Preprint Article Version 1 This version is not peer-reviewed

Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study

Version 1 : Received: 8 June 2018 / Approved: 11 June 2018 / Online: 11 June 2018 (10:24:14 CEST)

A peer-reviewed article of this Preprint also exists.

Brunsteiner, M.; Khinast, J.; Paudel, A. Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study. Pharmaceutics 2018, 10, 101. Brunsteiner, M.; Khinast, J.; Paudel, A. Relative Contributions of Solubility and Mobility to the Stability of Amorphous Solid Dispersions of Poorly Soluble Drugs: A Molecular Dynamics Simulation Study. Pharmaceutics 2018, 10, 101.

Journal reference: Pharmaceutics 2018, 10, 101
DOI: 10.3390/pharmaceutics10030101

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.

Subject Areas

molecular dynamics simulation; amorphous; physical stability; hydrogen-bond; molecular mobility; mixing energy; molecular interactions