Stable Ivabradine crystal and preparation thereof

Abstract

The invention discloses a stable ivabradine hydrochloride crystal (formula I), which is verified by a DCS differential thermal analysis chart, a melting point and an X-ray powder diffraction diagram. By adopting the method, the ivabradine hydrochloride crystal (formula I) prepared by the method is very stable to temperature, illumination and humidity, thus being favorable for long-term storage. The solvent used in the crystal is safe, and is easy to be removed; therefore, the stable ivabradine hydrochloride crystal is applicable to industrialized production.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to stable ivabradine hydrochloride crystallization and preparation method thereof Background technique [0002] Ivabradine hydrochloride (Ivabradine) was developed by Servier and has become one of the most important advances in the field of cardiovascular therapy in the past 20 years. Ivabradine hydrochloride is the first pure heart rate-lowering drug that acts by selectively inhibiting the If channel responsible for controlling the automatic depolarization of the sinus node and regulating heart rate. Ivabradine hydrochloride acts selectively on the sinoatrial node and has no effect on intracardiac conduction, myocardial contractility, or ventricular repolarization. Unlike β-blockers, commonly used drugs for angina pectoris, ivabradine hydrochloride does not cause sexual dysfunction, respiratory system adverse reactions caused by airway constriction and spasm, and bradycardia or recur...

AI Technical Summary

Problems solved by technology

Such products are difficult to control in a definite crystal form. In differential thermal analysis and thermal analysis, they show instability of multiple melting points, easy to change color, easy to degrade and produce impurities, which is not conducive to preparation processing

[0007] Therefore, the above-mentioned patent describes different crystal forms of ivabradine and its hydrochloride and its preparation method. The preparation process is cumbersome, and the solvent used is not suitable for pharmaceutical use. For example, the patent CN200510051779.0 crystallizes with N-methylpyrrolidone and toluene to obtain α Crystal form, the toluene used is highly toxic, N-methylpyrrolidone has a high boiling point, and it is difficult to remove the disadvantages; or the obtained crystal form is not stable enough, such as patents CN200610058074.6, CN200610058076.5, CN200610058077.X, CN200610058078.4, CN200610132229.6 and CN200610132230.9 to obtain crystal forms containing water, too much water in the raw material will affect its stability, and it needs to be dried and dehydrated again, which is unfavorable to the integrity and stability of the obtained crystal form, and the preparation process is loaded down with trivial details

In addition, there is no research report on the melting point, differential thermal analysis (DSC chart), thermal weight loss and physical and chemical properties of the prepared crystal form.

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