Low Molecular Weight Supramolecular Gels as a Crystallization Matrix

Abstract

Advances in the solid-state formulations of active compounds have shown positive impressions on the drug’s properties. Starting from the late appearance of the second form of the anti-HIV drug Ritonavir to the cocrystal-based drug Entresto has been a scientific effort at the crossroads of major subject areas like pharmaceutical development and crystal engineering. Most studies pertaining to the crystallization avenues have been the key choice to understand, predict, and control the solid form and properties, particularly relevant in the case of oral medicines. Crystallization from solution or slow evaporation is studied extensively and is a conventional rolling practice. However, dozens of other impending crystallization approaches encompassing vapor diffusion, precipitation, sublimation and melt crystallization, crystallization in the presence of additives, neat and solvent drop grinding, lyophilization, laser-induced crystallization, sonocrystallization, crystallization by ionic liquids and supercritical liquids, etc. are still being explored. The application of supramolecular gels as a crystallization matrix to nucleate the desired drug’s phase preferably metastable forms has been under scientific investigation in the past decade. This Perspective discusses the strategic headway of using supramolecular organogels as a choice of crystallization media for small active molecules. The laboratory-shelved solvent trapped in the designed 3D network of gelator(s) acts as small confined containers to control the nucleation and growth process. Gel fibers act as nucleation-templating surfaces offering epitaxial growth and influencing crystallization outcomes via molecular recognitions and thus are highlighted. Besides highlighting the understanding of the physical properties of organogels, the techniques used to probe their properties and structures, and the thermodynamic concepts involved in gelator aggregation in organic liquids, this Perspective largely emphasizes the basic challenges that the drug manufacturing process faces related to the crystallization of the metastable phase and the role of a gel component(s) versus gel environment on the crystallization output.