Multi-component supramolecular gels for the controlled crystallization of drugs: synergistic and antagonistic effects

Abstract

The applicability of multi-component gels, based on the combination of Lys-based dendrons and alkyl amines, for the crystallization of common drugs is presented. The results presented herein demonstrate that active pharmaceutical ingredients (APIs) with no carboxylic acid in their structure readily crystallize inside the organogels formed by a second generation lysine-based dendron (G2-Lys) and aliphatic amines. The thermodynamic parameters (ΔH_diss, ΔS_diss and ΔG_diss) of the corresponding three-component mixture (API + G2-Lys dendron + amine) have been calculated by using VT ¹H NMR. Interestingly, the presence of carbamazepine (CBZ) in the mixture of G2-Lys and decylamine allows efficient gelation at room temperature in contrast with the behaviour observed for an unmodified G2-Lys dendron and decylamine mixture that only forms toluene gels at −20 °C – a synergistic effect in which the API enhances gelation. On the other hand, aspirin (ASP) or indomethacine (IND), that possess a carboxylic acid in their structure, do not crystallize inside the organogel formed by G2-Lys dendron and the amine – indeed they prevent formation of the gel. The K_a values of the complexes G2-Lys⋯decylamine and IND⋯decylamine have been calculated by ¹H NMR titrations in toluene-d8. The higher K_a value for the complex IND⋯decylamine justifies that this pair is thermodynamically favoured thus preventing the formation of the complex between the Lys-based dendron and the amine, which underpins gel fibre assembly, and also preventing effective crystallization of the API – an antagonistic effect. Overall, these results demonstrate the active roles played by all components when multi-component gels are used for API crystallisation.