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Incomplete cocrystalization of ibuprofen and nicotinamide and its interplay with formation of ibuprofen dimer and/or nicotinamide dimer: a thermodynamic analysis based on DFT data

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journal contribution
posted on 2020-11-25, 15:03 authored by Milad Asgarpour Khansary, Gavin M. Walker, Saeed Shirazian
Cocrystallization of ibuprofen and nicotinamide in hot melt extrusion process has been subject of many studies addressing low ibuprofen bioavailability. However, it is observed that the process of cocrystal formation of ibuprofen and nicotinamide might be incomplete. We hypothesized that formation of dimers of ibuprofen–ibuprofen or dimers nicotinamide– nicotinamide might be the cause of such poor cocrystalization process by altering the phase behaviour of the mixture. This paper addresses the molecular thermodynamics of mixtures of ibuprofen and nicotinamide, with special focus on the possibility of formation of these dimers and their corresponding interplay with mixture phase behaviour. For this purpose, density functional theory calculations are used to calculate electron donor-acceptor sizes on each molecule and accordingly possible dimers of each molecule are analysed. The free energies and phase diagram are determined for (1) when a dimer is formed or (2) no dimer is formed, over a wide operating temperature range of 273.15 K–390 K. The binding and solvation energies are calculated to identify/rank dimers. Calculations showed that formation of dimers requires an energy input which can be accessible noting to the external heating in hot melt extrusion process. The calculated solvation energies of the dimers suggest that addition of liquid binder (water) can mitigate the risk of dimer formations. Addition of proper binder/excipient is an easy route to compensate such dimer formation and to engineer ibuprofen and nicotinamide cocrystallization behaviour.


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International Journal of Pharmaceutics;591, 119992




peer-reviewed The authors have made available all associated files at:, using tag ID: 2020.CoCryM.Thermo as per (1) MSCA Open Data policy and (2) our transparency of research data.

Other Funding information

ERC, SFI, European Union (EU)


This is the author’s accepted version of a work that was accepted for publication in International Journal of Pharmaceutics, Volume 591, 15 December 2020, 119992 Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in International Journal of Pharmaceutics,



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