Crystal Energy Landscapes for Aiding Crystal Form Selection

Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules

“…Establishing the range of conformations that a potential drug molecule can adopt is not only relevant to drug design. Most drugs are formulated with the active molecule in the solid state, , and the physical properties of the crystalline forms of an API can be very dependent on the crystal structure, − with many pharmaceuticals having a range of solid-state structures (polymorphs) containing different conformations of the molecule. ,, Hence, in drug development, the pharmaceutical undergoes a screen for possible solid forms involving a diverse range of crystallization experiments. ,,− Since this cannot bring total reassurance that all relevant solid forms of the molecule are known, ,,, there is considerable interest in using computational modeling to predict the polymorphs of organic molecules. ,,,,, Such crystal structure prediction (CSP) studies should generate the observed structure and usually other structures that are within the likely energy range of possible polymorphism, which can be considered as putative polymorphs (PPMs). There are examples of using the predicted structure of a PPM to devise an experiment to find it. ,, CSP methods have been evolving rapidly, along with our understanding of why they may overpredict polymorphism .…”