A kind of tadalafil compound, and composition thereof

Abstract

The invention discloses a tadalafil compound. The tadalafil is a crystalline compound of which the molecule is combined with 2.5 water molecules; by detecting with an X-ray powder diffraction pattern, when 2theta DEG is 10.2+ / -0.1 DEG, 11.6+ / -0.1 DEG, 15.9+ / -0.1 DEG, 18.0+ / -0.1 DEG, 19.4+ / -0.1 DEG, 21.0+ / -0.1 DEG, 24.2+ / -0.1 DEG and 27.2+ / -0.1 DEG, characteristic peaks are shown. Further, the tadalafil hydrate is a crystalline compound, and the solubleness is improved to some extent. Common tablets, disintegrating tablets and chewable tablets, which are prepared from the tadalafil crystalline compound, are dissolved out within a short time, and the onset time of the tablets is shortened.

Description

technical field

[0001] The invention relates to a tadalafil compound, in particular to a tadalafil crystal compound and a pharmaceutical composition thereof. Background technique

[0002] Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). When sexual stimulation leads to local release of nitric oxide, PDE5 is inhibited by tadalafil, making Increased levels of cGMP in the corpus cavernosum of the penis lead to relaxation of smooth muscle and blood flow into the penile tissue, producing an erection, like asexual stimulation.

[0003] The structure of tadalafil is as follows:

[0004]

[0005] After oral administration, tadalafil is rapidly absorbed, reaching the mean maximum observed plasma concentration (Cmax) in a median of 2 hours after administration. The absolute bioavailability of this product after oral administration has not been determined. The rate and extent of tadalafil absorption are n...

Examples

Embodiment 1

[0095] Preparation of tadalafil hydrate crystals:

[0096] (1) Dissolve 10g of tadalafil in 100mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 40°C to obtain solution A. In the mixed solvent, acetone, dimethylformamide and The volume ratio of water is 8.0:3.8:1;

[0097] (2) Add anhydrous diethyl ether to solution A. The volume of anhydrous diethyl ether added is twice the volume of solution A. Under the condition of stirring, the temperature is lowered to -5°C within 2.5 hours, and the stirring speed is controlled at 400r / min, and then placed at -5°C for 8.0 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalafil crystals containing 2.5 crystal waters.

[0098] The obtained product tadalamorphic compound adopts Cu-Kα 1 X-ray powder diffraction for radiographic measurements such as figure 1 Shown, in (2θ±0.1) be 10.2 °, 11.6 °, 15.9 °, 18.0 °, 19.4 °, 21.0 °, 24.2 °, 27.2 ° place shows charac...

Embodiment 2

[0100] Preparation of tadalafil hydrate crystals:

[0101] (1) Dissolve 10g of tadalafil in 100mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 30°C to obtain solution A. In the mixed solvent, acetone, dimethylformamide and The volume ratio of water is 6.8:3.0:1;

[0102] (2) Add anhydrous diethyl ether to solution A, the volume of anhydrous diethyl ether is 1.5 times the volume of solution A, under the condition of stirring, lower the temperature to 0°C within 3 hours, and control the stirring speed at 450r / min , and then placed at 0°C for 8 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalamorph crystals containing 2.5 crystal water. The obtained product tadalamorphic compound adopts Cu-Kα 1 The X-ray powder diffraction analysis of X-ray measurement, and thermogravimetric (TG) analysis, its result is consistent with embodiment 1.

Embodiment 3

[0104] Preparation of tadalafil hydrate crystals:

[0105] (1) Dissolve 10 g of tadalafil in 100 mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 35° C. to obtain solution A. In the mixed solvent, acetone, dimethylformamide The volume ratio of amides and water is 8.0:4.5:1;

[0106] (2) Add anhydrous diethyl ether to solution A. The volume of anhydrous diethyl ether added is 1.5 times the volume of solution A. Under the condition of stirring, the temperature is lowered to -3°C within 2.5 hours, and the stirring speed is controlled at 450r / min, and then placed at -5°C for 10 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalamorph crystals containing 2.5 crystal waters. The obtained product tadalamorphic compound adopts Cu-Kα 1 The X-ray powder diffraction analysis of X-ray measurement, and thermogravimetric (TG) analysis, its result is consistent with embodiment 1.

technical field

[0001] The invention relates to a tadalafil compound, in particular to a tadalafil crystal compound and a pharmaceutical composition thereof. Background technique

[0002] Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). When sexual stimulation leads to local release of nitric oxide, PDE5 is inhibited by tadalafil, making Increased levels of cGMP in the corpus cavernosum of the penis lead to relaxation of smooth muscle and blood flow into the penile tissue, producing an erection, like asexual stimulation.

[0003] The structure of tadalafil is as follows:

[0004]

[0005] After oral administration, tadalafil is rapidly absorbed, reaching the mean maximum observed plasma concentration (Cmax) in a median of 2 hours after administration. The absolute bioavailability of this product after oral administration has not been determined. The rate and extent of tadalafil absorption are n...

Examples

Embodiment 1

[0095] Preparation of tadalafil hydrate crystals:

[0096] (1) Dissolve 10g of tadalafil in 100mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 40°C to obtain solution A. In the mixed solvent, acetone, dimethylformamide and The volume ratio of water is 8.0:3.8:1;

[0097] (2) Add anhydrous diethyl ether to solution A. The volume of anhydrous diethyl ether added is twice the volume of solution A. Under the condition of stirring, the temperature is lowered to -5°C within 2.5 hours, and the stirring speed is controlled at 400r / min, and then placed at -5°C for 8.0 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalafil crystals containing 2.5 crystal waters.

[0098] The obtained product tadalamorphic compound adopts Cu-Kα 1 X-ray powder diffraction for radiographic measurements such as figure 1 Shown, in (2θ±0.1) be 10.2 °, 11.6 °, 15.9 °, 18.0 °, 19.4 °, 21.0 °, 24.2 °, 27.2 ° place shows charac...

Embodiment 2

[0100] Preparation of tadalafil hydrate crystals:

[0101] (1) Dissolve 10g of tadalafil in 100mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 30°C to obtain solution A. In the mixed solvent, acetone, dimethylformamide and The volume ratio of water is 6.8:3.0:1;

[0102] (2) Add anhydrous diethyl ether to solution A, the volume of anhydrous diethyl ether is 1.5 times the volume of solution A, under the condition of stirring, lower the temperature to 0°C within 3 hours, and control the stirring speed at 450r / min , and then placed at 0°C for 8 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalamorph crystals containing 2.5 crystal water. The obtained product tadalamorphic compound adopts Cu-Kα 1 The X-ray powder diffraction analysis of X-ray measurement, and thermogravimetric (TG) analysis, its result is consistent with embodiment 1.

Embodiment 3

[0104] Preparation of tadalafil hydrate crystals:

[0105] (1) Dissolve 10 g of tadalafil in 100 mL of a mixed solvent of acetone, dimethylformamide and water at a temperature of 35° C. to obtain solution A. In the mixed solvent, acetone, dimethylformamide The volume ratio of amides and water is 8.0:4.5:1;

[0106] (2) Add anhydrous diethyl ether to solution A. The volume of anhydrous diethyl ether added is 1.5 times the volume of solution A. Under the condition of stirring, the temperature is lowered to -3°C within 2.5 hours, and the stirring speed is controlled at 450r / min, and then placed at -5°C for 10 hours, crystals were precipitated, filtered, washed with anhydrous ether, and dried to obtain tadalamorph crystals containing 2.5 crystal waters. The obtained product tadalamorphic compound adopts Cu-Kα 1 The X-ray powder diffraction analysis of X-ray measurement, and thermogravimetric (TG) analysis, its result is consistent with embodiment 1.

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