The polymorphism of active pharmaceutical ingredient (API) solid forms impacts their use far beyond challenges of stability and growth. A range of material properties can have a significant impact on developing a solid form. Of these, mechanical properties can affect the tabletability and processing of API solid forms. Recent work by a number of groups has highlighted how sensitive mechanical properties of simple molecular crystals can be to the treatment of dispersion interactions, as well as thermal and zero-point contributions.<br/><br/>In this contribution the elastic properties of a series of archetypal polymorphic APIs will be compared, both with recent dispersion-inclusive density-functional approximations and density-functional tight binding (DFTB) approaches. Preliminary results suggest that the general trends in elastic properties can be captured by the computational less-expensive DFTB approach, which would allow DFTB to be used for rapid assessment of elastic and mechanical response, potentially coupled with CSP calculations. However, elastic properties appear to be more sensitive to the specific parameterisation of the dispersion model, with further development requiring care in combining these models with the underlying DFTB method.

Exploring mechanical properties of pharmaceutical polymorphs with first-principles modelling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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