CN112972449B

CN112972449B - Pharmaceutical composition with high safety and preparation method thereof

Info

Publication number: CN112972449B
Application number: CN201911306074.7A
Authority: CN
Inventors: 陈大峰; 彭秀明; 傅霖; 陈功政; 陈刚
Original assignee: Sichuan Credit Pharmaceutical Co ltd
Current assignee: Sichuan Credit Pharmaceutical Co ltd
Priority date: 2019-12-18
Filing date: 2019-12-18
Publication date: 2023-03-21
Anticipated expiration: 2039-12-18
Also published as: CN112972449A

Abstract

The invention provides a pharmaceutical composition with high safety, which is characterized in that the pharmaceutical composition contains no less than 90% of sodium valproate and no more than 0.014% of 2-methylvaleric acid, wherein the content of the sodium valproate is preferably no less than 95%, and more preferably no less than 99%. Meanwhile, the invention also provides a preparation method and application of the pharmaceutical composition. The sodium valproate pharmaceutical composition and the preparation thereof provide an effective solution for improving the safety and stability of the medicament. Meanwhile, the preparation method of the sodium valproate pharmaceutical composition disclosed by the invention is simple in process, high in yield and high in purity, and is suitable for industrial mass production.

Description

Pharmaceutical composition with high safety and preparation method thereof

Technical Field

The invention belongs to antiepileptic drugs, and particularly relates to a sodium valproate pharmaceutical composition with high safety, and a preparation method and application thereof.

Background

Sodium Valproate (Sodium 2-propylvalerate, sodium Valproate) is the Sodium salt of a saturated fatty acid. The compound is proved to have the anti-epileptic effect for the first time by French Meitier in 1963, and the trial production in China is successful in 1977. At present, sodium valproate is one of the most commonly used antiepileptic drugs in clinic, and the mechanism of action and the inhibition of voltage sensitivity Na thereof ⁺ The channels are related; inhibit gamma-aminobutyric acid (GABA) metabolic enzyme, accumulate GABA in brain, inhibit excessive discharge of focus neuron, and inhibit abnormal discharge diffusion. The total effective rate of sodium valproate for various types of epilepsy is more than 83%, wherein the curative effect for simple unconsciousness attacks, generalized tonic-clonic attacks (GTC) and GTC combined unconsciousness attacks is the best, and the curative effects of simple partial attacks (SP) and complex partial attacks (CP) are the second to the curative effects, and the sodium valproate is also effective for benign central temporal gyrus epilepsy, acquired aphasia epilepsy, slow wave sleep phase sustained spike epilepsy and tonic attacks of children. At present, sodium valproate rises to be the first choice medicine for primary generalized epilepsy, and the first choice medicine for traditional grand mal, absence and complication of epileptic seizures such as tonic clonic seizures and juvenile myoclonic seizures is used.

The sodium valproate marketed preparation comprises a solid preparation and an injection, wherein the sodium valproate for injection is firstly produced by Sanofi of France and is separately packaged by Hangzhou Xenoffy company in China. The description of the product explicitly mentions: sodium valproate for injection should be dissolved in 0.9% physiological saline, or continuously administered by intravenous drip for more than 24 hours, or administered by intravenous drip for four times a day, and each time is about 1 hour. In long-term clinical practice, the sodium valproate product for injection is fed back by doctors in a large amount to have certain vascular irritation, and when patients use the product, pain, local red swelling and the like are easy to occur, so that the compliance of the patients is reduced. The adverse reaction of the specification of the sodium valproate for injection also refers to that the product can cause vascular abnormality, common hemorrhage and vasculitis, and local tissue necrosis can occur after repeated injection.

Often, the injection of drugs with vascular irritation is not only easy to cause pain at the injection site, but also may cause inflammatory reaction and swelling, and induration and tissue necrosis along the vein, finally forming phlebitis. Severe patients can also develop deep phlebitis, skin of affected limb appears brown erythema, then purple, dark, red and swollen, ulceration, muscular atrophy and necrosis, fever and discomfort of the whole body, severe pain of affected limb, inconvenient movement, severe patients and even amputation. Patients with phlebitis have substantial symptoms of thrombosis, which can be life threatening if the thrombus migrates to the lungs, blocking the pulmonary arteries and forming a pulmonary embolism.

The research progress of vascular irritation evaluation in the screening of injection prescription, which is published in the journal of the Chinese medical industry, 2012,43 (3) by the institute of pharmaceutical industry, such as Wu Shuang, is disclosed in: vascular irritation is the most common complication of intravenous therapy. The factors causing the irritation of blood vessels are many, including the toxicity of the medicine itself, the leakage of the medicine liquid, the change of the plasma osmotic pressure, the change of the plasma pH caused by the input of the medicine, the mechanical stimulation, bacterial toxin, various particle factors, the improper operation of medical staff and the like. The vascular irritation (phlebitis) pathogenesis is as follows: various stimulating factors cause vascular endothelial injury, promote the release of inflammatory mediators such as serotonin, bradykinin and histamine, relax blood vessels, increase vascular permeability, and cause the extravasation of proteins and plasma into intercellular spaces, which is clinically manifested as edema. Focal erythema and palpable cord-like stiffness are seen when the released histamine stimulates platelet aggregation, leading to thrombosis and even progression throughout the blood vessel. At the same time, the white blood cells migrate to the inflammatory site, enlarging the local edema; the cord-like hard strip further develops from palpable to visible, at which time palpation may feel local fever (the hypothalamus is stimulated by the heat source generated by leukocyte apoptosis to raise the body temperature). Venous irritation has been manifested by vasoconstriction, thickening, sensitization, formation of palpable cord-like stiffness, and inflammation typical of thermal pain, erythema and edema. Research shows that the mechanism of vascular irritation caused by different reasons is different, and the mechanism of vascular irritation caused by different drugs is also different.

Along with the improvement of medical level, the requirement of people on medication safety is increasingly improved, the vascular irritation caused by injection is increasingly not ignored, the reason that the sodium valproate injection has the vascular irritation is deeply researched, a product with the minimal vascular irritation is developed, the quality and the medication safety of the product are continuously improved, adverse reactions are avoided or reduced, and the improvement of the compliance of patients is significant.

Disclosure of Invention

The present inventors further isolated, purified and studied the structure of sodium valproate-related substance and its activity, and obtained surprising findings: the most widely used synthetic route for sodium valproate is currently two: (1) bromopropane route: diethyl malonate or methyl acetoacetate and bromopropane are used as reaction raw materials; (2) chloropropene route: diethyl malonate and chloropropene are used as reaction raw materials. The inventors have found that both diethyl methylmalonate impurities contained in diethyl malonate and methyl bromide impurities contained in bromopropane can evolve to produce 2-methylvaleric acid as a by-product of the reaction through the above synthetic route. Therefore, the residue of the impurity 2-methylvaleric acid in the sodium valproate bulk drug is higher at present. Pharmacological tests prove that the 2-methylvaleric acid has vascular irritation, and the sodium valproate injection has vascular irritation. Therefore, the 2-methylvaleric acid generated in the synthesis of sodium valproate bulk drug needs to be controlled so as to improve the quality and the clinical medication safety of the sodium valproate injection, reduce the vascular irritation and improve the patient compliance.

The invention aims to provide a pharmaceutical composition which is high in safety and can reduce the vascular irritation of a sodium valproate medicament for injection, wherein the pharmaceutical composition contains no less than 90% of sodium valproate and no more than 0.014% of 2-methylvaleric acid.

Further, the content of sodium valproate in the pharmaceutical composition is not less than 95%, more preferably not less than 99%.

The invention also aims to provide a method for preparing the pharmaceutical composition which has high safety and can reduce the vascular irritation of the sodium valproate medicine for injection, compared with other methods for preparing the sodium valproate pharmaceutical composition disclosed by the prior art, the method can more effectively remove 2-methylvaleric acid impurities generated in the synthesis process, has high yield and simple method, and is suitable for large-scale industrial production.

The invention provides a method for more effectively removing 2-methyl valeric acid impurities generated in the synthesis process, and the preparation method of the pharmaceutical composition comprises the following steps: recrystallizing the crude sodium valproate product by using ethyl acetate and purified water as a mixed solvent.

Further, in the recrystallization method, the mass ratio of the ethyl acetate to the crude sodium valproate is 5:1-10; the mass ratio of the purified water to the crude sodium valproate is 0.01; preferably 0.05.

Further, the recrystallization method comprises the following steps: mixing ethyl acetate, the crude sodium valproate product and purified water, heating to reflux, stirring, performing hot filtration, cooling filtrate for crystallization, filtering, and drying to obtain the finished sodium valproate product.

Further, the preparation method of the crude sodium valproate product comprises the steps of slowly dropwise adding valproic acid into a solution of sodium hydroxide and absolute ethyl alcohol, stirring, filtering after complete reaction, concentrating until the system is solid, adding ethyl acetate, heating and refluxing until the solid is dissolved, carrying out hot filtration, cooling and crystallizing the filtrate, filtering, washing, and drying to obtain the sodium valproate crude product.

Further, according to the preparation method of the crude sodium valproate, the internal temperature is controlled to be not more than 20 ℃ in the process of dripping valproic acid.

Further, according to the preparation method of the crude sodium valproate product, the mass ratio of the absolute ethyl alcohol to the valproic acid is 2:1-10; the mass ratio of the sodium hydroxide to the valproic acid is 0.22; the mass ratio of the ethyl acetate to the valproic acid is 3:1-10.

Another object of the present invention is to provide a pharmaceutical preparation with high safety, which is composed of the pharmaceutical composition of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical formulations of the present invention may be in a variety of dosage forms well known in the art. The dosage form suitable for the present invention is selected from oral preparations, external preparations or injections, preferably oral preparations or injections, more preferably injections. The injection is selected from injection (injection solution), transfusion, lyophilized powder or sterile subpackaged preparation. The pharmaceutical formulations of the present invention may be prepared using formulation techniques well known in the art.

The pharmaceutically acceptable carrier according to the present invention is a commonly used excipient or adjuvant for preparing the formulation, which is well known in the art. The excipients or adjuvants commonly used in oral or topical preparations include, but are not limited to, fillers (diluents), lubricants (glidants or antiadherents), dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, and the like.

Common excipients or adjuvants for such injections include, but are not limited to: antioxidants, for example phenols such as Butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), nordihydroguaiaretic acid (NDGA), sulfur-containing compounds such as thiodipropionic acid, sulfites, bisulfites, dithiocarbamates, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate; organic acids/alcohols/esters such as ascorbic acid, citric acid, malic acid, sorbitol, glycerol, propylene glycol, ascorbyl palmitate, esters such as hydroquinone, hydroxycoumarin, vitamin E, amines such as ethanolamine, soybean phospholipids, cephalin, vegetable phospholipids or animal phospholipids, inorganic acids or salts thereof, phosphoric acids or salts thereof, phosphorous acids or salts thereof; osmotic pressure regulators, such as sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, mannitol, and the like, preferably sodium chloride or glucose; bacteriostats such as 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol; a pH adjuster such as any one of hydrochloric acid, tartaric acid, citric acid, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, sodium acetate, lactic acid, citric acid, sodium citrate, sodium hydrogen carbonate, sodium carbonate, or a combination thereof; emulsifiers such as polysorbate-80, sorbitan-kotate, pluronic F-68, lecithin, soy lecithin; solubilizers, such as tween-80, bile, glycerol, propylene glycol, lecithin, polyoxyethylene castor oil, and the like; fillers or excipients, for example, lactose, mannitol, sorbitol, dextran, and the like.

The invention also aims to provide the application of the pharmaceutical composition or the pharmaceutical preparation thereof in the antiepileptic drugs.

Compared with the prior art, the invention has the following advantages:

1) The invention discovers that the impurity 2-methylvaleric acid in the sodium valproate pharmaceutical composition has vascular irritation, and reduces the vascular irritation of the pharmaceutical composition injection by controlling the content of 2-methylvaleric acid in the sodium valproate pharmaceutical composition, avoids or reduces adverse reactions in clinical use, and improves the medication safety and the compliance of patients.

2) The sodium valproate pharmaceutical composition prepared by the method has better stability and less impurity content than the sodium valproate product prepared by the prior art, so that the pharmaceutical composition provided by the invention has better quality and less adverse reaction than the sodium valproate pharmaceutical composition prepared by the prior art, and the stability and the medication safety of the product are improved.

3) Compared with the sodium valproate preparation method in the prior art, the preparation method can effectively remove 2-methylvaleric acid impurities which are inevitably generated due to side reactions in the synthesis of the sodium valproate, so that a sodium valproate pharmaceutical composition product with higher purity, lower impurity content and better quality can be obtained. And the preparation method has simple process and high yield, and is suitable for large-scale industrial production.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that the embodiments of the present invention are illustrative only and not limiting, and that various modifications and changes may be made without departing from the spirit and scope of the invention as defined by the appended claims.

The raw materials and equipment used in the invention are known products, and are obtained by purchasing products sold in the market.

The invention prepares and obtains the starting material valproic acid by the method disclosed by the prior art: reacting sodium ethoxide with diethyl malonate to generate diethyl malonate disodium salt, adding 1-bromopropane after the reaction is finished to generate dipropyl diethyl malonate, hydrolyzing under an alkaline condition to generate dipropyl disodium malonate, and decarboxylating to obtain valproic acid. (Synthesis of sodium valproate, wu Changzeng, chemical Engineer 2015, 08 th)

Example 1

At the temperature below 20 ℃, slowly dripping 12.00Kg of valproic acid (purity: 99.0%, 2-methyl valeric acid content: 0.1%) into a solution of 3.24Kg of sodium hydroxide and 36.00Kg of absolute ethyl alcohol, stirring, filtering after complete reaction, and concentrating the filtrate under reduced pressure to solid. Adding 48.00Kg of ethyl acetate, heating to reflux, hot filtering, cooling the filtrate and crystallizing. Filtering, washing and drying under reduced pressure to obtain 8.29Kg of crude sodium valproate.

8.00Kg of the crude sodium valproate, 5363 Kg of ethyl acetate 53.36Kg and 0.4Kg of purified water are mixed, heated to reflux and stirred. Hot filtering, cooling and crystallizing the filtrate, filtering, washing with ethyl acetate, and drying under reduced pressure to obtain 6.04Kg of sodium valproate finished product, with the yield about 75.5%, purity: 99.96%, 2-methylvaleric acid content: 0.010%.

Example 2

Slowly dripping 12.00Kg of valproic acid (purity: 99.0%, 2-methyl valeric acid content: 0.1%) into a solution of 2.64Kg of sodium hydroxide and 24.00Kg of absolute ethyl alcohol at a temperature below 20 ℃, stirring, filtering after complete reaction, and concentrating the filtrate under reduced pressure to solid. Adding 36.00Kg of ethyl acetate, heating to reflux, hot filtering, cooling the filtrate and crystallizing. Filtering, washing and drying under reduced pressure to obtain 8.29Kg of crude sodium valproate.

8Kg of the crude sodium valproate, 80.00Kg of ethyl acetate and 7.20Kg of purified water are mixed, heated to reflux and stirred. Hot filtering, cooling and crystallizing the filtrate, filtering, washing with ethyl acetate, and drying under reduced pressure to obtain 4.82Kg of sodium valproate finished product, with the yield about 60.2%, purity: 99.95%, HPLC content of 2-methylvaleric acid: 0.008 percent.

Example 3

Slowly dripping 12.00Kg of valproic acid (purity: 99.0%, 2-methyl valeric acid content: 0.1%) into a solution of 3.00Kg of sodium hydroxide and 120.00Kg of absolute ethyl alcohol at a temperature below 20 ℃, stirring, filtering after complete reaction, and concentrating the filtrate under reduced pressure to solid. Adding 120.00Kg of ethyl acetate, heating to reflux, hot filtering, and cooling the filtrate for crystallization. Filtering, washing and drying under reduced pressure to obtain 8.29Kg of crude sodium valproate.

8Kg of the crude sodium valproate, 40.00Kg of ethyl acetate and 0.08Kg of purified water are mixed, heated to reflux and stirred. Hot filtering, cooling and crystallizing the filtrate, filtering, washing with ethyl acetate, and drying under reduced pressure to obtain 6.34Kg of sodium valproate finished product, with the yield about 79.3%, and the purity: 99.97%, 2-methylvaleric acid content: 0.013%.

Example 4

Slowly dripping 12.00Kg of valproic acid (purity: 99.0%, 2-methyl valeric acid content: 0.1%) into a solution of 3.00Kg of sodium hydroxide and 36.00Kg of absolute ethyl alcohol at a temperature below 20 ℃, stirring, filtering after complete reaction, and concentrating the filtrate under reduced pressure to solid. Adding 48.00Kg of ethyl acetate, heating to reflux, hot filtering, cooling the filtrate and crystallizing. Filtering, washing and drying under reduced pressure to obtain 8.29Kg of crude sodium valproate.

8Kg of crude sodium valproate, 3242 Kg of ethyl acetate 53.36Kg and 2.4Kg of purified water are mixed, heated to reflux and stirred. Hot filtering, cooling and crystallizing the filtrate, filtering, washing with ethyl acetate, and drying under reduced pressure to obtain 5.47Kg of sodium valproate finished product, wherein the yield is about 68.4%, and the purity is as follows: 99.96%, 2-methylvaleric acid content: 0.008 percent.

Example 5

The sodium valproate pharmaceutical composition is prepared into freeze-dried powder injection for injection according to the following prescription and preparation method:

sodium valproate	40g
		Adding water to	500ml
Adjusting the pH	7.8

500ml of liquid medicine is prepared according to the prescription, the PH value is adjusted to 7.8, and the liquid medicine is subpackaged into 100 medium borosilicate glass tube bottles according to the prescription amount after the clarity is detected to be qualified.

Lyophilization was performed according to the following lyophilization procedure:

putting all the medium borosilicate glass tube bottles into a box, starting a freeze dryer, reducing the temperature to-50 ℃ within 40-120min, and keeping the temperature for 180-540min. After pre-freezing, starting a vacuum pump and controlling the pressure of the front box; heating to-10 deg.C within 40-120min, maintaining for 1200-3800min, and drying once. Setting for 120-500min, heating to 50 deg.C, and keeping the vacuum degree to the maximum; and (5) preserving the temperature until the freeze-drying is finished. After the freeze drying is finished, pressing the film-coated rubber plug, and pressing the aluminum-plastic combined cover on the film-coated rubber plug.

Example 6

The sodium valproate injection is prepared from the sodium valproate pharmaceutical composition according to the following formula and preparation method:

adding EDTA-2NaCa and sodium valproate in the prescribed amount into water for injection, stirring to completely dissolve, adjusting the pH value of the solution to 7.6, and then adding water for injection to fix the volume to a sufficient amount to prepare the required concentration; adding active carbon for injection, stirring for 30 min, filtering with 0.22um filter membrane, packaging the obtained medicinal liquid, and sterilizing under hot pressure.

Example 7

The sodium valproate sustained release tablet is prepared from the sodium valproate pharmaceutical composition according to the following formula and preparation method:

sodium valproate	33.3g
		HPMC K100M	7.5g
Microcrystalline cellulose	5g
		Silica gel micropowder	1g
Magnesium stearate	0.2g

Sodium valproate, hydroxypropyl cellulose and microcrystalline cellulose are sieved by a 60-mesh sieve according to the dosage of the prescription and mixed. Adding liquid valproic acid and 95% ethanol into the above mixture, making into soft mass, sieving with 20 mesh sieve to make into wet granule, drying at 60 deg.C for 2 hr, and grading with 20 mesh sieve. Adding the micro-powder silica gel and the lubricant into the obtained granules, uniformly mixing, and tabletting to obtain the sustained-release tablets.

Comparative example:

valproic acid (purity 99.0%, 2-methylvaleric acid content 0.1%) prepared by the prior art method was used to prepare sodium valproate by the following methods respectively:

comparative example 1:

according to the specific implementation mode disclosed in the specification of Chinese patent CN201010177052.8, sodium valproate is prepared by a method of carrying water in toluene.

Comparative examples 2 to 9:

the crude sodium valproate was prepared according to the procedure of example 1 of the present invention. 1Kg of crude sodium valproate was taken, mixed with the solvents listed in Table 1, stirred, and heated to reflux. Hot filtering, standing the filtrate, and naturally cooling to room temperature. Filtering, washing, and drying under reduced pressure to obtain the sodium valproate refined product. The types, amounts and proportions of solvents used for recrystallization, and the yields and impurity conditions of the sodium valproate product obtained after recrystallization are shown in table 1:

table 1 comparative test for solvent investigation

As can be seen from the above comparative examples, the process for preparing purified sodium valproate of the present invention can reduce the content of impurities in the product more effectively than the prior art processes, and especially has a better effect of removing 2-methylvaleric acid. The product has better quality and fewer adverse reactions, and the medication safety of the product is improved.

Experimental example 1:

vascular irritation test

The test animals were: 30 rabbits with unlimited male and female bodies and the weight of 2.5-3.0 kg are randomly divided into 5 groups of solvent control group and composition group of sodium valproate and 2-methylvaleric acid after being adapted to breeding, and each group comprises 6 rabbits.

Grouping tested medicines: the sodium valproate prepared in example 1 of the present invention and having a purity of 99.9% was added with a certain amount of 2-methylvaleric acid (manufacturer: shanghai Aladdin Biotech Co., ltd.) to form the following test drug groups:

group I: a composition having a weight ratio of sodium valproate to 2-methylvaleric acid of 1;

and (II) group: a composition of sodium valproate and 2-methylvaleric acid in a weight ratio of 1;

group III: a composition having a weight ratio of sodium valproate to 2-methylvaleric acid of 1;

group IV: a composition of sodium valproate and 2-methylvaleric acid in a weight ratio of 1.

The test method comprises the following steps: physiological saline is set as a negative control, and the ear vein is selected as the administration site. 30 rabbits (2.5 to 3.0kg in body weight) were randomly divided into the above negative control group and composition group. Each rabbit was dosed with 15mg/kg daily by 4 infusions for 7 consecutive days by intravenous drip. The volume of the valproic acid sodium injection is consistent with that of normal saline.

Rabbits were visually observed before and after each day and 48h after the last dose. Animals were sacrificed after 48h and histopathological examination was performed. After sacrifice, the rabbit ears were clipped 1cm from the injection site. Blood stain was washed with physiological saline and fixed in formalin solution. After staining, the irritant response to the rabbit ear vessels after injection was observed under a light microscope. The rabbit blood vessel hypersensitivity evaluation standard is as follows: grade 0, no obvious reaction at the administration part; grade 1, mild blood stasis and red swelling of vein at administration position; grade 2, moderate blood stasis and swelling of vein and blood vessel at administration position; grade 3, moderate blood stasis and swelling of vein vessel at administration position; grade 3, severe blood stasis in the vein at the administration site, severe red swelling of the surrounding tissue.

The various responses seen by the animals during intravenous infusion are shown in Table 2 below, and the tissue sections of the animals after intravenous infusion are shown in Table 3 below.

TABLE 2 various responses in animals following intravenous infusion

TABLE 3 animal tissue section following intravenous infusion

And (4) conclusion: the negative control group (normal saline group) and the sodium valproate group containing 0.014% of 2-methylvaleric acid have no obvious red and swollen and bleeding except the bleeding point at the needle insertion position before and after each instillation, and no obvious pathological changes appear after the observation of the blood vessel tissue section. In the sodium valproate group containing 0.02%, 0.05% and 0.10% of 2-methylvaleric acid, after 7 days of continuous intravenous drip, the blood vessels have the phenomena of blood stasis, red swelling and blood vessel congestion of different degrees, and the tissue pathological section shows that the blood vessels have the conditions of edema, endothelial cell swelling, inflammatory cell infiltration and the like of different degrees along with the increase of the content of the 2-methylvaleric acid. Experiments show that in the sodium valproate injection, the content of 2-methylvaleric acid impurities is controlled to be below 0.014%, so that the vascular irritation of the injection can be effectively reduced, and the safety and the compliance of the clinical medication of the sodium valproate injection are improved.

Experimental example 2

Stability study of pharmaceutical compositions of the invention

The test method comprises the following steps:

taking the sodium valproate pharmaceutical composition prepared in the embodiment 1 of the invention and the pharmaceutical compositions prepared in the comparative examples 1-3, adding water, adding dilute sulfuric acid for dissolving, extracting with heptane, and preparing into a test solution of 5 mg/ml; then taking part of the test solution to dilute by 100 times to be used as a reference solution; the 2-methylvaleric acid was dissolved in heptane and diluted to the mark and shaken well as used as the system suitability test solution. Performing gas chromatography detection by using a capillary column with the terephthalic acid modified polyethylene glycol as a stationary liquid as a chromatographic column according to a gas chromatography (appendix of 2010 edition of Chinese pharmacopoeia, second part) test, wherein the results are shown in Table 4.

TABLE 4 Long term stability study of pharmaceutical compositions

As shown in Table 4, the pharmaceutical composition prepared by the preparation method of the invention is stable, the content of 2-methyl valeric acid is still less than 0.14% after the pharmaceutical composition is stored for 24 months, the vascular irritation of the pharmaceutical composition can be effectively reduced, and the safety and the compliance of clinical medication of the sodium valproate injection can be improved, while the pharmaceutical composition prepared by the method of comparative examples 1 to 3 has higher content of 2-methyl valeric acid.

Claims

1. The preparation method of the pharmaceutical composition with high safety is characterized in that the pharmaceutical composition contains sodium valproate with the content not lower than 90% and 2-methylvaleric acid with the content not higher than 0.014%, and the preparation method is characterized in that ethyl acetate and purified water are used as mixed solvents to recrystallize a crude sodium valproate product, wherein the mass ratio of the ethyl acetate to the crude sodium valproate product is 5:1-10; the mass ratio of the purified water to the crude sodium valproate is (0.01);

the recrystallization comprises the steps of mixing ethyl acetate, a sodium valproate crude product and purified water, heating to reflux, stirring, carrying out hot filtration, cooling filtrate for crystallization, filtering, and drying to obtain a sodium valproate finished product;

the preparation method of the crude sodium valproate product comprises the steps of slowly dropwise adding valproic acid into a solution of sodium hydroxide and absolute ethyl alcohol, stirring, filtering after complete reaction, and concentrating the filtrate to be in a solid state; then adding ethyl acetate, heating and refluxing until the solid is dissolved, carrying out hot filtration, cooling and crystallizing the filtrate, filtering, washing, and drying to obtain a sodium valproate crude product; controlling the internal temperature not to exceed 20 ℃ in the process of dripping the valproic acid; the mass ratio of the absolute ethyl alcohol to the valproic acid is 2:1-10; the mass ratio of the sodium hydroxide to the valproic acid is 0.22; the mass ratio of the ethyl acetate to the valproic acid is 3:1-10.

2. The process for preparing a pharmaceutical composition according to claim 1, wherein the content of sodium valproate in the pharmaceutical composition is not less than 95%.

3. The process for preparing a pharmaceutical composition according to claim 1, wherein the content of sodium valproate in the pharmaceutical composition is not less than 99%.

4. A process for preparing a pharmaceutical composition according to claim 1, characterized in that: the mass ratio of the purified water to the crude sodium valproate is 0.05.