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Competition Between Halogen and Hydrogen Bonds and Stability of Celecoxib-Tramadol·HCl Cocrystal and Coamorphous Nanoparticles
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Resumo(s)
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.
Descrição
Tese de mestrado, Química (Química), 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Co-cristais Ligações de Halogénio Ligações de Hidrogénio Energética Teses de mestrado - 2023