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The elastic and mechanical properties of pharmaceutical solid forms from first principles and first principles based methods

Zwane, Reabetswe (2023) The elastic and mechanical properties of pharmaceutical solid forms from first principles and first principles based methods. PhD thesis, Dublin City University.

The elastic and mechanical properties of organic molecular crystals of active pharmaceutical ingredients (API) are crucial for their development into solid dosage forms. A drug substance with poor mechanical properties can have instability and formulation issues. Experimentally determining mechanical properties of molecular crystals can be time-consuming and often offer limited information. However, the maturity of dispersion-inclusive density-functional theory (DFT) over recent years has enabled the predictive investigation of stability and properties of molecular crystals. Furthermore, the development of faster DFT based methods such as density functional tightbinding (DFTB) has, when appropriately benchmarked, enabled economical alternatives for the study of large molecular crystals. Here, a benchmark study of DFT and DFTB is performed by determining the elastic constants of a series of archetypal crystal structures and APIs, including polymorphic forms of paracetamol and aspirin, urea and benzene. In addition, the structure-mechanics relations of the considered systems are established. DFT semi-quantitatively predicts elastic properties but shows excellent qualitative agreement when compared to experiment. Similarly, DFTB yields an excellent qualitative agreement with experiment. This demonstrates the possibility of DFTB to be employed as a DFT surrogate. Lastly, it is found that the direction of the largest resistance of the Young’s modulus coincides with key structural features, such as hydrogen bonding and π − π interactions. The established protocols for the determination of elastic properties open up the possibility of characterizing the elastic and mechanical properties of crystal structures that exhibit novel mechanical behaviour and even of those of postulated solid forms from crystal structure prediction studies.
Item Type:Thesis (PhD)
Date of Award:November 2023
Supervisor(s):Kellett, Andrew, Thompson, Damien and Reilly, Anthony
Uncontrolled Keywords:Computational Chemistry; First Principles; Elastic; Mechanical Properties
Subjects:Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 License. View License
Funders:Science Foundation Ireland
ID Code:29002
Deposited On:04 Mar 2024 16:16 by Andrew Kellett . Last Modified 04 Mar 2024 16:16

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Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0


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