Ivabradine hydrochloride, 3- {3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hydrochloride of Formula (I) has very valuable pharmacological and therapeutic properties, especially bradycardic properties, making it useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also of various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in the treatment of heart failure.

The preparation and therapeutic use of ivabradine and salts thereof with a pharmaceutically acceptable acid, and especially its hydrochloride, have been described in the European Patent EP 0534859. The patent describes the synthesis of ivabradine hydrochloride by reacting the compound of Formula (V-a) with the compound of Formula (IV-a):
to give a compound of Formula (II-a), the catalytic hydrogenation of which results in ivabradine, which is then converted into its hydrochloride:

The disclosed process yielding ivabradine hydrochloride in only a very low yield-less than 17% over the 3 steps as a whole.
Another process for preparing ivabradine is disclosed in U.S. Pat. No. 5,296,482. According to the process, (+)-isomer of ivabradine is treated with aqueous HCl and then recrystallization in acetonitrile leads to the formation of ivabradine hydrochloride salt having m.p. 135-140° C.
International (PCT) Publication WO 2008/146308 A2 discloses process for the preparation of ivabradine hydrochloride by treating ivabradine with alcoholic hydrogen chloride. The specification also discloses the amorphous form of ivabradine hydrochloride and process for its preparation using suitable acid addition salts of ivabradine.
International (PCT) Publication WO 2008/065681 A2 discloses a process for the preparation of ivabradine or the pharmaceutically acceptable salts thereof which is incorporated herein as a reference in its entirety.
International (PCT) Publication WO 2008/125006 A1 discloses a process for the preparation of a crystalline form of ivabradine or the pharmaceutically acceptable salts thereof which is incorporated herein as a reference in its entirety.
International (PCT) Publication WO 2011/098582 A2 discloses three crystalline forms of ivabradine hydrochlorides like Form X, Form Z and Form K, which are incorporated herein as a reference in its entirety.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. The polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58,911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
Several crystalline forms of ivabradine hydrochloride and their processes for preparation have been disclosed, for example in U.S. Pat. Nos. 7,176,197 B2, 7,384,932 B2, 7,361,652 B2, 7,361,651 B2, 7,361,650 B2, 7,361,649 B2, and 7,358,240 B2.
The known crystalline forms of ivabradine hydrochloride are pseudopolymorphs, which are very susceptible in presence of water. They are either hydrates like hemihydrate, monohydrate or tetrahydrate or anhydrous compounds. Therefore, the present invention provides new crystalline form of ivabradine hydrochloride, which is stable and useful for pharmaceutical compositions that include the crystalline ivabradine hydrochloride.
USPTO Backgrounds
USPTO Backgrounds