阅读说明：本技术 丙戊酸钠的新晶型及其制备方法 (Novel crystal form of sodium valproate and preparation method thereof ) 是由 郝忠言 马俊 谢福佳 谢楠 陈佳佳 周志慧 于 2020-07-31 设计创作，主要内容包括：本发明提供了一种丙戊酸钠新晶型,其X-射线粉末衍射图在2θ具有如下主要特征吸收峰：6.615、7.328、8.130、19.996、24.019,本发明还公开了该晶型的制备方法。本发明提供的丙戊酸钠新晶型,其引湿性低于目前文献报道的晶型,使得产品的质量更稳定；其溶解性非常好,在水中溶解速率优于已公布的晶型。(The invention provides a new crystal form of sodium valproate, which has the following main characteristic absorption peaks in an X-ray powder diffraction pattern at 2 theta: 6.615, 7.328, 8.130, 19.996 and 24.019, and the invention also discloses a preparation method of the crystal form. The hygroscopicity of the new crystal form of the sodium valproate provided by the invention is lower than that of the crystal form reported in the current literature, so that the quality of the product is more stable; the solubility is very good, and the dissolution rate in water is superior to that of the published crystal form.)

1. A novel crystalline form of sodium valproate characterized by: the X-ray powder diffraction pattern has the following main characteristic absorption peaks at 2 theta: 6.615, 7.328, 8.130, 19.996, 24.019.

2. A new crystalline form of sodium valproate according to claim 1, characterized in that: the differential scanning calorimetry endothermic peaks are respectively 91.47 ℃, 141.27 ℃ and 236.40 ℃.

3. A new crystalline form of sodium valproate according to claim 1, characterized in that: thermogravimetric analysis thereof showed no water of crystallization.

4. A new crystalline form of sodium valproate according to claim 1, process for its preparation comprising the steps of:

and adding the crude sodium valproate product into a mixed solvent of acetone and alcohols according to a certain proportion, heating to reflux, dissolving to be clear, slowly cooling to 0-10 ℃, cooling for crystallization, filtering, and drying to obtain the new crystal form sodium valproate product, wherein the alcohol solvent is preferably ethanol.

5. The process for preparing a new crystalline form of sodium valproate according to claim 4, characterized in that: the ratio (mass ratio) of the mixed solvent acetone to the ethanol is 8: 0.2-0.5.

6. The process for preparing a new crystalline form of sodium valproate according to claim 4, characterized in that: the mass ratio of the sodium valproate to the mixed solvent is as follows: 1: 6-10.

7. The process for preparing a new crystalline form of sodium valproate according to claim 4, characterized in that: the crystallization temperature is 0-10 ℃.

Technical Field

The invention provides a novel crystal form of sodium valproate, particularly provides a preparation method of the novel crystal form, and belongs to the field of medicaments.

Background

Valproic acid sodium is a broad-spectrum antiepileptic drug. The chemical structural formula is as follows:

the chemical name of the sodium valproate is 2-sodium valproate, and the molecular formula is C₈H₁₅NaO₂The molecular weight is 166.2, and the white crystalline powder is one of the most widely used antiepileptic drugs in the clinical application in China. For various types of epilepsy in human, such as for various types of seizures, myoclonic epilepsy, local seizures, grand mal seizures and mixed seizuresEffective in combination with epilepsy, and prevention and treatment of personality behavior disorder caused by epilepsy [ chemical engineers, 2015, 08: 10-12. The action mechanism of sodium valproate is related to the inhibition of voltage-sensitive sodium ion channels, and the sodium valproate enhances the inhibition of gamma-aminobutyric acid by influencing the synthesis or the metabolism of the gamma-aminobutyric acid and inhibits the excessive discharge of neurons so as to achieve the purpose of treatment.

Chinese patents CN102531878A, CN102603510A, CN102079699A and CN105017007B disclose four crystal forms of sodium valproate, namely I, II, III and IV, wherein I is prepared by solvent crystallization, and the other three are prepared by freeze-drying.

Disclosure of Invention

The technical scheme of the invention provides a new valproate sodium crystal form and a preparation method of the crystal form.

In a powder X-ray diffraction pattern of the sodium valproate crystal, diffraction angles 2 theta =6.615, 7.328, 8.130, 19.996, 24.019 and the like have characteristic absorption peaks, as shown in figure 1.

The X-ray powder diffraction of the compound has the following characteristics:

the differential scanning calorimetry endothermic peaks are respectively 91.47 deg.C, 141.27 deg.C, 236.40 deg.C, as shown in FIG. 2.

Thermogravimetric analysis showed no water of crystallization, as shown in FIG. 2.

The invention also provides a preparation method of the sodium valproate crystal form, which comprises the following specific operations:

dissolving the sodium valproate crude product in a mixed solvent of acetone and alcohols, heating to reflux, dissolving to be clear, slowly cooling to 0-10 ℃, cooling for crystallization, filtering, and drying to obtain sodium valproate crystals.

The ratio (mass ratio) of the acetone to the ethanol as the mixed solvent is 8: 0.2-0.5, preferably 8: 0.32.

The mass ratio of the sodium valproate to the mixed solvent is as follows: 1: 6-10, preferably 1: 8.32.

The water content of acetone and ethanol is 0.01% -1.0%, preferably the water content is less than 0.1%.

The sodium valproate crystals are dried under vacuum at 60-100 ℃, preferably 80 ℃.

The pH value of the sodium valproate product is measured according to pharmacopeia standards, and is 7.5-9.0.

The dissolution rate of the sodium valproate in water is compared as follows:

weighing 1g of sodium valproate product, adding 5ml of purified water, and shaking to dissolve for less than 30 seconds.

The hygroscopicity of the sodium valproate product (according to the operation of the chinese pharmacopoeia 2015, appendix XIX J of the second part) is as follows:

the hygroscopicity of the novel crystal form prepared by the invention is superior to that of the published crystal form, and the storage stability is better; the product has good solubility, and the dissolution rate in water is superior to that of the published crystal form.

Drawings

Figure 1 XRD pattern of sodium valproate crystals.

Figure 2 TG and DSC profile of sodium valproate crystals.

In the following examples, the crude sodium valproate is commercially available or prepared according to the prior art.

Example 1

Adding 19g of the crude product into a mixed solvent of acetone (152 g, water content of 0.3%) and ethanol (3 g, water content of 0.03%), heating to reflux, dissolving, cooling in ice bath, crystallizing for 4h, filtering, and drying at 80 ℃ in vacuum (< 100mbar) for 6h to obtain 14.8g of sodium valproate crystals with yield of 78%.