Purpose Development of a quantitative model and associated workflow for predicting the mechanical deformation properties (plastic deformation or cleavage fracture) of organic single crystals from their crystallographic structures using molecular and crystallographic modelling.Methods Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields with the data integrated into the analysis of lattice deformation as computed using a statistical approach.
ResultsThe approach developed comprises three main components. Firstly, the identification of the likely direction of deformation based on lattice unit cell geometry; secondly, the identification of likely lattice planes for facilitating deformation through the calculation of the strength and stereochemistry of interplanar intermolecular interactions, surface plane rugosity and surface energy; thirdly, identification of potential crystal planes for cleavage fracture by assessing intermolecular bonding anisotropy. Pentaerythritol is predicted to fracture by brittle cleavage on the {001} lattice planes by strong in-plane hydrogen-bond interactions in the <110>, whereas pentaerythritol tetranitrate is predicted to deform by plastic deformation through the slip system {110}<001>, with both predictions being in excellent agreement with known experimental data.
ConclusionA crystallographic framework and associated workflow for predicting the mechanical deformation of molecular crystals is developed through quantitative assessment of lattice energetics, crystal surface chemistry and crystal defects. The potential for the de novo prediction of the mechanical deformation of pharmaceutical materials using this approach is highlighted for its potential importance in the design 2 of formulated drug products process as needed for manufacture by direct compression.
The morphology of a crystal grown
in a solvent can change depending
on the solvent used during the crystallization process. Modification
of the morphology of a crystal can be engineered based on information
conferred by the functional groups of the facets of interest and the
functional groups of the solvent. This study aims to predict the effect
of the alcoholic functional group of amyl alcohol, benzyl alcohol,
and phenol on the {002}, {011}, and {110} facets of Form I paracetamol.
Prediction and simulation studies were carried out using an embedded
tool available in Material Studio. The interaction between the solvents
(phenol, benzyl alcohol, and amyl alcohol) and the surfaces used in
this study revealed that the {011} facet had the most negative nonbonded
energy, followed by the {110} and {002} facets. Overall, the nonbonded
interactions between the solvents and the facets were dominated by
Coulombic interactions, accounting for more than 90% of the energies,
which is within the range from −2566 to −3613 kcal/mol.
The binding energy for amyl and benzyl alcohols on the facets of the
crystal, ranked from the strongest to the weakest, was in the order
{002} > {110} > {011}, while for phenol, the rank was {002}
> {011}
> {110}. This result is in line with the observed crystal morphology
of Form I paracetamol crystallized in a polar protic solvent, in which
the most favorable solvent binding on the {002} facets delayed the
growth of the elongated hexagonal morphology along the c-axis and formed prismatic-like morphology. Using benzyl alcohol
as a case study, an assessment of synthon formation on facets {002}
and {011} showed that synthon B is an important synthon for the growth
of units of these facets, while synthon F is an important building
block synthon for the {110} facet.
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