Computational Dehydration of Crystalline Hydrates Using Molecular Dynamics Simulations

Abstract

Molecular dynamics (MD) simulations have evolved to an increasingly reliable and accessible technique and are today implemented in many areas of biomedical sciences. We present a generally applicable method to study dehydration of hydrates based on MD simulations and apply this approach to the dehydration of ampicillin trihydrate. The crystallographic unit cell of the trihydrate is used to construct the simulation cell containing 216 ampicillin and 648 water molecules. This system is dehydrated by removing water molecules during a 2200 ps simulation, and depending on the computational dehydration rate, different dehydrated structures were observed. Removing all water molecules immediately and removing water relatively fast (10 water molecules/10 ps) resulted in an amorphous system, whereas relatively slow computational dehydration (3 water molecules/10 ps) resulted in a crystalline anhydrate. The structural changes could be followed in real time, and in addition, an intermediate amorphous phase was identified. The computationally identified dehydrated structure (anhydrate) was slightly different from the experimentally known anhydrate structure suggesting that the simulated computational structure could represent a kinetically trapped dehydration intermediate.

Imaging of dehydration in particulate matter using Raman line-focus microscopy

“…Spectroscopic techniques such as Raman and near-infrared spectroscopy (NIR) are used at different stages of the drug development process and are well suited to monitor hydrate formation and dehydration during processing, but require long measurement times; risking dehydration on the hydrate 11,12 . Computational approaches have recently been used in order to determine the structural changes during dehydration and to identify an amorphous intermediate of ampicillin trihydrate 13 . These approaches provide a molecular-level understanding of dehydration pathways; however, they require experimental methods to confirm.…”

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery

“…Drugs often enter the body in crystalline form and dissolution of these crystals is the first step. Larsen et al (2017aLarsen et al ( ,b, 2019 have used MD simulation to study alteration to the crystal structure with varying levels of hydration. For systems with long range order such as this, a more accurate and computationally intensive COMPASS force field (Sun, 1998) is required, instead of the potential sets normally used for simulations of systems in the liquid state.…”

On the influence of water on THz vibrational spectral features of molecular crystals

“…A wide range of experimental techniques can be used to address the role of water in organic molecular structures: X-ray and neutron diffraction 2 , nuclear magnetic resonance (NMR) 3,4 and various optical spectroscopic techniques 5,6 . Computational studies (most commonly, Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulation) can complement the knowledge gained through experiments and offer a description of the macromolecule or the molecular crystal and solvent as well as their dynamics at the atomic scale [7][8][9][10][11] .…”

“…5,6 Computational studies (most commonly, Density Functional Theory (DFT) calculations and Molecular Dynamics (MD) simulation) can complement the knowledge gained through experiments and offer a description of the macromolecule or the molecular crystal and solvent as well as their dynamics at the atomic scale. [7][8][9][10][11] From the theoretical point of view, water offers the opportunity to enlarge our understanding of hydrogen bonding. 12 Several recent reviews exist on the role of water in the structure and dynamics of proteins, 13 its hydration and ligand recognition, 14 DNA 15,16 and other macromolecular structures.…”