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Combining drug salt formation with amorphous solid dispersions – a double edged sword

Glass transition temperature (T(g)) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through T(g) elev...

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Autores principales: Hiew, Tze Ning, Taylor, Lynne S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Publishers 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733678/
https://www.ncbi.nlm.nih.gov/pubmed/36206947
http://dx.doi.org/10.1016/j.jconrel.2022.09.056
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author Hiew, Tze Ning
Taylor, Lynne S.
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Taylor, Lynne S.
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description Glass transition temperature (T(g)) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through T(g) elevation. While salt formation has been reported to impact re-crystallization tendency, it is not known if this holds true for all drugs and if it is useful in the context of amorphous solid dispersion (ASD) formulations. In addition, little information on the impact of salt formation on drug release performance of ASD is available. Herein, the influence of salt formation and T(g) elevation on the release performance of lumefantrine (T(g) = 19.7 °C) when formulated as an ASD with copovidone (PVPVA) was examined. Lumefantrine salts and lumefantrine salt–PVPVA ASDs with drug loadings (DLs) ranging from 5 to 30% were prepared. The acids used for salt formation were benzoic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, p-toluenesulfonic acid, poly(ethylene) glycol 250 diacid (PEG 250 diacid), and sulfuric acid. Salt formation resulted in an elevation of T(g) compared to lumefantrine free base, with the largest increase in T(g) observed with lumefantrine sulfate. With a lower T(g) salt, ASDs could be formulated at higher DLs while ensuring drug release. In contrast, drug release ceased at a DL as low as 5% when T(g) of the salt was high. However, ASDs with lower T(g)s such as the benzoate and PEG 250 diacid salts showed poor stability against re-crystallization when stored under stress storage conditions. When using a salt in an ASD formulation, attention should be paid to the T(g) of the salt, since it may show opposing effects on physical stability and drug release, at least for PVPVA-based ASDs.
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spelling pubmed-97336782022-12-12 Combining drug salt formation with amorphous solid dispersions – a double edged sword Hiew, Tze Ning Taylor, Lynne S. J Control Release Article Glass transition temperature (T(g)) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through T(g) elevation. While salt formation has been reported to impact re-crystallization tendency, it is not known if this holds true for all drugs and if it is useful in the context of amorphous solid dispersion (ASD) formulations. In addition, little information on the impact of salt formation on drug release performance of ASD is available. Herein, the influence of salt formation and T(g) elevation on the release performance of lumefantrine (T(g) = 19.7 °C) when formulated as an ASD with copovidone (PVPVA) was examined. Lumefantrine salts and lumefantrine salt–PVPVA ASDs with drug loadings (DLs) ranging from 5 to 30% were prepared. The acids used for salt formation were benzoic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, p-toluenesulfonic acid, poly(ethylene) glycol 250 diacid (PEG 250 diacid), and sulfuric acid. Salt formation resulted in an elevation of T(g) compared to lumefantrine free base, with the largest increase in T(g) observed with lumefantrine sulfate. With a lower T(g) salt, ASDs could be formulated at higher DLs while ensuring drug release. In contrast, drug release ceased at a DL as low as 5% when T(g) of the salt was high. However, ASDs with lower T(g)s such as the benzoate and PEG 250 diacid salts showed poor stability against re-crystallization when stored under stress storage conditions. When using a salt in an ASD formulation, attention should be paid to the T(g) of the salt, since it may show opposing effects on physical stability and drug release, at least for PVPVA-based ASDs. Elsevier Science Publishers 2022-12 /pmc/articles/PMC9733678/ /pubmed/36206947 http://dx.doi.org/10.1016/j.jconrel.2022.09.056 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hiew, Tze Ning
Taylor, Lynne S.
Combining drug salt formation with amorphous solid dispersions – a double edged sword
title Combining drug salt formation with amorphous solid dispersions – a double edged sword
title_full Combining drug salt formation with amorphous solid dispersions – a double edged sword
title_fullStr Combining drug salt formation with amorphous solid dispersions – a double edged sword
title_full_unstemmed Combining drug salt formation with amorphous solid dispersions – a double edged sword
title_short Combining drug salt formation with amorphous solid dispersions – a double edged sword
title_sort combining drug salt formation with amorphous solid dispersions – a double edged sword
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733678/
https://www.ncbi.nlm.nih.gov/pubmed/36206947
http://dx.doi.org/10.1016/j.jconrel.2022.09.056
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