Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study
Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a...
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| Format: | Article |
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MDPI AG
2018-07-01
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| Series: | Pharmaceutics |
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| Online Access: | http://www.mdpi.com/1999-4923/10/3/101 |
| _version_ | 1797999544532729856 |
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| author | Michael Brunsteiner Johannes Khinast Amrit Paudel |
| author_facet | Michael Brunsteiner Johannes Khinast Amrit Paudel |
| author_sort | Michael Brunsteiner |
| collection | DOAJ |
| description | Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development. |
| first_indexed | 2024-04-11T11:05:06Z |
| format | Article |
| id | doaj.art-612f443cc561470b89e008ab4885c5fc |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T11:05:06Z |
| publishDate | 2018-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-612f443cc561470b89e008ab4885c5fc2022-12-22T04:28:21ZengMDPI AGPharmaceutics1999-49232018-07-0110310110.3390/pharmaceutics10030101pharmaceutics10030101Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation StudyMichael Brunsteiner0Johannes Khinast1Amrit Paudel2Research Center Pharmaceutical Engineering Gmbh, 8010 Graz, AustriaResearch Center Pharmaceutical Engineering Gmbh, 8010 Graz, AustriaResearch Center Pharmaceutical Engineering Gmbh, 8010 Graz, AustriaAmorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here, we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer–small molecule drug combinations for which stability data are available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.http://www.mdpi.com/1999-4923/10/3/101molecular dynamics simulationamorphousphysical stabilityhydrogen-bondmolecular mobilitymixing energymolecular interactions |
| spellingShingle | Michael Brunsteiner Johannes Khinast Amrit Paudel Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study Pharmaceutics molecular dynamics simulation amorphous physical stability hydrogen-bond molecular mobility mixing energy molecular interactions |
| title | Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study |
| title_full | Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study |
| title_fullStr | Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study |
| title_full_unstemmed | Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study |
| title_short | Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study |
| title_sort | relative contributions of solubility and mobility to the stability of amorphous solid dispersions of poorly soluble drugs a molecular dynamics simulation study |
| topic | molecular dynamics simulation amorphous physical stability hydrogen-bond molecular mobility mixing energy molecular interactions |
| url | http://www.mdpi.com/1999-4923/10/3/101 |
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