.org/10.1021/acs.cgd.2c00678
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