Competition Between Halogen and Hydrogen Bonds and Stability of Celecoxib-Tramadol·HCl Cocrystal and Coamorphous Nanoparticles

Abstract

Cocrystals have, over the years, gained considerable interest due to their potential to improve material properties without changing the molecular structure. In this work, two studies were performed, the first involving a fundamental study on how hydrogen and halogen bonds compete/cooperate, in the formation of a cocrystal, the second concerning the thermodynamic stability of a Tramadol∙HCL:Celecoxib cocrystal and its comparison with recently described coamorphous nanoparticles and cocrystalline nanoparticles produced through CO2 assisted nano spray drying. The study of halogen and hydrogen bonds competition/cooperation involved a cocrystal screening with donor (halogenophenols) acceptor (pyrazine, hexamethylenetetramine and 1,4-diazabicyclo[2.2.2]octane) molecules that could form both types of bonds. 25 new cocrystals were synthesized and 6 had the structure determined. Only one of the structures (4-iodophenol with hexamethylenetetramine) resulted in the formation of a halogen bond, despite the concomitant presence of two hydrogen bonds. All other structures only presented hydrogen bonds between the donor and acceptor molecules. Computed interaction energies between dimers of halogenophenols with 1,4-diazabicyclo[2.2.2]octane revealed that: (i) hydrogen bonds are the strongest among the studied interactions; (ii) the ring substituent pattern impacts the bond strength with closer substituents resulting in stronger bonds; (iii) changing the halogen atom affords an increase of the bond strength as we go down on the periodic table halogen group, an effect enhanced for halogenhalogen bonds. Solution calorimetry and solubility measurements of the Tramadol∙HCL:Celecoxib crystalline and amorphous samples revealed that: (i) both crystalline samples are stable against decomposition into their precursors, ΔrG°m>0; (ii) the stability of the cocrystal produced through solution crystallization is of enthalpic nature, ΔrH°m>|TΔrS°m|, while the stability of the cocrystalline sample produced through spray drying is of entropic nature, ΔrH°m<|TΔrS°m|; (iii) on enthalpic grounds, smaller particle sizes seem to correlate with higher instability. (iv) amorphous samples presented lower stability.