Crystal structures and properties of two hydrated conglomerate forms of the heart-rate-lowering agent ivabradine hydrochloride

Ivabradine hydrochloride (IVA-HCl) (systematic name: {[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl}[3-(7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)propyl]methylazanium), is a novel medication used for the symptomatic management of stable angina pectoris. In many recent patents, it has been claimed to exist in a very large number of polymorphic, hydrated and solvated phases, although no detailed analysis of the structural features of these forms has been published to date. Here, we have successfully crystallized the tetrahydrate form of IVA-HCl (form β), C₂₇H₃₇N₂O₅⁺·Cl^-·4H₂O, and elucidated its structure for the first time. Simultaneously, a new crystal form of IVA-HCl, i.e. the hemihydrate (form II), C₂₇H₃₇N₂O₅⁺·Cl^-·0.5H₂O, was discovered. Its crystal structure was also accurately determined and compared to that of the tetrahydrate form. While the tetrahydrate form of IVA-HCl crystallized in the orthorhombic space group P2₁2₁2₁, the new form (hemihydrate) was solved in the monoclinic space group P2₁. Detailed conformational and packing comparisons between the two forms have allowed us to understand the role of water in the crystal assembly of this hydrochloride salt. The stabilities of the two forms were compared theoretically by calculating the binding energy of the water in the crystal lattice using differential scanning calorimetry (DSC). The stability experiments show that the tetrahydrate is stable under high-humidity conditions, while the hemihydrate is stable under high-temperature conditions.