Preparation method of ertapenem sodium for injection

Abstract

The present invention relates to the technical field of medical, dental, or cosmetic preparations, and in particular to a method for preparing ertapenem sodium for injection. The preparation method comprises: S1, adding a prescribed amount of sodium bicarbonate to water, cooling and stirring to obtain a sodium bicarbonate solution; S2, adding half the prescribed amount of ertapenem sodium to water, stirring at low temperature to dissolve, then adding the sodium bicarbonate solution, then adding the remaining ertapenem sodium, adjusting the pH with sodium hydroxide solution, adding modified magnolol, adding water to a fixed amount, sterile filtering, packaging, and freeze-drying to obtain the product. This method provides a more stable preparation, thereby ensuring its stability during the preparation process, transportation, and long-term storage.

Description

Technical Field

[0001] The present invention relates to the technical field of medical, dental or cosmetic preparations, and in particular to a preparation method of ertapenem sodium for injection. Background Art

[0002] Ertapenem sodium is a carbapenem antibiotic, chemically named (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]thio-6-(1R-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt. In its molecular structure, the methyl group at the C-1 position of the nucleus confers strong resistance to renal dehydropeptidase-I (DHP-I); the trans-hydroxyethyl group at the C-6 position provides strong resistance to lactamase; and the benzoic acid group on the C-2 side chain has strong electron-withdrawing properties, enabling broad protein binding and extending the drug's half-life. These structural features contribute to ertapenem's excellent broad-spectrum antibacterial activity and pharmacokinetic properties, along with a long half-life and the need for co-administration with drugs that inhibit DHP-I. It has a wide range of antibacterial activity, including against Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria. Its main mechanism of action is to inhibit the synthesis of bacterial cell walls and bind to penicillin-binding proteins (PBPs) to exert a bactericidal effect. Ertapenem is stable to a variety of β-lactamases, but can be hydrolyzed by metallo-β-lactamases. The indications of ertapenem sodium include the treatment of moderate to severe infections caused by sensitive strains, such as secondary abdominal infections, complicated skin and appendage infections, community-acquired pneumonia, complicated urinary tract infections (including pyelonephritis), acute pelvic infections and bacteremia.

[0003] CN109134469A relates to a solid pharmaceutical composition of ertapenem sodium and a method for preparing the same. The composition comprises ertapenem sodium represented by Formula 1, a compound represented by Formula 2, or its sodium salt, hydrate, or solvate, and pharmaceutically acceptable excipients. The solid pharmaceutical composition of ertapenem sodium provided by this invention contains the compound represented by Formula 2, or its pharmaceutically acceptable salt, hydrate, or solvate, accounting for over 80%, significantly improving the stability of the final ertapenem sodium formulation.

[0004] CN116196272A relates to an ertapenem preparation and its preparation method, comprising the following steps: 1) dissolving sodium bicarbonate in water to obtain a sodium bicarbonate solution; 2) mixing i) the sodium bicarbonate solution obtained in step 1), ii) ertapenem sodium or its solution, and iii) sodium hydroxide or its solution at a temperature of 0-5°C to prepare a solution, controlling the pH of the solution to 7.0-7.5, thereby obtaining an ertapenem solution; 3) adjusting the pH of the ertapenem solution obtained in step 2) to 7.5-8.0 using sodium hydroxide solution; and 4) obtaining the ertapenem preparation. The ertapenem preparation obtained by improving the formulation and preparation process significantly reduces degradation of the raw material ertapenem sodium, significantly reduces impurity content, and improves stability. Furthermore, the ertapenem freeze-dried preparation prepared by further improving the freeze-drying process exhibits uniform crystal nuclei size, good properties, and significantly improved preparation stability.

[0005] Ensuring the stability of ertapenem sodium is a challenge because it easily decomposes under acid, alkali, high temperature, as well as oxidation and hydrolysis conditions. Its main decomposition products include open-ring compounds and dimers. During the formulation process, the stability of this compound may be affected by factors such as temperature, addition order, and pH adjustment, leading to increased impurity levels. In addition, the entire supply chain from production to pre-use, including transportation and storage, as well as actual use, the formulation may be at risk of degradation, which may lead to further increases in impurity levels. To improve the quality and stability of ertapenem sodium formulations, improvements need to be made to the existing preparation methods to reduce factors that may affect product quality throughout the supply chain. This includes optimizing the production process, improving transportation and storage conditions, and ensuring stability during use. Through these measures, degradation and impurity formation can be minimized, thereby ensuring the safety and efficacy of the formulation. Summary of the Invention

[0006] In view of the above-mentioned defects in the prior art, the technical problem to be solved by the present invention is to provide a preparation method of ertapenem sodium for injection.

[0007] Studies have shown that ertapenem sodium is unstable under conditions such as acid, alkali, oxidation, high temperature, and light. The main degradation product is a ring-opening degradation product. It is also unstable after being formulated into an aqueous solution. With the increase of storage time, the content of impurities such as ring-opening degradation products and polymers increases significantly, and the content of the main component decreases significantly. Therefore, the present invention provides an antioxidant - magnolol is one of the main active ingredients of magnolia bark. Magnolia bark has significant antioxidant capacity, can inhibit various intermediates produced during the oxidative stress process, and can also capture peroxyl radicals. The phenolic hydroxyl group in its molecular structure can donate hydrogen atoms to free radicals, thereby neutralizing free radicals and reducing oxidative stress. Therefore, magnolol and its derivatives have broad application prospects in the fields of medicine and health products, especially in terms of anti-oxidation. As a natural antioxidant, it is also safer than other commonly used antioxidants. However, magnolol is poorly soluble in water, so its effectiveness in aqueous solutions is greatly limited. In the present invention, magnolol is modified and a nitrogen heterocycle is grafted onto the magnolol. Since the nitrogen atom on the nitrogen heterocycle has a lone pair of electrons and can form hydrogen bonds with water molecules, the hydrophilicity is good. After grafting, the water solubility of magnolol can be improved. The modified magnolol is added to ertapenem sodium for injection to play an antioxidant role, thereby reducing the oxidative degradation of ertapenem sodium and enhancing the stability of the preparation.

[0008] To achieve the above object, the present invention provides a method for preparing ertapenem sodium for injection, comprising the following steps:

[0009] S1. Add the prescribed amount of sodium bicarbonate to water and cool it to 0-5°C to obtain a sodium bicarbonate solution;

[0010] S2. Add half of the prescribed amount of ertapenem sodium to water, stir and dissolve at 0-5°C, then add sodium bicarbonate solution, and then add the remaining ertapenem sodium. Adjust the pH to 7.3-7.6 with sodium hydroxide solution, add modified magnolol, add water to the quantitative amount, and stir evenly. After sterile filtration, divide the package and freeze-dry to obtain ertapenem sodium for injection.

[0011] The preparation method of the modified magnolol comprises the following steps:

[0012] X1. Add 2-6 parts by weight of magnolol, 0.4-1 parts by weight of sodium hydroxide and 0.6-1.5 parts by weight of 37% formaldehyde solution to 20-50 parts by weight of ethanol, stir at room temperature for 20-30 hours, add ethyl acetate for extraction, separate the organic phase, wash with brine, dry, concentrate under reduced pressure to remove the solvent, and then purify by silica gel column and dissolve in 10-30 parts by weight of dichloromethane. After cooling to 0-5°C, add 1-3 parts by weight of thionyl chloride dropwise. After stirring at room temperature for 0.5-1 hour, add saturated sodium bicarbonate aqueous solution for washing, dry, filter, concentrate under reduced pressure to remove the solvent, and then add to 8-25 parts by weight of acetonitrile. Continue to add 0.6-2 parts by weight of 4-Boc-aminopiperidine, 1-3 parts by weight of cesium carbonate and 0.01-0.05 parts by weight of potassium iodide. After heating and stirring for 16-24 hours, cool to room temperature, dilute with water and extract with ethyl acetate. The combined organic phases are washed with brine, dried and purified by silica gel column for the next step.

[0013] X2. Dissolve 3 to 5 parts by weight of the product from the previous step in 10 to 30 parts by weight of dichloromethane, add 0.2 to 0.5 parts by weight of trifluoroacetic acid at 0 to 5°C, stir for 0.5 to 1 hour, and then remove the solvent to obtain a residue. Add the residue to a saturated aqueous sodium bicarbonate solution and extract with ethyl acetate. Wash the organic phase with brine, dry it, and concentrate it under reduced pressure to remove the solvent. Then, purify it on a silica gel column to obtain modified magnolol.

[0014] Furthermore, the temperature range of the heating in step X1 is 70-80°C.

[0015] Furthermore, the prescription amount of the sodium bicarbonate is 185 to 200 g.

[0016] Furthermore, the prescription amount of ertapenem sodium is 1045-1155g.

[0017] Furthermore, the concentration of the sodium hydroxide solution is 1 mol / L.

[0018] Furthermore, the added amount of the modified magnolol is 0.05-0.1 wt % of the total amount.

[0019] Furthermore, the final quantitative amount of water is 11000 g.

[0020] Furthermore, the packaging is 11 g per bottle.

[0021] Furthermore, the sterilizing filtration membrane is 0.22 to 0.24 μm.

[0022] Beneficial effects of the present invention:

[0023] 1. Compared with the prior art, the present invention obtains a preparation with better stability by adding modified magnolol in the preparation of ertapenem sodium injection, thereby ensuring its stability during the preparation process, transportation, and long-term storage.

[0024] 2. The present invention modifies magnolol and grafts a nitrogen heterocycle onto the magnolol. Since the nitrogen atom on the nitrogen heterocycle has a lone pair of electrons and can form hydrogen bonds with water molecules, it has good hydrophilicity. After grafting, the water solubility of magnolol can be improved. Adding the modified magnolol to ertapenem sodium for injection can play an antioxidant role, thereby reducing the oxidative degradation of ertapenem sodium and enhancing the stability of the preparation. DETAILED DESCRIPTION

[0025] Example 1

[0026] A method for preparing ertapenem sodium for injection comprises the following steps:

[0027] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5°C to obtain a sodium bicarbonate solution;

[0028] S2: Add 570 g of ertapenem sodium to 7 L of water for injection, stir and dissolve at 5°C, then add sodium bicarbonate solution, then add 570 g of ertapenem sodium, adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution, add modified magnolol in an amount of 0.05 wt%, add water to a quantitative amount of 11,000 g, and stir evenly. After sterile filtration through a 0.22 μm filter membrane, divide into 11 g bottles and freeze-dry to obtain ertapenem sodium for injection.

[0029] The preparation method of the modified magnolol comprises the following steps:

[0030] X1, magnolol 2.5g, sodium hydroxide 0.4g, 37% formaldehyde solution 0.6g were added to 30g ethanol, stirred at room temperature for 24h, and then ethyl acetate was added for extraction. After separation of the organic phase, the mixture was washed with brine, dried, and concentrated under reduced pressure to remove the solvent, and then purified by silica gel column and dissolved in 25g dichloromethane. After cooling to 0°C, thionyl chloride 1g was added dropwise. After completion of the addition, the mixture was stirred at room temperature for 0.5h, saturated sodium bicarbonate aqueous solution was added, washed, dried, and filtered. After removal of the solvent, the mixture was concentrated under reduced pressure and then added to 20g acetonitrile. 4-Boc-aminopiperidine 0.7g, cesium carbonate 1.4g, and potassium iodide 0.01g were added. After heating to 75°C and stirring for 18h, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried, and purified by silica gel column for the next step.

[0031] X2. Dissolve 3 g of the product from the previous step in 30 g of dichloromethane, add 0.3 g of trifluoroacetic acid at 0°C, stir for 0.5 h, and remove the solvent to obtain a residue. Add the residue to a saturated aqueous sodium bicarbonate solution and extract with ethyl acetate. Wash the organic phase with brine, dry it, and concentrate it under reduced pressure to remove the solvent. Purify it on a silica gel column to obtain modified magnolol.

[0032] Example 2

[0033] The process is basically the same as Example 1, except that the amount of modified magnolol added is 0.06 wt %.

[0034] Example 3

[0035] The process is basically the same as Example 1, except that the amount of modified magnolol added is 0.08 wt %.

[0036] Example 4

[0037] The process is basically the same as Example 1, except that the amount of modified magnolol added is 0.1 wt %.

[0038] Comparative Example 1

[0039] A method for preparing ertapenem sodium for injection comprises the following steps:

[0040] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5°C to obtain a sodium bicarbonate solution;

[0041] S2: Add 570 g of ertapenem sodium to 7 L of water for injection, stir and dissolve at 5°C, then add sodium bicarbonate solution, then add 570 g of ertapenem sodium, adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution, add water to a quantitative volume of 11,000 g, and stir evenly. After sterile filtration through a 0.22 μm filter membrane, divide the volume into 11 g per bottle and freeze-dry to obtain ertapenem sodium for injection.

[0042] Comparative Example 2

[0043] A method for preparing ertapenem sodium for injection comprises the following steps:

[0044] S1. Add 200 g of sodium bicarbonate to 1 L of water for injection and cool to 5°C to obtain a sodium bicarbonate solution;

[0045] S2: Add 570 g of ertapenem sodium to 7 L of water for injection, stir and dissolve at 5°C, then add sodium bicarbonate solution, then add 570 g of ertapenem sodium, adjust the pH to 7.5 with 1 mol / L sodium hydroxide solution, add magnolol in an amount of 0.05 wt%, add water to a quantitative amount of 11,000 g, and stir evenly. After sterile filtration through a 0.22 μm filter membrane, divide the mixture into 11 g bottles and freeze-dry to obtain ertapenem sodium for injection.

[0046] Test Example 1

[0047] The ertapenem sodium for injection prepared in the Examples and Control Examples was added to water for injection to prepare a 1 mg / mL solution. After preparation, the content of each active ingredient was determined by HPLC. The content of the active ingredient was also determined after standing at room temperature for 1, 3, and 6 months. The test results are shown in Table 1.

[0048] Table 1 Stability test results of ertapenem sodium aqueous solution for injection

[0049]

[0050]

[0051] Studies have shown that ertapenem sodium is unstable under conditions such as acid, alkali, oxidation, high temperature, and light. Its main degradation product is a ring-opening degradation product, and it is also unstable after being formulated into an aqueous solution. As can be seen from the data in Table 1, the content of impurities such as ring-opening degradation products and polymers increases significantly with increasing storage time, and the total impurities also increase significantly. Comparing the Example with the Reference Example 1, it was found that the degradation of ertapenem sodium was significantly slowed after the addition of modified magnolol as an antioxidant. This may be due to the significant antioxidant capacity of magnolol, which can inhibit various intermediates produced during oxidative stress and also capture peroxyl radicals. The phenolic hydroxyl groups in its molecular structure can donate hydrogen atoms to free radicals, thereby neutralizing them and reducing oxidative stress. Therefore, the ertapenem sodium aqueous solution in the Example is more stable. The aqueous solution in the Example is also more stable than that in the Reference Example 2. This may be due to the poor solubility of magnolol in water, which greatly limits its effectiveness in aqueous solutions, making it difficult to exert its antioxidant properties in aqueous solutions. In the examples, the present invention modifies magnolol by grafting a nitrogen heterocycle onto it. Because the nitrogen atoms on the nitrogen heterocycle have lone pairs of electrons and can form hydrogen bonds with water molecules, the hydrophilicity is improved. The grafting can increase the water solubility of magnolol. Therefore, the modified magnolol has a stronger effect on enhancing the stability of the formulation. The stability difference between Example 1 and the other examples is not significant. Therefore, considering comprehensive cost and other aspects, the dosage in Example 1 is the optimal.

[0052] Test Example 2

[0053] The long-term toxicity test of the ertapenem sodium for injection prepared in the examples and control examples was carried out. Healthy SD rats weighing (135±10) g were taken, 30 in each group, half male and half female. The experimental group was intravenously administered at a dose of 20 mg / kg per day, and the blank control group was injected with an equal amount of normal saline. One week of observation before administration showed no abnormalities in the activities, eating, feces, etc. of the animals in each group, and then administration began. The rats were administered once a day on time for 60 consecutive days, and the body weights were weighed once a week. The dosage was adjusted according to the changes in body weight. General observations such as appearance signs, behavioral activities, fecal characteristics, food intake, and changes in body weight were performed. After the end of the medication, blood was taken from the eyeballs for hemogram and blood biochemistry examinations, and the five organs of the heart, liver, spleen, lungs, and kidneys were weighed to calculate the organ weight ratio.

[0054] The test results show that the ertapenem sodium injection preparation prepared by the present invention has no significant effect on the physical signs, behavioral activities, stool characteristics, food intake, and body weight of mice, and the blood count, blood biochemistry, and organs all appear normal.

[0055] The above describes in detail the preferred embodiments of the present invention. It should be understood that those skilled in the art can make numerous modifications and variations based on the concepts of the present invention without inventive effort. Therefore, any technical solutions that can be derived by those skilled in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A method for preparing ertapenem sodium for injection, characterized in that: The steps include: S1. Add the prescribed amount of sodium bicarbonate to water and cool it to 0-5°C to obtain a sodium bicarbonate solution; S2. Add half the prescribed amount of ertapenem sodium to water, stir and dissolve at 0-5°C, then add sodium bicarbonate solution, then add the remaining ertapenem sodium, adjust the pH to 7.3-7.6 with 1 mol / L sodium hydroxide solution, add 0.05-0.1 wt% modified magnolol, add water to the quantitative amount, stir evenly, sterilize and filter, then divide and freeze-dry to obtain ertapenem sodium for injection; The preparation method of the modified magnolol comprises the following steps: X1. Add 2-6 parts by weight of magnolol, 0.4-1 parts by weight of sodium hydroxide and 0.6-1.5 parts by weight of 37% formaldehyde solution to 20-50 parts by weight of ethanol, stir at room temperature for 20-30 hours, add ethyl acetate for extraction, separate the organic phase, wash with brine, dry, concentrate under reduced pressure to remove the solvent, and then purify by silica gel column and dissolve in 10-30 parts by weight of dichloromethane. After cooling to 0-5°C, add 1-3 parts by weight of thionyl chloride dropwise. After stirring at room temperature for 0.5-1 hour, add saturated sodium bicarbonate aqueous solution for washing, dry, filter, concentrate under reduced pressure to remove the solvent, and then add to 8-25 parts by weight of acetonitrile. Continue to add 0.6-2 parts by weight of 4-Boc-aminopiperidine, 1-3 parts by weight of cesium carbonate and 0.01-0.05 parts by weight of potassium iodide. After heating and stirring for 16-24 hours, cool to room temperature, dilute with water and extract with ethyl acetate. The combined organic phases are washed with brine, dried and purified by silica gel column for the next step. X2. Dissolve 3 to 5 parts by weight of the product from the previous step in 10 to 30 parts by weight of dichloromethane, add 0.2 to 0.5 parts by weight of trifluoroacetic acid at 0 to 5°C, stir for 0.5 to 1 hour, and then remove the solvent to obtain a residue. Add the residue to a saturated aqueous sodium bicarbonate solution and extract with ethyl acetate. Wash the organic phase with brine, dry it, and concentrate it under reduced pressure to remove the solvent. Then, purify it on a silica gel column to obtain modified magnolol.

2. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The temperature range of the heating in step X1 is 70-80°C.

3. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The prescription amount of the sodium bicarbonate is 185-200g.

4. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The prescription amount of ertapenem sodium is 1045-1155g.

5. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The final quantitative amount of the water is 11000 g.

6. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The packaging is 11g / bottle.

7. The method for preparing ertapenem sodium for injection according to claim 1, wherein: The sterilizing filtration membrane has a thickness of 0.22 to 0.24 μm.

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