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Stable hydrochloric acid Ivabradine II crystal form and preparation method

A technology of ivabradine hydrochloride and crystal form, which is applied in the field of medicinal chemistry and can solve problems such as easy discoloration, poor fluidity, and unfavorable preparation processing

Active Publication Date: 2013-07-03
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, crystallization from mixed solvents requires toxic and harmful solvents such as acetonitrile, or N-methylpyrrolidone, 2-methoxyethanol, etc., which have a high boiling point and are difficult to control organic residues, resulting in relatively difficult control of corresponding solvent residues in pharmaceuticals Difficult and not conducive to industrial application
On the other hand, the ivabradine hydrochloride crystal form prepared by the above method is unstable in thermal analysis, has poor fluidity, is easy to change color, and is easy to degrade to generate impurities, which is not conducive to preparation processing
In addition, the amorphous crystalline forms reported in patents CN200810111115.2 and CN200910013935.2 are easy to absorb water and unstable; patent CN200710044290.X reports mixed crystals of multiple crystal forms or a single disclosed single crystal form

Method used

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  • Stable hydrochloric acid Ivabradine II crystal form and preparation method
  • Stable hydrochloric acid Ivabradine II crystal form and preparation method
  • Stable hydrochloric acid Ivabradine II crystal form and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Add 1 g of ivabradine hydrochloride into 60 ml of acetone solution, stir and heat up to reflux, add 0.2 mL of distilled water dropwise until the drug is completely dissolved, and continue to reflux for 30 minutes. Natural cooling and crystallization, the crystallization stopped when the temperature dropped to 55°C, suction filtration, and drying at 80°C to obtain 0.78 g of Ivabradine Hydrochloride Form II.

[0086] Thermogravimetric (TG) curve ( figure 1 ) shows that in the range from room temperature to 150°C, the weight loss rate is 1.7%, indicating that the structure contains 0.5 parts of crystal water;

[0087] Differential thermal analysis (DSC) curve ( figure 2 ) (~154°C has a large endothermic peak; ~160°C has an exothermic peak, and the melting decomposition temperature is 194°C (peak value))

[0088] X-ray powder diffraction spectrum ( image 3 )(Table 1)

[0089] Infrared spectra( Figure 4 ) (at 3464cm -1 , 2932cm -1 , 1645cm -1 , 1520cm -1 , 1459cm...

Embodiment 2

[0095] Add 5 grams of ivabradine hydrochloride to 250 milliliters of tetrahydrofuran and ethyl acetate in a mixed solvent (v / v=2:1 of the ratio of tetrahydrofuran and ethyl acetate), heat to reflux (65-73 ° C), stir After 30 minutes, slowly add 4.5 ml of distilled water dropwise, continue to stir until it is completely dissolved, then cool down naturally to crystallize, stop the crystallization at 55°C, filter with suction, and dry at 80°C to obtain 3.5 grams of Ivabradine Hydrochloride Form II .

[0096] X-ray powder diffraction spectrum ( Figure 11 )

Embodiment 3

[0098]10 grams of ivabradine hydrochloride was added to a mixed solvent of 500 milliliters of tetrahydrofuran and ethyl acetate (v / v=2:1 of the ratio of tetrahydrofuran and ethyl acetate), heated to reflux (65-73 ° C), stirred for 30 Minutes later, slowly add 8.8 milliliters of distilled water dropwise, continue to stir until completely dissolved, naturally cool down to crystallize, stop crystallization at 50°C, filter with suction, and dry at 80°C to obtain 8 grams of ivabradine hydrochloride II crystal form .

[0099] X-ray powder diffraction spectrum ( Figure 12 )

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Abstract

The invention provides a stable hydrochloric acid Ivabradine II crystal form, a thermogravimetry spectrogram shows that each part of hydrochloric acid Ivabradine molecule contains 0.5 parts of crystal water. The differential scanning calorimetry (DSC) spectrum diagram shows that a large endothermic peak is generated at -154 DEG C, a heat release peak is generated at -160 DEG C, wherein the fusion decomposition temperature is 194 DEG C (summit value), wherein the hydrochloric acid Ivabradine II crystal form is a monoclinic system, its space group is P21, the cell parameter comprises: a=5.48740(10)Angstrom, b=43.4767(7)Angstrom, c=11.4892(2)Angstrom, beta= 98.144 (2) degrees, and a crystal cell volume is 2713.38(8)Angstrom<3>. A characteristic diffraction spectral line of its X-powder diffraction describes hydrochloric acid Ivabradine new crystal form as II crystal form. The Ivabradine new crystal form enables difficult water absorption and deliquescence, and has the advantages of good stability and convenient storage. The preparation method is simple and easy to be carried out, a solvent with high boiling point and large toxicity is not used, the preparation method is in favor of environmental protection, is suitable for industrial production, and has large application value.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a crystal form of ivabradine hydrochloride and a preparation method thereof. In particular, it relates to a stable solvent-containing or crystal water-containing ivabradine hydrochloride II crystal form and a preparation method thereof. Background technique [0002] Ivabradine (Ivabradine) is a drug developed by Swiss Sewell Company (also known as Servier Company) for the treatment of chronic stable angina pectoris with contraindication or intolerance to β-blockers and normal sinus rhythm . Its chemical name is: (+)-3-[3-[N-[4,5-dimethoxybenzocyclobutanyl-1(S)-methyl]-N-methylamino]propyl ]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzene -2-one hydrochloride. Formula I as follows: [0003] [0004] Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated ion I f Channel selective blocker, belonging to HCN (hyperpolarization activated cyclic nucleotide gated) ion channel f...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 胡秀荣顾建明金志平黄悦黄建勋
Owner ZHEJIANG JINGXIN PHARMA
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