Salts of Hydrates of Imiquimod, an Immune Response Modifier

Imiquimod free base 1, an immune response modifier, its hydrochloride salt 2, hydrochloride salt monohydrate 3, salts with maleic acid 4, fumaric acid 5, succinic acid 6, adipic acid 7, and 4-hydroxybenzoic acid 8 have been prepared and characterized by single crystal X-ray diffraction. The carboxylic acid salts 4-8 were obtained by solution crystallization experiments of imiquimod hydrochloride with carboxylic acid group containing molecules, Imiquimod contains a 2-aminopyridine moiety which is known to form salts when crystallized with acidic carboxylic acid moiety containing molecules. During the crystallization, hydrochloride was liberated from the imiquimod and the basic pyridine moiety was protonated by the carboxylic acids. Dicarboxylic acid salts 5-7 crystallized in 2:1 stoichiometry, however, 2, 4, and 8 crystallized in a 1: 1 ratio. Imiquimod maleate salt 4 crystallized as sesquihydrate. whereas imiquimod fumarate (5) crystallized as hexahydrate. Two aliphatic-alpha,omega-dicarboxylic acid salts of imiquimod (6 and 7) crystallized as tetrahydrates. Notably, all the dicarboxylic acid salts of imiquimod are crystallized as hydrates. Imiquimod hydrochloride salt was isolated as both anhydrous and hydrous forms (2 and 3). Molecular arrangements in these salt crystal structures are described With supramolecular homo- and heterosynthons. Imiquimod free base 1 forms a molecular tape through 2-aminopyridine-aminoimidazole heterosynthon III. All the carboxylic acid salts of imiquimod 4-8 form robust and recurring charge-assisted 2-aminopyridinium-carboxylate supramolecular heterosynthon V and aminoimidazole homosynthon II. All the salt formers in this study are US-FDA Generally Recognized As Safe (GRAS) substances. The present examples suggest that co-crystallization experiments are useful not only to make co-crystals but also to discover unexpected novel forms of active pharmaceutical ingredients.