(586ac) Effect of Plasticizer On Glass Transition Temperature of Amorphous Pharmaceuticals - A Computational Study

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 technique for predicting glass
transition temperature (Tg) and (ii) to computationally evaluate the
effect of plasticizer (water) on Tg of a model amorphous compound (sucrose,


periodic in-silico models of amorphous SUC containing 0%, 3% and 5%w/w
water were constructed at 298K.  COMPASS forcefield was utilized for the MD
simulations.  The cells were energy minimized
(steepest descent, conjugate gradient), and then equilibrated (2ns) using
canonical (NVT) and isothermal-isobaric (NPT) ensembles at 440K.  Each system
was quench cooled from 440K to 265K at intervals of 5K.  The specific volumes (V) were computed using the
cell densities and plotted as a function of the corresponding temperature (T). 
Three independent simulations for each system were performed to improve
sampling statistics.


computed specific density of the amorphous SUC cells at 298K was in agreement
with experimentally determined value.  A gradual increase in density of the
amorphous cells, along with corresponding decrease in specific volume, was noted
as each system was quenched.  As the system approached glassy state, a
discontinuity in V-T curve was observed. This characteristic ?kink' represents
the transition from less stable ?rubbery state' to a kinetically stable ?glassy
state'.  Statistical regression analysis of the data corresponding to the
glassy and the rubbery region identified the Tg to be 367K.  The RSD
for data points corresponding to the rubbery phase was greater than that for
the glassy state, attributable to greater molecular mobility in the rubbery
state.  Increasing the water content progressively decreased the system Tg
The MD computed Tg values for amorphous SUC containing 3% and 5% w/w
water, were 352K and 343K respectively.


Tg of amorphous SUC was successfully computed by means of full
atomistic based MD simulations. Enhanced mobility in the rubbery state was also
manifested as increased scatter of data points in the high temperature
regimes.  The simulated plasticization effect corroborated well with
theoretical model predictions and reported experimental data.  The technique
can thus provide a molecular level insight in to the physical stability of
amorphous formulations during product development.