An In-Silico Approach for Investigating Molecular Interactions in Carbohydrate-Water Mixtures

 

PURPOSE

The objectives were (i) to develop a molecular dynamics (MD) based approach for determination of radial distribution function (RDF) and (ii) to delineate the specific interactions in a model carbohydrate (sucrose, SUC) and water system.

METHODS

MD construct comprised of periodic amorphous cells of SUC containing 0-5%w/w water.  The COMPASS force-field was utilized.  The cells were subjected to energy minimization (conjugate gradient), and then equilibration (2ns) using canonical (NVT) and isothermal-isobaric (NPT) ensembles at 440K.  Each system was cooled at 5K intervals spanning temperature range of 440-265K.  The configurations corresponding to the average density values, obtained from NPT, were subjected to NVT simulations (200ps). The RDF was calculated from the terminal 50ps simulation time for water-oxygens (O_w) around SUC hydroxyl-oxygens (O_HS) and around SUC acetal-oxygens (O_AS). 

RESULTS

The RDF is measure of probability of finding a given pair of atoms at a distance r with respect to bulk phase in a random distribution. For O_HS -O_w pairs, a sharp primary and a broad secondary peak were observed at 2.8°A and 5.5°A, respectively.  The sharp peak suggested strong hydrogen-bond interactions and was ascribed to the first hydration shell with water molecules structurally arranged within the shell (width 1°A).  The broad peak suggested the presence of second hydration shell wherein the water molecules were less structurally arranged.

A lesser degree of hydrogen-bonding was observed for O_AS -O_w pairs as evident by the presence of distorted/less pronounced first peak. This was attributed to O_AS constrained ring geometry, bulky neighboring groups and less accessibility to surrounding water molecules. The RDF data suggests that water disrupts H-bond network between SUC-SUC and forms hydrogen-bond between SUC-water thereby destabilizing SUC.  The magnitude of interactions was dependant temperature of the system and correlated to molecular mobility.

CONCLUSIONS

The RDF measurements revealed strong hydrogen-bond interactions between SUC hydroxyl-oxygens and water-oxygen.  Steric effects led to weak interactions between SUC acetal-oxygens and water-oxygen.  Molecular interactions play critical role in stabilization or phase separation of multi-component amorphous systems.  MD is thus a powerful tool for assessing the stability risks during development of an amorphous drug product.