Crystallization process of sulbactam sodium

Abstract

The invention discloses a sulbactam sodium crystallization process, a sulbactam sodium product prepared by the crystallization process is good in fluidity, low in impurity content and good in stability, the product quality can be improved, the medication safety can be guaranteed, the preparation process is simple and rapid, the production cost can be saved, and the sulbactam sodium crystallization process is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a crystallization process of sulbactam sodium. Background Art

[0002] Sulbactam Sodium, chemical name is (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate sodium-4,4-dioxide, and its structural formula is:

[0003]

[0004] Sulbactam sodium is a synthetic, irreversible competitive β-lactamase inhibitor used to treat respiratory system, urinary system, skin and soft tissue, bone and joint infections, abdominal infections, and sepsis. It is effective for peripheral infections of gonococci and meningococci when used alone; sulbactam sodium is used in combination with ampicillin or cefoperazone to treat respiratory tract, urinary tract, obstetrics and gynecology, intra-abdominal, skin and soft tissue, eye, otolaryngology, bone and joint infections, sepsis, meningitis, etc. caused by sensitive bacteria.

[0005] The prior art generally uses a solvent crystallization method to prepare sulbactam sodium, but the raw materials prepared by the existing solvent crystallization method have a high impurity content and poor stability, which affects the product quality. Summary of the invention

[0006] The purpose of the present invention is to provide a crystallization process of sulbactam sodium, which adopts a mixed solvent method for preparation and solves the quality problems of high impurity content and poor stability in the preparation process of sulbactam sodium.

[0007] The technical solution provided by the present invention is a crystallization process of sulbactam sodium, and the crystallization process comprises the following steps:

[0008] 1) Dissolve sodium acetate in a mixed solvent of methanol and water, and stir until dissolved;

[0009] 2) dissolving sulbactam acid in an alcohol solvent;

[0010] 3) Add 1) dropwise into 2) and stir;

[0011] 4) adding ethanol, raising the temperature to a certain temperature for crystallization, then lowering the temperature for crystal growth, and centrifugally drying to obtain sulbactam sodium.

[0012] Preferably, in step 2), the alcohol solvent is at least one of methanol, ethanol or isopropanol, and the mass volume ratio of sulbactam acid to the alcohol solvent is 1:2 to 1:5 g / ml, more preferably 1:2 to 1:4 g / ml; and the dissolution temperature is 20-25°C.

[0013] Preferably, the heating temperature in step 4) is 30-40°C, more preferably 32-36°C; and the crystal growing temperature is 5-10°C.

[0014] Compared with the prior art, the beneficial technical effects of the present invention are:

[0015] (1) Through the crystallization process of sulbactam, the content of impurities in sulbactam sodium is reduced, and the product quality is improved;

[0016] (2) The product prepared by the present invention has better stability and lower degradation impurities, thereby reducing the risk of allergic reactions to antibiotic products during use;

[0017] (3) The process of the present invention is simple to operate, and the prepared product has good fluidity, which is suitable for commercial production. DETAILED DESCRIPTION

[0018] The content of the invention of the present invention is further described in detail below through specific embodiments, but the content of the present invention is not limited thereto.

[0019] Source of sulbactam raw materials: Jiangxi Fuxiang Pharmaceutical Co., Ltd., purity: 99.85%.

[0020] Example 1

[0021] Preparation of sodium acetate solution: Add 300 ml of methanol, 100 ml of water for injection, and 77.4 g of anhydrous sodium acetate into a reaction bottle, heat to 20-25°C, and stir to dissolve.

[0022] Add 600 ml of methanol to another reaction bottle, add 200 g of sulbactam acid under stirring, heat to 20-25°C, and stir to dissolve. Keep the temperature at 20-25°C, slowly add the prepared sodium acetate methanol aqueous solution to the reaction bottle, stir for 30 minutes after the addition, then add 1000 ml of ethanol, stir for 30 minutes, heat the reaction solution to 32-36°C, stir for 6 hours, cool to 5-10°C, grow crystals for 2 hours, filter, wash with 200 ml of ethanol, dry the filter cake at 50-55°C for 5 hours, and discharge to obtain 205.5 g of white powder sulbactam sodium, with a yield of 93.9% and a purity of 99.99%.

[0023] Example 2

[0024] Preparation of sodium acetate solution: Add 300 ml of methanol, 100 ml of water for injection, and 77.4 g of anhydrous sodium acetate into a reaction bottle, heat to 20-25°C, and stir to dissolve.

[0025] Add 800 ml of methanol to another reaction bottle, add 200 g of sulbactam acid under stirring, heat to 20-25°C, and stir to dissolve. Keep the temperature at 20-25°C, slowly add a methanol aqueous solution of sodium acetate to the reaction bottle, stir for 30 minutes after the addition, then add 1000 ml of ethanol, stir for 30 minutes, heat the reaction solution to 32-36°C, stir for 6 hours, cool to 5-10°C, grow crystals for 2 hours, filter, wash with 200 ml of ethanol, dry the filter cake at 50-55°C for 5 hours, and discharge to obtain 202.4 g of white powder sulbactam sodium, with a yield of 92.5% and a purity of 99.99%.

[0026] Example 3

[0027] Preparation of sodium acetate solution: Add 300 ml of methanol, 100 ml of water for injection, and 77.4 g of anhydrous sodium acetate into a reaction bottle, heat to 20-25°C, and stir to dissolve.

[0028] Add 1000 ml of methanol to another reaction bottle, add 200 g of sulbactam acid under stirring, heat to 20-25°C, and stir to dissolve. Keep the temperature at 20-25°C, slowly add a methanol aqueous solution of sodium acetate to the reaction bottle, stir for 30 min after the addition, then add 1000 ml of ethanol, stir for 30 min, heat the reaction solution to 40°C, stir for 6 h, cool to 5-10°C, grow crystals for 2 h, filter, wash with 200 ml of ethanol, dry the filter cake at 50-55°C for 5 h, and discharge to obtain 200 g of white powder sulbactam sodium, with a yield of 91.6% and a purity of 99.95%.

[0029] Example 4

[0030] Preparation of sodium acetate solution: Add 300 ml of methanol, 100 ml of water for injection, and 77.4 g of anhydrous sodium acetate into a reaction bottle, heat to 20-25°C, and stir to dissolve.

[0031] Add 400 ml of ethanol to another reaction bottle, add 200 g of sulbactam acid under stirring, heat to 20-25°C, and stir to dissolve. Keep the temperature at 20-25°C, slowly add a methanol aqueous solution of sodium acetate to the reaction bottle, stir for 30 minutes after the addition, then add 1000 ml of ethanol, stir for 30 minutes, heat the reaction solution to 30°C, stir for 6 hours, cool to 5-10°C, grow crystals for 2 hours, filter, wash with 200 ml of ethanol, dry the filter cake at 50-55°C for 5 hours, and discharge to obtain 204.6 g of white powder sulbactam sodium, with a yield of 93.5% and a purity of 99.98%.

[0032] Example 5

[0033] Preparation of sodium acetate solution: Add 300 ml of methanol, 100 ml of water for injection, and 77.4 g of anhydrous sodium acetate into a reaction bottle, heat to 20-25°C, and stir to dissolve.

[0034] Add 600 ml of isopropanol to another reaction bottle, add 200 g of sulbactam acid under stirring, heat to 20-25 ° C, and stir to dissolve. Keep warm at 20-25 ° C, slowly add a methanol aqueous solution of sodium acetate to the reaction bottle, stir for 30 min after addition, then add 1000 ml of ethanol and stir for 30 min. Heat the reaction solution to 40 ° C, stir for 6 h, cool to 5-10 ° C, grow crystals for 2 h, filter, wash with 200 ml of ethanol, dry the filter cake at 50-55 ° C for 5 h, and discharge to obtain 205.7 g of white powder sulbactam sodium, with a yield of 94.0% and a purity of 99.98%.

[0035] 1. Data on relevant substances

[0036] Experimental method: The products prepared in Examples 1-5 of the present invention and commercially available products (purchased from Hainan Huluwa Pharmaceutical Group Co., Ltd.) were tested for relevant substances, and the test results are shown in Table 1.

[0037] Table 1: Comparison of relevant substance data

[0038] Experimental comparison Related substances Example 1 Impurity A: 0.01%, single impurity: not detected, total impurity 0.01% Example 2 Impurity A: 0.08%, single impurity: not detected, total impurity 0.01% Example 3 Impurity A: Not detected, Single impurity: 0.02%, Total impurities: 0.05% Example 4 Impurity A: 0.02%, single impurity: not detected, total impurity 0.02% Example 5 Impurity A: 0.02%, single impurity: not detected, total impurity 0.02% Commercially available products Impurity A: 0.05%, single impurity: 0.03%, total impurity 0.12%

[0039] As can be seen from Table 1, the product obtained by the present invention has lower related substances, lower single impurities and lower total impurities, and higher product quality.

[0040] 2. Stability test

[0041] Experimental method: The sulbactam sodium of Examples 1-5 and a commercially available product (purchased from Hainan Huluwa Pharmaceutical Group Co., Ltd.) were respectively subjected to high temperature tests. The simulated commercially available packaging of sulbactam sodium was placed in a light-proof environment at a temperature of 60° C. and observed after 5 days, 10 days, and 30 days. The experimental results are shown in Table 2 below.

[0042] Table 2: Comparison of stability test data

[0043]

[0044]

[0045] As can be seen from Table 2, after the product prepared by the present invention was placed for one month, the increase in the maximum single impurity and total impurity content was relatively low, indicating that the product prepared by the present invention has better stability.

[0046] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the present invention, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A crystallization process of sulbactam sodium, characterized in that: The crystallization process comprises the following steps: 1) Dissolve sodium acetate in a mixed solvent of methanol and water, and stir until dissolved; 2) dissolving sulbactam acid in an alcohol solvent; 3) Add 1) dropwise into 2) and stir; 4) adding ethanol, raising the temperature to a certain temperature for crystallization, then lowering the temperature for crystal growth, and centrifugally drying to obtain sulbactam sodium.

2. The crystallization process of sulbactam sodium according to claim 1, characterized in that: In step 2), the alcohol solvent is at least one of methanol, ethanol or isopropanol.

3. The crystallization process of sulbactam sodium according to claim 1, characterized in that: In the step 2), the mass volume ratio of sulbactam acid to alcohol solvent is 1:2 to 1:5 g / ml.

4. The crystallization process of sulbactam sodium according to claim 3, characterized in that: In the step 2), the mass volume ratio of sulbactam acid to alcohol solvent is 1:2 to 1:4 g / ml.

5. The crystallization process of sulbactam sodium according to claim 1, characterized in that: The dissolving temperature in step 2) is 20-25°C.

6. The crystallization process of sulbactam sodium according to claim 1, characterized in that: The heating temperature in step 4) is 30-40°C, and the crystal growing temperature is 5-10°C.

7. The crystallization process of sulbactam sodium according to claim 6, characterized in that: The heating temperature in step 4) is 32-36°C.

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