On the structure of prilocaine in aqueous and amphiphilic solutions

Abstract

The solvation of prilocaine has been investigated in pure water and in an amphiphilic methanol/water solution using a combination of neutron diffraction with isotopic substitution augmented by Empirical Potential Structure Refinement (EPSR) simulations. This combination of techniques allows for details of the solvation structure on the atomic scale to be unravelled. The hydration of prilocaine is significantly altered relative to when this molecule is in pure water (as a hydrochloride salt) or in an amphiphilic environment (as a freebase compound). Interestingly, there is not a significant change in hydration around the amine group on prilocaine hydrochloride compared with prilocaine as a freebase. Despite this group being an ammonium group in water and an amine group in methanol/water solutions, the hydration of this motif remains largely intact. The changes in hydration between prilocaine as a free base and prilocaine·HCl instead appears to arise from a change in hydration around the aromatic ring and the amide group in the prilocaine molecule.

Genuine antiplasticizing effect of water on a glass-former drug

“…This indicates that water binds mainly to the carbonyl oxygen. This is consistent with the results recently reported by some of us through the study of prilocaine by means of neutron diffraction and Empirical Potential Structure Refinement simulation 53 .…”

“…H-bonding of water to prilocaine is energetically favored with respect to inter-prilocaine H-bonding since hydrogen bonds with oxygen donors are stronger than with nitrogen donors, which in the case of pure prilocaine may be expected to be even weaker as they involve chain nitrogens. Water molecules might donate two H-bonds to a single prilocaine molecule, binding to the carbonyl oxygen and simultaneously to a chain nitrogen, for example 53 , or else bridge together two distinct prilocaine molecules. Given that the addition of water has little effect on the N-H vibration and a large on the C=O band (Fig.…”

Tuning molecular dynamics by hydration and confinement: antiplasticizing effect of water in hydrated prilocaine nanoclusters

“…Prilocaine hydrochloride salt was purchased from Sigma Aldrich and reacted to form the free base prilocaine, as described previously 21,22 . The water-saturated prilocaine liquid L 1 was obtained by mixing equal amounts of purified water and pure prilocaine, and keeping the mixture in the liquid state in a thermal bath at 323 K for 2 days.…”

“…The reason for this lowering in T g is likely the reduction of the size of cooperatively rearranging clusters upon confinement. In the bulk system, prilocaine and water molecules are linked through hydrogen bonds 22 . Under confinement, the characteristic size of the H-bonded clusters (that is prilocaine molecules bridged by water) is necessarily smaller because of the lack of space.…”

On the hydration of DOPE in solution

“…As a result, Empirical Potential Structure Refinement (EPSR) simulations were employed, where this Monte Carlo-based simulation technique has been specifically designed to generate a computational model of a disordered system which fits a set of measured diffraction data in order to extract a full set of correlations for any given system. 19,20 This analysis method has been used to explore a range of chemical and biological solutions, [21][22][23][24][25][26][27][28][29][30] as well as specifically for the hydration of lipid molecules. 10,[12][13][14]31 Here EPSR simulations were performed on a box containing 10 DOPE, 50 H 2 O and 3000 CHCl 3 molecules at the temperature and atomic number density of the measurement (298 K and 0.0374 atoms/Å 3 ).…”