Elastic properties of pharmaceutical molecules using classical simulations

Organic crystals are of particular interest in pharmaceutical industry, because the majority of drugs are produced and distributed in crystalline form. Molecular crystals play also an important role as agrochemicals, pigment dyes, and organic photovoltaics [1]. The applicability and also properties like the elastic properties depend very much on the crystal morphology of these compounds.

 

A well-known pharmaceutical crystal is aspirin for which the crystalline structure is shown in Figure 1.

 

c4-f1-elastic-properties-aspirin
Figure 1: Crystalline structure of aspirin.

For industrial applications, several properties of a product are of vital importance, and many of these do depend strongly on the structure. Mechanical properties are of special interest since they are critical to the powder processing for tableting. Various parameters impact the overall mechanical properties, the elastic properties of the undisturbed crystal are among them. Computational methods can help to predict these properties based on the calculation of the young modulus [2].

 

In this application note, we consider the elastic properties of aspirin The molecular structures of Aspirin is shown in Figure 2.

 

c4-f2-elastic-properties-aspirin
Figure 2: Structure formula of aspirin.

The properties of the compound were studied with classical MD simulation. The Young modulus was calculated by tensing the crystal progressively in each one of the three dimensions and monitoring the stress as a function of strain. The rate of the applied stress is indicative (0.5 atm/ps) and perhaps adjustments to it are needed for better accuracy. We have used an automated procedure through MAPS which makes use of MAPS python scripting functionality..

 

The initial size of the box lengths was around 22.86Å, 26.36Å and 22.79Å for x,y,z dimensions respectively (Fig 3). Simulations have been performed using 1000ps NPT runs progressively applying a tensile stress up to 500 Atm. The Pcff forcefields was assigned.

 

c4-f3-elastic-properties-aspirin
Figure 3: Snapshot of aspirin crystal. The red atoms are oxygens and the grey carbons.

The results are presented in figures 4 and 5 while the experimental ones are presented in figure 6 [2].

 

c4-f4-elastic-properties-aspirin
Figure 4: Stress versus strain plot for aspirin in z direction of the crystal. Young modulus is calculated as the slope of the graph at 9.07 GPa. Pcff forcefield was used and a rate of 0.5 atm/ps.

c4-f5-elastic-properties-aspirin
Figure 5: Stress versus strain plot for aspirin in x direction of the crystal. Young modulus is calculated as the slope of the graph at 5.79 GPa. Pcff forcefield was used and a rate of 0.5 atm/ps.

c4-f6-elastic-properties-aspirin
Figure 6: Young modulus for aspirin in two directions of the crystal from ref 2.

Conclusions
In summary, the simulation results for aspirin demonstrate that important processing properties, like for example the Youngs modulus, can be calculated using atomistic modeling tools within an acceptable error range, and hence molecular modeling can assist in the development process of drugs and related materials and enhance the quality of final products.

 

References:

  1. G. Desiraju, J. Chem. Sci., 122 (2010) 667-675 .
  2. Solid State Characterization of Pharmaceuticals Richard A. Storey, Ingvar Ymen April 2011, Wiley-Blackwell.