Micro-Solvation of Propofol in Propylene Glycol-Water Binary Mixtures: Molecular Dynamics Simulation Studies

The water micro-structure around propofol plays a crucial role in controlling their solubility in the binary mixture. The unusual nature of such water micro-structure can influence both translational and reorientational dynamics, as well as the water hydrogen bond network near propofol. We have carried out the all atom molecular dynamics (MD) simulations of five different compositions of propylene glycol (PG): water binary mixture containing propofol (PFL) molecules to investigate the differential behavior of water micro-solvation shells around propofol, which is likely to control the propofol solubility. It is evident from the simulation snapshots for various composition that the PG at high molecular ration favors the water cluster and extended chainlike net- work that percolates within the PG matrix, where the propofol is in the disperse state. We estimated the radial distribution function indicates higher ordered water micro- structure around propofol for high PG content, as compared to the lower PG content 1in the PG:Water mixture. So, the hydrophilic propylene glycol regulates the stability of water micro-network around propofol and their solubility in the binary mixture. We observed the translational and rotational mobility of water belonging to the propofol micro-solvation shell is hindered for high propylene glycol content, and relaxed towards the low propylene glycol molecular ration in the PG:Water mixture. It has been noticed that the structural relaxation of the hydrogen bond formed between the propofol and the water molecules present in the propofol micro-solvation shell for all five compositions, is found slower for high PG content, and becomes faster on the way to low PG content in the mixture. Simultaneously, we calculated the intermittent residence time correlation function of the water molecules belonging to the micro-solvation shell around the propofol for five different compositions, and found a faster short time decay followed up with a long time components. Again, the origin of such long time decay primarily from the structural relaxation of the micro-solvation shell around the propofol, where the high propylene glycol content shows the slower structural relaxation that turns faster as the propylene glycol content approaches to the other end of the compositions. So, our studies showed that the slower structural relaxation of the micro-solvation shell around propofol for high propylene glycol molecular ration in the PG:Water mixture, correlate well with the extensive ordering of water micro-structure and restricted water mobility, facilitates the dissolution process of propofol in the binary mixture.