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Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency

In this study, a method is described to determine the monolayer loading capacity (MLC) of the drugs naproxen and ibuprofen, both having high recrystallization tendencies, in mesoporous silica (MS), a well known carrier that is able to stabilize the amorphous form of a drug. The stabilization has bee...

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Autores principales: Antonino, Rayane S.C.M.Q., Ruggiero, Michael, Song, Zihui, Nascimento, Thais Leite, Lima, Eliana Martins, Bohr, Adam, Knopp, Matthias Manne, Löbmann, Korbinian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733286/
https://www.ncbi.nlm.nih.gov/pubmed/31517291
http://dx.doi.org/10.1016/j.ijpx.2019.100026
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author Antonino, Rayane S.C.M.Q.
Ruggiero, Michael
Song, Zihui
Nascimento, Thais Leite
Lima, Eliana Martins
Bohr, Adam
Knopp, Matthias Manne
Löbmann, Korbinian
author_facet Antonino, Rayane S.C.M.Q.
Ruggiero, Michael
Song, Zihui
Nascimento, Thais Leite
Lima, Eliana Martins
Bohr, Adam
Knopp, Matthias Manne
Löbmann, Korbinian
author_sort Antonino, Rayane S.C.M.Q.
collection PubMed
description In this study, a method is described to determine the monolayer loading capacity (MLC) of the drugs naproxen and ibuprofen, both having high recrystallization tendencies, in mesoporous silica (MS), a well known carrier that is able to stabilize the amorphous form of a drug. The stabilization has been suggested to be due to direct absorption of the drug molecules onto the MS surface, i.e. the drug monolayer. In addition, drug that is not in direct contact with MS surface can fill the pores up to its pore filling capacity (PFC) and is potentially stabilized by confinement due to the pore size being smaller than a crystal nuclei. For drugs with high recrystallization tendencies, any drug outside the pores crystallizes due to its poor physical stability. The drug monolayer does not contribute to the glass transition temperature (T(g)) in the DSC, however, the confined amorphous drug above MLC has a T(g) and the heat capacity (ΔC(p)) over the T(g) increases with an increasing fraction of confined amorphous drug. Hence, several drug loading values above the MLC were investigated towards the presence of a T(g) and ΔC(p) using differential scanning calorimetry (DSC). A linear correlation between the amount of confined amorphous drug and its ΔC(p) was identified for the mixtures between the MLC and PFC. By subsequent extrapolation to zero ΔC(p) the experimental MLC could be determined. Using theoretical density functional theory (DFT) and ab initio Molecular Dynamics (AIMD), the binding energies for the monolayer suggested that the monolayer in fact is thermodynamically more favorable than the crystalline form, whereas the confined amorphous form is thermodynamically less favorable. Consequently, a physical stability study showed that the confined amorphous drugs above the MLC were thermodynamically unstable and consequently flowing out of the pores in order to crystallize, whereas the monolayer remained physically stable.
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spelling pubmed-67332862019-09-12 Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency Antonino, Rayane S.C.M.Q. Ruggiero, Michael Song, Zihui Nascimento, Thais Leite Lima, Eliana Martins Bohr, Adam Knopp, Matthias Manne Löbmann, Korbinian Int J Pharm X Article In this study, a method is described to determine the monolayer loading capacity (MLC) of the drugs naproxen and ibuprofen, both having high recrystallization tendencies, in mesoporous silica (MS), a well known carrier that is able to stabilize the amorphous form of a drug. The stabilization has been suggested to be due to direct absorption of the drug molecules onto the MS surface, i.e. the drug monolayer. In addition, drug that is not in direct contact with MS surface can fill the pores up to its pore filling capacity (PFC) and is potentially stabilized by confinement due to the pore size being smaller than a crystal nuclei. For drugs with high recrystallization tendencies, any drug outside the pores crystallizes due to its poor physical stability. The drug monolayer does not contribute to the glass transition temperature (T(g)) in the DSC, however, the confined amorphous drug above MLC has a T(g) and the heat capacity (ΔC(p)) over the T(g) increases with an increasing fraction of confined amorphous drug. Hence, several drug loading values above the MLC were investigated towards the presence of a T(g) and ΔC(p) using differential scanning calorimetry (DSC). A linear correlation between the amount of confined amorphous drug and its ΔC(p) was identified for the mixtures between the MLC and PFC. By subsequent extrapolation to zero ΔC(p) the experimental MLC could be determined. Using theoretical density functional theory (DFT) and ab initio Molecular Dynamics (AIMD), the binding energies for the monolayer suggested that the monolayer in fact is thermodynamically more favorable than the crystalline form, whereas the confined amorphous form is thermodynamically less favorable. Consequently, a physical stability study showed that the confined amorphous drugs above the MLC were thermodynamically unstable and consequently flowing out of the pores in order to crystallize, whereas the monolayer remained physically stable. Elsevier 2019-07-22 /pmc/articles/PMC6733286/ /pubmed/31517291 http://dx.doi.org/10.1016/j.ijpx.2019.100026 Text en © 2019 The Authors. Published by Elsevier B.V. http://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
Antonino, Rayane S.C.M.Q.
Ruggiero, Michael
Song, Zihui
Nascimento, Thais Leite
Lima, Eliana Martins
Bohr, Adam
Knopp, Matthias Manne
Löbmann, Korbinian
Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title_full Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title_fullStr Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title_full_unstemmed Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title_short Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
title_sort impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733286/
https://www.ncbi.nlm.nih.gov/pubmed/31517291
http://dx.doi.org/10.1016/j.ijpx.2019.100026
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