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Prediction of the Mechanical Deformation Properties of Organic Crystals Based upon their Crystallographic Structures: Case Studies of Pentaerythritol and Pentaerythritol Tetranitrate

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Abstract

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.

Results

The 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 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.

Conclusion

A 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 of formulated drug products process as needed for manufacture by direct compression.

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Abbreviations

API:

Active Pharmaceutical Ingredients

BFDH:

Bravais, Friedel, Donnay, and Harker

NA:

Avogadro’s number

PET:

Pentaerythritol

PETN:

Pentaerythritol tetranitrate

RMS:

Root means square

Å:

Angstrom

A:

Dislocation constant

b:

Burgers vector

dhkl :

Interplanar spacing

\({E}_{att}^{hkl}\) :

Attachment energy

\({E}_{sl}^{hkl}\) :

Slice energy

Ecore :

Dislocation core energy

Ecr :

Lattice energy

Edisloc :

Dislocation energy

Eline :

Dislocation line energy

K:

Modulus of elasticity

γ:

Specific surface energy

Z:

Number of asymmetric units

Synthons:

Atomic pairwise intermolecular interactions

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Authors and Affiliations

  1. Malaysian Institute of Chemical & Bioengineering Technology (MICET), Universiti Kuala Lumpur, 1988, 7800, Vendor City, Taboh Naning, Malaysia

    S. Fatimah Ibrahim

  2. Centre for the Digital Design of Drug Products, School of Chemical and Process Engineering, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK

    S. Fatimah Ibrahim, Jonathan Pickering, Vasuki Ramachandran & Kevin J. Roberts

  3. School of Computing, University of Leeds, Woodhouse Lane, LS2 9JT, Leeds, UK

    Jonathan Pickering

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Ibrahim, S.F., Pickering, J., Ramachandran, V. et al. Prediction of the Mechanical Deformation Properties of Organic Crystals Based upon their Crystallographic Structures: Case Studies of Pentaerythritol and Pentaerythritol Tetranitrate. Pharm Res 39, 3063–3078 (2022). https://doi.org/10.1007/s11095-022-03314-x

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