Sodium valproate crystals, process for their preparation and use

Abstract

The present application relates to the technical field of crystal preparation, and particularly relates to sodium valproate crystal and a preparation method and application thereof. The sodium valproate crystal provided by the present application has diffraction peaks at least at the following diffraction angles 2theta 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°. The sodium valproate crystal provided by the present application has good stability, good water solubility, significantly reduced hygroscopicity, ensures the quality stability within the effective period of the medicine, and significantly shortens the dissolution time of the product, and the product has good redissolution.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal preparation, in particular to sodium valproate crystal and its preparation method and application. BACKGROUND

[0002] Sodium valproate is a first-line broad-spectrum antiepileptic drug. Its chemical structural formula is Sodium valproate is sodium 2-propylvalerate, and its molecular formula is C8H 15 O2Na, and its molecular weight is 166.20. It is a white crystalline powder and can be administered as an oral solution or an injection. It is mainly used for treating epilepsy, including general epilepsy and partial epilepsy. For example, simple or complex absence seizures, myoclonic seizures, clonic seizures, atonic seizures and mixed seizures. It can also be used for treating mania associated with bipolar disorder.

[0003] Because sodium valproate is easily hygroscopic during storage and transportation, the main drug degrades and impurities increase. 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 disclose five crystal forms of sodium valproate, namely, crystal form I, crystal form II, crystal form III, crystal form IV and new crystal form. The crystal form I and the new crystal form are prepared by crystallization of ketone or alcohol solvents, and the other three crystal forms are prepared by freeze-drying. Although the above-mentioned sodium valproate crystals improve the stability of sodium valproate to some extent, there are still problems such as strong hygroscopicity of sodium valproate, difficulty in recovering the crystallization solvent, high manufacturing cost, low content, etc. Therefore, there is still room for further improvement.

[0005] In view of this, the present application is proposed. SUMMARY

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

[0007] In order to achieve this purpose, the technical solutions of the present application are as follows:

[0008] In the first aspect, the present application 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°.

[0009] As preferred, the sodium valproate crystal according to the present application 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.

[0010] As preferred, the sodium valproate crystal according to the present application has diffraction peaks at least at diffraction angles 2θ of 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°.

[0011] The present application, through a large number of researches, obtains a sodium valproate crystal, which has good stability, good water solubility, significantly reduced hygroscopicity, ensures the quality stability within the effective period of the drug, and has good reconstitution property, significantly shortens the dissolution time of the product.

[0012] As a preferred technical solution of the present application, the XRPD pattern analysis data of the sodium valproate crystal are shown in Table 1.

[0013] Table 1

[0014]

[0015] As a preferred technical solution of the present application, the sodium valproate crystal according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 2 and / or Figure 3 or the X-ray powder diffraction pattern thereof is substantially the same as the X-ray powder diffraction pattern as shown in Figure 2 and / or Figure 3 .

[0016] In a second aspect, the present application provides a preparation method of the sodium valproate crystal, comprising:

[0017] S1: dissolving sodium valproate crude product in a crystallization solvent comprising ethyl acetate, heating to reflux until clear; adding acid, heating and stirring to obtain a first mixed liquid;

[0018] S2: filtering the first mixed liquid while hot, and cooling the obtained filtrate to crystallize; obtaining a second mixed liquid;

[0019] S3: adding sodium valproate crystal seeds to the second mixed liquid for crystal growth.

[0020] The prior art discloses that ethyl acetate single solvent recrystallization, ethyl acetate-methanol composite solvent recrystallization, ethyl acetate-acetone composite solvent recrystallization and the like are adopted, but there are still problems of high hygroscopicity of obtained sodium valproate product, poor stability within an effective period, great difficulty in recovery of a crystallization solvent, high production cost, low content and the like. The present application finds that, when acid and sodium valproate are introduced as crystal seeds during recrystallization, a new crystal form of sodium valproate is prepared, the hygroscopicity is significantly reduced, and the uniformity and stability of the sodium valproate raw material and preparation crystal form can be improved.

[0021] In the present application, the "sodium valproate crude product" and the "sodium valproate crystal seed" are both known compounds, which can be obtained through various channels.

[0022] As an optional embodiment of the present application, the "sodium valproate crude product" is prepared from the reaction of valproic acid and a methanol solution of sodium methoxide. The specific preparation method comprises: adding a methanol solution of sodium methoxide dropwise into valproic acid, performing reaction at 60±5℃, and obtaining the sodium valproate crude product through desolventization under reduced pressure after the reaction is completed.

[0023] As an optional embodiment of the present application, the content of the sodium valproate crude product is ≥95.0wt%.

[0024] As an optional embodiment of the present application, the "sodium valproate crystal seed" refers to the sodium valproate crystal form I disclosed in patent CN102531878A, and the content is ≥99.0wt%.

[0025] Preferably, the pH of the first mixed liquid is 7.0-7.5.

[0026] 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; and the inorganic acid is selected from dilute hydrochloric acid.

[0027] The present application finds that changing the acidity value of the crystallization system to the above range is helpful to obtain the new crystal form of sodium valproate, to obtain the sodium valproate crystal of the present application, and to stabilize the crystallization system and enhance the stability of the sodium valproate crystal form.

[0028] As a preferred embodiment of the present application, the acid is the organic acid.

[0029] Further preferably, when the acid is valproic acid, it is helpful to further reduce the hygroscopicity of the sodium valproate crystal, to enhance the stability of the sodium valproate crystal form, and to reduce the risk of impurity introduction.

[0030] As a preference, the amount of the acid is 0.05-0.5wt% relative to the amount of ethyl acetate, for example, it can be any of 0.05wt%, 0.1wt%, 0.15wt%, 0.2wt%, 0.25wt%, 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt% and 0.5wt%, or a range of values with any two of the above values as the end points.

[0031] As a preference, the amount of the sodium valproate seed crystal is 0.01wt%-0.05wt% relative to the amount of ethyl acetate; preferably, the content of the sodium valproate seed crystal is ≥99.0wt%.

[0032] As a preference, the mass ratio of the ethyl acetate to the sodium valproate crude product is (16-20):1.

[0033] Specifically, the mass ratio of the crystallization solvent to the sodium valproate crude product can be any of 16:1, 17:1, 18:1, 19:1 and 20:1, or a range of values with any two of the above values as the end points. The present application finds that when the amount of ethyl acetate exceeds the above range, the yield of sodium valproate crystal is lower.

[0034] As a preference, S3 comprises adding sodium valproate seed crystal to the second mixed liquid, controlling the temperature at 55±2℃, stirring and incubating for crystal growth, to obtain a third mixed liquid; and then cooling the third mixed liquid to 20-25℃ at a rate of 4.5-5.5℃ per 0.5h, and incubating for crystal growth.

[0035] The present application finds that under the above incubation conditions, it is more conducive to improving the quality of the sodium valproate crystal and the stability of the crystal form, has superior water solubility, and further reduces the hygroscopicity of the product.

[0036] As a preferred embodiment of the present application, the preparation method of the sodium valproate crystal comprises:

[0037] S1': dissolving sodium valproate crude product in ethyl acetate, heating to reflux, after the solution is clear, adding valproic acid to obtain a first mixed liquid with a pH of 7.0-7.5;

[0038] S2': hot-press filtering the first mixed liquid, and cooling the filtrate to 50-60℃ at a rate of 9.5-10.5℃ / h to obtain a second mixed liquid;

[0039] S3': adding sodium valproate seed crystal into the second mixed solution, controlling temperature at 55±2℃, stirring and incubating for crystal growth to obtain a third mixed solution; the amount of sodium valproate seed crystal added is 0.01wt%-0.05wt% based on the amount of ethyl acetate; preferably, the stirring speed is 10-15r / min; preferably, the incubation time is 1-2h;

[0040] S4': cooling the third mixed solution to 20-25℃ at a rate of 4.5-5.5℃ per 0.5h, and incubating for crystal growth to obtain a fourth mixed solution; preferably, the incubation time is 0.5-1.5h;

[0041] S5': centrifuging, filtering and drying the fourth mixed solution in sequence to obtain the sodium valproate crystal.

[0042] Preferably, the drying conditions include: vacuum degree -0.09--0.07MPa, temperature 65-70℃, and drying for 8±0.5h; more preferably, the vacuum degree is -0.07MPa, the temperature is 68℃, and the drying time is 8h.

[0043] In a third aspect, the present application provides a pharmaceutical composition containing the sodium valproate crystal or the sodium valproate crystal prepared by the preparation method.

[0044] In some embodiments of the present application, the pharmaceutical composition contains the sodium valproate crystal of the present application and a pharmaceutically acceptable carrier, and other pharmacologically active substances can also be present.

[0045] In the present application, the "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coating materials, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc. and combinations thereof, and an isotonic agent such as a sugar, sodium chloride or a polyol such as mannitol or sorbitol can be included in the composition. Other auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, etc. can also be included.

[0046] The pharmaceutical composition in the present application 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), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories, etc. In the case of capsules, tablets and pills, the dosage form can also include a buffer or can be prepared with an enteric coating. The specific form depends on the intended mode of administration and therapeutic application.

[0047] Preferably, the pharmaceutical composition is a sodium valproate sustained-release tablet.

[0048] The sodium valproate crystal has high content, low hygroscopicity and good stability, ensures the curative effect in clinical medication, and continuously and stably provides the drug in the form of sustained-release tablets, improves the compliance of patients during treatment, and obtains good clinical effect.

[0049] In a fourth aspect, the present application provides the sodium valproate crystal, the sodium valproate crystal prepared by the preparation method or the pharmaceutical composition for any of the following applications:

[0050] 1) for preparing a drug for treating epilepsy;

[0051] 2) for preparing a drug for treating bipolar affective disorder.

[0052] The sodium valproate crystal provided by the present application has good stability, good water solubility, significantly reduced hygroscopicity, ensures the quality stability within the effective period of the drug, and also significantly shortens the dissolution time of the product, and the reconstitution property of the product is good. The preparation process of the present application is relatively simple, the production efficiency is high, the equipment requirement level is low, the organic solvent used has relatively small toxicity, is easy to obtain and recycle, and is an environment-friendly green production process. BRIEF DESCRIPTION OF DRAWINGS

[0053] In order to more clearly illustrate the technical solutions in the present application or prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0054] Figure 1 It is the X-ray powder diffraction pattern of the sodium valproate crude product used in the present application.

[0055] Figure 2 It is the X-ray powder diffraction pattern of the sodium valproate crystal in Example 1 provided by the present application.

[0056] Figure 3 It is the X-ray powder diffraction pattern of the sodium valproate crystal in Example 2 provided by the present application.

[0057] Figure 4 It is the X-ray powder diffraction pattern of the sodium valproate crystal in Comparative Example 1 provided by the present application.

[0058] Figure 5 It is the X-ray powder diffraction pattern of the sodium valproate crystal in Comparative Example 2 provided by the present application.

[0059] Figure 6 It is the X-ray powder diffraction pattern of the sodium valproate crystal in Comparative Example 3 provided by the present application.

[0060] Figure 7 is the crystal habit result of sodium valproate crystal in Example 1 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0061] Figure 8 is the crystal habit result of sodium valproate crystal in Example 2 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0062] Figure 9 is the crystal habit result of sodium valproate crystal in Example 3 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0063] Figure 10 is the crystal habit result of sodium valproate crystal in Example 4 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0064] Figure 11 is the crystal habit result of sodium valproate crystal in Example 5 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0065] Figure 12 is the crystal habit result of sodium valproate crystal in Example 6 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0066] Figure 13 is the crystal habit result of sodium valproate crystal in Comparative Example 1 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0067] Figure 14 is the crystal habit result of sodium valproate crystal in Comparative Example 2 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture.

[0068] Figure 15 is the crystal habit result of sodium valproate crystal in Comparative Example 3 provided by the present application, wherein the left picture is a microscope picture and the right picture is a polarized light microscope picture. DETAILED DESCRIPTION

[0069] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions in the present application will be described clearly and completely below with reference to the drawings in the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0070] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples are commercially available or prepared according to conventional methods in the art unless otherwise specified.

[0071] Content detection method: potentiometric titration, comprising the following steps:

[0072] Take about 0.5 g of the product, accurately weigh, dissolve in 30 ml of water, then add 30 ml of diethyl ether, according to the potentiometric titration (general rule 0701), use glass-saturated calomel electrode, use hydrochloric acid titrant (0.1 mol / L) to titrate to pH 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 C8H 15 NaO2.

[0073] C8H 15 NaO2%=16.62 / 1000×(V1-V0)×(c / 0.1) / m / (1-w%)×100%

[0074] In the formula: m is the mass of the test sample, g;

[0075] V1 is the volume of hydrochloric acid standard solution consumed for titrating the content of sodium valproate, ml;

[0076] V0 is the volume of hydrochloric acid standard solution consumed for titrating the blank solution, ml;

[0077] c is the concentration of the hydrochloric acid standard titration solution, mol / L;

[0078] w is the drying loss value of sodium valproate, %;

[0079] 16.62 is the mass of C8H 15 NaO2 equivalent to 1 ml of hydrochloric acid titrant (0.1 mol / L) consumed.

[0080] XRD detection equipment: TD3500.

[0081] In the following examples, the preparation of sodium valproate crude product:

[0082] 1.2 kg of sodium methoxide in methanol solution was added dropwise to 1 kg of valproic acid, the concentration of sodium methoxide in the sodium methoxide in methanol solution was 30 wt%, the temperature was controlled at 60±5℃, stirring for 1 h, and then the sodium valproate crude product was obtained by solvent removal under reduced pressure, the content of the sodium valproate crude product was ≥95.0 wt%.

[0083] The X-ray powder diffraction pattern of the sodium valproate crude product is shown in Figure 1 .

[0084] In the following examples, the sodium valproate seed crystals are prepared by the method of patent CN102531878A example 1.

[0085] Example 1

[0086] The present example provides a new crystal form of sodium valproate, and the preparation method thereof comprises the following steps:

[0087] Take 1 kg of sodium valproate crude product in a refining kettle, add 18 kg of ethyl acetate, heat to reflux until clear, add 9 g of propionic acid to adjust the pH to 7.5; continue to heat and stir, while hot, press filter the kettle contents through a microporous filter to a crystallization kettle, slowly cool the kettle contents in a clear solution state to 55°C at a rate of 9.5~10.5℃ / h, add 9 g of sodium valproate seed crystals, control the temperature at 55±2℃, set the stirring speed at 10~15 r / min, maintain 55±2℃ for 1.5 h, control the circulating water flow to slowly cool to 20℃, centrifuge after 1 h of crystal growth, vacuum dry the filter cake, control the temperature of the material at 68℃, dry for 8 h, obtain 0.75 kg of sodium valproate crystals with a content of 99.29%, a yield of 75%.

[0088] The X-ray powder diffraction pattern of the sodium valproate crystals is shown in Figure 2 .

[0089] Example 2

[0090] The present example provides a new crystal form of sodium valproate, and the preparation method thereof comprises the following steps:

[0091] Take 3 kg of sodium valproate crude product in a refining kettle, add 54 kg of ethyl acetate, heat to reflux until clear, add 27 g of propionic acid to adjust the pH to 7.4; continue to heat and stir, while hot, press filter the kettle contents through a microporous filter to a crystallization kettle, slowly cool the kettle contents in a clear solution state to 55°C at a rate of 9.5~10.5℃ / h, add 27 g of sodium valproate seed crystals, control the temperature at 55±2℃, set the stirring speed at 10~15 r / min, maintain 55±2℃ for 1.5 h, control the circulating water flow to slowly cool to 20℃, centrifuge after 1 h of crystal growth, vacuum dry the filter cake, control the temperature of the material at 68℃, dry for 8 h, obtain 2.3 kg of sodium valproate crystals with a content of 99.44%, a yield of 76.67%.

[0092] The X-ray powder diffraction pattern of the sodium valproate crystals is shown in Figure 3 . The XRD pattern is studied and compared, the diffraction angles 2θ of each diffraction peak differ from the crystal form of example 1 by ±0.20°, and the diffraction peak area intensity is comparable to the crystal form of example 1, confirming that the product is the crystal form of example 1.

[0093] Example 3

[0094] The present embodiment provides a new crystal form of sodium valproate, a preparation method thereof comprising the following steps:

[0095] Take 5 kg of crude sodium valproate in a refining kettle, add 90 kg of ethyl acetate, heat to reflux until clear, add 45 g of valproic acid to adjust the pH to 7.5; continue to heat and stir, while hot, press filter the kettle contents through a microporous filter into a crystallization kettle, slowly cool the kettle contents in a clear solution state to 55°C at a rate of 9.5-10.5°C / h, add 45 g of sodium valproate seed crystals, control the temperature at 55±2°C, set the stirring speed at 10-15 r / min, maintain 55±2°C for 1.5 h, control the circulating water flow to slowly cool to 20°C, centrifuge after 1 h of crystal growth, vacuum dry the filter cake, vacuum degree -0.07 MPa, control the temperature of the material at 68°C, dry for 8 h, obtain 3.8 kg of sodium valproate crystals with a content of 100.50% and a yield of 76%.

[0096] The XRD pattern of the product is compared with that of the crystal form of Example 1, the diffraction angles 2θ of the diffraction peaks are within ±0.20° of the crystal form of Example 1, and the area intensity of each diffraction peak is comparable to that of the crystal form of Example 1, so the product is determined to be the crystal form of Example 1.

[0097] Example 4

[0098] The present embodiment provides a new crystal form of sodium valproate, a preparation method thereof comprising the following steps:

[0099] Take 5 kg of crude sodium valproate in a refining kettle, add 90 kg of ethyl acetate, heat to reflux until clear, add 45 g of valproic acid to adjust the pH to 7.5; continue to heat and stir, while hot, press filter the kettle contents through a microporous filter into a crystallization kettle, slowly cool the kettle contents in a clear solution state to 55°C at a rate of 9.5-10.5°C / h, add 45 g of sodium valproate seed crystals, control the temperature at 55±2°C, set the stirring speed at 10-15 r / min, maintain 55±2°C for 1.5 h, control the circulating water flow to slowly cool to 20°C, centrifuge after 1 h of crystal growth, vacuum dry the filter cake, vacuum degree -0.07 MPa, control the temperature of the material at 68°C, dry for 8 h, obtain 3.8 kg of sodium valproate crystals with a content of 100.50% and a yield of 76%.

[0100] The XRD pattern of the product is compared with that of the crystal form of Example 1, the diffraction angles 2θ of the diffraction peaks are within ±0.20° of the crystal form of Example 1, and the area intensity of each diffraction peak is comparable to that of the crystal form of Example 1, so the product is determined to be the crystal form of Example 1.

[0101] Example 5

[0102] The present example provides a new crystal form of sodium valproate, the preparation method of which is only different from that of Example 1 in that sodium valproate is used to adjust the pH value to 7.8.

[0103] The XRD pattern of the product is studied and compared, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is different from that of the crystal form of Example 1, so it is determined that the product is different from the crystal form of Example 1.

[0104] Example 6

[0105] The present example provides a new crystal form of sodium valproate, the preparation method of which is only different from that of Example 1 in that sodium valproate is used to adjust the pH value to 7.8.

[0106] The XRD pattern of the product is studied and compared, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is different from that of the crystal form of Example 1, so it is determined that the product is different from the crystal form of Example 1.

[0107] Comparative Example 1

[0108] The present example provides a new crystal form of sodium valproate, the preparation method of which is only different from that of Example 1 in that sodium valproate is used to adjust the pH value to 7.8.

[0109] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 4 The XRD pattern of the product is studied and compared, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is different from that of the crystal form of Example 1, so it is determined that the product is different from the crystal form of Example 1.

[0110] Comparative Example 2

[0111] The present example provides a new crystal form of sodium valproate, which is sodium valproate sustained-release tablets produced by Sanofi.

[0112] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 5 The XRD pattern of the product is studied and compared, the diffraction angle 2θ at which each diffraction peak is located is different from that of the crystal form of Example 1 by ±0.20°, and the area intensity of each diffraction peak is different from that of the crystal form of Example 1, so it is determined that the product is different from the crystal form of Example 1.

[0113] Comparative Example 3

[0114] The present example provides a new crystal form of sodium valproate, which is sodium valproate raw material produced by Xufu in Taiwan Province, China.

[0115] The X-ray powder diffraction pattern of the sodium valproate crystal is shown in Figure 6 The XRD pattern was studied and compared, the diffraction angle 2 theta of each diffraction peak was different from the crystal form of Example 1, and the area intensity of each diffraction peak was different from the crystal form of Example 1, so it was determined that Comparative Example 1 was different from the crystal form of Example 1.

[0116] Test Example

[0117] 1. Crystal habit detection

[0118] Test method: Take an appropriate amount of sodium valproate API and lay it on a glass slide, observe under 100 times, take pictures, rotate the polariscope by 90 degrees, observe the crystallinity, and take pictures again.

[0119] The test results are shown in Figure 7~Figure 15 .

[0120] The results show that:

[0121] Example 1, short rod-shaped, particle size about 8-54 μm, crystalline, same as the left figure of Figure 7 ;

[0122] Example 2, rod-shaped, particle size about 18-477 μm, crystalline, same as the left figure of Figure 8 ;

[0123] Example 3, rod-shaped, particle size about 18-477 μm, crystalline, same as the left figure of Figure 9 ;

[0124] Example 4, rod-shaped, particle size about 20-438 μm, crystalline, same as the left figure of Figure 10 ;

[0125] Example 5, rod-shaped, particle size about 30-190 μm, crystalline, same as the left figure of Figure 11 ;

[0126] Example 6, blocky, rod-shaped, particle size about 40-200 μm, crystalline, same as the left figure of Figure 12 ;

[0127] Comparative Example 1, needle-shaped, particle size about 20-200 μm, crystalline, same as the left figure of Figure 13 ;

[0128] Comparative Example 2, blocky, particle size about 30-300 μm, crystalline, same as the left figure of Figure 14 ;

[0129] Comparative Example 3, blocky, particle size about 30-300 μm, crystalline, same as the left figure of Figure 15 .

[0130] The above shows that the crystal habit of Examples 1-5 is completely different from the needle-like and block-like crystal habit of the comparative examples, and is short rod-like or rod-like, which has more excellent physical and chemical properties and preparation processing performance in the pharmaceutical industry, and has obvious advantages in improving the uniformity, stability and efficiency of the preparation.

[0131] 2. Dissolution test

[0132] Test method: According to the quality standard of sodium valproate sustained-release tablets (I) in Chinese Pharmacopoeia 2020 edition, the main medium of the product is DH6.8 phosphate buffer, 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 according to the method of the main medium.

[0133] The test results are shown in Table 2.

[0134] Table 2

[0135]

[0136] Comparative Example 1: The dissolution decreased by about 0-7% under the condition of 60°C, and the dissolution decreased by about 0-7% under the accelerated condition, and the dissolution increased after 6h, the decrease was higher than that of the examples, and the stability was poor;

[0137] Comparative Example 2: The dissolution decreased by about 0-6% under the condition of 60°C, and the decrease was higher than that of the examples, and the stability was poor;

[0138] Comparative Example 3: The dissolution decreased by about 0-9% under the condition of 60°C, and the dissolution decreased by about 0-8% under the accelerated condition, and the decrease was higher than that of the examples, and the stability was poor;

[0139] Example 1: The dissolution decreased by about 0-3% under the condition of 60°C, and the dissolution decreased by about 0-2% under the accelerated condition, and the decrease was lower than that of the comparative examples, and the stability was good;

[0140] Example 2: The dissolution decreased by about 0-3% under the condition of 60°C, and the decrease was lower than that of the comparative examples, and the stability was good;

[0141] Example 3: The dissolution degree was basically the same as that of other examples at 0 days, and the stability was good;

[0142] Example 4: The dissolution decreased by about 0-4% under the condition of 60°C, and the decrease was lower than that of the comparative examples, and the stability was good;

[0143] Example 5: The dissolution decreased by about 0-4% under the condition of 60°C, and the decrease was lower than that of the comparative examples, and the stability was good;

[0144] Example 6: The dissolution decreased by about 0-6% under the condition of 60°C, and the decrease was higher than that of the other examples, and the stability was relatively poor.

[0145] The above shows that the amplitude of the examples is lower than that of the comparative examples, and the stability is good.

[0146] 2. Hygroscopicity test

[0147] The sodium valproate crystals of the examples and the comparative examples were used as the test samples, and the hygroscopicity of each test sample was tested.

[0148] Test method: Dry stoppered glass weighing bottles were placed in a suitable 25±1℃ constant temperature dry box or constant temperature and humidity incubator one day before the experiment, and the weight (m1) was accurately measured. Take the appropriate test sample, spread it in the above weighing bottle, the thickness of the test sample is generally about 1mm, and the weight (m2) is accurately measured. The weighing bottle was opened, and the cap was placed in the above constant temperature and humidity conditions for 24 hours. Close the weighing bottle cap, and accurately measure the weight (m3).

[0149] Calculation: weight gain percentage = (m3-m2) / (m2-m1) x 100%.

[0150] In the formula: m1 is the weight of the weighing bottle, g;

[0151] m2 is the original weight of the weighing bottle and the test sample, g;

[0152] m3 is the original weight of the weighing bottle and the test sample after 24 hours under constant temperature and humidity conditions, g.

[0153] The test results are shown in Table 3:

[0154] Table 3

[0155]

[0156] The above shows that the hygroscopicity of the examples is generally lower than that of the comparative examples, and the hygroscopicity is lower.

[0157] 3. Water solubility test

[0158] The sodium valproate crystals of the examples and the comparative examples were used as the test samples, and the water solubility of each test sample was tested.

[0159] Test method: 1g of the product was placed in a 10ml beaker, and 1ml of water was added for dissolution.

[0160] The test results are shown in Table 4:

[0161] Table 4

[0162]

[0163] 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.

[0164] 4. Stability

[0165] The crystal of sodium valproate of Example 1 and Comparative Example 2 (original research preparation) is taken as the sample to be tested, and the crystal stability of each sample to be tested is tested respectively.

[0166] Test method: After the batch of Example 1 is placed under high temperature, high humidity, strong light and accelerated conditions for one month, it is detected with respect to related substances, content and dissolution curve as the indexes for observation to judge the stability of the self-made product.

[0167] The test results are shown in Tables 5 and 6:

[0168] Table 5 Stability results of Example 1 (related substances and content)

[0169]

[0170] Table 6 Stability results (pH 6.8 medium dissolution curve)

[0171]

[0172] The related substances of the samples of 30 days and accelerated 30 days do not have obvious changes, the dissolution curve of Example 1 is similar to that of Comparative Example 2 (original research preparation), but the dissolution is relatively low, which indicates that the product has good stability.

[0173] Finally, it should be pointed out that: the above examples are only used to illustrate the technical solutions of the present application, but not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part 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 each embodiment of the present application.

Claims

1. A method for preparing sodium valproate crystals, characterized by, The sodium valproate crystal has diffraction peaks at least at 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° in an X-ray powder diffraction spectrum; The sodium valproate crystal is prepared by the following method: S1': dissolving sodium valproate crude product in ethyl acetate, heating to reflux, after dissolving, adding valproic acid to obtain a first mixed liquor with pH of 7.0-7.5; the mass ratio of ethyl acetate to sodium valproate crude product is (16-20):1; S2': hot-press filtering the first mixed liquor, cooling the filtrate to 50-60°C at a rate of 9.5-10.5°C / h to obtain a second mixed liquor; S3': adding sodium valproate crystal seeds to the second mixed liquor, controlling the temperature at 55±2°C, stirring and incubating to grow crystals to obtain a third mixed liquor; the addition amount of sodium valproate crystal seeds is 0.01wt%-0.05wt% based on the amount of ethyl acetate; the stirring speed is 10-15r / min; S4': cooling the third mixed liquor to 20-25°C at a rate of 4.5-5.5°C per 0.5h, incubating to grow crystals to obtain a fourth mixed liquor; S5': sequentially centrifuging, filtering and drying the fourth mixed liquor to obtain the sodium valproate crystal.

2. The method for preparing sodium valproate crystals according to claim 1, characterized in that, The sodium valproate crystal further comprises diffraction peaks at diffraction angles 2θ of 7.30°±0.2° and / or 20.00°±0.2° in an X-ray powder diffraction spectrum.

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