Disclosing the extensive crystal of chemistry Ivabradine hydrochloride, in its pure and solvated phases

[3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl] methyl}(methyl)amino)propyl]- 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one], known as Ivabradine, is a novel medication used for the symptomatic management of a number of diseases (among which stable angina pectoris and inappropriate sinus tachycardia) and is marketed worldwide as a hydrochloride salt (IvaHCl) under the trade names Procoralan, Coralan and Corlentor. Like most active pharmaceutical ingredients, IvaHCl is formulated with a number of excipients and additives, in small tablets for oral ingestion. In the scientific literature and, particularly, in a number of patents, IvaHCl is reported to exist in an extremely large (possibly redundant) number of different polymorphic, hydrated or solvated phases. Controlling the nature, composition and structure of the actual solid form is of vital importance, since they directly influence the chemical stability, solubility, bioavailability of the drug, as well as rheological issues at the flowing, pressing and tableting processing steps. We have prepared monophasic samples of six different IvaHCl forms, certified by the uniqueness of their indexed patterns and, eventually, by their completely solved, and refined, crystal structures, determined uniquely from laboratory powder diffraction data. Exposure to water vapors, at RT, of the anhydrous delta-d form generated powders of the pure tetrahydrate form (the Beta-form, structure known form single-crystal analysis). Two different anhydrous forms (Beta-d and Alpha) were prepared by gentle, or extensive, heating of the Beta and delta-d forms, respectively. The acetonitrile solvate, called delta1, was obtained by precipitation methods from concentrated solutions. Similarly, the acetone solvate, here called delta2, was obtained from concentrated IvaHCl solution.