Grid-based molecular modeling for pharmaceutical salt screening: Case example of 3,4,6,7,8,9-hexahydro-2H-pyrimido...

The development of modeling capabilities for improving the efficiency with which solid-state pharmaceutical products can be developed is a key strategic goal for the pharmaceutical research and development sector. In this context, an important topic is the salt-selection process associated with drug-product formulation development. In this study, a systematic (grid-based) search method is used to predict the host/counter-ion binding for a simple but representative organic salt (i.e., a type I organic acid salt former having a single ionisable group): 3,4,6,7,8,9-hexahydro-2H-pyrimido (1,2-a) pyrimidinium acetate ([H2hpp][O2CCH3]). The relative disposition of the two ionic moieties in the asymmetric unit and, from this, the crystal packing in this compound are also predicted using the systematic grid-based search method linked to the known crystallographic unit cell dimensions. The overall strategy adopted encompasses three main steps: molecular pair search; optimization and clustering; and crystal lattice search and optimization. The predicted results, using this method, reveal a good agreement between the calculated crystal structure and that obtained from the Cambridge Crystallographic Structure Database (CCSD), indicating that the approach offers considerable promise for application as part of an integrated strategy for pharmaceutical salt selection.