CN111777507A - Novel crystal form of sodium valproate and preparation method thereof - Google Patents
Novel crystal form of sodium valproate and preparation method thereof Download PDFInfo
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- CN111777507A CN111777507A CN202010762235.XA CN202010762235A CN111777507A CN 111777507 A CN111777507 A CN 111777507A CN 202010762235 A CN202010762235 A CN 202010762235A CN 111777507 A CN111777507 A CN 111777507A
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- sodium valproate
- crystalline form
- crystal form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/126—Acids containing more than four carbon atoms
- C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
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.
Description
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%.
Example 2
Adding 28g of the crude product into a mixed solvent of acetone (200 g, water content of 0.02%) and ethanol (11 g, water content of 0.03%), heating to reflux, dissolving, cooling in ice bath for crystallization for 4h, filtering, and drying at 80 ℃ in vacuum (< 100mbar) for 6h to obtain 17g of sodium valproate crystals with yield of 46%.
Example 3
Adding 10.5g of the crude product into a mixed solvent of acetone (84 g, water content of 0.05%) and ethanol (3.35 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 9.5g of sodium valproate crystals with yield of 90.5%.
Example 4
Dissolving 400g of crude sodium valproate in a mixed solvent of acetone (3200 g, water content of 0.05%) and ethanol (128 g, water content of 0.03%), heating to reflux, dissolving, cooling in ice bath for crystallization for 4h, filtering, and drying at 80 ℃ under vacuum (< 100mbar) for 6h to obtain 317g of sodium valproate with yield of 79%.
Example 5
1300g of crude sodium valproate is dissolved in a mixed solvent of acetone (10.4 kg, water content of 0.05%) and ethanol (416 g, water content of 0.03%), heated to reflux, dissolved and clear, cooled in ice bath for 4h, filtered, and dried under vacuum (less than 100mbar) at 80 ℃ for 9h to obtain 1147g of sodium valproate with yield of 88%.
Claims (7)
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 ℃.
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| CN202010762235.XA CN111777507A (en) | 2020-07-31 | 2020-07-31 | Novel crystal form of sodium valproate and preparation method thereof |
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| CN202010762235.XA CN111777507A (en) | 2020-07-31 | 2020-07-31 | Novel crystal form of sodium valproate and preparation method thereof |
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Application publication date: 20201016 |