Abstract
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 273.15K-390K. 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.
Highlights
The common use of ibuprofen (IBF) is to treat pain associated with rheumatoid arthritis and osteoarthritis, and fever [1], mostly through oral delivery route
The molecular structure of IBF and NCTA were retrieved from National Institute of Standards and Technology (NIST) Reference Database Number 69
The calculated solvation energy for IBF is -60.18 kJ/mol and -66.96 kJ/mol for NCTA, meaning that NCTA have much higher solubility than IBF which is in agree with experimental observations [41, 42], and the spirit of NCTA as the coformer [43]
Summary
The common use of ibuprofen (IBF) is to treat pain associated with rheumatoid arthritis and osteoarthritis, and fever [1], mostly through oral delivery route. Quick availability of IBF in the blood is important in order to achieve fast relief [2]. The solubility of ibuprofen and its dissolution rate affect IBF absorption rate into the blood [1]. In order to enhance the IBF bioavailability [5], nicotinamide (NCTA) has been used as a coformer in hot melt extrusion (HME) process to produce IBF–NCTA cocrystals. An undesirable incomplete cocrystal formation of IBF–NCTA has been observed [6, 7]. To mitigate such incomplete cocrystal formation, addition of an inert excipient with low melting point temperature is sought in literature [6, 7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
