Preparation method of high-purity penicillin V potassium

Abstract

The application discloses a preparation method of penicillin V potassium, which mainly aims at improving the crystal habit of penicillin V potassium and reducing the content of a key impurity, 4-hydroxy penicillin V potassium. The application also relates to a penicillin V heavy crystal and a method for preparing a potassium salt from penicillin V, which comprises the following operation steps: dissolving raw materials, reacting with alkali to form a salt, solvus crystallization, suction filtration and drying. The method is simple and easy to operate and can be used for preparing penicillin V potassium by using a low-toxicity solvent, and the content of the key impurity, 4-hydroxy penicillin V potassium, can be reduced by more than 50%. The process is low in cost, low in energy consumption, high in efficiency and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the crystallization technology field of raw material medicine, and particularly relates to a crystallization technology of penicillin V and a potassium salt thereof. BACKGROUND

[0002] The penicillin V potassium (also known as phenoxymethyl penicillin potassium) involved in the present application is a natural penicillin, and compared with penicillin G, the penicillin V potassium is stable to acid, is not easily destroyed by gastric acid, is well absorbed orally, and has better enzyme resistance, so that the penicillin V potassium is more effective than the penicillin G in treating infections caused by drug-resistant Staphylococcus aureus; the penicillin V potassium does not need to be administered by injection, and has high safety. The penicillin V potassium is suitable for treating upper respiratory tract and lower respiratory tract infections, skin and soft tissue infections, otitis media, purulent meningitis, pneumonia, gonorrhea and the like caused by penicillin-sensitive bacteria, and can also be used for preventing rheumatism and bacterial endocarditis.

[0003] In addition to being processed into oral preparations for clinical use, the penicillin V raw material can also be processed into intermediates such as 6-APA and 7-ADCA, and further processed into various semi-synthetic penicillins such as ampicillin, amoxicillin and the like, and semi-synthetic cephalosporins such as cephalexin, cephradine and the like.

[0004] During the fermentation process of the penicillin V, many impurities are produced, and 4-hydroxy penicillin V is one of the main impurities. Since the physicochemical properties of the impurity and the target product are very similar, it is difficult to remove the impurity. The presence of the impurity seriously affects the quality of the intermediates such as 6-APA and 7-ADCA, and further affects the quality of subsequent products.

[0005] At present, most of the preparation processes of the penicillin V potassium are as follows: the fermentation broth is filtered, solvent extraction is performed, acid crystal powder is obtained, then decolorization is performed, a salt-forming agent is reacted to generate a salt, then a lower alcohol is mixed, and the penicillin V potassium is obtained by azeotropic crystallization. For example, in the Chinese patent CN101321771B, the butyl acetate solution of the penicillin V is mixed with a potassium source to form a salt, a certain amount of the mixture is evaporated, then methanol is added and stirred to obtain a suspension, filtration and washing are performed, and the penicillin V potassium salt in the form of crystals is obtained.

[0006] The production steps in CN101747341B include fermentation, acidification extraction, decolorization filtration, carbonic acid salt solution extraction, azeotropic crystallization, washing, drying and the like. In CN1432572A, penicillin V fermentation filtrate is acidified to obtain acidified precipitate, then butyl acetate is added for extraction, potassium carbonate solution is added for stirring to obtain penicillin V potassium salt solution, decolorization is performed, butanol is added, azeotropic distillation is performed to obtain penicillin V potassium salt crystals. These methods all need high temperature, high power consumption, and in addition, recovery of high-boiling-point solvents (such as n-butanol, butyl acetate) also needs to consume a large amount of power. Moreover, these methods have little effect on removal of 4-hydroxy penicillin V, and can only control the content of the impurity to about 1.0-1.5%, which is much higher than the content in the original research product of Shanduo Pharmaceutical Co., Ltd., and the XRD pattern of the crystals is different from that of the original research product, showing that the crystal morphology, i.e. crystal habit, is different from that of the original research product. The crystal form and crystal habit of the raw material are one of the key quality factors affecting the in vivo absorption and distribution of oral solid preparations, and are also important factors affecting the stability of the raw material and the preparation. This has become a great obstacle for the consistency evaluation of penicillin V potassium through generic drugs. Therefore, it is of great significance for the product to find a low-cost, low-energy purification method to improve the crystal morphology, reduce the content of the key impurity 4-hydroxy penicillin V potassium, and improve the quality of the product. SUMMARY

[0007] The present application provides a preparation method of penicillin V potassium, which mainly aims to improve the crystal habit of penicillin V potassium and reduce the content of the key impurity 4-hydroxy penicillin V potassium in penicillin V potassium raw material.

[0008] The present application is realized by the following steps:

[0009] The low-level ketone is added dropwise to the penicillin V potassium solution under stirring, the crystals are filtered, washed and dried after precipitation to obtain penicillin V potassium.

[0010] Further, the volume of the added low-level ketone is 5-20 times the volume of the penicillin V potassium solution.

[0011] Further, after the crystals precipitate, the addition of the low-level ketone is stopped, the crystals are aged for 10-30 minutes, and then the remaining low-level ketone is added; the low-level ketone used is acetone; and the volume of the added low-level ketone is 10-15 times the volume of the penicillin V potassium solution.

[0012] The low-level ketone is a water-miscible ketone with five carbons or less, and is preferably acetone.

[0013] Preferably, the penicillin V potassium solution is prepared by the following steps:

[0014] a. Penicillin V crude powder is dissolved in an organic solvent to prepare a solution with a certain concentration, and the organic solvent is a low-level ketone or a low-level alcohol;

[0015] b. Add water to the solution obtained in step a. under stirring to precipitate crystals;

[0016] c. Filter, wash and dry the crystal slurry obtained in step b. to obtain penicillin V crystal powder;

[0017] d. Add the penicillin V crystal powder obtained in step c. to an organic solvent in a certain proportion to prepare a suspension, wherein the organic solvent is a lower ketone or a lower alcohol;

[0018] e. Adjust the pH of the suspension obtained in step d. to a potassium salt with a potassium ion-containing alkaline solution to obtain a penicillin V potassium solution.

[0019] The lower ketone and the lower alcohol are ketones and alcohols with five carbons or less that are miscible with water, and are preferably ethanol or acetone.

[0020] In step a, the organic solvent for dissolving penicillin V includes a lower ketone and a lower alcohol, and is preferably ethanol or acetone; the concentration of the dissolved penicillin V is 0.1 g / ml-0.5 g / ml, and is preferably controlled to be between 0.2-0.4 g / ml.

[0021] In step b, purified water is added to the penicillin V solution, and the volume of the added water should be more than 2 times, and preferably 5-10 times, the volume of the organic solvent used for dissolving penicillin V; after a certain amount of purified water is added to precipitate crystals, the water addition is stopped, and the crystals are aged for 10-30 minutes, and then the remaining purified water is continuously added.

[0022] In step d, the organic solvent for dissolving penicillin V is a lower ketone or a lower alcohol, and the preferred solvents are ethanol and acetone, which are mixed to prepare a suspension; the preparation proportion of penicillin V crystal powder to the organic solvent is preferably controlled to be between 0.2 g-1.5 g: 1 ml, and the preferred concentration is between 0.5 g-1.0 g: 1 ml.

[0023] In step e, the penicillin V suspension is adjusted to a potassium salt with a potassium ion-containing alkaline solution to prepare a penicillin V potassium solution. The preferred potassium ion-containing alkaline solution is a 18-25% potassium carbonate solution, and the pH of the solution is adjusted to be between 5.0-8.0, and the more preferred pH range is 6.5-7.5.

[0024] Alternatively, the penicillin V potassium solution is prepared by the following steps:

[0025] A. Penicillin V crude powder is added to an organic solvent to prepare a suspension, and the pH is adjusted to a potassium salt with a potassium ion-containing alkaline solution to obtain a penicillin V potassium solution, wherein the organic solvent is a lower ketone or a lower alcohol;

[0026] B. The penicillin V potassium solution obtained in step a. is added to an organic solvent under stirring to precipitate crystals, and the crystals are filtered, washed and dried to obtain penicillin V potassium crystal powder, wherein the organic solvent is a lower ketone or a lower alcohol;

[0027] C. The penicillin V potassium crystalline powder is dissolved in water to obtain a penicillin V potassium solution.

[0028] The ratio of the penicillin V crude powder to the organic solvent is 0.2g-1.5g:1ml, preferably 0.5g-1.0g:1ml, the organic solvent is ethanol or acetone, the basic solution containing potassium ions is 18-25% potassium carbonate solution, the pH of the penicillin V potassium salt solution is adjusted to 5.0-8.0, preferably 6.5-7.5, and the ratio of the penicillin V potassium crystalline powder to water is 1g:0.8-1.5ml, preferably 1g:1-1.2ml.

[0029] Advantages

[0030] The present application provides a method for preparing high-purity penicillin V potassium by crystallization, which can efficiently remove 4-hydroxy penicillin V at normal temperature and pressure, and has a yield of more than 80%, a cost and energy consumption far lower than the original process, and an X-ray diffraction spectrum of the prepared product basically consistent with that of the original product of Sandoz Company. The method can prepare penicillin V potassium by a simple and easy procedure with a low-toxicity solvent, and is suitable for industrial production with low cost, low energy consumption and high efficiency. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 HPLC detection spectrum of penicillin V potassium obtained in Comparative Example 2

[0032] Figure 2 HPLC detection spectrum of penicillin V potassium obtained in Comparative Example 3

[0033] Figure 3 HPLC detection spectrum of penicillin V potassium obtained in Example 1

[0034] Figure 4 Comparison of powder X-ray diffraction patterns of penicillin V potassium crystals from different sources DETAILED DESCRIPTION

[0035] The penicillin V fermentation broth used in the present application is provided by Huabei Pharmaceutical Group New Drug Research and Development Co., Ltd. The reagents are all commercially available. The penicillin V potassium used in the comparative examples is provided by Huabei Pharmaceutical Co., Ltd. The reagents used are all commercially available.

[0036] Comparative Example 1:

[0037] 10.0g of penicillin V potassium was dissolved in 10ml of purified water while stirring, and 100ml of ethanol was added dropwise to the solution. After the dropwise addition was completed, the stirring was continued for 20 minutes. The crystalline powder was filtered, washed and dried to obtain 8.9g of penicillin V potassium with a 4-hydroxy penicillin V potassium content of 0.59%. The XRD spectrum of the crystal is shown in Figure 4(Comparative Example 1), wherein the diffraction angles at 29.7° and 35.4° have large differences in diffraction peak intensity from the original sample, indicating that the crystal has different crystal habits from the original sample.

[0038] Comparative Example 2: (CN101747341B method)

[0039] The fermentation broth of penicillin V was filtered, the filtrate was adjusted to be acidic with H2SO4, extracted with butyl acetate, the butyl acetate extract was subjected to activated carbon decolorization treatment, then adjusted to be alkaline with a sodium carbonate solution, and penicillin V was extracted into the water phase. The water phase was adjusted to be acidic to make the crystal precipitate, and the crystal was filtered, washed with water, and dried to obtain crude penicillin V powder. 5.0 g of the crude penicillin V powder was dissolved in n-butanol, and co-boiling evaporation crystallization was performed by adding a potassium carbonate solution dropwise and supplementing water. Filtration, washing, and drying were performed, and finally 4.4 g of penicillin V potassium was obtained. The content of 4-hydroxy penicillin V potassium (retention time 7.284 min in the HPLC spectrum) was 1.025%, and the HPLC detection spectrum of the obtained penicillin V potassium is shown in Figure 1 , and the XRD spectrum of the crystal is shown in Figure 4 (Comparative Example 2). Among them, the diffraction angles at 29.7° and 35.4° have large differences in diffraction peak intensity from the original sample, indicating that the crystal has different crystal habits from the original sample.

[0040] Table 1. Peak table of the HPLC detection spectrum of penicillin V potassium in Comparative Example 2

[0041] Peak No. Retention Time Area Height Area % 1 6.692 34435 2202 1.025 2 20.437 3324074 62608 98.975 Total 3358509 64811 100.000

[0042] Comparative Example 3: (CN101321771B method)

[0043] The fermentation broth of penicillin V was filtered, the filtrate was adjusted to be acidic with H2SO4, extracted with butyl acetate, the butyl acetate extract was subjected to activated carbon decolorization treatment, then adjusted to be alkaline with a sodium carbonate solution, and penicillin V was extracted into the water phase. The water phase was adjusted to be acidic to make the crystal precipitate, and the crystal was filtered, washed with water, and dried to obtain crude penicillin V powder. 5.0 g of the crude penicillin V powder was dissolved in n-butanol, and co-boiling evaporation crystallization was performed by adding a potassium carbonate solution dropwise and supplementing water. Filtration, washing, and drying were performed, and finally 4.4 g of penicillin V potassium was obtained. The content of 4-hydroxy penicillin V potassium (retention time 7.284 min in the HPLC spectrum) was 1.025%, and the HPLC detection spectrum of the obtained penicillin V potassium is shown in Figure 2 , and the XRD spectrum of the crystal is shown in

[0044] Table 2. Peak table of the HPLC detection spectrum of penicillin V potassium in Comparative Example 3

[0045] Peak No. Retention Time Area Height Area % 1 6.983 34702 2186 1.049 2 21.977 3272365 59605 98.951 Total 3307067 61791 100.000

[0046] The application is further described below through specific examples.

[0047] Example 1

[0048] The crude penicillin V powder obtained in Comparative Example 2, 10.0 g, was dissolved in 30 ml of acetone heated to 40°C, and 300 ml of purified water was added dropwise to the solution at a rate of 6 ml / min while stirring. When the solution began to crystallize, the addition of purified water was stopped, and stirring was continued for 30 minutes. The remaining purified water was then added dropwise. The crystalline powder was filtered, washed, and dried to obtain heavy crystal powder of penicillin V. The heavy crystal powder was suspended in 9 ml of acetone, and the pH was adjusted to 6.98 with a 20% potassium carbonate solution to convert it to a potassium salt. Acetone was added dropwise to the solution at a rate of 9 ml / min while stirring. When the solution began to crystallize, the addition of acetone was stopped, and the solution was aged for 20 minutes. The remaining acetone was then added dropwise, for a total of 130 ml. After the experiment, the crystalline powder was filtered, washed twice with acetone, and dried under vacuum at a reduced pressure to obtain 8.7 g of powder with a 4-hydroxy penicillin V potassium content of 0.298%. The HPLC spectrum is shown in Figure 3 , and the peak table is shown in Table 3. The XRD spectrum of the crystal is shown in Figure 4 (Example 1), and the powder X-ray diffraction patterns of penicillin V potassium crystals from different sources were compared. The spectrum of the sample of this example was similar to that of the original research product as a whole, but the intensity of the diffraction peak at 29.7° and 35.4° differed greatly from that of the sample of Comparative Example 2.

[0049] Table 3 Peak table for HPLC detection of penicillin V potassium obtained in Example 1

[0050] Peak No. Retention Time Area Height Area % 1 6.938 10190 636 0.298 2 21.372 3406750 59635 99.702 Total 3416940 60270 100.000

[0051] Example 2

[0052] The crude penicillin V powder obtained in Comparative Example 2, 5.0 g, was dissolved in 15 ml of ethanol heated to 40°C, and 75 ml of purified water was added dropwise to the solution at a rate of 5 ml / min while stirring. When the solution began to crystallize, the addition of purified water was stopped, and stirring was continued for 20 minutes. The remaining purified water was then added dropwise. The crystalline powder was filtered, washed, and dried to obtain 4.5 g of heavy crystal powder of penicillin V. The heavy crystal powder was suspended in 3 ml of acetone, and the pH was adjusted to 6.94 with a 20% potassium carbonate solution to convert it to a potassium salt. Acetone was added dropwise to the solution at a rate of 4.5 ml / min while stirring. When the solution began to crystallize, the addition of acetone was stopped, and the solution was aged for 20 minutes. The remaining acetone was then added dropwise, for a total of 65 ml. After the experiment, the crystalline powder was filtered, washed twice with acetone, and dried under vacuum at a reduced pressure to obtain 4.4 g of powder with a 4-hydroxy penicillin V potassium content of 0.31%. The XRD spectrum of the crystal was similar to that of Example 1 and the original research product as a whole.

[0053] Example 3

[0054] The penicillin V crude powder obtained in Comparative Example 2, 5.0 g, was weighed out, and 5 ml of ethanol was added to prepare a suspension. The suspension was adjusted to pH 6.98 with 20% potassium carbonate solution, and ethanol was added dropwise to the solution at a rate of 5 ml / min while stirring. When crystals were precipitated in the solution, the addition was stopped, and the solution was allowed to stand for 20 minutes. The remaining ethanol was added dropwise, and a total of 72 ml of ethanol was added. After the experiment, the crystalline powder was suction filtered, washed with ethanol twice, and dried under vacuum and reduced pressure to obtain 5.1 g of penicillin V potassium crystalline powder having a 4-hydroxy penicillin V potassium content of 0.61%. The obtained penicillin V potassium was dissolved in 7.5 ml of purified water, and acetone was added dropwise to the solution at a rate of 5 ml / min while stirring. When crystals were precipitated in the solution, the addition was stopped, and the solution was allowed to stand for 20 minutes. The remaining acetone was added dropwise, and a total of 115 ml was added. Stirring was continued for 20 minutes. The crystalline powder was suction filtered, washed, and dried to obtain 4.6 g of penicillin V potassium having a 4-hydroxy penicillin V potassium content of 0.33%. The XRD spectrum of the crystals was similar to that of Example 1 and was similar to the spectrum of the original research product as a whole.

[0055] Example 4

[0056] The penicillin V potassium obtained in Comparative Example 2, 10.0 g, was dissolved in 12 ml of purified water, and 120 ml of acetone was added dropwise to the solution while stirring. After the addition, stirring was continued for 15 minutes. The crystalline powder was suction filtered, washed, and dried to obtain 9.1 g of penicillin V potassium having a 4-hydroxy penicillin V potassium content of 0.56%. The XRD spectrum of the crystals was similar to that of Example 1 and was similar to the spectrum of the original research product as a whole.

Claims

1. A method for preparing penicillin V potassium salt, characterized in that... Includes the following steps: A lower ketone was added dropwise to a potassium penicillin V solution with stirring. After crystals precipitated, the solution was filtered and dried to obtain potassium penicillin V. The volume of the lower ketone added was 5-20 times the volume of the potassium penicillin V solution. After crystals precipitated, the addition of the lower ketone was stopped, and the crystals were allowed to grow for 10-30 minutes before the remaining lower ketone was added. The lower ketone used was acetone. The penicillin V potassium solution is prepared by the following steps: a. The crude penicillin V powder is dissolved in an organic solvent to prepare a solution of a certain concentration, wherein the organic solvent is ethanol or acetone; b. Add water to the solution obtained in step a while stirring, and crystals will precipitate; c. Filter and dry the crystal slurry obtained in step b to obtain penicillin V barite powder; d. Add the penicillin V barite powder obtained in step c to an organic solvent in a certain proportion to prepare a suspension, wherein the organic solvent is ethanol or acetone; e. Adjust the pH of the suspension obtained in step d with an alkaline solution containing potassium ions to convert it into potassium salt, thus obtaining a penicillin V potassium salt solution; Alternatively, the penicillin V potassium solution can be prepared by the following steps: A. A suspension is prepared by adding crude penicillin V powder to an organic solvent, and the pH is adjusted by using an alkaline solution containing potassium ions to convert it into potassium salt, thus obtaining a penicillin V potassium salt solution. The organic solvent is ethanol or acetone. B. Add an organic solvent dropwise to the penicillin V potassium solution obtained in step A while stirring. After the crystals precipitate, filter and dry to obtain penicillin V potassium crystalline powder. The organic solvent is ethanol or acetone. C. Penicillin V potassium crystal powder is dissolved in water to obtain a penicillin V potassium salt solution.

2. The preparation method according to claim 1, characterized in that: In step a, the concentration of the penicillin V solution is 0.1 g / ml - 0.5 g / ml; in step b, the volume of water added is more than twice the volume of the organic solvent used to dissolve penicillin V; during the water addition process, after crystals precipitate, stop adding water, allow the crystals to grow for 10-30 minutes, and then continue adding water; in step d, the ratio of penicillin V barite powder to organic solvent is 0.2 g - 1.5 g: 1 ml; in step e, the alkaline solution containing potassium ions is an 18-25% potassium carbonate solution, and the pH of the penicillin V potassium salt solution is adjusted to 5.0-8.

0.

3. The preparation method according to claim 2, characterized in that, In step a, the concentration of the penicillin V solution is 0.2 g / ml - 0.4 g / ml; in step b, the volume of water added is 5-10 times the volume of the organic solvent used to dissolve penicillin V; in step d, the ratio of penicillin V barite powder to organic solvent is 0.5 g - 1.0 g: 1 ml; in step e, the pH of the penicillin V potassium solution is adjusted to 6.5-7.5.

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