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.