Piracetam injection and preparation method thereof

Abstract

The invention discloses a piracetam injection and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations, the piracetam injection is composed of the following components: piracetam, sodium acetate trihydrate, water for injection and glacial acetic acid, the content of piracetam is 200 mg / ml, the content of sodium acetate trihydrate is 0.8-1.2 mg / ml, and the pH value of the injection is 5.78-5.81. The piracetam injection prepared by the invention can achieve a complete impurity-free degree, and is relatively good in stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation preparation, and particularly relates to a piracetam injection and a preparation method thereof. Background Art

[0002] Piracetam, with the structural formula shown below, has a chemical name of 2-oxo-1-pyrrolidinyl acetamide. Its main indications are acute and chronic cerebrovascular disease, brain trauma, various toxic encephalopathy and other causes of memory loss and mild and moderate brain dysfunction. It can also be used for children with intellectual retardation. In the EU, piracetam injection is used to treat cortical myoclonus (alone or in combination with other drugs) and is suitable for vertigo and related balance disorders (except vasomotor or psychogenic vertigo).

[0003]

[0004] The main component of piracetam injection is piracetam, and the excipients include pH buffer, pH adjuster, etc. However, the piracetam injection preparation prepared by the prior art has a fast growth of impurities during the stability period, poor stability, and certain safety hazards. For example, Chinese patent CN202111394100.3 discloses a method for preparing piracetam injection, first adding sodium acetate and then adding the raw material, and then adding acid to adjust the pH of the preparation, which has unsatisfactory results for impurity control, and the total impurities of the sample can be detected on day 0 after sterilization. Chinese patent CN202410305016.7 also discloses a batch production process for piracetam injection, which uses most of the batch amount of water for injection to dissolve the batch amount of sodium acetate, glacial acetic acid, and piracetam in sequence under stirring. This invention is also not conducive to the control of impurities.

[0005] The piracetam injection in the prior art has the technical problems of rapid growth of impurities during storage, low stability and certain safety hazards. Therefore, it is necessary to develop a new piracetam injection and a preparation method thereof to reduce the growth of process impurities and impurities during stability and improve the stability of piracetam injection. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a piracetam injection and a preparation method and application thereof, which can effectively control the total impurities of the sample on day 0 after production, and effectively control the problem of impurity growth of the prepared piracetam injection preparation during the stability period, thereby improving the long-term stability of the piracetam injection.

[0007] In order to achieve the above-mentioned purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides a piracetam injection, which is composed of the following components: piracetam, sodium acetate trihydrate, water for injection and glacial acetic acid, wherein the content of piracetam is 200 mg / ml, the content of sodium acetate trihydrate is 0.8-1.2 mg / ml, the pH value of the injection is 5.78-5.81, and the content of impurity II in the injection is less than 0.01%.

[0009] The impurity II described in the present invention is 2-oxo-1-pyrrolidinyl acetic acid, the structural formula of which is

[0010] In some embodiments, the sodium acetate trihydrate content is 1 mg / ml.

[0011] In some embodiments, the piracetam injection is an injection packaged in an ampoule and sterilized at 121° C. for 15 minutes, and the total impurity content of the injection is less than 0.01%, preferably less than 0.01% on day 0 of production.

[0012] In some embodiments, the total impurities of the piracetam injection stored under accelerated or long-term conditions are less than 0.20%, more preferably less than 0.15%, and further less than 0.10%.

[0013] In a second aspect, the present invention provides a method for preparing the above-mentioned piracetam injection, comprising the following steps:

[0014] (1) Take the water for injection that accounts for part of the batch and cool it down;

[0015] (2) Add the prescribed amount of sodium acetate trihydrate and stir to dissolve;

[0016] (3) adding the prescribed amount of piracetam and stirring to dissolve;

[0017] (4) adjusting the pH value of the mixed solution obtained in step (3) to 5.78-5.81, preferably 5.80, using glacial acetic acid solution;

[0018] (5) Add water for injection to make up to the final volume and stir to mix.

[0019] The use of a glacial acetic acid solution with a concentration of 15-60% in step (4) of the present invention is beneficial to increasing the liquid preparation speed, and the produced sample can also be completely free of impurities.

[0020] Preferably, the concentration of the glacial acetic acid solution is 20-40%; more preferably 20-30%; most preferably 30%.

[0021] In some embodiments, the adjustment in step (4) is: first add 1 / 2-2 / 3 of the theoretical amount of glacial acetic acid solution at one time, stir for 1-5 minutes, and then add the remaining amount of glacial acetic acid solution.

[0022] In some embodiments, the addition time of the remaining glacial acetic acid solution is controlled within 20 minutes, preferably within 16 minutes, and more preferably within 10 minutes.

[0023] In some embodiments, the portion of water for injection in step (1) accounts for 65-84% of the batch, preferably 70-84%, and more preferably 70-80%.

[0024] To ensure the stability of the product, the temperature of the injection water must be cooled before adding the materials and then proceeding to the subsequent steps, and there is no need to continue to control the temperature in the subsequent steps.

[0025] In some preferred embodiments, the cooling is to cool to 0-65°C, preferably room temperature-40°C; more preferably room temperature.

[0026] In some embodiments, the purpose of stirring and dissolving in step (2) and step (3) is to form a uniform solution of sodium acetate trihydrate and piracetam in water for injection, and the stirring is a conventional technical means in the art. In some specific embodiments, the stirring and dissolving time is more than 5 minutes; preferably 5-30 minutes; more preferably 5-10 minutes.

[0027] In some embodiments, the time to complete steps (2) to (5) is no more than 4 hours.

[0028] In some embodiments, the preparation method further includes the steps of filtering, filling, sealing, sterilization and leak detection.

[0029] Specifically:

[0030] (6) sterilizing and filtering the mixed solution obtained in step (5), filling it into an ampoule bottle, filling it with nitrogen before and after filling, and sealing it by melting;

[0031] (7) sterilizing the sample obtained in step (6);

[0032] (8) Perform leak detection and light inspection on the sample obtained in step (7).

[0033] In some embodiments, the time from the completion of step (6) to step (7) is no more than 10 hours, preferably no more than 8 hours.

[0034] In some specific embodiments, the sterilization filtration in step (6) is: the mixed solution is filtered through a 0.45 μm filter and a 0.22 μm filter in a cycle. Preferably, the cycle filtration time is 10-40 min, more preferably 15-30 min, and even more preferably 15-25 min.

[0035] In some specific embodiments, the sterilization in step (7) is: sterilization at 121° C. for 15 min, F0 ≥ 15.

[0036] In some specific embodiments, the piracetam injection of the present invention is prepared by the following method:

[0037] (1) Take 65-84% of the water for injection and cool it to 0-65°C;

[0038] (2) Add the prescribed amount of sodium acetate trihydrate and stir to dissolve;

[0039] (3) adding the prescribed amount of piracetam and stirring to dissolve;

[0040] (4) using glacial acetic acid to adjust the pH value of the mixed solution obtained in step (3) to 5.78-5.81. During the adjustment process, 1 / 2-2 / 3 of the theoretical amount of glacial acetic acid solution is first added at one time, stirred for 1-5 minutes, and then the remaining amount of glacial acetic acid solution is added; the glacial acetic acid is a glacial acetic acid solution with a concentration of 15-60%;

[0041] (5) adding water for injection to make up to the final volume, stirring and mixing; the time to complete step (2) to step (5) is no more than 4 hours;

[0042] (6) sterilizing and filtering the mixed solution obtained in step (5), filling it into an ampoule bottle, filling it with nitrogen before and after filling, and sealing it by melting;

[0043] (7) sterilizing the sample obtained in step (6); the time from the completion of step (6) to step (7) is no more than 10 hours;

[0044] (8) Perform leak detection and light inspection on the sample obtained in step (7).

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] (1) During the research on related substances of piracetam injection, it was found that the main degradation impurity of this product is impurity II (EP impurity D), which is a degradation impurity produced by the hydrolysis of piracetam and is greatly affected by the pH value of the drug solution. The present invention optimizes the formula and strictly controls the conditions and process of adjusting the pH value of the glacial acetic acid solution to produce samples that are completely free of impurities. Even when stored under accelerated or long-term conditions, the impurity content is far below the total impurity control requirement of 0.5%.

[0047]

[0048] (2) Compared with the prior art, the piracetam injection prepared by the present invention has fewer process impurities, achieving the effect of no impurities detected even after high-temperature sterilization, and the product stability is better. DETAILED DESCRIPTION

[0049] The present invention is further described below in conjunction with examples. This example is implemented based on the technology of the present invention. Detailed implementation methods and specific operating processes are now given to illustrate that the present invention is creative, but these examples do not limit the scope of the present invention.

[0050] In order to better understand the present invention but not to limit the scope of the present invention, all numerals and other numerical values ​​of expression dosage, percentage used in this application.Each numerical parameter should at least be regarded as obtained according to the reported significant digits and by conventional rounding methods.

[0051] The piracetam injection of the present invention is a small-volume injection. In the embodiment, the specification of the piracetam injection is 20 ml: 4 g.

[0052] In the preparation process of the Chinese medicinal liquid of the present invention, the density of the medicinal liquid (1.044 g / ml) is converted into weight for constant volume, and no impurities are detected in the used piracetam raw material.

[0053] In the present invention, normal temperature is 10-30°C, preferably 10°C, 15°C, 20°C, 25°C, 30°C or any range between the values.

[0054] In the present invention, batch refers to the production volume of one batch, and the water for injection in step (1) accounts for the portion of the batch. For example, if the batch is 400L, and the water for injection in step (1) accounts for 70-80% of the batch, it means that 280L-320L of water for injection is taken in step (1).

[0055] The concentration of the glacial acetic acid solution in the present invention refers to the volume ratio. For example, to prepare a 30% glacial acetic acid solution, take 60 ml of glacial acetic acid and dilute it to 200 ml with water for injection. Prepare it before use.

[0056] In the present invention, 0 day refers to no more than 24 hours after the product is produced and the sample is obtained.

[0057] The stirring speed of the stirring in the present invention is 20 Hz. The molecular formula of the sodium acetate trihydrate of the present invention is C 2 H 3 NaO 2 ·3H 2 O.

[0058] In the present invention, the pH test uses a pH meter of model S220 (manufacturer: METTLER TOLEDO).

[0059] The experimental methods used in the following examples are all conventional methods unless otherwise specified; the raw materials, reagents, etc. used are all raw materials and reagents that can be obtained from conventional commercial channels, etc. unless otherwise specified.

[0060] The piracetam injection prescription of Example 1-6 and Comparative Example 1-2

[0061] Table 1 Amount of raw materials in Examples 1-6 and Comparative Examples 1-2

[0062]

[0063]

[0064] Example 1 Preparation of Piracetam Injection (Production Batch No. 22102103)

[0065] (1) Take 80% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0066] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0067] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0068] (4) Use 30% (V / V) glacial acetic acid solution to adjust the pH value to 5.80. During the adjustment process, add 2 / 3 of the theoretical amount of glacial acetic acid at one time, stir for 2 minutes, and slowly add the remaining amount within 10 to 15 minutes. The amount added is based on adjusting the pH to 5.80;

[0069] (5) Add purified water (20-25°C) to make up to volume and stir for 20 minutes;

[0070] The time to complete step (2) to step (5) is no more than 3.5 hours;

[0071] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0072] (7) Sterilize the ampoule at 121°C for 15 min.

[0073] The time from the completion of step (6) to step (7) is no more than 8 hours;

[0074] (8) Leak detection and light inspection.

[0075] Example 2 Preparation of Piracetam Injection (Production Batch No. 22102401)

[0076] (1) Take 75% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0077] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0078] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0079] (4) Using 20% ​​(V / V) glacial acetic acid solution to adjust the pH value to 5.78, during the adjustment process, first add 2 / 3 of the theoretical amount of glacial acetic acid solution at one time, stir for 5 minutes, and then slowly add the remaining amount within 10 minutes, with the amount added being based on adjusting the pH to 5.78;

[0080] (5) Add purified water (20-25°C) to make up to volume and stir for 20 minutes;

[0081] The time to complete step (2) to step (5) is no more than 4 hours;

[0082] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into an ampoule according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 1% and 3%;

[0083] (7) Sterilize the ampoule at 121°C for 15 min;

[0084] The time from the completion of step (6) to step (7) is no more than 8 hours;

[0085] (8) Leak detection and light inspection.

[0086] Example 3 Preparation of Piracetam Injection (Production Batch No. 22102601)

[0087] (1) Take 70% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0088] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0089] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0090] (4) Using 25% (V / V) glacial acetic acid solution to adjust the pH value to 5.81, during the adjustment process, first add 2 / 3 of the theoretical amount of glacial acetic acid at one time, stir for 1 min, and then slowly add the remainder within 16 min. The amount added is based on adjusting the pH to 5.81;

[0091] (5) Add purified water (20-25°C) to make up to volume and stir for 20 minutes;

[0092] The time to complete step (2) to step (5) is no more than 4 hours;

[0093] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0094] (7) Sterilize the ampoule at 121°C for 15 min;

[0095] The time from the completion of step (6) to step (7) is no more than 9 hours;

[0096] (8) Leak detection and light inspection.

[0097] Example 4 Preparation of Piracetam Injection (Production Batch No. 2022011201-04)

[0098] (1) Take 70% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0099] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0100] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0101] (4) Using 40% (V / V) glacial acetic acid solution to adjust the pH value to 5.80, during the adjustment process, first add 2 / 3 of the theoretical amount of glacial acetic acid at one time, stir for 3 minutes, and then slowly add the remaining amount within 10 minutes, with the amount added being based on adjusting the pH to 5.80;

[0102] (5) Add purified water (20-25°C) to make up to volume and stir for 20 minutes.

[0103] The time to complete step (2) to step (5) is no more than 4 hours;

[0104] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter + a 0.22 μm filter for 20 min and then filled into an ampoule according to the dosage. Nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0105] (7) Sterilize the ampoule at 121°C for 15 min.

[0106] The time from the completion of step (6) to step (7) is no more than 8 hours;

[0107] (8) Leak detection and light inspection.

[0108] Example 5 Preparation of Piracetam Injection (Production Batch No. 2022011201-05)

[0109] (1) Take 75% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0110] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0111] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0112] (4) Using 40% (V / V) glacial acetic acid solution to adjust the pH value to 5.81, during the adjustment process, add 1 / 2 of the theoretical amount of glacial acetic acid at one time, stir for 2 minutes, and then slowly add the remaining amount within 10 minutes. The amount added is based on adjusting the pH to 5.81;

[0113] (5) Add purified water (room temperature) to make up to volume and stir for 20 minutes;

[0114] The time to complete step (2) to step (5) is no more than 4 hours;

[0115] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0116] (7) Sterilize the ampoule at 121°C for 15 min;

[0117] The time from the completion of step (6) to step (7) is no more than 10 hours;

[0118] (8) Leak detection and light inspection.

[0119] Example 6 Preparation of Piracetam Injection (Production Batch No. 2022011201-06)

[0120] (1) Take 75% (V / V) of the purified water in the batch and cool it to 20-25°C;

[0121] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0122] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0123] (4) Using 40% (V / V) glacial acetic acid solution to adjust the pH value to 5.80, during the adjustment process, add 95% of the theoretical amount of glacial acetic acid at one time, stir for 2 minutes, and slowly add the remainder within 5 minutes. The amount added is based on adjusting the pH to 5.80;

[0124] (5) Add purified water (room temperature) to make up to volume and stir for 20 minutes;

[0125] The time to complete step (2) to step (5) is no more than 4 hours;

[0126] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0127] (7) Sterilize the ampoule at 121°C for 15 min.

[0128] The time from the completion of step (6) to step (7) is no more than 10 hours;

[0129] (8) Leak detection and light inspection.

[0130] Comparative Example 1 Preparation of Piracetam Injection

[0131] (1) Take 75% (V / V) of the purified water in the batch and cool it to 40-45°C;

[0132] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0133] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0134] (4) Use 12% (V / V) glacial acetic acid solution to adjust the pH value to 6.10. During the adjustment process, add the glacial acetic acid solution all at once and stir for 2 minutes. The amount of glacial acetic acid solution added is based on adjusting the pH to 6.10;

[0135] (5) Add purified water (room temperature) to make up to volume and stir for 20 minutes;

[0136] The time to complete step (2) to step (5) is no more than 3 hours;

[0137] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0138] (7) Sterilize the ampoule at 121°C for 15 min;

[0139] The time from the completion of step (6) to step (7) is no more than 8 hours;

[0140] (8) Leak detection and light inspection.

[0141] Comparative Example 2 Preparation of Piracetam Injection

[0142] (1) Take 75% (V / V) of the purified water in the batch and cool it to 40-45°C;

[0143] (2) Add weighed sodium acetate trihydrate and stir to dissolve for 5 minutes;

[0144] (3) Add the weighed piracetam and stir to dissolve for 10 min;

[0145] (4) Use 12% (V / V) glacial acetic acid solution (about 2 mol / L) to adjust the pH value to 5.90. During the adjustment process, first add 2 / 3 of the theoretical amount of glacial acetic acid, stir for 2 minutes, and then slowly add the remaining amount. The amount added is based on adjusting the pH to 5.90;

[0146] (5) Add purified water (room temperature) to make up to volume and stir for 20 minutes;

[0147] The time to complete step (2) to step (5) is no more than 3 hours;

[0148] (6) After constant volume stirring and mixing, the mixture is filtered through a 0.45 μm filter and a 0.22 μm filter for 20 min; after filtration, the mixture is filled into ampoules according to the dosage, and nitrogen is filled before and after filling to control the residual oxygen content in the headspace of the product to be between 3% and 5%;

[0149] (7) Sterilize the ampoule at 121°C for 15 min;

[0150] The time from the completion of step (6) to step (7) is no more than 8 hours;

[0151] (8) Leak detection and light inspection.

[0152] Example 7 Stability Test of Piracetam Injection

[0153] For the preparations prepared in the above-mentioned embodiments and comparative examples, the changing trends of impurity II and total impurities in the samples were detected after sterilization (0d) and under accelerated conditions of 6 months (40℃±2℃, 75%RH±5%RH) and long-term conditions of 12 months (30℃±2℃, 65%RH±5%RH).

[0154] (1) The testing of related substances shall be carried out in accordance with the high performance liquid chromatography method (General Chapter 0512 of the Chinese Pharmacopoeia 2020 Edition, Part IV).

[0155] Test solution Take an appropriate amount of the product and dilute it with mobile phase to make a solution containing approximately 1 mg of Piracetam per 1 ml.

[0156] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to make a solution containing approximately 1 g of piracetam per 1 ml.

[0157] System suitability solution: Accurately weigh about 10 mg of piracetam reference substance, about 5 mg of impurity II reference substance, and accurately measure about 10 ml of impurity I reference substance, place them in the same 100 ml volumetric flask, add mobile phase to dissolve and dilute to the scale, and shake well.

[0158] Chromatographic conditions

[0159] Octadecylsilane bonded silica gel was used as filler (chromatographic column model: SyncronisC18 250x4.6mm, 5um); 1.0g potassium dihydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid)-(80:20) was used as mobile phase; the detection wavelength was 205nm, the injection volume was 20μL, the flow rate was 1.0ml per minute, and the column temperature was 30℃. The order of elution of each impurity was impurity II, piracetam, and impurity I.

[0160] System suitability requirements

[0161] In the system suitability solution chromatogram, the number of theoretical plates calculated based on the piracetam peak should be no less than 5000, and the separation between the piracetam peak and the impurity peak should be greater than 3.0.

[0162] Determination method

[0163] Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram until 8 times the retention time of the main component peak.

[0164] limit

[0165] If there is a chromatographic peak in the chromatogram of the test solution with the same retention time as the impurity II peak, its peak area multiplied by the relative correction factor 0.83 shall not be greater than 15 times (0.15%) the main peak area of ​​the control solution; the area of ​​other individual impurity peaks shall not be greater than the main peak area of ​​the control solution (0.1%); the sum of the areas of all impurity peaks after correction shall not be greater than 5 times (0.5%) the main peak area of ​​the control solution.

[0166] Among them, the chemical name of impurity I is 2-pyrrolidone (European Pharmacopoeia impurity A); the chemical name of impurity II is 2-oxo-1-pyrrolidinyl acetic acid (European Pharmacopoeia impurity D).

[0167] (2) Content determination

[0168] Test solution

[0169] Accurately measure an appropriate amount of this product and quantitatively dilute it with the mobile phase to make a solution containing approximately 0.1 mg of Piracetam per 1 ml.

[0170] Reference solution Take an appropriate amount of piracetam reference substance, weigh accurately, add mobile phase to dissolve and quantitatively dilute to make a solution containing approximately 0.1 mg per 1 ml.

[0171] System suitability solutions, chromatographic conditions and system suitability requirements are listed under Related Substances.

[0172] Determination method

[0173] Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0174] The specific test results of the single impurity and total impurity contents (%) of the finished piracetam injections prepared in Examples 1-6 and Comparative Examples 1-2 are shown in Table 2 below.

[0175] Table 2 Results of investigation on impurity content

[0176]

[0177] From the above research results, it can be seen that the pH value of piracetam injection preparations has a significant impact on impurities. The samples produced under this condition can be completely free of impurities, and the impurity content even when stored under accelerated or long-term conditions is far below the total impurity control requirement of 0.5%.

Claims

1. A piracetam injection, characterized in that: The injection comprises the following components: piracetam, sodium acetate trihydrate, water for injection and glacial acetic acid. The content of piracetam is 200 mg / ml, the content of sodium acetate trihydrate is 0.8-1.2 mg / ml, the pH value of the injection is 5.78-5.81, and the content of 2-oxo-1-pyrrolidinoacetic acid in the injection is less than 0.01%.

2. The piracetam injection according to claim 1, characterized in that: The injection is an injection packaged in an ampoule bottle and sterilized at 121° C. for 15 minutes; further, the content of sodium acetate trihydrate is 1 mg / ml; the total impurity content of the injection is less than 0.01%, preferably the total impurity content is less than 0.01% on the 0th day of production.

3. The method for preparing the piracetam injection according to claim 1, characterized in that: The steps include: (1) Take the water for injection that accounts for part of the batch and cool it down; (2) Add the prescribed amount of sodium acetate trihydrate and stir to dissolve; (3) adding the prescribed amount of piracetam and stirring to dissolve; (4) adjusting the pH value of the mixed solution obtained in step (3) to 5.78-5.81 using glacial acetic acid; (5) Add water for injection to make up to the final volume and stir to mix; The glacial acetic acid in step (4) is a glacial acetic acid solution with a concentration of 15-60%, preferably 20-40%; more preferably 20-30%.

4. The preparation method according to claim 3, characterized in that: The adjustment in step (4) is as follows: first add 1 / 2-2 / 3 of the theoretical amount of glacial acetic acid solution at one time, stir for 1-5 minutes, and then add the remaining amount of glacial acetic acid solution.

5. The preparation method according to claim 3, characterized in that: The portion of water for injection in step (1) accounts for 65-84% of the batch, preferably 70-84%, and more preferably 70-80%.

6. The preparation method according to claim 3, characterized in that: The cooling in step (1) is to cool to 0-65°C, preferably room temperature-40°C; more preferably room temperature.

7. The preparation method according to claim 3, characterized in that: The pH value in step (4) is 5.

80.

8. The preparation method according to claim 3, characterized in that: It also includes the steps of filtration, filling, sealing, sterilization and leak detection, specifically: (6) sterilizing and filtering the mixed solution obtained in step (5), filling it into an ampoule bottle, filling it with nitrogen before and after filling, and sealing it by melting; (7) sterilizing the sample obtained in step (6); (8) Perform leak detection and light inspection on the sample obtained in step (7).

9. The preparation method according to claim 8, characterized in that: The time from step (2) to step (5) is no more than 4 hours; the time from step (6) to step (7) is no more than 10 hours, preferably no more than 8 hours.

10. A piracetam injection, characterized in that: Prepared by the following method: (1) Take 65-84% of the water for injection and cool it to 0-65°C; (2) Add the prescribed amount of sodium acetate trihydrate and stir to dissolve; (3) adding the prescribed amount of piracetam and stirring to dissolve; (4) using glacial acetic acid to adjust the pH value of the mixed solution obtained in step (3) to 5.78-5.

81. During the adjustment process, 1 / 2-2 / 3 of the theoretical amount of glacial acetic acid solution is first added at one time, stirred for 1-5 minutes, and then the remaining amount of glacial acetic acid solution is added; the glacial acetic acid is a glacial acetic acid solution with a concentration of 15-60%; (5) Add water for injection to make up to the final volume and stir to mix; The time to complete step (2) to step (5) is no more than 4 hours; (6) sterilizing and filtering the mixed solution obtained in step (5), filling it into an ampoule bottle, filling it with nitrogen before and after filling, and sealing it by melting; (7) sterilizing the sample obtained in step (6); the time from the completion of step (6) to step (7) is no more than 10 hours; (8) Perform leak detection and light inspection on the sample obtained in step (7).

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