Relative contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of poorly soluble drugs: A Molecular Dynamics Simulation study

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Abstract

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 is 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.
Original languageEnglish
Article number101
Number of pages20
JournalPharmaceutics
Volume10
Issue number3
DOIs
Publication statusPublished - 21 Jul 2018

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Molecular Dynamics Simulation
Solubility
Excipients
Polymers
Pharmaceutical Preparations
Drug Combinations
Thermodynamics
Computer Simulation

Keywords

  • molecular dynamics simulation
  • Amorphous
  • physical stability
  • hydrogen-bond
  • molecular mobility
  • mixing energy
  • molecular interactions

Cite this

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title = "Relative contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of poorly soluble drugs: A Molecular Dynamics Simulation study",
abstract = "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 MolecularDynamics simulations to determine properties of blends of eight different polymer-small molecule drug combinations for which stability data is 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, candetermine 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 givendrug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.",
keywords = "molecular dynamics simulation, Amorphous, physical stability, hydrogen-bond, molecular mobility, mixing energy, molecular interactions",
author = "Michael Brunsteiner and Johannes Khinast and Amrit Paudel",
year = "2018",
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doi = "10.3390/pharmaceutics10030101",
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T1 - Relative contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of poorly soluble drugs: A Molecular Dynamics Simulation study

AU - Brunsteiner, Michael

AU - Khinast, Johannes

AU - Paudel, Amrit

PY - 2018/7/21

Y1 - 2018/7/21

N2 - 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 MolecularDynamics simulations to determine properties of blends of eight different polymer-small molecule drug combinations for which stability data is 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, candetermine 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 givendrug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.

AB - 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 MolecularDynamics simulations to determine properties of blends of eight different polymer-small molecule drug combinations for which stability data is 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, candetermine 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 givendrug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.

KW - molecular dynamics simulation

KW - Amorphous

KW - physical stability

KW - hydrogen-bond

KW - molecular mobility

KW - mixing energy

KW - molecular interactions

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DO - 10.3390/pharmaceutics10030101

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VL - 10

JO - Pharmaceutics

JF - Pharmaceutics

SN - 1999-4923

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ER -