Designing Heat-Set Gels for Crystallizing APIs at Different Temperatures: A Crystal Engineering Approach

Abstract

An organic salt crystallizes through different kinds of charge-assisted hydrogen-bonded networks depending on carboxylic functionality number and the degree of amine. These H-bonded packing patterns are often robust and predictable, so one can design a supramolecular salt with a certain purpose. In some cases, two different crystalline packing patterns can be found in Primary Ammonium Dicarboxylate (PAD) salts at different temperatures. Two kinds of supramolecular bonding, namely, charge-assisted hydrogen bonding and weak van der Waals interactions stabilize the two states. A small increase in the carbon chain length in a primary amine enhances the additional van der Waals interactions with the packing so that the 2D hydrogen-bonded network (HBN) transforms into a 1D HBN at room temperature. Such van der Waals interactions can be controlled by external heat, so a temperature-dependent 1D to 2D phase change is feasible. When certain moieties, such as azo and bipyridine, are introduced into the carboxylic acid backbone, the acids become insoluble in most organic solvents, raising their melting point, and resulting in heat-set gels. In the presence of an API, temperature and solvent-dependent polymorphic crystals can be grown in the heat-set gel medium and by simply cooling down the mixture, the API crystals can be separated easily.