TYC@Imperial: Active Pharmaceutical Ingredients Addressed at Electronic Structure Level: From their Physico-Chemical Properties to their Nucleation/Growth Mechanisms

Professor Loredana Valenzano
Michigan Technological University, USA

Monday 26th June 2017
Time: 12.00pm
Venue: Room G01, Royal School of Mines, Imperial College London
Contact: Ms Hafiza Bibi
Tel: 0207594 7252

Molecular crystals (i.e., organic solids) are crystalline materials formed by molecules bonded by weak van der Waals forces and/or hydrogen bonds. Examples of such materials are explosives (energetic materials, EM) and drugs (active pharmaceutical ingredients, API). Since over 70% of all solid drugs are manufactured via a crystallization process, properties of API crystals under different conditions play a crucial role in quality control, tablet processing, and in vivo drug uptake.

In order to identify the properties of molecular crystals, the nature of the inter- and intra-molecular interactions needs to be understood. This can be addressed either by comparing properties characterizing different polymorphs of the same material or by studying evolution of properties of a same polymorph with respect to different thermodynamic conditions.
Taking as benchmarks two common APIs (aspirin - acetylsalicylic acid, and paracetamol –acetaminophen,

Fig. 1a and 1b) we first report a study performed at hybrid semi-empirical density functional level (B3LYPD2*) of the physico-chemical properties of the two drugs in their most stable crystalline forms. By comparing our calculated results with experimental values reported at temperatures far from 0K, we show how effects arising from volumetric expansions related to changes in temperature, dramatically influence structural, energetic, mechanical, and vibrational properties of the materials. Our study shows that the proposed approach is reliable enough to reproduce neffects of volumetric expansion on lattice energies and other measurable physico-chemical observables related to the presence of inter-molecular forces (Fig. 1c).[1,2] A second example is discussed that described the changes induced by the application of a hydrostatic pressure up to 5.0 GPa to polymorphs of paracetamol and aspirin (form I and II). A detailed discussion on the changes in the hydrogen bonds, and a comparison among the species under investigation, allows describing the anisotropic modifications that the materials undergo in relation not only to geometrical features, but also to spectroscopic considerations. The investigation of the latter aspect allows concluding, for the first time, that aspirin crystals do not undergo any pressure-induced phase transition in the range of pressures considered.[3]
Last but not least I will also discuss our recent attempts in defining the nucleation/growing mechanism of the paracetamol-oxalic acid cocrystal (PCA-OXA) through the assessment of local softness/hardness reactivity descriptors based on concepts related to frontier orbital theory (i.e., Fukui and Parr functions). Through the use of a molecular cluster approach, a comparison between four different PCA-OXA monomers is allowing us to reveal what we believe to be the description of the embryonic phase of the PCA-OXA crystalline phase.

[1] K. Adhikari, K.M. Flurchick, L. Valenzano, Chem. Phys. Lett. 621 (2015) 109.
[2] K. Adhikari, K.M. Flurchick, L. Valenzano, Chem. Phys. Lett. 630 (2015) 44.
[3] K. Adhikari, K.M. Flurchick, L. Valenzano, Comp. Theo. Chem. 1062 (2015) 90.
[4] J.-H. Ko, T.H. Kim, K.-S. Lee, S. Kojima, J. Non-Cryst. Solids 357 (2011) 547.


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