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-α,ω-dicarboxylic acid salts of imiqu...