A kind of preparation method of famotidine injection

Abstract

The present invention belongs to the field of pharmaceutical preparations, and specifically discloses a method for preparing famotidine injection, which comprises the following steps: 1) taking lactic acid, adding water to dilute it into a solution of 100-300 mg / ml, and then heating it at 80-121°C for 30min-8h to obtain a lactic acid solution; 2) taking water and filling it with nitrogen, adding the lactic acid solution obtained in step 1), nicotinamide, mannitol, famotidine and vitamin C to dissolve, adjusting the pH value to 5.8-6.2, supplementing the remaining water, mixing well, filtering, and obtaining. When the famotidine injection prepared by the present invention is stored at room temperature and under accelerated conditions, the pH does not decrease, the content and related substances remain stable, the color remains colorless, and it has practical promotion and application value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of famotidine injection. Background Art

[0002] Famotidine is an H2 receptor blocker of the guanidine thiazole type, which has the characteristics of high affinity for H2 receptors, significantly inhibits gastric acid secretion, and inhibits basal secretion and the increase of gastric acid and pepsin caused by various stimuli. Famotidine is a basic compound with a pKa value of about 7.1, which is easily soluble in acidic conditions but has poor stability. It is extremely difficult to dissolve in neutral and alkaline solutions (solubility is below 0.1 w / v%). Therefore, in order to develop a famotidine injection with high solubility and good stability, excipients that can improve the solubility of famotidine need to be selected.

[0003] Currently, the commercially available famotidine injections are mainly as follows. In the United States, the famotidine injection produced by Merck is mainly representative. Aspartic acid is added as a solubilizer in its formulation, and the product has poor stability and needs to be stored at 2 - 8°C. In Japan, there are 2 types. One is the original developed formulation of famotidine injection produced by LTL Company, and the trade name is Its solubilizing substance is nicotinamide, and its formulation composition and preparation method are disclosed in Patent CN100438871C. The other is a generic famotidine injection solubilized with acetic acid, and this famotidine injection is packed in a plastic ampoule bottle with an oxygen scavenger in a barrier package. The formulation of the famotidine injection in the Chinese market is unknown, but generally, it is a formulation containing aspartic acid or propylene glycol. On April 16, 2020, the Expert Committee on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs of the National Medical Products Administration reviewed and determined, and issued the Catalogue of Reference Preparations for Generic Drugs (the 25th batch). Among them, the famotidine injection produced by LTL Pharma Co., Ltd. in Japan is announced at No. 25 - 6, and the trade name is as the reference preparation; at the same time, on May 14, 2020, the Center for Drug Evaluation of the National Medical Products Administration issued the "Announcement on Carrying out the Work of Consistency Evaluation of the Quality and Efficacy of Generic Chemical Injections", which means that the famotidine injections produced by domestic manufacturers must use as the target for research, and their formulations and processes must be kept consistent.

[0004] Referring to the The instructions state that the prescription composition is that each 1 ml of injection contains 10 mg of famotidine, 50 mg of nicotinamide, 1 mg of ascorbic acid, 20 mg of D-mannitol, and appropriate amounts of lactic acid / pH regulator / water for injection. The research was conducted according to the preparation process of CN100438871C. The results showed that the stability of the prepared famotidine injection product was inferior to that of the reference preparation. The samples were placed at 50°C, 40°C and 25°C for 1 month, and the pH of the product decreased from 6.0 to 5.4-5.6, and the color changed from colorless to light yellow to yellow. The trend of increase in related substances and decrease in content was higher than that of the reference preparation. Summary of the invention

[0005] To solve the above problems, the present invention provides a method for preparing famotidine injection, which is prepared from famotidine and an auxiliary material containing lactic acid; the pretreatment method of the lactic acid is: firstly diluting the lactic acid with water to form a solution of 100-300 mg / ml, and heating at 80-121°C for 30min-8h to obtain a lactic acid solution.

[0006] Furthermore, the method specifically includes the following steps:

[0007] 1) Take lactic acid, dilute it with water to a solution of 100-300 mg / ml, and heat it at 80-121°C for 30 min-8 h to obtain a lactic acid solution;

[0008] 2) taking water and filling it with nitrogen, adding the lactic acid solution obtained in step 1), nicotinamide, mannitol, famotidine and ascorbic acid to dissolve, adjusting the pH value to 5.8-6.2, adding the remaining amount of water, filtering, and obtaining;

[0009] Each 100 ml of the famotidine injection contains 0.5-1.5 g, 2.5-7.5 g, 1-3 g, 0.05-0.15 g, and 0.25-0.45 g of famotidine, nicotinamide, mannitol, ascorbic acid, and lactic acid.

[0010] Furthermore, in step 1), the lactic acid is diluted with water to form a solution of 200-300 mg / ml; preferably, the lactic acid is diluted with water to form a solution of 200 mg / ml.

[0011] Furthermore, in step 1), the lactic acid solution is heated to 80° C. for 2 to 8 hours; or, the lactic acid solution is heated to 121° C. for 30 minutes to 2 hours.

[0012] Furthermore, in step 1), the lactic acid solution is heated to 80° C. for 8 hours; or, the lactic acid solution is heated to 121° C. for 2 hours.

[0013] Furthermore, in step 2), 80% of the formula amount of water is dissolved, and then the remaining amount of water is added; the temperature of the water is 20-30°C.

[0014] Furthermore, in step 2), nitrogen is added until the dissolved oxygen value is less than 1 ppm.

[0015] Furthermore, in step 2), the filtration is firstly filtered through a 0.45 μm + 0.22 μm PVDF filter, and then filtered through a 0.45 μm + 0.22 μm PVDF filter.

[0016] Furthermore, the solution for adjusting the pH in step 2) is a sodium hydroxide solution with a concentration of 0.1 to 5 mol / L, preferably 1 mol / L.

[0017] Furthermore, the famotidine injection contains 10 mg / ml famotidine, 50 mg / ml nicotinamide, 20 mg / ml mannitol, 1 mg / ml ascorbic acid, and 3.5 mg / ml lactic acid.

[0018] The mass percentage concentration of the "lactic acid" described in the present invention is 90% (m / m). Unless otherwise specified, the "lactic acid" can be selected from DL-lactic acid, L-lactic acid and D-lactic acid; preferably DL-lactic acid.

[0019] The present invention is through comparing the reference preparation The analysis of the prescription found that the source of lactic acid affected the solubility and stability of famotidine injection. In order to prepare famotidine injection with good stability according to the prescription, the lactic acid raw material must come from a specific supplier in Japan. This makes it difficult for famotidine injection that meets the generic drug evaluation standards to be successfully prepared by manufacturers that cannot obtain this specific lactic acid.

[0020] The method for preparing famotidine injection provided by the present invention comprises the following steps: heating a lactic acid aqueous solution at a specific temperature for a specific time, and then dissolving the solution in water with famotidine, nicotinamide, ascorbic acid and D-mannitol under nitrogen flow; when the prepared famotidine injection is stored at room temperature and under accelerated conditions, the pH value will not decrease, the color remains colorless, the contents of related substances and famotidine do not change significantly, the quality is stable, and the evaluation standards for generic drugs can be met without the need for lactic acid from a specific source, thereby having practical promotion and application value.

[0021] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Detection spectrum of related substances

[0023] Figure 2 Lactic acid monomer content detection spectrum in Comparative Example 1

[0024] Figure 3 Detection spectrum of lactic acid monomer content in Example 1 DETAILED DESCRIPTION

[0025] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0026] The raw materials, reagents and equipment used in the present invention can all be obtained through commercial purchase.

[0027] In the present invention, when it is described as "lactic acid is added to distilled water to make 200 mg / ml", it means that 90% (m / m) lactic acid is diluted with water so that 200 mg of 90% lactic acid is contained in 1 ml of the solution.

[0028] Embodiment 1 Famotidine injection of the present invention

[0029] prescription:

[0030]

[0031] Preparation method:

[0032] 1) Preparation of 1 mol / L sodium hydroxide: weigh 300 g of sodium hydroxide, slowly add it into a 10 L stainless steel barrel containing 7200 g of water for injection, and stir to dissolve;

[0033] Preparation of lactic acid: weigh 1.75 kg of lactic acid into a 10 L sealable stainless steel pressure vessel, add water for injection to 8.75 kg to make a 200 mg / ml lactic acid solution, seal, and heat at 121 °C for 2 h;

[0034] 2) Liquid preparation: Add 80% of the injection water in the batch into the liquid preparation tank, cool to 20-30°C, start stirring (the speed is set to 20-50HZ), and fill with nitrogen until the dissolved oxygen value is less than 1ppm;

[0035] 3) Add the lactic acid obtained in step 1), 25 kg nicotinamide, and 10 kg mannitol, and stir for 5-10 minutes until completely dissolved;

[0036] 4) Add 5 kg of famotidine and stir until completely dissolved;

[0037] 5) Add 500 g of ascorbic acid and stir until completely dissolved;

[0038] 6) Use 1 mol / L sodium hydroxide to adjust the solution to 5.8-6.2;

[0039] 7) Add water for injection to 500L and continue stirring for no less than 5 minutes;

[0040] 8) Filtration: The drug solution is filtered through a 0.45 μm + 0.22 μm PVDF filter into a receiving tank; then the drug solution is filtered through a 0.45 μm + 0.22 μm PVDF filter into a buffer tank;

[0041] 9) Filling: Take the ampoule and fill it with the liquid medicine, the filling volume is 2ml / bottle, nitrogen is filled and sealed during the filling process.

[0042] Embodiment 2 Famotidine injection of the present invention

[0043] prescription:

[0044]

[0045] Preparation method:

[0046] 1) Take the prescribed amount of lactic acid, add distilled water to make it 200 mg / ml, and heat it at 121°C for 30 minutes;

[0047] 2) Add 160 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0048] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0049] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0050] 5) Add distilled water to 200 ml and stir evenly;

[0051] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0052] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0053] Example 3 Famotidine injection of the present invention

[0054] prescription:

[0055]

[0056] Preparation method:

[0057] 1) Take the prescribed amount of lactic acid, add distilled water to make a 200 mg / ml lactic acid solution, and heat at 121°C for 1 h;

[0058] 2) Add 160 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0059] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0060] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0061] 5) Add distilled water to 200 ml and stir evenly;

[0062] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0063] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0064] Embodiment 4 Famotidine injection of the present invention

[0065] prescription:

[0066]

[0067]

[0068] Preparation method:

[0069] 1) Take the prescribed amount of lactic acid, add distilled water to make a 300 mg / ml lactic acid solution, and heat at 121°C for 30 min;

[0070] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0071] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0072] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0073] 5) Add distilled water to 100 ml and stir evenly;

[0074] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0075] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0076] Example 5 Famotidine injection of the present invention

[0077] prescription:

[0078]

[0079] Preparation method:

[0080] 1) Take the prescribed amount of lactic acid, add distilled water to make a 200 mg / ml lactic acid solution, and heat at 80°C for 2 h;

[0081] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0082] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0083] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0084] 5) Add distilled water to 100 ml and stir evenly;

[0085] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0086] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0087] Example 6 Famotidine injection of the present invention

[0088] prescription:

[0089]

[0090] Preparation method:

[0091] 1) Take the prescribed amount of lactic acid, add distilled water to make a 200 mg / ml lactic acid solution, and heat at 80°C for 8 hours;

[0092] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0093] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0094] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0095] 5) Add distilled water to 100 ml and stir evenly;

[0096] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0097] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0098] Example 7 Famotidine injection of the present invention

[0099] prescription:

[0100]

[0101] Preparation method:

[0102] 1) Take the prescribed amount of lactic acid, add distilled water to make a 200 mg / ml lactic acid solution, and heat at 121°C for 2 hours;

[0103] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid solution treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0104] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0105] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0106] 5) Add distilled water to 100 ml and stir evenly;

[0107] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0108] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0109] Comparative Example 1

[0110] prescription:

[0111]

[0112]

[0113] Preparation method:

[0114] 1) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the prescribed amount of DL-lactic acid, and continue to add the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir until completely dissolved;

[0115] 2) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0116] 3) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0117] 4) Add distilled water to 100 ml and stir evenly;

[0118] 5) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0119] 6) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0120] Comparative Example 2

[0121] prescription:

[0122]

[0123] Preparation method:

[0124] 1) Take the prescribed amount of lactic acid and add distilled water to dilute it into a 100 mg / ml lactic acid aqueous solution;

[0125] 2) Add 1g of famotidine, 5g of nicotinamide, and 2g of mannitol to a 200ml beaker, add 75ml of distilled water, 6.1ml of a 100mg / ml lactic acid aqueous solution, and 3ml of 1mol / L sodium hydroxide, and stir to dissolve.

[0126] 3) After famotidine is dissolved, add 0.1 g of ascorbic acid while passing nitrogen into the solution to dissolve it;

[0127] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 6.1;

[0128] 5) Add distilled water to 100 ml and stir evenly;

[0129] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0130] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0131] Comparative Example 3

[0132] prescription:

[0133]

[0134] Preparation method:

[0135] 1) Take the prescribed amount of lactic acid, add distilled water to make a 200 mg / ml lactic acid solution, and heat at 121°C for 2 hours;

[0136] 2) Add 80 ml of distilled water to a 200 ml beaker, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0137] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0138] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0139] 5) Add distilled water to 100 ml and stir evenly;

[0140] 6) Filter the drug solution with a 0.22 μm sterilizing filter;

[0141] 7) Fill the drug solution (2 ml / bottle) into a 2 ml colorless medium borosilicate ampoule, and immediately seal the ampoule after filling to obtain the prepared famotidine injection without nitrogen filling.

[0142] Comparative Example 4

[0143] prescription:

[0144]

[0145]

[0146] The preparation method comprises the following steps:

[0147] 1) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add 0.35 g of L-lactic acid, and continue to add the prescribed amount of nicotinamide, mannitol, and famotidine API, stirring until completely dissolved;

[0148] 2) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0149] 3) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0150] 4) Add distilled water to 100 ml and stir evenly;

[0151] 5) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0152] 6) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0153] Comparative Example 5

[0154] prescription:

[0155]

[0156] Preparation method:

[0157] 1) Take the prescribed amount of lactic acid and add distilled water to make it 200 mg / ml;

[0158] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid diluted in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir until completely dissolved;

[0159] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0160] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0161] 5) Add distilled water to 100 ml and stir evenly;

[0162] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0163] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0164] Comparative Example 6

[0165] prescription:

[0166]

[0167] Preparation method:

[0168] 1) Take the prescribed amount of lactic acid, add distilled water to make it 200 mg / ml, and heat at 40℃ for 4h;

[0169] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0170] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0171] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0172] 5) Add distilled water to 100 ml and stir evenly;

[0173] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0174] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0175] Comparative Example 7

[0176] prescription:

[0177]

[0178] Preparation method:

[0179] 1) Take the prescribed amount of lactic acid, add distilled water to make it 200 mg / ml, and heat at 60℃ for 2h;

[0180] 2) Add 80 ml of distilled water to a 200 ml beaker, fill with nitrogen until the dissolved oxygen value is less than 1 ppm, add the lactic acid treated in step 1), the prescribed amount of nicotinamide, mannitol, and famotidine API, and stir to completely dissolve;

[0181] 3) Add the prescribed amount of ascorbic acid and stir until completely dissolved;

[0182] 4) Use 1 mol / L sodium hydroxide to adjust the pH of the solution to 5.8-6.2;

[0183] 5) Add distilled water to 100 ml and stir evenly;

[0184] 6) Filter the drug solution with a 0.22 μm sterilizing filter and continue to fill with nitrogen;

[0185] 7) Flushing a 2 ml colorless medium borosilicate ampoule with nitrogen and filling it with the drug solution (2 ml / bottle), flushing it with nitrogen again after filling, and immediately sealing the ampoule with nitrogen to obtain famotidine injection.

[0186] The beneficial effects of the present invention are further illustrated by test examples below.

[0187] Test Example 1 Quality Test of Famotidine Injection

[0188] 1. Methods

[0189] Take three batches of commercial products Conduct quality inspections;

[0190] The famotidine injections prepared in Examples 1 to 6 and Comparative Examples 1 to 7 were stored in environments with different temperatures for 1 month, and then samples were taken to observe the appearance of the injections, and the contents of lactic acid monomer, famotidine and its related substances were detected. The specific quality detection method is as follows:

[0191] 1) Lactic acid monomer content detection method

[0192] Flow rate: lml / min

[0193] Column temperature: 40°C

[0194] Detection wavelength: 210nm

[0195] Injection volume: 10 μl

[0196] Chromatographic column: YMC-Pack ODS-AQ 4.6mm×250mm, 5μm

[0197] Mobile phase A: Weigh 4.950 g of tetramethylammonium hydroxide in 400 ml of H2O, adjust the pH to 2.01 with phosphoric acid, dilute to 450 ml with water, filter, add 50 ml of acetonitrile, mix, and obtain by ultrasonication.

[0198] Mobile phase B: Weigh 4.958 g of tetramethylammonium hydroxide into 150 ml of H2O, adjust the pH to 1.97 with phosphoric acid, dilute with water to 200 ml, filter, add 300 ml of acetonitrile, mix, and obtain by ultrasonication.

[0199] Diluent: Measure 450 ml of water, adjust the pH to 3.51 with glacial acetic acid, add 50 ml of acetonitrile and mix well.

[0200] The gradient program is as follows:

[0201] T(min) A％ B％ 0 90 10 24 30 70 29 30 70 30 90 10 35 90 10

[0202] 2) Famotidine injection content detection method

[0203] Column: Kromasil C18, 4.6 mm × 250 mm, 5 μm

[0204] Flow rate: 1.5ml / min

[0205] Column temperature: 35°C

[0206] Injection volume: 20 μl

[0207] Detection wavelength: 270nm

[0208] Mobile phase: Acetate buffer (take 13.6g of sodium acetate, put it in 900ml of water, adjust the pH to 6.0±0.2 with glacial acetic acid, and add water to 1000ml)

[0209] 3) Detection methods of related substances in famotidine injection

[0210] Column: Kromasil C18, 4.6 mm × 250 mm, 5 μm

[0211] Flow rate: 1.5ml / min

[0212] Column temperature: 35°C

[0213] Injection volume: 20 μl

[0214] Detection wavelength: 270nm

[0215] Mobile phase A: Acetate buffer (take 13.6g of sodium acetate, put it in 900ml of water, adjust the pH to 6.0±0.2 with glacial acetic acid, and add water to 1000ml)

[0216] Mobile phase B: acetonitrile

[0217] Gradient elution was as follows:

[0218]

[0219] 2. Results

[0220] Commercially available products The test results are shown in Table 1. Figure 1 The test results of famotidine injection obtained by different preparation methods are shown in Tables 1 to 4. Figures 2-3 .

[0221] The lactic acid monomer content refers to the mass percentage of lactic acid monomer in lactic acid.

[0222] Table 1 Test results of famotidine injection on day 0

[0223]

[0224] Table 2 Stability results of famotidine injection at 50℃ for 1 month

[0225]

[0226]

[0227] Table 3 Stability results of famotidine injection at 40°C for 1 month

[0228]

[0229] Table 4 Results of famotidine injection at 25°C for 1 month

[0230]

[0231]

[0232] From the above results, it can be seen that: ① When preparing famotidine injection, the lactic acid is diluted to a certain concentration and heated, and the lactic acid monomer content is higher than that of the lactic acid that has not been heated; during the stability storage period, the pH value of the famotidine injection prepared after dilution and heating of lactic acid did not show an obvious downward trend, the change trend of related substances and contents was smaller, and the quality was more stable.

[0233] ② During the stability storage period, the pH of the famotidine injection prepared without lactic acid treatment showed a significant downward trend, and the related substances showed a significant increase and decrease in content.

[0234] ③ After heating lactic acid, famotidine injection was prepared without nitrogen filling. During the stability storage period, the pH did not show a downward trend, but the color of the solution changed significantly.

Claims

1. A method for preparing famotidine injection, characterized in that: It specifically includes the following steps: 1) Take lactic acid, dilute it with water to make a 200 mg / ml solution, heat it at 80°C for 2 hours, or heat it at 121°C for 30 minutes to obtain a lactic acid solution; 2) Take water and fill it with nitrogen, add the lactic acid solution obtained in step 1), nicotinamide, mannitol, famotidine and ascorbic acid to dissolve, adjust the pH value to 5.8-6.2, add the remaining amount of water, filter, and obtain; Each 100 ml of the famotidine injection contains 10 mg / ml of famotidine, 50 mg / ml of nicotinamide, 20 mg / ml of mannitol, 1 mg / ml of ascorbic acid, and 3.5 mg / ml of lactic acid.

2. The preparation method according to claim 1, characterized in that In step 2), 80% of the formula amount of water is dissolved, and then the remaining amount of water is added; the temperature of the water is 20-30°C.

3. The preparation method according to claim 1, characterized in that: Step 2) The nitrogen is filled until the dissolved oxygen value is less than 1 ppm.

4. The preparation method according to claim 1, characterized in that: Step 2) The filtration is first through a 0.45 μm + 0.22 μm PVDF filter, and then through a 0.45 μm + 0.22 μm PVDF filter; the solution for adjusting the pH value is a sodium hydroxide solution with a concentration of 1 mol / L.

5. The preparation method according to any one of claims 1 to 4, characterized in that The lactic acid is selected from the group consisting of DL-lactic acid, L-lactic acid and D-lactic acid.

6. The preparation method according to claim 5, characterized in that: The lactic acid is DL-lactic acid.

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