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Preparation method of beta crystal form silodosin

A technology of silodosin and β crystal form, which is applied in the field of preparation of silodosin β crystal form, can solve the problems of increased silodosin oxidized impurities, high scale-up production cost, low crystallization yield, etc., and achieves product High yield, easy operation, guaranteed high yield effect

Active Publication Date: 2018-04-13
ZHEJIANG TIANYU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The heating temperature of this method is too high, and under the condition of oxygen in the air atmosphere, the oxidized impurities of silodosin will increase during the crystallization process.
[0007] CN103159664 discloses a method for preparing silodosin in the β crystal form. The β crystal form is obtained by directly cooling the ethyl acetate solution of crude silodosin to -20°C to 30°C for crystallization. Higher solubility in ethyl acetate, resulting in lower crystallization yields and higher scale-up production costs
[0008] Therefore, a new preparation method of silodosin in β crystal form is needed to solve the problem of mixed crystals produced by crystal detonation in the prior art methods, crystallization under air atmosphere leads to increased impurities, low crystallization yield, and enlarged production costs. higher question

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  • Preparation method of beta crystal form silodosin
  • Preparation method of beta crystal form silodosin
  • Preparation method of beta crystal form silodosin

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Under the protection of nitrogen, add 10g of silodosin and 50mL of isopropanol into the three-necked flask, stir, raise the temperature to 50-60°C, and keep it warm for 1 hour. The silodosin is completely dissolved. Slowly drop it into 50mL of n-heptane preheated to 50-60°C, keep stirring the crystallization feed liquid for 2 hours after dropping, then control the cooling rate at 10°C / hour, and cool the feed liquid to 0-10°C , heat preservation and crystallization for 2 hours, filter under nitrogen protection, wash the crystals with a small amount of n-heptane, and vacuum-dry the gained crystals to obtain silodosin in β crystal form of 8.8g, with a yield of 88%. The XRD detection spectrum results of the samples are shown in the attached figure 2 As shown in table 2, the DSC detection spectrum result of sample is as attached image 3 As shown, the crystal melting range is 105.31°C-106.95°C.

[0047] Table 2 Comparison Table of Main 2θ Diffraction Angles in XRD Detectio...

Embodiment 2

[0050]Under the protection of nitrogen, add 10g of silodosin and 50mL of isopropanol into the three-necked flask, stir, raise the temperature to 50-60°C, and keep it warm for 1 hour. The silodosin is completely dissolved. Slowly drop it into 40mL of n-heptane preheated to 50-60°C, keep stirring the crystallization feed liquid for 2 hours after dropping, then control the cooling rate at 10°C / hour, and cool the feed liquid to 0-10°C , heat preservation and crystallization for 2 hours, filter under the protection of nitrogen, wash the crystals with a small amount of n-heptane, and vacuum-dry the obtained crystals to obtain 8.5 g of silodosin in the β crystal form, with a yield of 85%. The results of the XRD detection spectrum of the sample are attached Figure 4 As shown in table 3, the DSC detection spectrum result of sample is as attached Figure 5 As shown, the crystal melting range is 105.70°C-107.30°C.

[0051] Table 3 Comparison Table of Main 2θ Diffraction Angles in XRD ...

Embodiment 3

[0054] Under the protection of nitrogen, add 10g of silodosin and 60mL of isopropanol into the three-necked flask, stir, raise the temperature to 50-60°C, and keep it warm for 1 hour. The silodosin is completely dissolved. Slowly drop it into 50mL n-heptane preheated to 50-60°C. After dropping, keep the crystallization feed liquid for 2 hours and then control the cooling rate at 15°C / hour to cool the feed liquid to 0-10°C. , heat preservation and crystallization for 2 hours, filtered under nitrogen protection, washed the crystals with a small amount of n-heptane, and vacuum-dried the obtained crystals to obtain 8.1 g of silodosin in the β crystal form, with a yield of 81%. The results of the XRD detection spectrum of the sample are attached Image 6 As shown in table 4, the DSC detection spectrum result of sample is as attached Figure 7 As shown, the melting range of silodosin in the β crystal form obtained in this example is 105.40°C-106.96°C.

[0055] Table 4 Comparison T...

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Abstract

The invention relates to a preparation method of beta crystal form silodosin. The preparation method comprises the following steps of (1) mixing silodosin and isopropanol to obtain a mixture; (2) warming the mixture to dissolve and make a silodosin solution clear, obtaining a silodosin clear solution, and dropwise adding the silodosin clear solution into n-heptane which is preheated to have a temperature difference with the silodosin clear solution being less than or equal to 10 DEG C; (3) after finishing dropwise adding the silodosin clear solution, obtaining a mixed liquor, keeping the mixedliquor warm, and ageing; (4) cooling the aged mixed liquor to be at the temperature of 0 to 10 DEG C, crystallizing, and obtaining a beta crystal form silodosin crystal. The beta crystal form silodosin prepared by the method provided by the invention is high in purity, single in crystal form variety and high in product yield. The method provided by the invention is high-efficient, stable in repetitive rate, easy to operate, and particularly suitable for industrial application.

Description

technical field [0001] The invention relates to the preparation of drug polymorphs, in particular to the preparation method of silodosin in beta crystal form. Background technique [0002] Silodosin is an α1-adrenergic receptor antagonist jointly developed and marketed by Japan's original research Tachibana and Japan's Daiichi Pharmaceutical Sankyo, and is used for the treatment of benign prostatic hyperplasia. Its chemical structural formula is as follows: [0003] [0004] Japan's original Tachibana patent (notification number: CN1321111C) discloses three crystal forms of silodosin, namely α, β, and γ crystal forms. The β crystal form, like the α crystal form, can be used as an active ingredient of an oral solid drug. The method provided by this patent is as follows: by dissolving the crude crystals of silodosin in an appropriate amount of methanol under heating conditions, adding petroleum ether as a poor solvent, vigorously stirring the reaction mixture, and forcing...

Claims

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Application Information

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IPC IPC(8): C07D209/08
CPCC07B2200/13C07D209/08
Inventor 屠勇军朱国荣舒波杨会林王臻
Owner ZHEJIANG TIANYU PHARMA
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