Lithium valproate and crystal forms thereof, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to lithium valproate and crystal forms thereof, a preparation method therefor, a pharmaceutical composition thereof and the use thereof. The crystal forms of lithium valproate comprise crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI and crystal form VII.

Description

Lithium valproate and its crystal forms, preparation methods, pharmaceutical compositions and applications

[0001] Related applications

[0002] This application claims priority to Chinese patent application No. 2024119170120, filed on December 24, 2024, entitled "Lithium valproate and its crystal forms, preparation methods, pharmaceutical compositions and applications", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pharmaceutical technology, and in particular to lithium valproate, its crystal form, preparation method, pharmaceutical composition and application. Background Technology

[0004] Neurological disorders refer to diseases occurring in the central nervous system, peripheral nervous system, and autonomic nervous system, characterized primarily by sensory, motor, consciousness, and autonomic nervous system dysfunction. Neurological disorders can potentially lead to epilepsy, mania, schizophrenia, bipolar disorder, anxiety, depression, and agitation, resulting in impaired motor and sensory functions, cognitive and psychological disturbances, and severely impacting patients' normal lives.

[0005] Epilepsy is a chronic brain disorder characterized by recurrent seizures, triggered by abnormal electrical discharges in brain neurons. These seizures are characterized by their recurrence and brevity. Valproic acid is an antiepileptic drug that has varying degrees of antagonistic effect against seizures induced by various methods. It is effective against various types of epilepsy, including petit mal seizures, myoclonic seizures, focal seizures, grand mal seizures, and mixed epilepsy. Sodium valproate is a commonly used antiepileptic drug, currently available in both immediate-release and extended-release formulations. The dosage for adults taking extended-release sodium valproate tablets in the treatment of epilepsy or mania is initially 500 mg / day, divided into two doses, once in the morning and once in the evening, increasing to 1500 mg / day after one week, with a maintenance dose of 1000-2000 mg / day. This means that patients taking extended-release sodium valproate tablets will also ingest excessively high levels of sodium.

[0006] Depression, also known as depressive disorder, is a mental disorder with a high incidence, high clinical cure rate, but low treatment acceptance rate and high relapse rate. Its main characteristic is significant and persistent low mood. Patients may exhibit self-harm or suicidal behavior, accompanied by psychotic symptoms such as delusions and hallucinations. Drug treatment is the primary means of managing depression. Currently, the mainstream antidepressants used clinically are mainly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). These drugs generally take 2-4 weeks to become effective. Due to their slow onset of action, especially in severely depressed patients, adverse reactions often occur before the therapeutic effect appears. Patients often refuse to adhere to medication for 1-2 weeks during this period, and may even attempt suicide, which is a major clinical challenge in antidepressant treatment.

[0007] Agitation is a common acute syndrome in psychiatry, a comorbid feature of various neurological disorders including schizophrenia, anxiety, depression, dementia, and Alzheimer's disease. It can manifest as agitation in schizophrenia, psychotic agitation in patients with psychotic disorders, anxiety-induced agitation in severe anxiety, psychomotor agitation in agitated depression or bipolar disorder with depressive episodes or mixed episodes, and agitation in Alzheimer's disease. In clinical practice, agitation presents as a series of mental activities, emotions, and behaviors of varying degrees of excitement, with an inability to calm down. Patients often exhibit marked restlessness and excessive physical activity, accompanied by anxiety. In severe cases, it can manifest as impulsive excitement, threats, aggression, and self-harm. The neurobiological mechanisms of agitation are currently unclear. A summary of relevant studies suggests that abnormally increased dopamine and norepinephrine activity and decreased gamma-aminobutyric acid (GABAergic) activity in the individual brain may be potential mechanisms for agitation, while abnormal serotonergic activity may also be related to its occurrence. These neurotransmitter systems regulate and influence each other, playing a crucial role in the occurrence and development of agitation. Currently, there are no FDA-approved effective drugs for treating symptoms including schizophrenic agitation, anxiety agitation, depressive agitation, and Alzheimer's agitation. Clinicians have historically relied on the off-target effects of existing marketed anti-schizophrenic drugs, anti-anxiety drugs, and antidepressants to attempt to control agitation symptoms. The efficacy of these drugs in treating agitation is limited. Therefore, there is an urgent need to develop a class of safe and effective drugs for treating or controlling agitation to improve overall patient outcomes. Summary of the Invention

[0008] Based on this, one or more embodiments of this application provide lithium valproate and its crystal form, preparation method, pharmaceutical composition and application.

[0009] The technical solution of this application includes the following:

[0010] A lithium valproate has the following structure:

[0011] Furthermore, the lithium valproate is a lithium salt of valproic acid, wherein the chemical ratio of valproic acid to lithium is 1:1.

[0012] Furthermore, the lithium salt of the valproic acid is a crystalline salt.

[0013] A method for preparing lithium valproate includes the following steps:

[0014] The first solution is obtained by mixing valproic acid, lithium hydroxide and an aqueous solution of alcohol at 0℃~10℃;

[0015] The first solution is stirred at 20℃~40℃ for 12h~20h to obtain the second solution;

[0016] The second solution was filtered, and the solid was collected to obtain the lithium valproate.

[0017] The structure of lithium valproate is as follows:

[0018] One of the crystal forms of lithium valproate described above is selected from any one of the following groups:

[0019] (1) Crystal form I: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.710±0.2°, 7.853±0.2°, 21.674±0.2°, 19.067±0.2°, 20.070±0.2°, 23.617±0.2°, 20.445±0.2° and 15.699±0.2°;

[0020] (2) Crystal form II: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.660±0.2°, 7.503±0.2°, 18.813±0.2°, 19.522±0.2°, 20.058±0.2°, 22.453±0.2°, 22.729±0.2° and 15.093±0.2°;

[0021] (3) Crystal form III: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.703±0.2°, 7.869±0.2°, 21.636±0.2°, 23.632±0.2°, 19.080±0.2°, 20.054±0.2°, 15.713±0.2° and 27.420±0.2°;

[0022] (4) Crystal form IV: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.753±0.2°, 7.883±0.2°, 19.169±0.2°, 21.880±0.2°, 20.263±0.2°, 23.716±0.2°, 15.755±0.2° and 10.930±0.2°;

[0023] (5) Crystal form V: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.741±0.2°, 7.914±0.2°, 21.680±0.2°, 23.673±0.2°, 19.134±0.2°, 20.094±0.2°, 15.756±0.2° and 10.847±0.2°;

[0024] (6) Crystal form VI: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.784±0.2°, 7.946±0.2°, 21.743±0.2°, 19.152±0.2°, 23.707±0.2°, 20.502±0.2°, 20.150±0.2° and 21.164±0.2°; and,

[0025] (7) Crystal form VII: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.729±0.2°, 7.702±0.2°, 18.991±0.2°, 20.702±0.2°, 21.741±0.2°, 22.051±0.2°, 22.533±0.2° and 28.957±0.2°.

[0026] Furthermore, the lithium valproate crystal form has at least one of the following characteristics:

[0027] (1) The differential scanning calorimetry curve of crystal form I has an endothermic peak at 359.2±3℃;

[0028] (2) The differential scanning calorimetry curve of the crystal form II has an endothermic peak at 361.8±3℃;

[0029] (3) The differential scanning calorimetry curve of the crystal form III has an endothermic peak at 331.8±3℃;

[0030] (4) The differential scanning calorimetry curve of the crystal form V has an endothermic peak at 357.2±3℃;

[0031] (6) The differential scanning calorimetry curve of crystal form VI has an endothermic peak at 362.3±3℃; and,

[0032] (7) The differential scanning calorimetry curve of the crystal form VII has an endothermic peak at 362.2±3℃.

[0033] A method for preparing the crystal form of lithium valproate as described above includes the following steps:

[0034] Lithium valproate is crystallized using at least one of the following methods: dissolution crystallization, antisolvent crystallization, evaporation crystallization, volatilization crystallization, and melt crystallization; wherein the solvent used includes at least one of ethanol, dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, petroleum ether, butyl acetate, methyl tert-butyl ether, n-butanol, dimethyl sulfoxide, tert-butanol, isopropanol, toluene, and N,N-dimethylformamide.

[0035] A pharmaceutical composition, characterized in that the pharmaceutical composition comprises at least one of a pharmaceutically active ingredient and a pharmaceutically acceptable excipient and a carrier;

[0036] The active pharmaceutical ingredient includes lithium valproate;

[0037] The structure of lithium valproate is as follows:

[0038] The use of lithium valproate or a pharmaceutical composition as described above in the preparation of a medicament for the treatment and / or prevention of neurological diseases.

[0039] Furthermore, the neurological disorders include at least one of epilepsy, mania, schizophrenia, bipolar disorder, anxiety, depression, and agitation.

[0040] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Attached Figure Description

[0041] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0042] Figure 1 is the XPRD pattern of lithium valproate crystal form I prepared in Example 2 of this application;

[0043] Figure 2 shows the XPRD pattern of lithium valproate crystal form II prepared in Example 2 of this application;

[0044] Figure 3 shows the XPRD pattern of lithium valproate crystal form III prepared in Example 2 of this application;

[0045] Figure 4 shows the XPRD pattern of lithium valproate crystal form IV prepared in Example 2 of this application;

[0046] Figure 5 shows the XPRD pattern of the crystal form V of lithium valproate prepared in Example 2 of this application;

[0047] Figure 6 shows the XPRD pattern of crystal form VI of lithium valproate prepared in Example 2 of this application;

[0048] Figure 7 shows the XPRD pattern of lithium valproate crystal form VII prepared in Example 2 of this application;

[0049] Figure 8 shows the weight changes of mice during the establishment of the mouse depression model in Example 5 of this application (***p<0.001, compared with the normal group);

[0050] Figure 9 is a statistical graph of the resting time of the mouse depression model in Example 5 of this application (***p<0.001, compared with the normal group);

[0051] Figure 10 is a statistical graph of the open field experiment data of the mouse depression model in Example 5 of this application (***p<0.05, compared with the normal group);

[0052] Figure 11 is a statistical graph of the sugar water preference rate of the mouse depression model of Example 5 of this application under the influence of the test drug (**p<0.01, compared with the normal group);

[0053] Figure 12 is a statistical graph of the resting time of the mouse depression model in Example 5 of this application under the influence of the test drug in the tail suspension test;

[0054] Figure 13 shows the statistical results of the forced swimming behavior of the mouse depression model in Example 5 of this application under the influence of the test drug;

[0055] Figure 14 shows the statistical results of the open field behavior of the mouse depression model of Example 5 of this application under the influence of the test drug (***p<0.001, compared with the normal group);

[0056] Figure 15 shows the statistical results of the effect of lithium valproate on the movement distance of model animals in Example 6 of this application. In Figure 15, A is the distance moved by each group of mice within 10 minutes after injection of MK-801 during the experiment. A total of 120 minutes were recorded, which is a line graph of the movement distance of mice within 12 10-minute intervals. In Figure 15, B is the total movement distance of each group of mice within 120 minutes. Detailed Implementation

[0057] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0059] The term "and / or" as used herein includes any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations encompass any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," or "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B.

[0060] In this document, terms such as "preferred," "better," and "more preferred" are merely descriptions of implementation methods or examples that achieve better results, and should be understood as not constituting a limitation on the scope of protection of this application.

[0061] In this application, "further" is used to describe the purpose and indicate differences in content, but should not be construed as a limitation on the scope of protection of this application.

[0062] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0063] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, optional numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0064] Unless otherwise specified, the temperature parameters in this application are permitted to be either constant-temperature treatment or variations within a certain temperature range. It should be understood that constant-temperature treatment allows temperature fluctuations within the precision range of the instrument control. Fluctuations are permitted within ranges such as ±0.5℃, ±0.4℃, ±0.3℃, ±0.2℃, and ±0.1℃.

[0065] The room temperature in this application generally refers to 20℃~40℃.

[0066] In this application, weight can be a well-known unit of mass in the chemical industry, such as μg, mg, g, or kg.

[0067] The compounds of this application

[0068] In this application, the compound refers to lithium valproate.

[0069] The structural formula of lithium valproate is:

[0070] Valproate has crystal forms including crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI and crystal form VII.

[0071] The lithium valproate of this application has a more comprehensive therapeutic effect on nervous system diseases, with good efficacy and stability. The crystal form of the lithium valproate of this application has the advantages of being non-hygroscopic and having good stability.

[0072] crystallization

[0073] Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of a compound. This can be done in various ways, such as dissolving the compound at a relatively high temperature and then cooling the solution below its saturation limit, or by reducing the liquid volume through boiling, atmospheric evaporation, vacuum drying, or other methods. The solubility of the compound can also be reduced by adding an antisolvent, a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative method is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd Edition, JW Mullens, Butterworth Heineman Ltd. 1993, ISBN 0750611294.

[0074] Identification and properties of crystal forms

[0075] After preparing compounds with different crystal forms, this application investigated their properties using various methods and instruments.

[0076] X-ray powder diffraction (XRPD)

[0077] Methods for determining crystal form using X-ray powder diffraction (XRPD) are known in the art. XRPD can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions in an XRPD spectrum mainly depend on the structure of the crystal form. The measurement of 2θ in XRPD spectra may vary slightly between different instruments; therefore, the value of 2θ cannot be considered absolute. Based on the instruments used in the experiments of this application, the diffraction peaks exhibit an error of ±0.2°. It is understood that the range of error is not absolute for different testing instruments and testing conditions. The compound of this application has a specific crystal morphology, which manifests as specific characteristic peaks in the XRPD spectrum.

[0078] In this application, "the X-ray powder diffraction pattern has a characteristic diffraction peak at a specific 2θ angle" means that the peak value is within the indicated numerical range, the indicated numerical point, the vicinity of the indicated numerical range, or the vicinity of the indicated numerical point.

[0079] Due to variations in measuring instruments and conditions, the positions of certain peaks or peak values ​​in the actual obtained X-ray powder diffraction pattern may slightly deviate, meaning they may differ slightly from the characteristic peak combinations or X-ray powder diffraction patterns indicated in this application. However, it is understood that those skilled in the art can discern, as a whole, whether slightly different characteristic peak combinations or X-ray powder diffraction patterns substantially constitute the crystal form described in this application. Therefore, those substantially considered consistent with the crystal form of this application should be considered within the scope of protection of this application.

[0080] For example, the statement "The X-ray powder diffraction pattern shows a peak at a diffraction angle of 6.710 ± 0.2°" means that the peak value can be located within or near the range of 6.710 ± 0.2°, as long as it does not affect the overall identification of the crystal form. Furthermore, "±0.2" here only indicates the error in the position of the peak value at the diffraction angle and is unrelated to the peak shape or width.

[0081] In this application, the word "basically" in "X-ray powder diffraction pattern is basically as characterized by a specific pattern" should also be interpreted similarly. As long as it can be determined from the whole that a certain X-ray powder diffraction pattern is substantially consistent with the X-ray powder diffraction pattern described in this application, it should be considered to fall within the protection scope of this application.

[0082] It is understood that the differential scanning calorimetry curves and the positions of the endothermic peaks shown therein in this application should also be interpreted similarly. Slight discrepancies with the specific values, ranges, or spectra disclosed in this application are permissible. However, as long as it can be determined from the overall perspective that some or all of the endothermic peak positions in the differential scanning calorimetry curves, or the entire curves, are substantially consistent with this application, they should be considered to fall within the protection scope of this application.

[0083] Understandably, a similar interpretation can be made for other spectra that characterize crystal types.

[0084] Differential scanning calorimetry (DSC)

[0085] Also known as "differential calorimetry," DSC is a technique that measures the relationship between the energy difference between the analyte and a reference material and temperature during heating. The peak positions, shapes, and numbers on the DSC spectrum are related to the properties of the substance and can therefore be used qualitatively to identify it. This method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, and heat of reaction. The peak positions in DSC spectra may vary slightly between different instruments; therefore, the numerical values ​​of the peak positions of the endothermic peaks in the DSC spectrum should not be considered absolute. Depending on the instruments used in the experiments described in this application, the experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C.

[0086] Identification and properties of crystal forms

[0087] X-ray powder diffraction

[0088] The compounds of this application have specific crystal forms and specific characteristic peaks in X-ray powder diffraction (XPRD) patterns.

[0089] XPRD patterns were acquired using an X-ray powder diffractometer, and the instrument parameters are shown in Table 1.

[0090] Table 1

[0091] In X-ray powder diffraction patterns, the position of each peak is determined by 2θ (°). It is understood that different instruments and / or conditions can lead to slight variations in the generated data, resulting in changes in the position and relative intensity of each peak. The intensity division of peaks only reflects the approximate size of the peaks at each position. In this application, each crystal form uses its highest diffraction peak as the base peak, defining its relative intensity as 100%, as I0. The ratio of the peak height of each other peak to the base peak height is used as its relative intensity I / I0. The definitions of the relative intensities of each peak are shown in Table 2.

[0092] Table 2

[0093] Sodium valproate and lithium carbonate are commonly used antiepileptic drugs in clinical practice. The maintenance dose during treatment is 1000mg to 2000mg / day. Excessive dosage often leads to related adverse reactions. Furthermore, blood lithium concentration needs to be monitored when using lithium carbonate clinically, while sodium valproate is associated with high sodium intake. Magnesium valproate can be used to avoid the high sodium intake associated with sodium valproate; however, magnesium valproate has a slower onset of action and a longer duration of action.

[0094] To address the aforementioned issues, this application designs and successfully synthesizes lithium valproate, which avoids high salt intake and is more effective than lithium carbonate or sodium valproate alone at the same dosage. Furthermore, compared to sodium valproate and magnesium valproate, it has therapeutic and / or preventative effects on neurological diseases at low doses.

[0095] The lithium valproate of this application embodiment has the following structure:

[0096] In some embodiments, lithium valproate is a lithium salt of valproic acid.

[0097] In some embodiments, the chemical ratio of valproic acid to lithium is 1:1.

[0098] In some embodiments, the lithium salt of valproic acid is a crystalline salt.

[0099] One or more embodiments of this application provide a method for preparing lithium valproate, comprising the following steps:

[0100] The first solution is obtained by mixing valproic acid, lithium hydroxide and an aqueous solution of alcohol at 0℃~10℃;

[0101] The first solution is stirred at 20℃~40℃ for 12h~20h to obtain the second solution;

[0102] The second solution was filtered, and the solid was collected to obtain lithium valproate;

[0103] The structure of lithium valproate is as follows:

[0104] In some embodiments, the aqueous solution of alcohol contains an alcohol to water volume ratio of 15 to 25:1, for example 15:1, 20:1, 25:1, etc.

[0105] In some embodiments, the alcohol is selected from organic alcohols such as ethanol and methanol.

[0106] In some embodiments, the mass-to-volume ratio of valproic acid and alcohol in the aqueous solution is 8-12 g:100 mL, such as 8 g:100 mL, 9 g:100 mL, 10 g:100 mL, 11 g:100 mL, 12 g:100 mL, etc., which can ensure that valproic acid is fully dissolved.

[0107] In some embodiments, the molar ratio of valproic acid to lithium hydroxide is 2:(1 to 1.5), for example 2:1, 2:1.2, 2:1.5, etc. A slight excess of lithium valproate can ensure sufficient reaction, and valproic acid can be easily removed from the system afterward.

[0108] In some embodiments, valproic acid, lithium hydroxide, and alcohol are mixed at 0°C to 10°C to obtain a first solution, comprising:

[0109] After mixing valproic acid and an aqueous solution of alcohol, solid lithium hydroxide is added at 0℃~10℃. After the addition is complete, the mixture is stirred for a period of time to fully dissolve the solution, thus obtaining the first solution.

[0110] In some embodiments, the first solution is stirred at 20°C to 40°C for 12 to 20 hours to obtain the second solution. The first solution is stirred thoroughly at a suitable temperature to fully react and generate lithium valproate.

[0111] In some embodiments, filtering the second solution to collect the solid and obtain lithium valproate includes:

[0112] The second solution is filtered at room temperature, which is typically 20°C to 40°C.

[0113] After filtration, the solution was concentrated at 40–60°C and 10–20 bar.

[0114] After concentration, the solid was vacuum dried at 40–60 °C and below 0.09 MPa to obtain lithium valproate.

[0115] The currently disclosed crystal form of sodium valproate exhibits high hygroscopicity. High hygroscopicity may cause the drug to absorb moisture during storage, thereby reducing its chemical or physical stability and affecting its shelf life. This application develops a crystal form of lithium valproate with low hygroscopicity, ensuring a lower water content in the product and making lithium valproate more stable in quality during storage.

[0116] One or more embodiments of this application provide a crystalline form of lithium valproate, selected from any one of the following groups:

[0117] (1) Crystal form I: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.710±0.2°, 7.853±0.2°, 21.674±0.2°, 19.067±0.2°, 20.070±0.2°, 23.617±0.2°, 20.445±0.2° and 15.699±0.2°;

[0118] (2) Crystal form II: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.660±0.2°, 7.503±0.2°, 18.813±0.2°, 19.522±0.2°, 20.058±0.2°, 22.453±0.2°, 22.729±0.2° and 15.093±0.2°;

[0119] (3) Crystal form III: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.703±0.2°, 7.869±0.2°, 21.636±0.2°, 23.632±0.2°, 19.080±0.2°, 20.054±0.2°, 15.713±0.2° and 27.420±0.2°;

[0120] (4) Crystal form IV: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.753±0.2°, 7.883±0.2°, 19.169±0.2°, 21.880±0.2°, 20.263±0.2°, 23.716±0.2°, 15.755±0.2° and 10.930±0.2°;

[0121] (5) Crystal form V: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.741±0.2°, 7.914±0.2°, 21.680±0.2°, 23.673±0.2°, 19.134±0.2°, 20.094±0.2°, 15.756±0.2° and 10.847±0.2°;

[0122] (6) Crystal form VI: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.784±0.2°, 7.946±0.2°, 21.743±0.2°, 19.152±0.2°, 23.707±0.2°, 20.502±0.2°, 20.150±0.2° and 21.164±0.2°; and,

[0123] (7) Crystal form VII: Its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.729±0.2°, 7.702±0.2°, 18.991±0.2°, 20.702±0.2°, 21.741±0.2°, 22.051±0.2°, 22.533±0.2° and 28.957±0.2°.

[0124] In some embodiments, lithium valproate has a crystal form having at least one of the following characteristics:

[0125] (1) The X-ray powder diffraction pattern of crystal form I is basically shown in Figure 1;

[0126] (2) The X-ray powder diffraction pattern of crystal form II is basically shown in Figure 2;

[0127] (3) The X-ray powder diffraction pattern of crystal form III is basically shown in Figure 3;

[0128] (4) The X-ray powder diffraction pattern of crystal form IV is basically shown in Figure 4;

[0129] (5) The X-ray powder diffraction pattern of crystal form V is basically shown in Figure 5;

[0130] (6) The X-ray powder diffraction pattern of crystal form VI is basically shown in Figure 6; and,

[0131] (7) The X-ray powder diffraction pattern of crystal form VII is shown in Figure 7.

[0132] In some embodiments, lithium valproate has a crystal form having at least one of the following characteristics:

[0133] (1) The differential scanning calorimetry curve of crystal form I has an endothermic peak at 359.2±3℃;

[0134] (2) The differential scanning calorimetry curve of crystal form II has an endothermic peak at 361.8±3℃;

[0135] (3) The differential scanning calorimetry curve of crystal form III has an endothermic peak at 331.8±3℃;

[0136] (4) The differential scanning calorimetry curve of crystal form V has an endothermic peak at 357.2±3℃;

[0137] (6) The differential scanning calorimetry curve of crystal form VI has an endothermic peak at 362.3±3℃; and,

[0138] (7) The differential scanning calorimetry curve of crystal form VII has an endothermic peak at 362.2±3℃.

[0139] One or more embodiments of this application provide a method for preparing the crystal form of lithium valproate described above, comprising the following steps:

[0140] Lithium valproate is crystallized using at least one of the following methods: solution crystallization, antisolvent crystallization, evaporation crystallization, volatilization crystallization, and melt crystallization. The solvents used include at least one of ethanol, dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, petroleum ether, butyl acetate, methyl tert-butyl ether, n-butanol, dimethyl sulfoxide, tert-butanol, isopropanol, toluene, and N,N-dimethylformamide. Ethyl acetate, dichloromethane, and acetonitrile are sparingly soluble solvents; isopropanol, tert-butanol, butyl acetate, methyl tert-butyl ether, tetrahydrofuran, and toluene are slightly soluble solvents; n-butanol is a soluble solvent; and methanol, ethanol, and water are readily soluble solvents.

[0141] In this article, sparingly soluble solvents refer to solvents in which compounds do not dissolve under ultrasound or heating, forming a white turbid liquid; slightly soluble solvents refer to solvents in which compounds do not dissolve under heating or ultrasound, but are dispersed as a white dispersion system; soluble solvents refer to solvents in which compounds dissolve under ultrasound, forming a colorless and clear liquid; and readily soluble solvents refer to solvents in which compounds dissolve when mixed, forming a colorless and clear liquid.

[0142] In this paper, dissolution crystallization is the process of preparing a saturated solution of a compound in a readily soluble solvent, then adding it dropwise to another heated readily soluble solvent and mixing, followed by crystal precipitation; antisolvent crystallization is the process of mixing a compound with at least one of a sparingly soluble solvent, a soluble solvent, and a slightly soluble solvent, heating to dissolve, and then cooling to precipitate crystals; evaporation crystallization is the process of mixing and dissolving a compound with a readily soluble solvent and at least one of a sparingly soluble solvent, a soluble solvent, and a slightly soluble solvent, then concentrating the mixture to precipitate crystals; evaporation crystallization is the process of dissolving a compound in a readily soluble solvent and then evaporating to precipitate crystals; melt crystallization is the process of heating and melting a compound, followed by cooling to crystallize; in this application, the heating and melting temperature is 300°C, and the heating time is 2–24 h.

[0143] One or more embodiments of this application provide a pharmaceutical composition comprising a pharmaceutically active ingredient and at least one of pharmaceutically acceptable excipients and carriers;

[0144] The active pharmaceutical ingredient includes lithium valproate;

[0145] The structure of lithium valproate is as follows:

[0146] As used herein, a “pharmaceuticalally acceptable carrier” should, in principle, be non-toxic and inert. The form of a pharmaceutically acceptable carrier is not particularly limited, and includes, but is not limited to, solid, semi-solid, and liquid states. The pharmaceutically acceptable carrier should be compatible with the patient. The patient is preferably a mammal, more preferably a human. One function of a pharmaceutically acceptable carrier is to facilitate the delivery of an active agent to the target site without terminating the agent's activity. As used herein, the term “pharmaceuticalally acceptable carrier” includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be “pharmaceutically acceptable” in the sense of compatibility with other components in the formulation and harmlessness to the patient.

[0147] As used herein, "pharmaceuticalally acceptable excipients" include, but are not limited to, diluents, wetting agents, binders, disintegrants, lubricants, color and flavor modifiers, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH adjusters, and isotonic or isotropic modifiers. Further examples include: diluents such as starch, sucrose, cellulose, and inorganic salts; wetting agents such as water and ethanol; binders such as starch paste, dextrin, sugar, cellulose derivatives, gelatin, povidone, and polyethylene glycol; disintegrants such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium bicarboxymethyl cellulose, crospovidone, surfactants, and flaking disintegrants; lubricants such as talc, calcium stearate, magnesium stearate, magnesium dodecyl sulfate, micronized silica gel, and polyethylene glycol; and color and flavor modifiers such as pigments, fragrances, and sweeteners. Flavoring agents, adhesives, and deodorants, such as fuchsin and xylitol; solvents, such as water, oil, ethanol, glycerin, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oils, and ethyl acetate; solubilizers, such as Tween compounds, maltose compounds, polyoxyethylene fatty alcohol ethers, soaps, sulfates, and sulfonates; cosolvents, such as organic acids (e.g., citric acid) and their salts, amides and amines, inorganic salts, polyethylene glycol, povidone-iodine, and glycerin; emulsifiers, such as Span compounds, Tween compounds, maltose compounds, benzyl esters, glyceryl fatty acid esters, and high-methylene glycol. Fatty acid salts, sulfates, sulfonates, gum arabic, tragacanth gum, gelatin, pectin, phospholipids, agar, sodium alginate, hydroxides, silica, bentonite, etc.; suspending agents, such as glycerin, syrup, gum arabic, tragacanth gum, agar, sodium alginate, cellulose derivatives, povidone, carboplatin, polyvinyl alcohol, thixotropic gum, etc.; antioxidants, such as sulfites, metabisulfites, bisulfites, ascorbic acid, gallic acid and its esters, etc.; metal complexing agents, such as disodium ethylenediaminetetraacetate, polycarboxylic acid compounds, etc.; inert gases, such as... Nitrogen, carbon dioxide, etc.; preservatives, such as parabens, organic acids and their salts (e.g., sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols, and volatile oils; local analgesics, such as benzyl alcohol, chlorobutanol, lidocaine, and procaine; pH adjusters, such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, citric acid, and citrates; isotonic or isotonic regulators, such as glucose, sodium chloride, sodium citrate, sorbitol, and xylitol.It is understood that the diluent described in the embodiments of this application can also be called a filler, and it plays the same role in pharmaceutical preparations; the water described in the embodiments of this application is water that meets the requirements of pharmaceutical preparations, such as water for injection, purified water, etc., and the oil is oil for injection; the preservative described in the embodiments of this application can also be called an antibacterial agent, and it plays a role in inhibiting microbial growth and extending shelf life in the preparation; the lubricant described in the embodiments of this application contains flow aids, anti-adhesion agents, etc.; the sugar described in the embodiments of this application can be sugar powder or syrup, and the type of sugar is not limited to glucose; the fragrance described in the embodiments of this application includes, but is not limited to, flavorings.

[0148] In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the active pharmaceutical ingredient.

[0149] As used herein, "therapeutic effective amount" means the amount of the compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0150] One or more embodiments of this application provide the use of the lithium valproate or pharmaceutical composition described above in the preparation of a medicament for treating and / or preventing neurological diseases.

[0151] As used herein, “prevention and / or treatment” means to reduce, slow the progression of, attenuate, prevent, or maintain an existing disease or condition, such as a neurological disorder. Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of the disease or condition.

[0152] In some embodiments, the neurological disorder includes at least one of epilepsy, mania, schizophrenia, bipolar disorder, anxiety, depression, and agitation.

[0153] Furthermore, the agitation includes at least one of schizophrenic agitation, anxiety agitation, depressive agitation, and Alzheimer's agitation.

[0154] In some embodiments, the subjects of the drugs for treating and / or preventing neurological diseases are mammals.

[0155] As used in this article, "subject" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including animals such as cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

[0156] In some embodiments, mammals include at least one of humans and mice.

[0157] In some embodiments, the dosage forms of the medicine for treating and / or preventing neurological diseases include solid dosage forms, semi-solid dosage forms, or liquid dosage forms.

[0158] In some embodiments, the dosage forms of the medicine for treating and / or preventing neurological diseases include tablets, capsules, granules, powders, granules, pills, ointments, creams, suspensions, and solutions.

[0159] There are no particular restrictions on the manner of application of the compounds in this application.

[0160] Representative administration methods include, but are not limited to: oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, local administration, and inhalation.

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound in such compositions may be delayed in a portion of the digestive tract. Examples of encapsulating components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0162] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. For example, suspensions may contain suspending agents, specifically, for example, ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0163] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0164] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalers. They are prepared by mixing the active ingredient under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0165] It is understood that the drugs in the embodiments of this application can be prepared into suitable clinical dosage forms by adding different pharmaceutically acceptable excipients, including but not limited to the dosage forms described above.

[0166] In some implementations, the administration frequency is 1 to 3 times per day, for example, once per day, twice per day, or three times per day.

[0167] In some implementations, the dosage is 250–1000 mg / day.

[0168] In some implementations, the subjects are mice, and the dosage is 30–200 mg / kg.

[0169] In some implementations, the subject is a human, and the dosage is 4–20 mg / kg.

[0170] In some implementations, the administration method is oral.

[0171] In some embodiments, the administration method is gavage. In this application, gavage refers to dissolving the drug in a solvent (such as ultrapure water) and using a gavage device to directly inject the drug solution into the animal's stomach through the animal's mouth.

[0172] Currently, the mainstream antidepressants in clinical practice are mainly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which generally take 2-4 weeks to take effect. Due to their slow onset of action, adverse reactions often occur before the therapeutic effect appears, especially in severely depressed patients. Patients often refuse to adhere to medication for 1-2 weeks during this period, and some even attempt suicide, which is a major clinical challenge for antidepressants. The lithium valproate described in this application has a rapid onset of action, achieving therapeutic effects in 8-10 days, effectively improving patient compliance and enhancing efficacy.

[0173] The lithium valproate of this application has an ameliorative effect on the manifestations of various neurological diseases, including epilepsy, mania, schizophrenia, bipolar disorder, anxiety, depression, and agitation. Agitation is a common acute syndrome in psychiatry and is a comorbid feature of various neurological diseases, including schizophrenia, anxiety, depression, dementia, and Alzheimer's disease. Currently, there are no effective drugs for treating agitation symptoms, including schizophrenic agitation, anxiety agitation, depressive agitation, and Alzheimer's agitation. Clinically, off-target effects of existing marketed anti-schizophrenic drugs, anti-anxiety drugs, and antidepressants are often used to try to control agitation symptoms, but the efficacy is very limited. The lithium valproate of this application has a significant anti-agitation effect and can be used to prepare drugs for the treatment and / or prevention of agitation. The anti-agitation mechanism of lithium valproate of this application includes delaying the onset of hyperactivity induced by MK-801 and reducing the degree of hyperactivity induced by MK-801.

[0174] The following are some specific examples.

[0175] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0176] All or part of the raw materials involved in the following specific embodiments are shown in Table 1, and the reagents are shown in Table 2. The remaining raw materials and reagents can be obtained commercially or prepared by those skilled in the art using known methods.

[0177] Table 3

[0178] Table 4

[0179] In the following specific embodiments, the crystal form judgment criteria refer to the 2020 edition of the Chinese Pharmacopoeia 9015 Guidelines for Drug Crystal Form Research and Crystal Form Quality Control. If it is determined that the crystal form of two crystalline samples is consistent, powder X-ray diffraction tests should be performed in parallel, and the following conditions should be met: the number of diffraction peaks is the same, the position error of the 2θ diffraction peaks is within 0.2°, the relative peak intensity error of the diffraction peaks at the same position is within ±5%, and the order of the intensity of the diffraction peaks should be consistent. If it is determined that the crystal form of two amorphous samples is consistent, the geometric topological shape of the diffuse diffraction peaks should be completely consistent.

[0180] The experiments conducted in the following examples and their underlying principles are as follows:

[0181] The tail suspension test (TST) is a classic and rapid method for evaluating the efficacy of antidepressants, stimulants, and sedatives. The principle involves suspending a mouse's tail, causing it to attempt to escape but ultimately give up and enter a specific state of depressive immobility. The duration of immobility is recorded to reflect the depressive state; antidepressants and stimulants can significantly shorten or alter this state.

[0182] The open field test (OFT) is a method used to assess the behavior of laboratory animals, particularly in neuropsychiatric research. It is commonly used to measure spontaneous activity, exploratory behavior, and anxiety- and depression-like behaviors. The OFT can measure the level of spontaneous activity and exploratory behavior in animals in new environments; depressed patients often exhibit reduced activity and lack of interest.

[0183] The sucrose preference test is a classic experiment for detecting anhedonia, a typical symptom of depression. It utilizes the rodent's preference for sweet tastes to determine whether they exhibit anhedonia, a depressive symptom. After a period of fasting, animals are simultaneously given plain water and a low-concentration sucrose solution. The degree of craving for the sucrose solution (sucrose preference) is used as an indicator to detect whether the animal exhibits anhedonia.

[0184] The mice used in the following examples are C57BL / 6j mice. This species is commonly used for efficacy studies of test products intended for human use, and is widely used in pharmacological, pharmacodynamic, and disease model exploration. Regarding sex, considering that changes in sex hormones in female mice can significantly affect behavior and neurochemical indicators, male C57BL / 6j mice are recommended.

[0185] The term (+)-MK-801 is a highly effective, selective, and strongly inhibitory non-competitive NMDA receptor antagonist that can mimic the typical positive, negative, and cognitive impairment symptoms of schizophrenia, and is considered one of the best schizophrenia modeling drugs.

[0186] Example 1: Preparation of Lithium Valproate

[0187] 1.1 Synthetic Route

[0188] 1.2 Preparation method

[0189] (1) Prepare a 1L three-necked flask, add valproic acid (28.8g, 2mol) and ethanol / purified water (273.6mL / 14.4mL), cool the system to 0℃~10℃, add lithium hydroxide solid (5.7g, 2.4mol, 1.2 equivalents) to the system, mix well and stir overnight at room temperature (20℃~30℃) for about 18 hours;

[0190] (2) Filtration at room temperature, concentration of the filtrate at 50°C and 14 bar, and vacuum drying at 50°C and below 0.09 MPa to obtain lithium valproate powder.

[0191] 1.3 Characterization Results

[0192] HRMS data: [M+H] + Calculated value = 151.1305; [M+H] + Actual value = 151.1306;

[0193] Hydrogen spectrum data: 1 H NMR (CD3OD, 400MHz): δ2.19(1H,m),1.59~1.48(2H,m),1.42–1.25(6H,m),0.90(6H,t,J=7.2Hz);

[0194] Carbon spectrum data: 13 C NMR (CD3OD, 101MHz): δ185.3, 50.2, 36.9, 22.0, 14.5.

[0195] Example 2: Preparation of the crystal form of lithium valproate

[0196] 2.1 Crystal form I

[0197] (1) Take crude lithium valproate (1.0 g, 6.7 mmol) into a round-bottom flask of appropriate size, add tetrahydrofuran (30 mL), and react overnight at reflux temperature.

[0198] (2) Filter while hot and wash the filter cake with tetrahydrofuran (10 mL). Dry under vacuum at 100 °C and less than 0.09 MPa for 18 hours.

[0199] 2.2 Crystal Form II

[0200] (1) Take a round-bottom flask of appropriate size, add acetonitrile (100mL), heat to 60℃ and keep warm; add 10mL of saturated aqueous solution of lithium valproate (3.6g, 24mmol) to the above hot acetonitrile, stir for 20min after the addition is complete, turn off the heating and stir overnight at room temperature.

[0201] (2) Filter at room temperature, wash the filter cake with a small amount of acetonitrile, and vacuum dry for 7 hours at 50°C and less than 0.09 MPa.

[0202] 2.3 Crystal Form III

[0203] (1) Take a round-bottom flask of appropriate size, add solvent II (100mL / 150mL, 100V / 150V), heat to 60℃, and dropwise add saturated solution I (2.8V / 10V) of crude lithium valproate (3.6g / 3.0g / 1.5g, 24mmol / 20mmol / 10mmol, 1.0 equivalent) into solvent II. After the addition is complete, stir for 20min, turn off the heating, and stir overnight at room temperature.

[0204] (2) Filter at room temperature, wash the filter cake with a small amount of solvent II, and vacuum dry it for 7 hours at 50℃ / <0.09MPa. Then take a sample and send it for testing.

[0205] 2.4 Crystal form IV

[0206] (1) Take crude lithium valproate (1.0 g, 6.7 mmol) into a round-bottom flask of appropriate size, add ethyl acetate (100 mL) and ethanol (20 mL), dissolve by sonication, filter at room temperature, concentrate to a total solvent volume of 24 mL-36 mL at a suitable temperature, and crystallize overnight at room temperature.

[0207] (2) Filter at room temperature and wash the filter cake with ethyl acetate (5 mL). Dry under vacuum at 100 °C and less than 0.09 MPa for 18 hours.

[0208] 2.5 Crystal Form V

[0209] (1) Preparation of crude lithium valproate solution: Take a 40mL sample bottle, add 200mg of crude lithium valproate, and dissolve it with 2mL of methanol under ultrasonic conditions. Filter through cotton to obtain a clear 100mg / mL crude lithium valproate methanol solution for later use.

[0210] (2) Take 1.5 mL of EP tube, add 15-25 mg of crude lithium valproate solution to each EP tube, and add an equal volume of petroleum ether. The partially crystallized system is dissolved under ultrasonic conditions. The EP tube cap is slightly open and stored at room temperature in the dark. The solvent evaporation is observed and recorded every day until the solvent is completely evaporated. Vacuum drying is carried out at 100℃ / <0.09 MPa.

[0211] 2.6 Crystal form VI

[0212] Crude lithium valproate was placed in a muffle furnace and baked at 300°C for 2 hours, then cooled.

[0213] 2.7 Crystal form VII

[0214] (1) Take a round-bottom flask of appropriate size, add tetrahydrofuran (100mL), heat to 60℃, add 10mL of saturated aqueous solution of crude lithium valproate (3.6g, 24mmol) to the tetrahydrofuran, stir for 20min after the addition is complete, turn off the heating and stir overnight at room temperature.

[0215] (2) Filter at room temperature, wash the filter cake with a small amount of tetrahydrofuran, and vacuum dry at 50℃ / <0.09MPa for 7 hours. Take a sample and send it for testing.

[0216] 2.8 Summary of Crystal Forms

[0217] Table 5 Summary of Crystal Forms

[0218] Example 3: Hygroscopicity of Lithium Valproate with Different Crystal Forms

[0219] 3.1 Reagents and Equipment

[0220] Drug testing information is shown in Table 6, and equipment information is shown in Table 7.

[0221] Table 6

[0222] In Table 6, the hygroscopicity curve of crystal form VI was examined after melting at 300°C in a muffle furnace for 2 hours.

[0223] Table 7

[0224] 3.2 Examination Methods

[0225] The determination should be performed according to the guidelines for drug hygroscopicity testing (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 9103), including the following steps:

[0226] (1) Take a dry stoppered glass weighing bottle and place it in a suitable constant temperature desiccator (select the saturated aqueous solution according to different humidity) or artificial climate chamber (temperature is 25℃±1℃, set a series of humidity) for pre-saturation one day before the test, and accurately weigh it (m1).

[0227] (2) Accurately take an appropriate amount of the test sample and spread it evenly in the weighing bottle above. The thickness of the test sample is about 1 mm. Accurately weigh (m2).

[0228] (3) Leave the weighing bottle open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours. Accurately weigh (m3).

[0229] (4) Calculation formula:

[0230] (5) Description of hygroscopic characteristics and definition of hygroscopic weight gain:

[0231] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0232] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0233] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0234] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0235] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0236] 3.3 Observation Results

[0237] Table 8 Results of Hygroscopic Curve Examination

[0238] Based on the statistical data in Table 8, analysis reveals that lithium valproate in all crystal forms is less hygroscopic and more stable than sodium valproate. Lithium valproate crystal forms I, III, IV, and V are hygroscopic, while crystal form VI is non-hygroscopic. Crystal form VI is the most stable crystal form.

[0239] Example 4: Application of lithium valproate in the preparation of antiepileptic drugs

[0240] This embodiment provides the application of lithium valproate of this application in the preparation of antiepileptic drugs, which is verified through an exploratory experiment using an acute pentylenetetrazol epilepsy ignition model. The reagents used in this embodiment were prepared under sterile conditions.

[0241] 4.1 Experimental Materials

[0242] (1) Drug testing

[0243] An exploratory experiment was conducted on an acute pentylenetetrazol epilepsy ignition model using lithium valproate prepared in Example 1.

[0244] Ultrapure water was used as the solvent for preparation. Taking the preparation of 2 mL of test sample as an example, the preparation parameters are shown in Table 9.

[0245] Table 9

[0246] Positive control 1: Sodium valproate (Shanghai Aladdin Biochemical Technology Co., Ltd., white solid powder, 500g / bottle)

[0247] Preparation of positive control 1: Ultrapure water was used as the solvent for preparation. Taking the preparation of 2 mL of test sample as an example, the preparation parameters are shown in Table 10.

[0248] Table 10

[0249] Positive control 2: Lithium carbonate (Shanghai Jizhi Biochemical Technology Co., Ltd.; white solid powder; 25g / bottle)

[0250] Preparation of positive control 2: Ultrapure water was used as the solvent for preparation. Taking the preparation of 2 mL of test sample as an example, the preparation parameters are shown in Table 11.

[0251] Table 11

[0252] (2) Reagents

[0253] Modeling reagent: Pentylenetetrazole (Sigma-Aldrich (Shanghai) Trading Co., Ltd., white powder)

[0254] Preparation of modeling reagents: Use physiological saline to prepare the reagents. For example, prepare 15 mL of solution. The preparation parameters are shown in Table 12.

[0255] Table 12

[0256] Other main reagents:

[0257] Sodium chloride injection (Shandong Qidu Pharmaceutical Co., Ltd., 0.9g / 100mL, batch number G124040605)

[0258] (3) Equipment

[0259] Electronic analytical balance: Manufacturer METTLLER TOLEDO, model ML2001.

[0260] 4.2 Selection of experimental animals

[0261] SPF-grade C57BL / 6j mice were selected and provided by Chengdu Yaokang Biotechnology Co., Ltd.

[0262] 4.3 Animal modeling and grouping

[0263] Modeling time: 1 hour after administration of the test sample;

[0264] Model animals: All groups of animals;

[0265] Modeling method: One hour after oral administration of the test sample, pentylenetetrazol (60 mg / kg, 10 mL / kg) was injected intraperitoneally.

[0266] Group design: model control group, sodium valproate group, lithium carbonate group, lithium valproate group;

[0267] Number of animals: 48 in total, 12 in each group;

[0268] Sex ratio: All males;

[0269] Grouping method: Random numbers were assigned to mice based on their body weight. The random numbers were then sorted in descending order and designated as groups 1, 2, 3, and 4 from lowest to highest random number. These groups represent the model control group, the lithium valproate sodium group, the lithium carbonate group, and the lithium valproate group, respectively. Specific grouping information is shown in Table 13.

[0270] Table 13

[0271] In Table 13, the first digit of the animal number represents the group (1, 2, 3, 4 represent the model control group, sodium valproate group, lithium carbonate group, and lithium valproate group, respectively). The second letter represents the sex (M for male), and the last three digits represent the animal serial number, with "-" indicating that it is not applicable.

[0272] For dosage, concentration, and volume, please refer to Table 13;

[0273] Dosage frequency and cycle: once daily;

[0274] The day of administration is defined as day 1 of the trial (D1).

[0275] 4.4 Animal condition monitoring

[0276] (1) General condition observation

[0277] Observation period: once a day;

[0278] Animals observed: All surviving animals enrolled in the group;

[0279] Observation content: The main observation content includes, but is not limited to, the administration site (whether there are symptoms such as redness, swelling, or bleeding), behavioral status, and symptoms of the eyes, mouth, nose and mouth, ears, hair, feces, urine, and genitals.

[0280] (2)Weight

[0281] Measurement time: Weigh at least twice during the adaptation period, and weigh once before administration;

[0282] Animals tested: all animals during the adaptation period and all animals enrolled during the experimental period.

[0283] (3) Epilepsy Score

[0284] Animals tested: All groups of animals;

[0285] Testing time: Testing should be conducted immediately after model creation;

[0286] Detection method: Mice were immediately placed in a transparent glass cylinder after being injected with pentylenetetrazol. Their behavior was observed and recorded for 30 minutes, and the video was recorded. The epileptic seizure latency, number of seizures within 30 minutes, total seizure duration within 30 minutes, highest Racine grade of seizure, and Racine epilepsy grading criteria are recorded as shown in Table 14.

[0287] Table 14

[0288] 4.5 Experimental Results

[0289] (1) General condition observation

[0290] During the experiment, none of the animals showed any obvious abnormalities.

[0291] (2)Weight

[0292] The weight data of the mice are shown in Table 15. Throughout the experimental period, the weight of mice in each group increased steadily, with a consistent growth trend and no significant differences.

[0293] Table 15 Animal weight data

[0294] The data in Table 15 are expressed as mean ± standard deviation (SD).

[0295] (3) Seizures

[0296] A single high-dose administration of pentylenetetrazol induces acute epileptic seizures in animals. In this experiment, all mice injected with pentylenetetrazol experienced grade 5 seizures, with a seizure rate of 100%. Therefore, the antiepileptic effects of each drug can be demonstrated by statistically analyzing the latency of grade 5 seizures in each group of mice. The latency of grade 5 seizures in mice is shown in Table 16. According to Table 16, after pentylenetetrazol injection, the latency of grade 5 seizures in each group of mice was 123.0±25.5s for the model control group, 178.6±73.0s for the sodium valproate group, 142.5±40.7s for the lithium carbonate group, and 255.6±190.3s for the lithium valproate group. Among them, sodium valproate prolonged the average latency of grade 5 seizures in mice by about 50s, lithium carbonate prolonged the average latency of grade 5 seizures in mice by about 20s, and lithium valproate prolonged the average latency of grade 5 seizures in mice by about 130s.

[0297] The results above show that lithium valproate can significantly delay grade 5 epileptic seizures induced by pentylenetetrazol, and at the same dose, its effect is better than that of sodium valproate and lithium carbonate.

[0298] Table 16 Latent period of epileptic seizures

[0299] The data in Table 16 are expressed as mean ± standard deviation (SD).

[0300] Example 5: Study on the rapid antidepressant effect of lithium valproate

[0301] 5.1 Selection of laboratory animals

[0302] Forty-two male SPF-grade C57BL / 6J mice (7 weeks old) were used. (Manufacturer: Zhejiang Vital River Laboratory Animal Technology Co., Ltd., License No.: SCXK(Su)2023-0009). Housing conditions: standard feed, temperature 20–26℃, humidity 40%–70%.

[0303] Animals are treated with the best interests of the animal during transportation, feeding, modeling, and euthanasia. Stress, pain, and harm are prevented or minimized. Animal life is respected, and barbaric acts against animals are prohibited. Animals are disposed of using methods that cause the least pain. Animal experimental methods and purposes comply with human ethical standards and international practices.

[0304] 5.2 Experimental Materials

[0305] (1) Experimental reagents and instruments are listed in Tables 17-18.

[0306] Table 17 Reagent Information

[0307] Table 18 Main Instrument Information

[0308] (2) Reagent preparation method

[0309] Preparation of 0.1 mg / ml corticosterone drinking water: Weigh 420 mg corticosterone and add 42 ml anhydrous ethanol. Stir magnetically at 1000 r / min until dissolved, then add 4158 ml pure water. Use in the dark.

[0310] Preparation of fluoxetine (10mg / kg, 10ml / kg, 1mg / ml): Add 125mg CMC-Na to 25ml of pure water and stir magnetically until dissolved. Then add 25mg fluoxetine and stir magnetically until dissolved (2000r / min).

[0311] Low, medium, and high dose groups were prepared using lithium valproate powder prepared in Example 1.

[0312] Preparation of low doses (45.5 mg / kg, 10 ml / kg, 4.55 mg / ml): Weigh 53.9 mg of lithium valproate and add it to 11.84 ml of pure water, and dissolve it completely.

[0313] Preparation of medium doses (90.1 mg / kg, 10 ml / kg, 9.01 mg / ml): Weigh 98.6 mg of lithium valproate and add it to 10.94 ml of pure water, and dissolve it completely.

[0314] Preparation of high doses (135.2 mg / kg, 10 ml / kg, 13.52 mg / ml): Weigh 142.4 mg of lithium valproate and add it to 10.53 ml of pure water, and dissolve it completely.

[0315] 5.3 Animal modeling and grouping

[0316] (1) Grouping of animals

[0317] Normal control group (no intervention) (N=8)

[0318] Model + solvent group (test substance treated with solvent, administered by gavage, once a day for 12 consecutive days) (N=6 animals)

[0319] Model + positive drug group (fluoxetine treatment, dose: 10 mg / kg, administered by gavage, once a day for 12 consecutive days) (N = 7 animals)

[0320] Model + Low-dose - Test drug group (treatment with test compound, dose: 45.5 mg / kg, administered by gavage, once / animal / day, for 12 consecutive days) (N = 7 animals)

[0321] Model group + medium-dose test drug group (treatment with test compound, dose: 90.1 mg / kg, administered by gavage, once a day for 12 consecutive days) (N = 7 animals)

[0322] Model group + high-dose test drug group (treatment with test compound, dose: 135.2 mg / kg, administered by gavage, once a day for 12 consecutive days) (N = 7 animals)

[0323] (2) Animal modeling

[0324] After acclimatization, all animals were weighed. The normal control group was not stimulated and was given normal drinking water. Except for the normal control group, all mice were housed in individual cages and were given 0.1 mg / ml corticosterone in drinking water and chronic unpredictable mild stimulation. The specific time schedule is shown in Tables 3 and 4. Model validation was carried out starting on the 27th day after modeling, including tail suspension test, forced swimming test and open field test.

[0325] 5.4 Animal Experiments

[0326] After successful model establishment, the animals were divided into groups according to section 5.3 for treatment. Except for the blank control group, which received no intervention, the other groups were treated with the corresponding drugs (solvent, positive control drug, low, medium, and high doses of the test drug) by gavage, once a day for 12 consecutive days, while maintaining the model intervention during the treatment period. Behavioral experiments were conducted 24 hours after the 10th treatment, including the tail suspension test, open field test, sucrose preference test, and forced swimming test.

[0327] (1) Tail suspension test

[0328] On day 27 of modeling and day 9 of treatment, the tail suspension experiment was performed. A 3cm long wooden stick was tied to the base of the tail to prevent the animal from climbing on its tail and to fix the tip of the tail, so that the mouse was suspended upside down for 6 minutes. The resting time of each mouse in the last 4 minutes was recorded. The resting time refers to the duration during which the animal stopped struggling and all four limbs remained still.

[0329] (2) Forced swimming

[0330] Forced swimming experiments were conducted on day 28 of modeling and day 15 of treatment. Animals were placed individually in plastic baskets filled with water (30cm long, 20cm wide, 15cm high, 10cm deep) and forced to swim for 6 minutes. The KEMaze animal behavior video analysis software system was used to automatically record and analyze the mice's activity over 6 minutes, and to calculate the cumulative immobility time (immobility meaning the mouse stopped struggling or floated, with slight movements of the limbs to keep the head above water). The water was changed after each animal test to remove the influence of odors from other mice.

[0331] (3) Open field test

[0332] Open field experiments were conducted on modeling day 30 and treatment day 10. Animals were placed in the central area of ​​the open field box and allowed to move freely in the experimental box for 1 minute to adapt. The KEMaze animal behavior video analysis software system was used to automatically record and analyze the activity status and movement trajectory of the mice within 5 minutes. The open field box was cleaned before each experiment to avoid the residual information of the animals (such as the animals' feces, odor) affecting the results of the next test.

[0333] (4) Sugar water preference test

[0334] A saccharide preference test was conducted from day 10 to day 13 of treatment. On day 10, all animals began saccharide preference training and were given two bottles of 3% saccharide solution (100ml / bottle). On day 11, all animals were given one bottle of 3% saccharide solution and one bottle of pure water (100ml / bottle), and the positions of the bottles were switched at approximately 11:00, 14:00, and 18:00. On day 12, all animals began fasting and abstaining from water for 24 hours. On day 13, after the fasting and water abstaining period ended, the saccharide preference test officially began. All animals were given one bottle of 3% saccharide solution and one bottle of pure water (100ml / bottle), and the initial weights of the two types of bottles were recorded. The positions of the bottles were switched at 17:30, 9:00 the next day, and 12:00 the next day. After 24 hours, the saccharide test ended, and the remaining weights of the two types of bottles were weighed and recorded. The saccharide preference index was calculated.

[0335] 5.5 Experimental Results

[0336] 5.5.1 Evaluation of the mouse model of depression

[0337] (1) Changes in body weight during modeling

[0338] Figure 8 shows the weight changes of mice during the establishment of the mouse depression model in Example 5. As can be seen from Figure 8, the weight of the model group was significantly lower than that of the normal group.

[0339] (2) Tail suspension behavior experiment in depressed mice

[0340] Figure 9 shows the statistical graph of the resting time in the tail suspension test of the mouse depression model in Example 5 (***p<0.001, compared with the normal group). In the tail suspension test, the total resting time of the model group was significantly higher than that of the normal group (P<0.001).

[0341] (3) Open field behavior experiment of depressed mice

[0342] Figure 10 is a statistical graph of the open field experiment data of the mouse depression model in Example 5. In the open field experiment, the total distance and average speed of the model group were significantly reduced (P<0.001), while the time spent at rest was significantly increased (P<0.001).

[0343] Based on the results of the above-mentioned weight, tail suspension, and open field experiments, it can be concluded that the model was successfully established.

[0344] 5.6.2 Evaluation of the efficacy of the test drug

[0345] (1) Effects of the test drug on sucrose preference behavior in depressed mice

[0346] Figure 11 shows the statistical graph of sucrose preference rate in the mouse depression model of Example 5 under the influence of the test drug. In the sucrose preference test, compared with the control group, the sucrose preference rate of the model group mice decreased significantly (P<0.01), with a decrease rate of 15.6%, indicating loss of pleasure. The positive drug and low-dose test drug groups had no significant effect on sucrose preference. The medium- and high-dose test drug groups showed a significant increase in sucrose preference after treatment. The sucrose preference rate of the medium-dose group increased by 8.2% compared with the model group, and that of the high-dose group increased by 10.1%, suggesting that the medium- and high-dose groups increased the pleasure experience and alleviated the depressive symptoms.

[0347] (2) Effects of the test drug on the behavioral behavior of the tail suspension test in depressed mice

[0348] Figure 12 shows the statistical graph of the quiescent time in the tail suspension test of the mouse depression model in Example 5 under the influence of the test drug. In the tail suspension test, the total quiescent time of the model group was higher than that of the normal group, increasing by 43.4%. Due to abnormalities in individual mice, the differences within the groups were large but not statistically significant. The average quiescent time of the positive drug group and the high-dose test drug group was lower than that of the model group. The quiescent time of the positive drug group decreased by 9.2%, and the quiescent time of the high-dose test drug group decreased by 18.5%, indicating that the test drug can shorten the "quiescent state" and its effect is stronger than that of the positive drug group.

[0349] (3) Effects of the test drug on the forced swimming behavior of depressed mice

[0350] Figure 13 shows the effect of the test drug on the forced swimming behavior in the mouse depression model of Example 5. In forced swimming, compared with the model group, the resting time in the positive drug group was significantly reduced, with a reduction rate of 9.5%. The resting time in the low, medium and high dose groups was also significantly reduced, with reduction rates of 4.2%, 11.2% and 15.8%, respectively, suggesting that the treatment effect of the medium and high dose groups is better than that of the positive drug group.

[0351] Figure 14 shows the effects of the test drug on open field behavior in the mouse depression model of Example 5. In the open field test, the total distance traveled and the average speed in the model group were significantly reduced (P<0.001), while the time spent standing still was significantly increased (P<0.001). However, the positive control drug and the test drug had no significant effect on the depressed mice. The open field test is an important experiment for assessing anxiety and exploratory behavior. The efficacy of the positive control drug and the test drug is mainly reflected in their antidepressant effects, and the dosages for anxiety and depression are different. The dosage used in this experiment was calculated based on the clinical dosage for treating depression, therefore it had no significant effect on the various indicators of the open field test.

[0352] The behavioral results after treatment showed that the test drug improved the depressive behavior of mice, reduced the resting time of tail suspension and forced swimming, and increased the sugar water preference rate. Moreover, the high dose of the test drug was significantly more effective than the positive control drug.

[0353] In summary, the lithium valproate of this application has a better antidepressant effect than the positive control drug, and it also has a rapid antidepressant effect.

[0354] Example 6: Anti-excitation experiment induced by lithium valproate on MK801

[0355] 6.1 Experimental Materials

[0356] (1) Drug testing

[0357] The lithium valproate prepared in Example 1 was used to conduct MK801-induced anti-excitation experiments.

[0358] Ultrapure water was used as the solvent for preparation. Taking the preparation of 2 mL of test sample as an example, the preparation parameters are shown in Table 19.

[0359] Table 19

[0360] (2) Reagents

[0361] Modeling reagent: (+)-MK-801 maleate (MK801) (Sigma-Aldrich (Shanghai) Trading Co., Ltd., white powder) Preparation of modeling reagent: Use physiological saline to prepare. For example, to prepare 10 mL of solution, refer to Table 20 for preparation parameters.

[0362] Table 20

[0363] Other main reagents:

[0364] Sodium chloride injection (Shandong Qidu Pharmaceutical Co., Ltd., 0.9g / 100mL, batch number G124040605)

[0365] (3) Equipment

[0366] See Table 21 for equipment information.

[0367] Table 21

[0368] 6.2 Selection of Laboratory Animals

[0369] SPF-grade C57BL / 6j mice were selected and provided by Chengdu Yaokang Biotechnology Co., Ltd.

[0370] 6.3 Animal modeling and grouping

[0371] Modeling time: 1 hour after administration of the test sample;

[0372] Model mice: model group, low-dose group, medium-dose group, high-dose group;

[0373] Modeling method: Four mice were used as a batch (one each in the model group, low-dose group, medium-dose group, and high-dose group). One hour after gavage administration of the test product, MK-801 (0.3 mg / kg, 10 mL / kg) was injected intraperitoneally. After injection, the mice were placed directly in an open field for open field testing. Video recording was performed, and the spontaneous activity of the mice within 2 hours was observed and recorded. After all model mice were tested, normal control mice were then tested.

[0374] Group design: normal control group, model control group, low-dose group, medium-dose group, and high-dose group;

[0375] Number of animals: 30 in total, 6 in each group;

[0376] Sex ratio: All males;

[0377] Grouping method: Random numbers were assigned to mice based on their body weight. The random numbers were then sorted in descending order and designated as groups 1, 2, 3, 4, and 5 from lowest to highest random number. These groups represent the normal control group, the model control group, and the three test drug dosage groups, respectively. Specific grouping information is shown in Table 22.

[0378] Table 22

[0379] In Table 22, the first digit of the animal number represents the group (1, 2, 3, 4, and 5 represent the normal control group, model control group, low-dose group, medium-dose group, and high-dose group, respectively). The second letter represents the sex (M for male), and the last three digits represent the animal serial number, with "-" indicating that it is not applicable.

[0380] For dosage, concentration, and volume, please refer to Table 23;

[0381] Dosage frequency and cycle: once daily;

[0382] The day of administration is defined as day 1 of the trial (D1).

[0383] 6.4 Animal condition monitoring

[0384] (1) General condition observation

[0385] Observation period: once a day;

[0386] Animals observed: All surviving animals enrolled in the group;

[0387] Observation content: The main observation content includes, but is not limited to, the administration site (whether there are symptoms such as redness, swelling, or bleeding), behavioral status, and symptoms of the eyes, mouth, nose and mouth, ears, hair, feces, urine, and genitals. If any abnormalities are found, they should be described in detail.

[0388] (2)Weight

[0389] Measurement time: Weigh at least twice during the adaptation period, and weigh once before administration;

[0390] Animals tested: all animals during the adaptation period and all animals enrolled during the experimental period.

[0391] (3) Open field test

[0392] Animals tested: All groups of animals;

[0393] Testing time: Testing should be conducted immediately after model creation;

[0394] Testing Method: The experiment was conducted in a quiet environment. Mice moved within an open-field box, the bottom of which was divided into a central area and an outer area. A camera was mounted on the top of the central area and connected to a recording system. At the start of the experiment, mice were placed in the central area, and their movement trajectories and spontaneous activities were recorded over two hours. After each batch of mice was recorded, feces and urine were removed, and the bottom and sides of the plastic box were thoroughly cleaned with benzalkonium chloride solution. The box was then ventilated and dried before the next batch of animals was tested to prevent odor interference.

[0395] 6.5 Experimental Results

[0396] (1) General condition observation

[0397] During the experiment, none of the animals showed any obvious abnormalities.

[0398] (2)Weight

[0399] The weight data of the mice are shown in Table 25. Throughout the experimental period, the mice in each group showed a stable increase with a consistent growth trend and no significant differences. The results indicate that the administration of lithium valproate by gavage had no significant effect on the weight of the mice.

[0400] Table 23 Animal weight data

[0401] The data in Table 23 are expressed as mean ± standard deviation (SD).

[0402] (3) Spontaneous activities in open spaces

[0403] Following a single dose of MK-801, animals exhibited hyperactivity, mimicking the positive symptoms of agitation in schizophrenia. The effect lasted for approximately 2 hours. Therefore, open field analysis was used to measure the distance mice moved within 2 hours after MK-801 injection to reflect the degree of hyperactivity. The movement distance of the mice is shown in Figure 15. Figure 15 presents the statistical results of the effect of lithium valproate on the movement distance of the model animals in Example 5. In Figure 15, A represents the distance moved by each group of mice within 10 minutes after MK-801 injection, recorded for a total of 120 minutes (12 10-minute intervals). Figure 15 B represents the total movement distance of each group of mice within 120 minutes. All data in Figure 15 are expressed as mean ± standard error (SEM).

[0404] According to Figure 15, within 10 minutes after injection of MK-801, the model group mice exhibited hyperactivity, with a movement distance greater than the normal control group; the hyperactivity peaked around 50-80 minutes after injection; after 80 minutes, the efficacy of MK-801 gradually decreased, and the movement distance of the model group mice also gradually decreased; the total movement distance of the model group mice within two hours after modeling was significantly increased compared with the normal control mice. Mice in all lithium valproate groups did not exhibit hyperactivity within 20 minutes after injection of MK-801, and their movement distance was similar to that of the normal control group. Hyperactivity gradually appeared only after 20 minutes of MK-801 injection, with movement distances lower than the model group every 10 minutes. 80 minutes after MK-801 injection, as the efficacy of MK-801 gradually decreased, the movement distances of the medium- and high-dose lithium valproate groups gradually approached and eventually equalized those of the model group, while the low-dose lithium valproate group consistently had lower movement distances than the model group every 10 minutes during the testing period. The total distance of movement of mice in each lithium valproate dose group within two hours after modeling was reduced to some extent compared with the model control mice, but the total distance of movement was similar among the dose groups.

[0405] The results above show that lithium valproate can delay the onset of hyperactivity caused by MK-801 to a certain extent, reduce the degree of hyperactivity by about 20%, and the efficacy is not significantly dose-dependent.

[0406] All references to this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the purpose and / or technical solution of this application, all cited references are incorporated herein by reference in their entirety and for all purposes. When references are cited in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. Examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0407] The technical features of the above embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0408] The above embodiments merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A lithium valproate, having the following structure:

2. The lithium valproate according to claim 1, characterized in that, The lithium valproate is a lithium salt of valproic acid, wherein the chemical ratio of valproic acid to lithium is 1:

1.

3. The lithium valproate according to claim 2, characterized in that, The lithium salt of the valproic acid is a crystalline salt.

4. A method for preparing lithium valproate, comprising the following steps: The first solution is obtained by mixing valproic acid, lithium hydroxide and an aqueous solution of alcohol at 0℃~10℃; The first solution is stirred at 20℃~40℃ for 12h~20h to obtain the second solution; The second solution was filtered, and the solid was collected to obtain the lithium valproate. The structure of the lithium valproate is as follows:

5. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form I, and its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.710±0.2°, 7.853±0.2°, 21.674±0.2°, 19.067±0.2°, 20.070±0.2°, 23.617±0.2°, 20.445±0.2° and 15.699±0.2°.

6. The crystalline form of lithium valproate of claim 5, characterized in that, The differential scanning calorimetry curve of crystal form I has an endothermic peak at 359.2±3℃.

7. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form II: its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°) angles: 6.660±0.2°, 7.503±0.2°, 18.813±0.2°, 19.522±0.2°, 20.058±0.2°, 22.453±0.2°, 22.729±0.2° and 15.093±0.2°.

8. The crystalline form of lithium valproate according to claim 7, characterized in that, The differential scanning calorimetry curve of crystal form II has an endothermic peak at 361.8±3℃.

9. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form III: its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°) angles: 6.703±0.2°, 7.869±0.2°, 21.636±0.2°, 23.632±0.2°, 19.080±0.2°, 20.054±0.2°, 15.713±0.2° and 27.420±0.2°.

10. The crystalline form of lithium valproate of claim 9, characterized in that, The differential scanning calorimetry curve of crystal form III has an endothermic peak at 331.8±3℃.

11. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form IV, and its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°): 6.753±0.2°, 7.883±0.2°, 19.169±0.2°, 21.880±0.2°, 20.263±0.2°, 23.716±0.2°, 15.755±0.2° and 10.930±0.2°.

12. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form V: its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°) angles: 6.741±0.2°, 7.914±0.2°, 21.680±0.2°, 23.673±0.2°, 19.134±0.2°, 20.094±0.2°, 15.756±0.2° and 10.847±0.2°.

13. The crystalline form of lithium valproate of claim 12, characterized in that, The differential scanning calorimetry curve of the crystal form V has an endothermic peak at 357.2±3℃.

14. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form VI: its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°) angles: 6.784±0.2°, 7.946±0.2°, 21.743±0.2°, 19.152±0.2°, 23.707±0.2°, 20.502±0.2°, 20.150±0.2° and 21.164±0.2°.

15. The crystalline form of lithium valproate of claim 14, characterized in that, The differential scanning calorimetry curve of crystal form VI has an endothermic peak at 362.3±3℃.

16. A crystalline form of lithium valproate according to any one of claims 1 to 3, characterized in that, The crystal form is crystal form VII: its X-ray powder diffraction pattern includes the following characteristic diffraction peaks at 2θ (°) angles: 6.729±0.2°, 7.702±0.2°, 18.991±0.2°, 20.702±0.2°, 21.741±0.2°, 22.051±0.2°, 22.533±0.2° and 28.957±0.2°.

17. The crystalline form of lithium valproate of claim 16, characterized in that, The differential scanning calorimetry curve of crystal form VII has an endothermic peak at 362.2±3℃.

18. A process for preparing the crystalline form of lithium valproate as described in any one of claims 5 to 17, characterized in that, Includes the following steps: Lithium valproate is crystallized using at least one of the following methods: dissolution crystallization, antisolvent crystallization, evaporation crystallization, volatilization crystallization, and melt crystallization; wherein the solvent used includes at least one of ethanol, dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, petroleum ether, butyl acetate, methyl tert-butyl ether, n-butanol, dimethyl sulfoxide, tert-butanol, isopropanol, toluene, and N,N-dimethylformamide.

19. A pharmaceutical composition comprising, The pharmaceutical composition includes at least one of a pharmaceutically acceptable excipient and a carrier; The active pharmaceutical ingredient includes lithium valproate; The structure of the lithium valproate is as follows:

20. The use of lithium valproate according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or preventing nervous system diseases.

21. The use of claim 20, wherein, The neurological disorders include at least one of epilepsy, mania, schizophrenia, bipolar disorder, anxiety, depression, and agitation.

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