Method for preparing erythromycin lactobionate

Abstract

The invention provides a method for preparing erythromycin lactobionate, which comprises the following steps: 1) taking lactobionic acid, and adding the lactobionic acid into water to obtain a lactobionic acid solution with the concentration range of 0.08-0.2 g / mL; 2) taking erythromycin, and adding the erythromycin into acetone to obtain an erythromycin solution with the concentration range of 0.1-0.4 g / mL; (3) dropwise adding the lactobionic acid solution into the erythromycin solution, carrying out salt forming reaction to obtain a turbid solution, and reacting for a period of time until the solution is clarified; 4) concentrating the obtained clear solution under reduced pressure until white solids are separated out, adding water to completely dissolve the white solids, filtering and collecting filtrate, and 5) freeze-drying the obtained filtrate to obtain the 2, 3, 5-trimethyl-1, 3-pentanediol monoisobutyrate.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing erythromycin lactobionate. Background Art

[0002] Erythromycin lactobionate belongs to the macrolide antibiotics and has antibacterial activity against Staphylococcus, various groups of Streptococcus and Gram-positive bacilli. Neisseria, Haemophilus influenzae, Bordetella pertussis and others may also be sensitive to erythromycin lactobionate. Erythromycin lactobionate also has antibacterial activity against various anaerobic bacteria except Bacteroides fragilis and Fusobacterium; it also has inhibitory effects on Legionella, Campylobacter fetus, some spirochetes, Mycoplasma pneumoniae, Rickettsia and Chlamydia.

[0003] Erythromycin lactobionate is hydrolyzed after absorption, releasing the active ingredient erythromycin. Erythromycin can penetrate the bacterial cell membrane and reversibly bind to the bacterial ribosome near the donor site, blocking the transfer RNA from binding to the donor site. It also blocks the displacement of the polypeptide chain from the acceptor site to the donor site, inhibiting bacterial cell protein synthesis, thereby playing an antibacterial role. Erythromycin lactobionate is used as an alternative drug for the treatment of the following infections in patients allergic to penicillin: acute tonsillitis, acute pharyngitis, sinusitis caused by hemolytic streptococci, pneumococcus, etc.; scarlet fever and cellulitis caused by hemolytic streptococci; diphtheria and diphtheria carriers; gas gangrene, anthrax, tetanus; actinomycosis; syphilis; monocytosis listeriosis, etc.

[0004] Erythromycin includes some erythromycin-related substances, such as erythromycin A, erythromycin B, erythromycin C and other isomers, and also contains erythromycin enol ether. Several isomers of erythromycin have similar physical and chemical properties, among which erythromycin A has the strongest antibacterial activity, while the antibacterial activity of erythromycin B and erythromycin C is only 30%-60% of that of erythromycin A, and erythromycin C is also toxic.

[0005] Erythromycin lactobionate for injection is a commonly used dosage form of erythromycin lactobionate in the prior art, and lyophilization is often used in the prior art to prepare erythromycin lactobionate for injection. The existing preparation method of erythromycin lactobionate usually uses water as a solvent, but since erythromycin is insoluble in water, the reaction efficiency is low, and the clarity of the obtained erythromycin lactobionate product is unqualified and the quality is unstable.

[0006] Therefore, it is necessary to provide an improved method for preparing erythromycin lactobionate to improve the reaction efficiency of preparing erythromycin lactobionate, ensure product quality, and thus improve the drug safety of erythromycin lactobionate solution. Summary of the invention

[0007] In view of the above technical problems, the object of the present invention is to provide a method for preparing erythromycin lactobionate, which has the advantages of high reaction efficiency, high clarity and stable quality of the obtained erythromycin lactobionate product, etc.

[0008] To achieve the object, the present invention provides a method for preparing erythromycin lactobionate, which comprises the following steps: 1) Take lactobionic acid and add it to water to obtain a lactobionic acid solution with a concentration range of 0.08-0.2 g / mL.

[0009] 2) Take erythromycin and add it to acetone to obtain an erythromycin solution with a concentration range of 0.1-0.4 g / mL.

[0010] 3) adding the lactobionic acid solution dropwise to the erythromycin solution to cause a salt-forming reaction to obtain a turbid solution, and reacting for a period of time until the solution becomes clear.

[0011] 4) The obtained clear solution is concentrated under reduced pressure until a white solid is precipitated, and then water is added to completely dissolve it, and the filtrate is filtered and collected. According to the method of the present invention, in this step, the requirements of product clarity and the like can be met without adding activated carbon; therefore, the method of the present invention further optimizes the reaction steps compared with the prior art method.

[0012] 5) The obtained filtrate is freeze-dried.

[0013] The product erythromycin lactobionate obtained by the method of the present invention is white fluffy powder.

[0014] In a preferred embodiment, in step 1), the concentration range of the lactobionic acid solution is 0.1-0.18 g / mL, preferably 0.12-0.16 g / mL; and / or in step 2), the concentration range of the erythromycin solution is 0.12-0.3 g / mL, preferably 0.16-0.25 g / mL.

[0015] In a preferred embodiment, in step 3), the dripping speed of the lactobionic acid solution is 5 mL / min-15 mL / min, preferably 5 mL / min-10 mL / min. Generally, when the feed amount is large, the dripping speed of the lactobionic acid solution can be appropriately relaxed to 15 mL / min, usually maintained at 5 mL / min-10 mL / min.

[0016] In a preferred embodiment, the molar ratio of lactobionic acid to erythromycin used in step 3) is (0.9-1.1):1, preferably (0.9-1):1, and more preferably (0.95-1):1.

[0017] In a preferred embodiment, the reaction time of the salt-forming reaction in step 3) is until the pH value of the reaction solution reaches pH 7.5-8.0, preferably pH 7.5-7.7, and most preferably pH 7.55.

[0018] Since erythromycin is particularly sensitive to acid, excessive local acidity during the preparation process will cause corresponding changes in the properties of erythromycin, produce a variety of by-products, and affect the yield and stability of the obtained erythromycin lactobionate. Therefore, in the method of the present invention, the concentrations of lactobionic acid and erythromycin solution are appropriate, and the dripping speed of the lactobionic acid solution is controlled, which can effectively solve the problem of excessive local acidity in the salt-forming reaction and improve the yield and stability of erythromycin lactobionate.

[0019] In a preferred embodiment, in step 3), the temperature of the erythromycin solution is 0-25°C, preferably 2-20°C, more preferably 5-15°C.

[0020] In a preferred embodiment, in step 5), the vacuum degree of the freeze dryer during the freeze drying process is less than 100 Pa, preferably in the range of 10-90 Pa. The present invention has no particular restrictions on the equipment used for freeze drying the erythromycin lactobionate solution sample, and a freeze dryer well known to those skilled in the art can be used. The freeze drying process of the method of the present invention can be carried out under low vacuum conditions, and the operating conditions are mild.

[0021] Beneficial effects of the present invention: The method for preparing erythromycin lactobionate adopts acetone as a solvent to dissolve erythromycin, so that the erythromycin reaction system is changed from a suspension in the prior art to a solution, has the advantages of high reaction efficiency, high clarity and stable quality of the obtained erythromycin lactobionate product, ensures the quality of the erythromycin lactobionate product, improves the drug safety of erythromycin lactobionate, and has important application value. DETAILED DESCRIPTION

[0022] The method of the present invention will be described and illustrated in more detail below in conjunction with specific embodiments. It will be understood by those skilled in the art that the purpose of providing these embodiments is only for illustrative purposes and does not constitute any limitation to the scope of the present invention.

[0023] The reagents, raw materials and equipment used in the present invention can all be purchased commercially. Unless otherwise specified, the reaction of the present invention is carried out at room temperature and normal pressure.

[0024] Example 1 1) At room temperature, add 10 g of lactobionic acid to 65 mL of water, stir and dissolve to obtain a lactobionic acid solution.

[0025] 2) At room temperature, add 20 g of erythromycin into 80 mL of acetone, stir and dissolve to obtain erythromycin solution.

[0026] 3) The lactobionic acid solution was slowly added dropwise to the erythromycin solution at 15°C at a rate of 6 mL / min while stirring, and a salt-forming reaction occurred to obtain a turbid solution. After 3 hours of reaction, the solution became clear and the pH value of the reaction solution reached 7.55.

[0027] 4) The obtained clear solution was concentrated under reduced pressure at room temperature until a white solid precipitated, and then 150 mL of water was added to completely dissolve it. The solution was vacuum filtered and the filtrate was collected.

[0028] 5) freeze-drying the obtained filtrate in a freeze dryer. The specific freeze-drying method is as follows: cool the freeze drying chamber of the freeze dryer to below -50°C, evacuate, and pre-freeze the filtrate containing erythromycin lactobionate for about 240 minutes; then heat it to 20°C at a rate of 3°C / h, and the cycle is about 2200 minutes to obtain the product erythromycin lactobionate, which is a white fluffy powder, with a molar yield of 90%.

[0029] 6) The pH value of the obtained erythromycin lactobionate powder is 6.46, and the clarity is <0.5.

[0030] Example 2 1) At room temperature, add 10 g of lactobionic acid to 80 mL of water, stir and dissolve to obtain a lactobionic acid solution.

[0031] 2) At room temperature, add 20 g of erythromycin into 125 mL of acetone, stir and dissolve to obtain erythromycin solution.

[0032] 3) The lactobionic acid solution was slowly added to the erythromycin solution at 12°C at a rate of 10 mL / min while stirring to cause a salt-forming reaction to obtain a turbid solution. After 5 hours of reaction, the solution became clear and the pH value of the reaction solution reached 7.6.

[0033] 4) The obtained clear solution was concentrated under reduced pressure at room temperature until a white solid precipitated, and then 150 mL of water was added to completely dissolve it. The solution was vacuum filtered and the filtrate was collected.

[0034] 5) The obtained filtrate was freeze-dried in a freeze dryer according to the method described in Example 1 to obtain the product erythromycin lactobionate as a white fluffy powder with a molar yield of 95%.

[0035] 6) The pH value of the obtained erythromycin lactobionate powder is 7.07 and the clarity is <0.5.

[0036] Comparative Example 1 1) At room temperature, add 10 g of lactobionic acid to 65 mL of water, stir and dissolve to obtain a lactobionic acid solution.

[0037] 2) At room temperature, add 20 g of erythromycin into 80 mL of water and stir to obtain an erythromycin suspension.

[0038] 3) The lactobionic acid solution was slowly added to the erythromycin suspension at 15°C at a rate of 6 mL / min while stirring to cause a salt-forming reaction to obtain a turbid solution. After 3 hours of reaction, the solution became clear and the pH value of the reaction solution reached 7.55.

[0039] 4) The obtained clear solution was concentrated under reduced pressure at room temperature until a white solid precipitated, and then 150 mL of water was added to completely dissolve it. The solution was vacuum filtered and the filtrate was collected.

[0040] 5) The obtained filtrate was freeze-dried in a freeze dryer according to the method described in Example 1 to obtain the product erythromycin lactobionate as an off-white fluffy powder with a molar yield of 85%.

[0041] 6) The pH value of the obtained erythromycin lactobionate powder is 7.0, but the clarity is much greater than 1.

[0042] Experimental Example 1 In this experimental example, the quality of the erythromycin lactobionate finished products obtained in the embodiments and comparative examples of the present invention was tested by the testing method described below. The results of various indicators are shown in Table 1.

[0043] Clarity determination method: Determine according to the visual method in the clarity inspection method in the "Pharmacopoeia of the People's Republic of China: 2020 Edition".

[0044] Table 1: Quality test results and yields of erythromycin lactobionate finished products obtained in various embodiments and comparative examples of the present invention.

[0045] Example 1 Example 2 Comparative Example 1 Characteristics White powder White powder Off-white powder Clarity <0.5 <0.5 >1 Yield 90% 95% 85% It can be seen from Table 1 that the erythromycin lactobionate product obtained by the method of the present invention has light color, high clarity and high yield.

[0046] Experimental Example 2-Stability Determination 1 g of erythromycin lactobionate obtained in Examples 1-2 and Comparative Example 1 was taken, 10 mL of water was added to prepare a solution with a concentration of 0.1 g / mL, and placed in a test box at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were taken at the end of the 0th, 1st, 2nd, 3rd and 6th month for stability inspection. The results are shown in Table 2.

[0047] Table 2: Accelerated test results

[0048] It can be seen from the experimental results in Table 2 that, compared with Comparative Example 1, the erythromycin lactobionate prepared in Example 1-2 has better stability, indicating that the preparation method provided by the present invention significantly improves the stability of erythromycin lactobionate and ensures the safety of erythromycin lactobionate.

[0049] In summary, the preparation method provided by the present invention significantly improves the yield of erythromycin lactobionate and improves the clarity, indicating that the preparation method provided by the present invention can improve the quality of erythromycin lactobionate; and the obtained erythromycin lactobionate has stable quality during long-term storage, thereby ensuring the safety of erythromycin lactobionate.

[0050] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing erythromycin lactobionate, characterized in that: It includes the following steps: 1) Take lactobionic acid and add it to water to obtain a lactobionic acid solution with a concentration range of 0.08-0.2 g / mL; 2) Take erythromycin and add it to acetone to obtain an erythromycin solution with a concentration range of 0.1-0.4 g / mL; 3) adding the lactobionic acid solution dropwise to the erythromycin solution to generate a salt-forming reaction to obtain a turbid solution, and reacting for a period of time until the solution becomes clear; 4) The obtained clear solution was concentrated under reduced pressure until a white solid precipitated, and then water was added to completely dissolve it, and the filtrate was filtered and collected; 5) The obtained filtrate is freeze-dried.

2. The method according to claim 1, characterized in that In step 1), the concentration range of the lactobionic acid solution is 0.1-0.18 g / mL; and / or in step 2), the concentration range of the erythromycin solution is 0.12-0.3 g / mL.

3. The method according to claim 1, characterized in that In step 3), the dropping speed of the lactobionic acid solution is 5 mL / min-15 mL / min.

4. The method according to claim 1, characterized in that: The molar ratio of lactobionic acid to erythromycin used in step 3) is (0.9-1.1):

1.

5. The method according to claim 1, characterized in that The reaction time of the salt-forming reaction in step 3) is until the pH value of the reaction solution reaches pH 7.5-8.

0.

6. The method according to claim 1, characterized in that In step 3), the temperature of the erythromycin solution is 0-25°C.

7. The method according to claim 1, characterized in that In step 5), the vacuum degree of the freeze dryer during the freeze drying process is less than 100 Pa.

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