Sodium valproate crystal as well as preparation method and application thereof

Abstract

The invention relates to the technical field of crystal preparation, in particular to a sodium valproate crystal and a preparation method and application thereof. In an X-ray powder diffraction pattern, the sodium valproate crystal provided by the invention has diffraction peaks at least at the following diffraction angles 2theta: 5.67 degrees + / -0.2 degrees, 6.73 degrees + / -0.2 degrees, 16.94 degrees + / -0.2 degrees, 18.18 degrees + / -0.2 degrees, 18.67 degrees + / -0.2 degrees, 20.16 degrees + / -0.2 degrees, 20.92 degrees + / -0.2 degrees, 21.13 degrees + / -0.2 degrees, 22.55 degrees + / -0.2 degrees and 24.45 degrees + / -0.2 degrees. The sodium valproate crystal provided by the invention is good in stability and water solubility, the hygroscopicity is remarkably reduced, the quality stability of a medicine within the validity period is ensured, the dissolution time of a product is also remarkably shortened, and the redissolvability of the product is good.

Description

Technical Field

[0001] The present invention relates to the technical field of crystal preparation, and particularly to sodium valproate crystals, a preparation method thereof, and an application thereof. Background Art

[0002] Sodium valproate is a first-line broad-spectrum anti-epileptic drug. Its chemical structural formula is . The chemical name of sodium valproate is sodium 2-propylvalerate, and its molecular formula is C 8 H 15 O 2 Na, with a molecular weight of 166.20. It is a white crystalline powder and can be administered as an oral solution or an injection. It is mainly used for the treatment of epilepsy, including generalized epilepsy and partial epilepsy. Such as simple or complex absence seizures, myoclonic seizures, tonic-clonic seizures, atonic seizures, and mixed seizures, etc., and can also be used for the treatment of manic episodes associated with bipolar disorder.

[0003] Since sodium valproate is extremely hygroscopic during storage and transportation, it causes the degradation of the main drug and an increase in impurities. Therefore, it is urgent to develop a sodium valproate crystal with lower hygroscopicity and better stability.

[0004] Chinese patent applications CN102531878A, CN102603510A, CN102079699A, CN105017007A, and CN111777507A respectively disclose five crystal forms of sodium valproate, namely crystal forms I, II, III, IV, and new crystal form. Among them, crystal forms I and the new crystal form are prepared by crystallization with ketone or alcohol solvents, and the other three are prepared by freeze-drying. Although the crystals of sodium valproate mentioned above have improved the stability of sodium valproate to a certain extent, there are still problems such as strong hygroscopicity of sodium valproate, difficulty in recovering the crystallization solvent, high manufacturing cost, and low content. Therefore, there is still room for further improvement.

[0005] In view of this, the present invention is particularly proposed. Summary of the Invention

[0006] The object of the present invention is to provide a sodium valproate crystal with good stability, good water solubility, low hygroscopicity, and high content, a preparation method thereof, and an application thereof.

[0007] To achieve this object, the technical solution of the present invention is as follows: In the first aspect, the present invention provides a sodium valproate crystal, which has diffraction peaks at least at the following diffraction angles 2θ in the X-ray powder diffraction pattern: 5.67° ± 0.2°, 6.73° ± 0.2°, 16.94° ± 0.2°, 18.18° ± 0.2°, 18.67° ± 0.2°, 20.16° ± 0.2°, 20.92° ± 0.2°, 21.13° ± 0.2°, 22.55° ± 0.2°, and 24.45° ± 0.2°.

[0008] Preferably, the sodium valproate crystal of the present invention further comprises diffraction peaks at diffraction angles 2θ of 7.30° ± 0.2° and / or 20.00° ± 0.2° in the X-ray powder diffraction pattern.

[0009] Preferably, it has diffraction peaks at least at the following diffraction angles 2θ: 5.67° ± 0.2°, 6.73° ± 0.2°, 7.30° ± 0.2°, 16.94° ± 0.2°, 18.18° ± 0.2°, 18.67° ± 0.2°, 20.00° ± 0.2°, 20.16° ± 0.2°, 20.92° ± 0.2°, 21.13° ± 0.2°, 22.55° ± 0.2° and 24.45° ± 0.2°.

[0010] Through a large number of studies, the present invention has obtained a sodium valproate crystal with good stability, good water solubility, significantly reduced hygroscopicity, ensuring the quality stability within the drug's shelf life, and at the same time, the product has good redissolvability and significantly shortens the dissolution time of the product.

[0011] As a preferred technical solution of the present invention, the XRPD pattern analysis data of the sodium valproate crystal are shown in Table 1: Table 1

[0012] As a preferred technical solution of the present invention, the sodium valproate crystal of the present invention has a substantially Figure 2 and / or Figure 3 shown X-ray powder diffraction pattern, or its X-ray powder diffraction pattern is substantially the same as the Figure 2 and / or Figure 3 shown X-ray powder diffraction pattern.

[0013] In a second aspect, the present invention provides a method for preparing the sodium valproate crystal, comprising: S1: Dissolve the crude sodium valproate in a crystallization solvent containing ethyl acetate, heat under reflux until clear; add an acid, heat and stir to obtain a first mixed material liquid; S2: Filter the first mixed material liquid while it is hot, and cool the obtained filtrate for crystallization; obtain a second mixed material liquid; S3: Add sodium valproate crystal seeds to the second mixed material liquid for crystal growth.

[0014] In the prior art, recrystallization using ethyl acetate as a single solvent, ethyl acetate-methanol composite solvent, ethyl acetate-acetone composite solvent, etc. has been disclosed. However, there are still problems such as high hygroscopicity of the obtained sodium valproate product, poor stability within the shelf life, difficult recovery of the crystallization solvent, high production cost, low content, etc. The present invention discovers that by introducing an acid and sodium valproate as crystal seeds during recrystallization, a new crystal form of sodium valproate is prepared, with significantly reduced hygroscopicity, which can improve the uniformity and stability of the crystal forms of sodium valproate raw materials and preparations.

[0015] In the present invention, both the "crude sodium valproate" and the "sodium valproate crystal seeds" are known compounds in the art and can be obtained through various channels.

[0016] As an optional embodiment of the present invention, the "crude sodium valproate" is prepared by reacting valproic acid with a methanol solution of sodium methoxide. The specific preparation method includes: dropping a methanol solution of sodium methoxide into valproic acid and reacting at 60 ± 5 °C. After the reaction, the solvent is removed under reduced pressure to obtain crude sodium valproate.

[0017] As an optional embodiment of the present invention, the content of the crude sodium valproate is ≥ 95.0 wt%.

[0018] As an optional embodiment of the present invention, the "sodium valproate crystal seeds" refer to the sodium valproate crystal form I disclosed in Patent CN102531878A, with a content of ≥ 99.0 wt%.

[0019] Preferably, the pH of the first mixed material liquid is 7.0 - 7.5.

[0020] More preferably, the acid is an organic acid and / or an inorganic acid; further preferably, the organic acid is selected from valproic acid and / or salicylic acid; the inorganic acid is selected from dilute hydrochloric acid.

[0021] The present invention discovers that by changing the acidity value of the crystallization system to the above range, it is helpful to obtain a new crystal form of sodium valproate and obtain the sodium valproate crystal described in the present invention; at the same time, it is helpful to stabilize the crystallization system and enhance the stability of the sodium valproate crystal form.

[0022] As a preferred embodiment of the present invention, the acid is the organic acid.

[0023] Further preferably, when the acid is valproic acid, it is helpful to further reduce the hygroscopicity of the sodium valproate crystal, enhance the stability of the sodium valproate crystal form, and reduce the risk of impurity introduction.

[0024] Preferably, the amount of the acid used is 0.05~0.5wt% relative to the amount of ethyl acetate, for example, it can be any value among 0.05wt%, 0.1wt%, 0.15wt%, 0.2wt%, 0.25wt%, 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt% and 0.5wt%, or a numerical range with any two of the above values ​​as endpoints.

[0025] Preferably, based on the amount of ethyl acetate used, the amount of the sodium valproate seed crystals added is 0.01wt%~0.05wt%; preferably, the content of the sodium valproate seed crystals is ≥99.0wt%.

[0026] Preferably, the mass ratio of the ethyl acetate to the crude sodium valproate is (16-20):1.

[0027] Specifically, the mass ratio of the crystallization solvent to the crude sodium valproate can be any ratio of 16:1, 17:1, 18:1, 19:1 and 20:1, or a ratio range with any two of the above ratios as endpoints. The present invention finds that when the amount of ethyl acetate used exceeds the above range, the yield of sodium valproate crystals is low.

[0028] Preferably, S3 comprises: adding sodium valproate seed crystals to the second mixed liquid, controlling the temperature at 55±2°C, stirring and keeping warm for growing crystals to obtain a third mixed liquid; and then cooling the third mixed liquid to 20~25°C at a rate of 4.5~5.5°C per 0.5h, and keeping warm for growing crystals.

[0029] The present invention finds that under the above crystal growing conditions, it is more conducive to improving the quality of the sodium valproate crystals and the stability of the crystal form, having excellent water solubility, and further reducing the hygroscopicity of the product.

[0030] As a preferred embodiment of the present invention, the preparation method of the sodium valproate crystals comprises: S1': dissolving crude sodium valproate in ethyl acetate, heating to reflux, adding valproic acid after the solution becomes clear, and obtaining a first mixed liquid with a pH of 7.0-7.5; S2': filter the first mixed liquid while hot, and cool the filtrate to 50-60°C at a rate of 9.5-10.5°C / h to obtain a second mixed liquid; S3': adding sodium valproate seed crystals to the second mixed liquid, controlling the temperature at 55±2°C, stirring and keeping the temperature to grow crystals, to obtain a third mixed liquid; based on the amount of ethyl acetate used, the amount of sodium valproate seed crystals added is 0.01wt%~0.05wt%; preferably, the stirring speed is 10~15r / min; preferably, the growing time is 1~2h; S4': Cool the third mixed material liquid to 20 - 25°C at a rate of 4.5 - 5.5°C per 0.5 h, and keep it warm for crystal cultivation to obtain the fourth mixed material liquid; preferably, the crystal cultivation time is 0.5 - 1.5 h; S5': Centrifuge, filter, and dry the fourth mixed material liquid in sequence to obtain the sodium valproate crystals.

[0031] Preferably, the drying conditions include: drying at a vacuum degree of -0.09 to -0.07 MPa and a temperature of 65 - 70°C for 8 ± 0.5 h; more preferably, the vacuum degree is -0.07 MPa, the temperature is 68°C, and the drying time is 8 h.

[0032] In the third aspect, the present invention provides a pharmaceutical composition containing the sodium valproate crystals as described above or the sodium valproate crystals prepared by the preparation method as described above.

[0033] In some embodiments of the present invention, the pharmaceutical composition contains the sodium valproate crystals as described in the present invention and a pharmaceutically acceptable carrier, and other pharmacologically active substances may also be present.

[0034] In the present invention, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coating materials, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. Examples of pharmaceutically acceptable carriers include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc. and one or more of their combinations, and the composition may contain isotonic agents such as sugars, sodium chloride, or polyols such as mannitol or sorbitol. Other auxiliary substances such as wetting agents or emulsifying agents, preservatives or buffering agents, etc. may also be included.

[0035] The pharmaceutical composition in the present invention can be in various forms, including for example liquid, semi - solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersants or suspensions, tablets, pills, powders, liposomes, and suppositories, etc. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents or can be prepared with enteric coatings. The specific form depends on the intended mode of administration and therapeutic application.

[0036] Preferably, the pharmaceutical composition is a sustained - release tablet of sodium valproate.

[0037] The sodium valproate crystals as described in the present invention have high content, low hygroscopicity, and good stability, ensuring their efficacy in clinical use. Moreover, by using the sustained - release tablet form for continuous and stable drug delivery, the compliance of patients during treatment is improved, and good clinical effects are obtained.

[0038] In the fourth aspect, the present invention provides any one of the following applications of the sodium valproate crystals as described above, the sodium valproate crystals obtained by the preparation method as described above, or the pharmaceutical composition as described above: 1) Use in the preparation of drugs for treating epilepsy; 2) Use in the preparation of drugs for treating bipolar disorder.

[0039] The sodium valproate crystals provided by the present invention have good stability, good water solubility, and significantly reduced hygroscopicity, ensuring the quality stability within the drug's shelf life. At the same time, it significantly shortens the dissolution time of the product, and the product has good redissolution property. Moreover, the preparation process of the present invention is relatively simple in operation, has high production efficiency, requires a relatively low level of equipment, and the organic solvents used have relatively low toxicity, are easily obtained and recyclable, and is an environmentally friendly green production process. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0041] Figure 1 It is the X-ray powder diffraction pattern of the crude sodium valproate used in the present invention.

[0042] Figure 2 It is the X-ray powder diffraction pattern of the sodium valproate crystals in Example 1 provided by the present invention.

[0043] Figure 3 It is the X-ray powder diffraction pattern of the sodium valproate crystals in Example 2 provided by the present invention.

[0044] Figure 4 It is the X-ray powder diffraction pattern of the sodium valproate crystals in Comparative Example 1 provided by the present invention.

[0045] Figure 5 It is the X-ray powder diffraction pattern of the sodium valproate crystals in Comparative Example 2 provided by the present invention.

[0046] Figure 6 It is the X-ray powder diffraction pattern of the sodium valproate crystals in Comparative Example 3 provided by the present invention.

[0047] Figure 7 It is the habit result of the sodium valproate crystals in Example 1 provided by the present invention. Among them, the left figure is the microscope image, and the right figure is the polarized light microscope image.

[0048] Figure 8 It is the habit result of the sodium valproate crystals in Example 2 provided by the present invention. Among them, the left figure is the microscope image, and the right figure is the polarized light microscope image.

[0049] Figure 9It is the habitus result of sodium valproate crystals in Example 3 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0050] Figure 10 It is the habitus result of sodium valproate crystals in Example 4 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0051] Figure 11 It is the habitus result of sodium valproate crystals in Example 5 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0052] Figure 12 It is the habitus result of sodium valproate crystals in Example 6 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0053] Figure 13 It is the habitus result of sodium valproate crystals in Comparative Example 1 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0054] Figure 14 It is the habitus result of sodium valproate crystals in Comparative Example 2 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image.

[0055] Figure 15 It is the habitus result of sodium valproate crystals in Comparative Example 3 provided by the present invention. Among them, the left figure is a microscope image, and the right figure is a polarized light microscope image. Detailed implementation manners

[0056] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions in the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0057] Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods. Unless otherwise specified, the materials, reagents, etc. used in the following embodiments can all be obtained from commercial channels or prepared according to conventional methods in the art.

[0058] Content detection method: potentiometric titration method, including the following steps: Take about 0.5 g of this product, weigh accurately, dissolve it in 30 ml of water, add 30 ml of ether, and according to the potentiometric titration method (General Principles 0701), use a glass-saturated calomel electrode, and titrate with hydrochloric acid titrant (0.1 mol / L) until the pH is 4.5, and correct the titration result with a blank test. Each 1 ml of hydrochloric acid titrant (0.1 mol / L) is equivalent to 16.62 mg of C 8 H 15 NaO 2 。

[0059] C 8 H 15 NaO 2 % = 16.62 / 1000×(V1 - V0)×(c / 0.1) / m / (1 - w%)×100% Where: m is the mass of the test sample, g; V1 is the volume of the hydrochloric acid standard solution consumed in titrating the content of sodium valproate, ml; V0 is the volume of the hydrochloric acid standard solution consumed in titrating the blank solution, ml; c is the concentration of the hydrochloric acid standard titration solution, mol / L; w is the value of the loss on drying of sodium valproate, %; 16.62 is the mass equivalent to C consumed by each 1 ml of hydrochloric acid titrant (0.1 mol / L) 8 H 15 NaO 2 in mg.

[0060] XRD detection equipment: TD3500.

[0061] In the following examples, the preparation of the crude sodium valproate used: Drop 1.2 kg of a methanol solution of sodium methoxide with a concentration of 30 wt% of sodium methoxide into 1 kg of valproic acid, control the temperature at 60 ± 5 °C, stir for 1 h, and remove the solvent under reduced pressure to obtain the crude sodium valproate, and the content of the crude sodium valproate ≥ 95.0 wt%.

[0062] The X-ray powder diffraction pattern of this crude sodium valproate is shown in Figure 1 。

[0063] In the following examples, the sodium valproate crystal seeds used were prepared by the method of Example 1 of Patent CN102531878A.

[0064] Example 1 This example provides a new crystal form of sodium valproate, and its preparation method includes the following steps: Take 1 kg of crude sodium valproate into a refining kettle, add 18 kg of ethyl acetate, heat and reflux until the solution is clear, add 9 g of valproic acid to adjust the pH to 7.5; continue heating and stirring, filter the liquid in the kettle through a microporous filter while hot to a crystallization kettle, slowly cool the clear material in the kettle to 55 ° C at a rate of 9.5-10.5 ° C / h after 1 hour, add 9 g of sodium valproate seeds, control the temperature at 55 ± 2 ° C, set the stirring speed to 10-15 r / min, maintain 55 ± 2 ° C for crystal growth for 1.5 hours, control the circulating water flow rate to slowly cool to 20 ° C, centrifuge after crystal growth for 1 hour, and vacuum dry the filter cake at a vacuum degree of -0.07 MPa. The material temperature is controlled at 68 ° C and dried for 8 hours to obtain 0.75 kg of sodium valproate crystals with a content of 99.29% and a yield of 75%.

[0065] The X-ray powder diffraction pattern of the sodium valproate crystals is shown in Figure 2 .

[0066] Example 2 This embodiment provides a new crystal form of sodium valproate, and its preparation method comprises the following steps: Take 3kg of crude sodium valproate into a refining kettle, add 54kg of ethyl acetate, heat and reflux until the solution is clear, add 27g of valproic acid to adjust the pH to 7.4; continue heating and stirring, filter the liquid in the kettle through a microporous filter while hot to a crystallization kettle, slowly cool the clear material in the kettle to 55°C at a rate of 9.5~10.5°C / h over 1h, add 27g of sodium valproate seeds, control the temperature at 55±2°C, set the stirring speed to 10~15r / min, maintain 55±2°C for crystal cultivation for 1.5h, control the circulating water flow rate to slowly cool to 20°C, centrifuge after crystal cultivation for 1h, vacuum dry the filter cake, the vacuum degree is -0.07MPa, the material temperature is controlled at 68°C, and dried for 8h to obtain 2.3kg of sodium valproate crystals with a content of 99.44% and a yield of 76.67%.

[0067] The X-ray powder diffraction pattern of the sodium valproate crystals is shown in Figure 3 The XRD spectrum was studied and compared, and the diffraction angle 2θ of each diffraction peak was different from that of the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak was equivalent to that of the crystal form of Example 1, and the product was determined to be the crystal form of Example 1.

[0068] Example 3 This embodiment provides a new crystal form of sodium valproate, and its preparation method comprises the following steps: 5 kg of crude sodium valproate was put into a refining kettle, 90 kg of ethyl acetate was added, the temperature was raised and refluxed until the solution was clear, and 45 g of valproic acid was added to adjust the pH to 7.5; heating and stirring were continued, and the liquid in the kettle was filtered through a microporous filter while hot to a crystallization kettle, and the clear material in the kettle was slowly cooled to 55°C at a rate of 9.5-10.5°C / h over 1 hour, 45 g of sodium valproate seeds were added, the temperature was controlled at 55±2°C, the stirring speed was set to 10-15 r / min, and the crystal was maintained at 55±2°C for 1.5 hours, the circulating water flow was controlled to slowly cool to 20°C, and the filter cake was vacuum dried at a vacuum degree of -0.07 MPa. The material was temperature controlled at 68°C and dried for 8 hours to obtain 3.8 kg of sodium valproate crystals with a content of 100.50% and a yield of 76%.

[0069] After studying and comparing its XRD spectrum, the diffraction angle 2θ at which each diffraction peak is located differs from the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is equivalent to the crystal form of Example 1, and it is determined that the product is the crystal form of Example 1.

[0070] Example 4 This embodiment provides a new crystal form of sodium valproate, and its preparation method comprises the following steps: Take 1 kg of crude sodium valproate into a refining kettle, add 18 kg of ethyl acetate, heat and reflux until the solution is clear, add 80 g of valproic acid to adjust the pH to 7; continue heating and stirring, filter the liquid in the kettle through a microporous filter while hot to a crystallization kettle, slowly cool the clear material in the kettle to 55 ° C at a rate of 9.5-10.5 ° C / h over 1 hour, add 4.5 g of sodium valproate seeds, control the temperature at 55 ± 2 ° C, set the stirring speed to 10-15 r / min, maintain 55 ± 2 ° C for crystal growth for 1.5 hours, control the circulating water flow rate to slowly cool to 25 ° C, centrifuge after crystal growth for 1 hour, and vacuum dry the filter cake at a vacuum degree of -0.09 MPa. The material temperature is controlled at 68 ° C and dried for 8 hours to obtain 0.73 kg of sodium valproate crystals with a content of 101.12% and a yield of 73%.

[0071] After studying and comparing its XRD spectrum, the diffraction angle 2θ at which each diffraction peak is located differs from the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is equivalent to the crystal form of Example 1, and it is determined that the product is the crystal form of Example 1.

[0072] Example 5 This embodiment provides a new crystal form of sodium valproate, and the preparation method thereof is different from that of Example 1 only in that valproic acid is used to adjust the pH value to 7.8.

[0073] After studying and comparing its XRD spectrum, the diffraction angle 2θ at which each diffraction peak is located differs from the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is equivalent to the crystal form of Example 1, and it is determined that the product is the crystal form of Example 1.

[0074] Example 6 This example provides a new crystal form of sodium valproate. The difference in its preparation method from that of Example 1 is only that valproic acid is replaced with dilute hydrochloric acid, and the pH is adjusted to be the same as that in Example 1.

[0075] Through research and comparison of its XRD pattern, the diffraction angle 2θ at which each diffraction peak is located differs from that of the crystal form in Example 1 by within ±0.20°, and the area intensity of each diffraction peak is comparable to that of the crystal form in Example 1. It is determined that the product is the crystal form of Example 1.

[0076] Comparative Example 1 This comparative example provides a new crystal form of sodium valproate. The difference in its preparation method from that of Example 1 is only that no sodium valproate crystal seeds are added, no valproic acid is added, the pH value is measured to be 8.5 - 9.0, and ethyl acetate is replaced with a mixture of ethyl acetate and methanol with a mass ratio of 16:0.05.

[0077] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 4 . Through research and comparison of its XRD pattern, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form in Example 1, and the area intensity of each diffraction peak is different from that of the crystal form in Example 1. It is determined that the crystal form of Comparative Example 1 is different from that of Example 1.

[0078] Comparative Example 2 This comparative example provides a new crystal form of sodium valproate, which is a sustained-release tablet of sodium valproate produced by Sanofi.

[0079] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 5 . Through research and comparison of its XRD pattern, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form in Example 1, and the area intensity of each diffraction peak is different from that of the crystal form in Example 1. It is determined that the crystal form of Comparative Example 1 is different from that of Example 1.

[0080] Comparative Example 3 This comparative example provides a new crystal form of sodium valproate, which is a sodium valproate raw material drug produced by Xufu in Taiwan, China.

[0081] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 6 . Through research and comparison of its XRD pattern, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form in Example 1, and the area intensity of each diffraction peak is different from that of the crystal form in Example 1. It is determined that the crystal form of Comparative Example 1 is different from that of Example 1.

[0082] Test Example 1. Crystal habit detection Testing method: Take an appropriate amount of sodium valproate API and spread it flat on a glass slide. Observe it under 100 times magnification, take a photo for record. Rotate the polarizing microscope by 90°, observe the crystallinity, and take a photo again for record.

[0083] The test results are shown in Figures 7 to 15 .

[0084] The results show that: For Example 1, it is short rod-shaped, with a particle size of about 8 - 54 μm, has crystallinity, and the properties are the same as Figure 7 the left figure of For Example 2, it is rod-shaped, with a particle size of about 18 - 477 μm, has crystallinity, and the properties are the same as Figure 8 the left figure of For Example 3, it is rod-shaped, with a particle size of about 18 - 477 μm, has crystallinity, and the properties are the same as Figure 9 the left figure of For Example 4, it is rod-shaped, with a particle size of about 20 - 438 μm, has crystallinity, and the properties are the same as Figure 10 the left figure of For Example 5, it is rod-shaped, with a particle size of about 30 - 190 μm, has crystallinity, and the properties are the same as Figure 11 the left figure of For Example 6, it is block-shaped and rod-shaped, with a particle size of about 40 - 200 μm, has crystallinity, and the properties are the same as Figure 12 the left figure of For Comparative Example 1, it is needle-shaped, with a particle size of about 20 - 200 μm, has crystallinity, and the properties are the same as Figure 13 the left figure of For Comparative Example 2, it is block-shaped, with a particle size of about 30 - 300 μm, has crystallinity, and the properties are the same as Figure 14 the left figure of For Comparative Example 3, it is block-shaped, with a particle size of about 30 - 300 μm, has crystallinity, and the properties are the same as Figure 15 the left figure of

[0085] The above shows that the crystal habits of Examples 1 - 5 are completely different from the needle-shaped and block-shaped of the comparative examples. They are all short rod-shaped or rod-shaped, and they have better physicochemical properties and formulation processing performance in the pharmaceutical industry, especially having obvious advantages in improving the uniformity, stability and efficiency of the formulation.

[0086] 2. Dissolution test Testing method: Refer to the quality standard of Sodium Valproate Sustained Release Tablets (I) in the second part of the Chinese Pharmacopoeia 2020 edition. Determine that the main medium of this product is DH6.8 phosphate buffer solution, the dissolution method is the first method (basket method), the medium volume is 1000 ml, and the rotation speed is 60 rpm. Other media are optimized with reference to the main medium method.

[0087] The test results are shown in Table 2.

[0088] Table 2

[0089] Comparative Example 1: The dissolution decreased by about 0 - 7% under the condition of 60°C, and decreased by about 0 - 7% under the accelerated condition. The dissolution increased after 6 hours, and the decreasing amplitude was higher than that of the examples, with poor stability. Comparative Example 2: The dissolution decreased by about 0 - 6% under the condition of 60°C, and the decreasing amplitude was higher than that of the examples, with relatively poor stability. Comparative Example 3: The dissolution decreased by about 0 - 9% under the condition of 60°C, and decreased by about 0 - 8% under the accelerated condition. The decreasing amplitude was higher than that of the examples, with relatively poor stability. Example 1: The dissolution decreased by about 0 - 3% under the condition of 60°C, and decreased by about 0 - 2% under the accelerated condition. The decreasing amplitude was lower than that of the comparative examples, with good stability. Example 2: The dissolution decreased by about 0 - 3% under the condition of 60°C, and the decreasing amplitude was lower than that of the comparative examples, with good stability. Example 3: The dissolution at 0 day was basically the same as that of other examples, with good stability. Example 4: The dissolution decreased by about 0 - 4% under the condition of 60°C, and the decreasing amplitude was lower than that of the comparative examples, with good stability. Example 5: The dissolution decreased by about 0 - 4% under the condition of 60°C, and the decreasing amplitude was lower than that of the comparative examples, with good stability. Example 6: The dissolution decreased by about 0 - 6% under the condition of 60°C, and the decreasing amplitude was higher than that of the other examples, with relatively poor stability.

[0090] The above shows that the decreasing amplitudes of the examples are all lower than those of the comparative examples, with good stability.

[0091] 2. Hygroscopicity test In the present invention, the sodium valproate crystals of the examples and comparative examples were used as the test samples, and the hygroscopicity of each test sample was tested respectively.

[0092] Test method: Take a dry stoppered glass weighing bottle and place it in a suitable constant temperature drying oven or constant temperature and humidity incubator at 25 ± 1°C one day before the experiment, and accurately weigh the weight (m1). Take an appropriate amount of the test substance and spread it evenly in the above-mentioned weighing bottle. The thickness of the test substance is generally about 1 mm, and accurately weigh the weight (m2). Open the weighing bottle and place the bottle cap in the above-mentioned constant temperature and humidity condition for 24 hours. Cover the weighing bottle cap and accurately weigh the weight (m3).

[0093] Calculation: Weight gain percentage = (m3 - m2) / (m2 - m1) × 100%.

[0094] In the formula: m1 is the weight of the weighing bottle, g; m2 is the original weight of the weighing bottle and the test substance, g; m3 is the original weight of the weighing bottle and the test substance after 24 hours under the constant temperature and humidity condition, g.

[0095] The test results are shown in Table 3 as follows: Table 3

[0096] The above shows that the hygroscopicity of the examples is generally lower than that of the comparative examples, and the moisture absorption is relatively low.

[0097] 3. Water solubility test In the present invention, the sodium valproate crystals of the examples and comparative examples are used as the samples to be tested, and the water solubility of each sample to be tested is measured respectively.

[0098] Test method: Take 1 g of this product and place it in a 10 ml beaker, add 1 ml of water to dissolve.

[0099] The test results are shown in Table 4 as follows: Table 4

[0100] The experimental results show that the shaking dissolution time of the examples is shorter than that of the comparative examples, and the water solubility is good.

[0101] 4. Stability In the present invention, the sodium valproate crystals of Example 1 and Comparative Example 2 (original developed formulation) are used as the samples to be tested, and the crystal stability of each sample to be tested is measured respectively.

[0102] Test method: After placing the batch of Example 1 under high temperature, high humidity, strong light and accelerated conditions for one month, it is detected, and the related substances, content and dissolution curve are used as the inspection indexes to judge the stability of the self-made product.

[0103] The test results are shown in Table 5 and Table 6 as follows: Table 5 Stability results of Example 1 (related substances and content)

[0104] Table 6 Stability results (dissolution curve in pH6.8 medium)

[0105] There is no obvious change in the related substances of the samples under the influence factors for 30 days and accelerated for 30 days. The dissolution curve of Example 1 is similar to that of Comparative Example 2 (original developed formulation), but the dissolution degree is relatively low, indicating that the product has good stability.

[0106] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A sodium valproate crystal, characterized in that: In the X-ray powder diffraction pattern, it has diffraction peaks at at least the following diffraction angles 2θ: 5.67°±0.2°, 6.73°±0.2°, 16.94°±0.2°, 18.18°±0.2°, 18.67°±0.2°, 20.16°±0.2°, 20.92°±0.2°, 21.13°±0.2°, 22.55°±0.2° and 24.45°±0.2°.

2. The sodium valproate crystal according to claim 1, characterized in that The X-ray powder diffraction pattern further comprises diffraction peaks at diffraction angles 2θ of 7.30°±0.2° and / or 20.00°±0.2°; Preferably, the X-ray powder diffraction pattern of the sodium valproate crystals is shown in Figure 2 and / or Figure 3.

3. The method for preparing the sodium valproate crystals according to claim 1 or 2, characterized in that: include: S1: dissolving crude sodium valproate in a crystallization solvent comprising ethyl acetate, heating and refluxing until the solution becomes clear; adding acid, heating and stirring to obtain a first mixed liquid; S2: filtering the first mixed liquid while it is hot, and cooling the obtained filtrate for crystallization to obtain a second mixed liquid; S3: adding sodium valproate seed crystals to the second mixed liquid for crystal growing.

4. The method for preparing sodium valproate crystals according to claim 3, characterized in that: The pH of the first mixed liquid is 7.0-7.5; preferably, the acid is an organic acid and / or an inorganic acid; more preferably, the organic acid is selected from valproic acid and / or salicylic acid; and the inorganic acid is selected from dilute hydrochloric acid.

5. The method for preparing sodium valproate crystals according to claim 3 or 4, characterized in that, Based on the amount of ethyl acetate used, the amount of sodium valproate seed crystals added is 0.01% to 0.05%.

6. The method for preparing sodium valproate crystals according to any one of claims 3 to 5, characterized in that: The mass ratio of the ethyl acetate to the crude sodium valproate is (16-20):

1.

7. The method for preparing sodium valproate crystals according to any one of claims 3 to 6, characterized in that: S3 includes: adding sodium valproate seed crystals to the second mixed liquid, controlling the temperature at 55±2°C, stirring and keeping the temperature to grow crystals, to obtain a third mixed liquid; then cooling the third mixed liquid to 20-25°C at a rate of 4.5-5.5°C per 0.5h, and keeping the temperature to grow crystals.

8. The method for preparing sodium valproate crystals according to any one of claims 3 to 7, characterized in that: include: S1': dissolving crude sodium valproate in ethyl acetate, heating to reflux, adding valproic acid after the solution becomes clear, and obtaining a first mixed liquid with a pH of 7.0-7.5; S2': filter the first mixed liquid while hot, and cool the filtrate to 50-60°C at a rate of 9.5-10.5°C / h to obtain a second mixed liquid; S3': adding sodium valproate seed crystals to the second mixed liquid, controlling the temperature at 55±2°C, stirring and keeping the temperature to grow crystals, to obtain a third mixed liquid; based on the amount of ethyl acetate used, the amount of the sodium valproate seed crystals added is 0.01wt%~0.05wt%; preferably, the stirring speed is 10~15r / min; S4': cooling the third mixed liquid to 20-25°C at a rate of 4.5-5.5°C per 0.5h, maintaining the temperature for crystal growth, and obtaining a fourth mixed liquid; S5': centrifuging, filtering and drying the fourth mixed liquid in sequence to obtain the sodium valproate crystals.

9. A pharmaceutical composition, characterized in that Containing the sodium valproate crystals according to claim 1 or 2 or the sodium valproate crystals prepared by the preparation method according to any one of claims 3 to 8; preferably, the pharmaceutical composition includes sodium valproate sustained-release tablets.

10. Any one of the following uses of the sodium valproate crystals according to claim 1 or 2, the sodium valproate crystals obtained by the preparation method according to any one of claims 3 to 8, or the pharmaceutical composition according to claim 9: 1) Use in the preparation of drugs for treating epilepsy; 2) Use in the preparation of drugs for treating bipolar disorder.

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