Developing Monte Carlo based high throughput screening tools for surface stability and dissolution of pharmaceutical crystals.

Abstract

This thesis aims to address the gap in high-throughput screening of phar-
maceutical compounds, which typically focuses on favourable docking be-
tween compounds and receptor proteins. Although the coupling properties
ensure that the candidate compounds are active with the target protein,
they do not consider large-scale production, formulation and in vivo release.
This work develops computational tools and novel Monte Carlo-based meth-
ods to quickly screen for crucial thermodynamic properties, such as surface
free energy, wetting free energy (contact angles) and solvation free energy.
The resulting free energies can be made consistent and applicable to various
materials by creating consistent, automated and self-contained approaches.
Transition Matrix Monte Carlo is used to allow highly efficient computational
parallelisation for all simulations presented in this work.
The surface switch Monte Carlo method was used to calculate the surface
free energy of ceria. This method efficiently addresses high-energy barriers
and differences in the energy landscapes of bulk and surface systems, thereby
providing an accurate approach for characterising surface properties. The
free energy of the ceria surfaces was calculated using the NVT and NPT
ensembles, and the surface stability was ranked in the order of {111} >
{110} > {100}. The method was stable and captured anharmonic vibrational
modes up to near-melting temperatures, and the {100} surface exhibited
higher surface excess entropy owing to surface oxygen site hopping.
The contact angles and wetting free energies of paracetamol were cal-
culated using the Grand Canonical Monte Carlo method. The key findings
show that the contact angles of paracetamol form II differ by surface ori-
entation, with the {001} surface being more hydrophobic than the {010}
and {110} surfaces because of the varying bonding strengths with water
molecules. The {010} surface with exposed hydroxyl and carbonyl groups
provided more hydrogen bonding sites, resulting in a lower contact angle.
The presence of solvents reduced the free energy of all surfaces, particularly
the {010} surface, indicating a higher affinity for the solvent. This study
also discovered that, for some systems, solvent molecules could simultane-
ously exhibit low affinity for the surface and a contact angle of less than
90°.
Finally, we calculated the solvation free energies of solute molecules on
paracetamol surfaces with various defects at different temperatures under
both vacuum and solvent (water) conditions. The results showed that the
solvation free energies decreased with increasing temperature, aiding solid
dissolution. Surface defects, such as edges, kinks and lone sites, lower the
solvation free energy and facilitate molecule removal. In vacuum, the {001}
surface has higher solvation free energies because multiple hydrogen bonds
must be broken. The addition of a solvent (water) significantly reduced the
solvation free energy and enhanced the dissolution. This reduction was more
pronounced on defective surfaces, with the hydrogen bonding of water com-
pensating for the loss of bonding interactions. On the less defective {001}
surface, this compensation is stronger, whereas on the {010} surface, the
water hydrogen bonding chains are disrupted, thereby increasing the solva-
tion free energy. For more defective surfaces, the effect reverses, favouring
dissolution from the {010} surface.

Date of Award	23 Jul 2025
Original language	English
Awarding Institution	University of Bath
Supervisor	Steve Parker (Supervisor), Thomas Underwood (Supervisor) & Chick Wilson (Supervisor)