(586ab) An In-Silico Approach for Investigating Molecular Interactions in Carbohydrate-Water Mixtures

Gupta, J., University of the Sciences
Nunes, C., Bristol Myers Squibb
Jonnalagadda, S., University of the Sciences



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.


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 (Ow)
around SUC hydroxyl-oxygens (OHS) and around SUC acetal-oxygens (OAS). 


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 OHS -Ow 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.

lesser degree of hydrogen-bonding was observed for OAS -Ow
pairs as evident by the presence of distorted/less pronounced first peak. This
was attributed to OAS 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.


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.