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The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers

The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly incre...

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Autores principales: Blaabjerg, Lasse I., Grohganz, Holger, Lindenberg, Eleanor, Löbmann, Korbinian, Müllertz, Anette, Rades, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320775/
https://www.ncbi.nlm.nih.gov/pubmed/30241425
http://dx.doi.org/10.3390/pharmaceutics10040164
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author Blaabjerg, Lasse I.
Grohganz, Holger
Lindenberg, Eleanor
Löbmann, Korbinian
Müllertz, Anette
Rades, Thomas
author_facet Blaabjerg, Lasse I.
Grohganz, Holger
Lindenberg, Eleanor
Löbmann, Korbinian
Müllertz, Anette
Rades, Thomas
author_sort Blaabjerg, Lasse I.
collection PubMed
description The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer.
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spelling pubmed-63207752019-01-11 The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers Blaabjerg, Lasse I. Grohganz, Holger Lindenberg, Eleanor Löbmann, Korbinian Müllertz, Anette Rades, Thomas Pharmaceutics Article The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer. MDPI 2018-09-21 /pmc/articles/PMC6320775/ /pubmed/30241425 http://dx.doi.org/10.3390/pharmaceutics10040164 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Blaabjerg, Lasse I.
Grohganz, Holger
Lindenberg, Eleanor
Löbmann, Korbinian
Müllertz, Anette
Rades, Thomas
The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title_full The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title_fullStr The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title_full_unstemmed The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title_short The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
title_sort influence of polymers on the supersaturation potential of poor and good glass formers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320775/
https://www.ncbi.nlm.nih.gov/pubmed/30241425
http://dx.doi.org/10.3390/pharmaceutics10040164
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