Dr. Jonathan Loh, Pfizer Institute for Pharmaceutical Materials Science, Univ. of Cambridge
Dr. William Ketterhagen, Pfizer Worldwide R&D, Groton CT
Dr. James Elliott, Pfizer Institute for Pharmaceutical Materials Science, Univ. of Cambridge

During drug development, computer modelling is often used by the pharmaceutical industry. Discrete element models can simulate the interaction between powder particles, like active pharmaceutical ingredients (APIs) and excipients. Quantum and molecular models operate on a smaller scale and can predict the crystal structures and mechanical properties of individual API particles. In the present work, a combination of the above modelling techniques and existing crystal structure information is used to predict the compaction behaviour of acetazolamide (an example API) from first principles.

Using ab initio self-consistent field calculations on a single molecule of acetazolamide, its equilibrium gas phase structure, interaction energy with water molecules, vibrational spectra and dihedral energy profiles were calculated. Applying the iterative CHARMM General Force Field parameterisation procedure to the acquired results, parameters for a molecular dynamics simulation of acetazolamide were obtained. By combining the calculated parameters with existing crystallographic data from scientific literature, the monoclinic and triclinic forms of acetazolamide were simulated. With these molecular simulations, the yield stress, Young’s modulus, Poisson ratio and surface energies of acetazolamide were calculated. These material properties were then set as inputs in discrete element method simulations. Using a modified version of LIGGGHTS (discrete element method software), which contained Thornton’s plastic model and a JKR cohesive force, the compaction behaviour of acetazolamide with microcrystalline cellulose was predicted. This procedure can be extended to other novel APIs to evaluate compaction behaviour at an early stage of drug development.