Novel process for preparing penicillin V potassium

Abstract

The invention relates to the technical field of production of penicillin V potassium, and particularly discloses a novel process for preparing penicillin V potassium, which comprises the following steps: a) carrying out flocculation treatment on penicillin fermentation liquor, and passing through drum filtering equipment; b) passing the drum filtrate through a roll-type ultrafiltration membrane device, and acidifying and crystallizing the roll-type ultrafiltration membrane to obtain penicillin V acid crystals I; c) recrystallizing the penicillin V acid crystal I to obtain a penicillin V acid crystal II; d) reacting and crystallizing the penicillin V acid crystal II and potassium isooctanoate to obtain penicillin V potassium; e) drying and storing; the molar yield and the quality index of the penicillin V potassium obtained by the novel process are greatly improved compared with those of the existing level.

Description

Technical Field

[0001] The present invention relates to the technical field of penicillin V potassium production, and particularly to a new process for preparing penicillin V potassium. Background Art

[0002] Penicillin V potassium is a β-lactamase antibiotic, with Chinese alias potassium (3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate), which is soluble in water and poorly soluble or insoluble in butanol, butyl acetate, and acetone. It is an important raw pharmaceutical material and pharmaceutical precursor. Compared with penicillin G potassium / sodium, it is stable to acid and slowly destroyed by enzymes, and can be used in the production of oral preparations, injection needles, and semi-synthetic penicillins and cephalosporins, which is convenient and highly safe. Due to its good bactericidal effect, it has become the first choice for treating infections caused by Gram-positive bacteria and some Gram-negative bacteria. At present, the global demand for penicillin V potassium is limited. The domestic enterprises with penicillin V potassium raw material drug batch numbers are North China Pharmaceutical Co., Ltd., China National Pharmaceutical Corporation Weichida Pharmaceutical Co., Ltd., and Jiangxi Dongfeng Pharmaceutical Co., Ltd. The foreign European manufacturer Sandoz has been monopolizing the international high-end market and impacting the domestic market with low prices.

[0003] Reference Figure 1 , the existing extraction and purification process of penicillin V potassium (the method of CN101321771B) utilizes the difference in the solubility of penicillin V in water and organic solvents when it exists in different chemical states - the free acid of penicillin V and the salts of penicillin V under different pH conditions, and achieves the purpose of concentration and purification through extraction, transfer, and separation processes. This process has problems such as a long production cycle and many impurities. Activated carbon is used in the operating environment, generating a large amount of solid waste, and the smell of butyl acetate in the workshop is relatively strong. The molar yield is 60 - 64%, and at the same time, the content of 4-hydroxy penicillin V potassium in the product affects the development of consistency evaluation work. Summary of the Invention

[0004] To solve the problems mentioned in the background art, the purpose of the present invention is to provide a new process for preparing penicillin V potassium.

[0005] The new process for preparing penicillin V potassium includes the following steps:

[0006] a) Flocculating the penicillin fermentation broth and then passing it through a drum filtration device;

[0007] b) Passing the drum filtrate through a spiral ultrafiltration membrane device, and acidifying and crystallizing the spiral ultrafiltrate to obtain penicillin V acid crystal I;

[0008] c) Recrystallizing penicillin V acid crystal I to obtain penicillin V acid crystal II;

[0009] d) Penicillin V acid crystal Ⅱ reacts with potassium isooctanoate to crystallize and obtain potassium penicillin V;

[0010] e) Dry and store.

[0011] In the above step d), potassium isooctanoate is used instead of potassium carbonate to react with penicillin V acid crystal Ⅱ, and the reaction formula is as follows:

[0012] Penicillin V acid + potassium isooctanoate → potassium penicillin V + isooctanoic acid

[0013] Potassium isooctanoate, as a pharmaceutical intermediate, is commonly used as a salt-forming agent for antibiotics. Its obvious advantages lie in its mildness and stability after salt formation, and it can dissolve in many organic solvents, which is beneficial to the separation of the anhydrous final product, improving the quality and yield of the product.

[0014] Using potassium isooctanoate can form salt in one step. The reaction is rapid and crystals can precipitate immediately after the reaction is completed, shortening the crystallization time. The original process needs to react with potassium carbonate first to form an alkaline solution and then carry out azeotropic crystallization in two steps. The reaction conditions are mild and can be carried out at low temperature and normal pressure, avoiding degradation caused by high temperature, which is beneficial to the stability of the finished product, and then improving the quality and yield of the finished product. Moreover, the solvent used in this reaction is a low-boiling solvent, and the recovery does not require a large amount of energy and power.

[0015] Furthermore, in the above step a), the flocculant used in the flocculation treatment of penicillin fermentation broth is polyacrylamide, with a concentration of 0.1 - 1.0%, the usage amount is controlled at 5 - 10% (v / v), the flocculation treatment temperature is 10 - 30 °C, and the time is 15 - 45 min.

[0016] Furthermore, the specific method of step b) is: Take the rotary drum filtrate through a spiral wound ultrafiltration membrane device, circulate and concentrate the rotary drum filtrate to obtain the dialysis solution before adding water, gradually add water to the dialysis solution before adding water to obtain the dialysis solution after adding water, and then pass the dialysis solution after adding water through a nanofiltration membrane for concentration to obtain a nanofiltration concentrate. Acidify and crystallize the dialysis solution before adding water and the nanofiltration concentrate respectively, and mix them to obtain penicillin V acid crystal Ⅰ; or acidify and crystallize to obtain penicillin V acid crystal Ⅰ after mixing the dialysis solution before adding water, the dialysis solution after adding water and the nanofiltration concentrate in a certain proportion.

[0017] Furthermore, in step b), the aperture model of the ultrafiltration membrane is 3 - 30K, the ultrafiltration operation pressure is controlled at 8 - 10 bar, the average membrane flux is 20 - 45 LMH, and the operating temperature is 8 - 15 °C.

[0018] Furthermore, the method for obtaining the dialysis solution after adding water is: First, circulate and concentrate the rotary drum filtrate by 5 - 15 times, and then gradually add 0.5 - 1.0 times of water to improve the yield.

[0019] Further, in step b), the acid used in the acidification crystallization process is one of sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.

[0020] Further, the recrystallization process in step c) is as follows: Dissolve penicillin V acid crystal I in an organic solvent and add water for precipitation. The organic solvent is one of methanol, ethanol, isopropanol or acetone. Among them, penicillin V acid crystal I (g): organic solvent (mL): water (mL) = 1: 3 - 6: 20 - 90, the recrystallization temperature is 10 - 30 °C, the crystal growth time is 10 - 45 min, the peristaltic pump feeding time is 45 - 90 min, and the water consumption for washing the filter cake (mL): penicillin V acid crystal II (g) = 4 - 10: 1.

[0021] Further, the specific method of step d) is as follows:

[0022] 1) Preparation of the bottom liquid: Penicillin V acid crystal: organic solvent I (one of methanol, butyl ester, butanol, acetone or isopropanol): cosolvent = 1: 5 - 20: 0.1 - 1.0. Dissolve until clear, filter through a membrane, rinse the bottle with organic solvent I (one of methanol, butyl ester, butanol, acetone or isopropanol), and transfer to the bottom liquid;

[0023] 2) Preparation of the feeding liquid: Penicillin V acid crystal: potassium isooctanoate = 1: 0.5 - 1.0, potassium isooctanoate: organic solvent II (one of methanol, butyl ester, butanol, acetone or isopropanol) = 1: 5 - 10. Dissolve until clear, filter through a membrane, rinse the bottle with organic solvent II (one of methanol, butyl ester, butanol, acetone or isopropanol), and transfer to the feeding liquid;

[0024] 3) Start the reaction crystallization. Slowly add the feeding liquid to the bottom liquid, with a rotation speed of 200 - 500 revolutions per minute, a reaction temperature of 10 - 30 °C, a reaction time of 1 - 3 h, and a crystal growth time of 1 - 2 h.

[0025] Further, in step e), the drying temperature is 50 - 65 °C, the drying time is 6 - 12 h, and after drying, it is stored in a drying vessel.

[0026] The beneficial effects of the present invention are as follows: Using a spiral ultrafiltration membrane device to treat the rotary drum filtrate can remove some proteins and pigments, greatly improving the light transmittance and color of the rotary drum filtrate; and eliminating steps such as extraction, decolorization, and back-extraction, simplifying the process, saving raw materials and improving the operating environment; after recrystallizing the penicillin V acid crystals formed by acidification with an organic solvent / water, the molar yield and quality indicators of the obtained penicillin V potassium finished product are greatly improved compared with the existing level, and impurities, especially 4-hydroxy penicillin V, are significantly reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a flow chart of the existing process for producing penicillin V potassium in the background art;

[0028] Figure 2 Flow chart of producing potassium penicillin V by the combined process of the present invention;

[0029] Figure 3 Comparison diagram of the rotary drum filtrate before and after crossflow ultrafiltration;

[0030] Figure 4 Comparison diagram of the appearance of penicillin V acid crystals, which are intermediate products in the process of producing potassium penicillin V by the existing process and the new process;

[0031] Figure 5 Appearance and crystal form diagram of potassium penicillin V by the new combined extraction process;

[0032] Figure 6 Comparison of liquid phase chromatograms of related substances and content of potassium penicillin V under two different processes of the existing refining process and the new combined extraction process. Detailed implementation manners

[0033] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention belong to the protection scope of the present invention.

[0034] Embodiment 1

[0035] a) Take 18 L of fermentation broth with batch number of the first batch, stir it with a stirrer, slowly add 1.44 L of polyacrylamide flocculant, stir at a speed of 250 r, temperature of 15 °C, and the flocculation treatment time is 30 min. After the experiment, let it stand for 5 min, and filter the filtrate through a rotary drum filtration device to obtain the rotary drum filtrate.

[0036] b) Take 15 L of the rotary drum filtrate and pass it through a crossflow ultrafiltration membrane filtration device with an ultrafiltration membrane pore size of 10K and a membrane core area of 3.9 m 2 . First, perform the ultrafiltration step at a pressure of 8 bar and an operating temperature of 13 °C, circulate and concentrate the rotary drum liquid by 10 times to obtain 13.5 L of dialysis solution before adding water, then gradually add 0.5 times of water to improve the recovery rate (1 L of water is added and 1 L of material is discharged), with an average membrane flux of 38 LMH, to obtain 7.5 L of dialysis solution after adding water; then concentrate the dialysis solution after adding water through a nanofiltration membrane to obtain 2.0 L of nanofiltration concentrate, and the total time for ultrafiltration + nanofiltration is 2.0 h.

[0037] c) Acidify and crystallize the dialysis solution before adding water and the nanofiltration concentrate respectively: Add 285 mL of 20% H 2 SO 4 to 13.5 L of the dialysis solution ，The pH value changes in the range from 5.92 to 2.63, the rotation speed is 350 r, the temperature is 20 °C, the crystal cultivation time is 25 min, and the total acidification time is 75 min; 20% H is added to 2.0 L of nanofiltration concentrate 2 SO 4 50 mL ， The pH value changes in the range from 6.00 to 2.67, the rotation speed is 350 r, the temperature is 20 °C, the crystal cultivation time is 25 min, and the total acidification time is 75 min; perform suction filtration, washing, and natural drying, and mix the two to obtain penicillin V acid crystal I.

[0038] d) Take 170 g of penicillin V acid crystal I, add 510 mL of acetone, and ultrasonically dissolve it completely. Stir with an electric stirrer, control the water temperature at 15 °C, the stirring speed at 250 r, and use a peristaltic pump to flow water until crystals appear. Cultivate crystals for 20 min, and then continue to flow add until the end point. A total of 3400 mL of water is used and it takes 75 min. Perform suction filtration, and wash the filter cake and the surface of the acid crystals twice with 1300 mL of water to obtain the wet material of penicillin V acid crystal II, and dry it under natural conditions.

[0039] e) Salt formation reaction of acid crystal II and potassium isooctanoate

[0040] (1) Preparation of bottom liquid: Weigh 10 g of penicillin V acid crystal II and place it in a container. Add 100 ml of acetone and 3 ml of water, stir until completely dissolved, filter through a membrane (organic system, 0.45 μm, twice), rinse the bottle with 50 mL of acetone, and transfer to bottom liquid I;

[0041] (2) Preparation of flowing liquid: Weigh 10 g of potassium isooctanoate and place it in a container. Add 60 ml of acetone, stir until completely dissolved, filter through a membrane (organic system, 0.45 μm, once), rinse the bottle with 50 mL of acetone, and transfer to flowing liquid I;

[0042] (3) Start the reaction crystallization: Slowly add flowing liquid I to bottom liquid I, with a rotation speed of 300 revolutions per minute, a reaction temperature of 20 °C, a reaction time of 1.5 hours, and crystal cultivation for 1 hour;

[0043] (4) Filter, wash with an appropriate amount of acetone to obtain the wet crystals of penicillin V potassium crystal I;

[0044] f) Place the wet material of penicillin V potassium in a vacuum drying oven, with a drying vacuum gauge pressure of -0.095 MPa, a drying temperature of 60 °C, and a time of 12 h to obtain the finished product of penicillin V potassium raw material medicine. After drying, store it in a drying vessel.

[0045] Example 2

[0046] a) Take 13 L of the original fermentation broth, batch number II. Stir it with a stirrer and slowly add 0.65 L of polyacrylamide flocculant. The stirring speed is 450 r, the temperature is 15 °C, and the flocculation treatment time is 30 min. After the experiment, let it stand for 5 min, and filter the filtrate through a drum filter to obtain the drum filtrate.

[0047] b) Take 10 L of the drum filtrate and pass it through a spiral ultrafiltration membrane filtration device. The pore size of the ultrafiltration membrane is 5K, and the membrane core area is 1.8 m 2 . The initial flux of the membrane core is 66 LMH (15 °C, 4 bar, 30 s / L). First, perform the ultrafiltration step at a pressure of 8 bar and an operating temperature of 11 °C. Circulate and concentrate the drum liquid 4 times to obtain 7.5 L of the dialysis solution before adding water. Then gradually add 0.55 times the amount of water to improve the recovery rate (add 1.5 L of water and discharge 2 L of material). The average membrane flux is 22 LMH, and 7.0 L of the dialysis solution after adding water is obtained. Then concentrate the dialysis solution after adding water through a nanofiltration membrane to obtain 1.7 L of the nanofiltration concentrate. The total time for ultrafiltration + nanofiltration is 2.5 h.

[0048] c) Acidify and crystallize the dialysis solution before adding water and the nanofiltration concentrate respectively: Add 1256 mL of 5% H 2 SO 4 to 7.5 L of the dialysis solution. The pH changes from 5.90 to 2.64. The rotation speed is 300 r, the temperature is 25 °C, and the crystal growth time is 40 min. The total acidification time is 60 min. Add 451 mL of 5% H 2 SO 4 to 1.7 L of the nanofiltration concentrate. The pH changes from 6.03 to 2.69. The rotation speed is 300 r, the temperature is 25 °C, and the crystal growth time is 40 min. The total acidification time is 60 min. Filter with suction, wash, and air-dry naturally. Mix the two to obtain penicillin V acid crystal II.

[0049] d) Take 220 g of penicillin V acid crystal I and divide it into two equal parts, each part being 110 g. Add 660 mL of acetone to each part and ultrasonically dissolve it until it is completely clear. Stir with an electric stirrer, control the water temperature at 18 °C, the stirring speed at 350 r, and use a peristaltic pump to flow in water until crystals appear. Let the crystals grow for 30 min, and then continue to flow in water until the end point. A total of 3300 mL of water is used, and the time taken is 90 min. Filter with suction, wash the filter cake and the surface of the acid crystals twice with 440 mL of water to obtain two portions of wet penicillin V acid crystal II. Mix them evenly and air-dry under natural conditions.

[0050] e) Salt formation reaction of acid crystal II and potassium isooctanoate

[0051] (1) Preparation of the bottom liquid: Weigh 10 g of acid crystal II and place it in a container. Add 100 ml of n-butanol and 3 ml of water, stir until it is completely dissolved and clear, filter through a membrane (organic system, 0.45 μm, twice), rinse the bottle with 50 mL of n-butanol, and transfer it to the bottom liquid II;

[0052] (2) Feed solution preparation: Weigh 10 g of potassium isooctanoate and place it in a container. Add 60 ml of n-butanol and stir until completely dissolved and clear. Filter through a membrane (organic system, 0.45 μm, once), rinse the bottle with 50 mL of n-butanol, and transfer to Feed solution II;

[0053] (3) Start the reaction and crystallization: Slowly add Feed solution II to Bottom solution II at a rotation speed of 300 revolutions per minute, reaction temperature of 20 °C, reaction time of 1.5 hours, and crystal growth for 1 hour;

[0054] (4) Filter and wash with an appropriate amount of n-butanol to obtain wet crystals of potassium penicillin V II;

[0055] f) Place the wet potassium penicillin V in a vacuum drying oven. The drying vacuum gauge pressure is -0.094 MPa, the drying temperature is 50 °C, and the time is 6 h to obtain the finished product of potassium penicillin V raw material. After drying, store it in a drying vessel.

[0056] Example 3

[0057] a) Take 16 L of the fermentation broth, batch number III. Use a stirrer to stir and slowly add 0.96 L of polyacrylamide flocculant. The stirring speed is 350 r, the temperature is 15 °C, and the flocculation treatment time is 20 min. After the experiment, let it stand for 5 min, and filter the filtrate through a rotary drum filtration device to obtain the rotary drum filtrate.

[0058] b) Take 12 L of the rotary drum filtrate and pass it through a spiral ultrafiltration membrane filtration device. The ultrafiltration membrane pore size is 5K, and the membrane core area is 1.8 m 2 , and the initial flux of the membrane core is 66 LMH (15 °C, 4 bar, 30 s / L). First, perform the ultrafiltration step at a pressure of 8 bar and an operating temperature of 10 °C. Circulate and concentrate the rotary drum liquid by 4 times to obtain 9.0 L of the dialysis solution before adding water. Then gradually add 0.55 times the amount of water to increase the yield (add 1.5 L of water and discharge 2 L of material). The average membrane flux is 26 LMH to obtain 11.2 L of the dialysis solution after adding water; then concentrate the dialysis solution after adding water through a nanofiltration membrane to obtain 1.5 L of the nanofiltration concentrate. The total time for ultrafiltration + nanofiltration is 2.5 h.

[0059] c) Acidify and crystallize the dialysis solution before adding water and the nanofiltration concentrate respectively: Add 450 mL of 10% H 2 SO 4 4 to 9.0 L of the dialysis solution. The pH changes from 6.45 to 2.70. The rotation speed is 250 r, the temperature is 15 °C, and the crystal growth time is 30 min. The total acidification time is 90 min; add 450 mL of 10% H 2 SO 4115 mL, the pH change range drops from 6.43 to 2.70, the rotation speed is 250 r, the temperature is 15 °C, the crystal cultivation time is 30 min, and the total acidification time is 90 min; filtration by suction, washing, and natural drying to obtain penicillin V acid crystal I from the mixture of the two.

[0060] d) Take 160 g of penicillin V acid crystal I, add 960 mL of acetone, and ultrasonically dissolve it until completely clear. Stir using an electric stirrer, control the water temperature at 15 °C, the stirring speed at 300 r, and use a peristaltic pump to flow in water until crystallization occurs. Crystal cultivation is carried out for 25 min, and then continue to flow in until the end point, using a total of 3200 mL of water and taking 60 min. Filter by suction, and wash the filter cake and the surface of the acid crystal twice with 960 mL of water to obtain the wet material of penicillin V acid crystal II, and dry it under natural conditions.

[0061] e) Salt formation reaction of acid crystal II and potassium isooctanoate

[0062] (1) Preparation of the bottom liquid: Weigh 10 g of acid crystal II and place it in a container. Add 100 ml of isopropanol and 3 ml of water, stir until dissolved and clear, filter through a membrane (organic system, 0.45 μm, twice), rinse the bottle with 50 mL of isopropanol, and transfer it to bottom liquid III;

[0063] (2) Preparation of the flowing liquid: Weigh 10 g of potassium isooctanoate and place it in a container. Add 60 ml of isopropanol, stir until completely dissolved and clear, filter through a membrane (organic system, 0.45 μm, once), rinse the bottle with 50 mL of isopropanol, and transfer it to flowing liquid III;

[0064] (3) Start the reaction crystallization: Slowly add flowing liquid III to bottom liquid III, with a rotation speed of 300 revolutions per minute, a reaction temperature of 20 °C, a reaction time of 1.5 hours, and crystal cultivation for 1 hour;

[0065] (4) Filter, wash with an appropriate amount of isopropanol to obtain the wet crystal of penicillin V potassium crystal III;

[0066] f) Place the wet material of penicillin V potassium in a vacuum drying oven, with a drying vacuum gauge pressure of -0.097 MPa, a drying temperature of 50 °C, and a time of 9 h to obtain the finished product of penicillin V potassium raw material drug. After drying, store it in a drying vessel.

[0067] Comparative Example 1 (Method of CN10174734B)

[0068] Take a certain amount of penicillin V fermentation drum filtrate, mix it with butyl acetate, adjust the acidity to acidic with dilute sulfuric acid, stand for phase separation to obtain the butyl acetate extract. After the extract is decolorized with activated carbon, adjust the alkalinity with sodium carbonate solution and then stand. After phase separation, obtain the back extraction solution. Slowly add dilute sulfuric acid to the back extraction solution, and penicillin V crystals will precipitate continuously. Filter the crystals by suction, wash them with water, and dry them to obtain penicillin V acid crystals. Take 10.0 g of the obtained penicillin V acid crystals, dissolve them with n-butanol, slowly dropwise add an aqueous potassium carbonate solution, and then carry out azeotropic evaporation crystallization. After reaching the crystallization end point, filter by suction, wash, and dry to finally obtain 9.0 g of penicillin V potassium. The total yield of the fermentation stock solution to penicillin V potassium by this method is 56.72%, and the content of 4-hydroxy penicillin V potassium is 0.99%.

[0069] Comparative Example 2 (Method of CN101321771B)

[0070] Take a certain amount of penicillin V fermentation drum filtrate, mix it with butyl acetate, adjust the acidity to acidic with dilute sulfuric acid, stand for phase separation to obtain the butyl acetate extract. The extract is decolorized with activated carbon, and the decolorized solution is adjusted to alkalinity with potassium carbonate solution and then stands for phase separation to obtain the back extraction solution. The back extraction solution is mixed with n-butanol for azeotropic evaporation crystallization to obtain an azeotropic mixture. Add methanol to the azeotropic mixture and stir at room temperature for 1 hour. Filter, wash, and dry to obtain 9.5 g of penicillin V potassium. The total yield of the fermentation stock solution to penicillin V potassium by this method is 58.65%, and the content of 4-hydroxy penicillin V potassium is 1.04%.

[0071] Table 1 reflects the molar yields of each step of the new combined extraction process of penicillin V potassium in Examples 1, 2, and 3. Compared with Comparative Example 1 and Comparative Example 2, the total yield of the new process is significantly higher than that of the existing refining process.

[0072] Table 1 Molar Yields of Each Step of the New Combined Extraction Process of Penicillin V Potassium

[0073]

[0074]

[0075] Table 2 reflects the comparative analysis of penicillin V potassium produced by the process provided by CN101321771B and the new combined extraction process. It can be concluded that under the conditions of the new process, the content of penicillin V potassium, related substances, especially 4-hydroxy penicillin V potassium, and molar yield are all better than those of the existing refining process, and the effect of Example 3 is the best. Compared with the existing process, the content of 4-hydroxy penicillin V potassium is reduced by 83.33%, and the total yield is increased by 16.68%.

[0076] Table 3 Comparison of Penicillin V Potassium Product Quality

[0077]

[0078] Reference Figure 3 , the addition of the roll-over process significantly improves the clarity of the drum filtrate, removes most of the proteins and some impurities, and can replace steps such as butyl acetate extraction, the use of demulsifiers, activated carbon decolorization, and back extraction in the existing refining process, simplifies the process, and improves the working environment.

[0079] Reference Figure 4 , the color of the penicillin V acid crystals, the intermediate product produced by the new extraction process, is significantly improved.

[0080] Figure 5 It reflects the appearance and crystal form diagram of penicillin V potassium of the new combined extraction process, which meets the BP / CP pharmacopoeia standards.

[0081] Figure 6 It reflects the comparison of the liquid phase chromatograms of the related substances and content of penicillin V potassium under two different processes of the existing refining process and the new combined extraction process.

[0082] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. All any modifications, equivalent replacements, improvements, etc. within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A new process for preparing penicillin V potassium, characterized in that: The steps include: a) Penicillin fermentation broth is flocculated and then passed through a drum filter; b) The drum filtrate passes through a roll-type ultrafiltration membrane device, and the roll-type ultrafiltration liquid is acidified and crystallized to obtain penicillin V acid crystals I; c) Penicillin V acid crystals I are recrystallized to obtain penicillin V acid crystals II; d) Penicillin V acid crystal II reacts with potassium isooctanoate to obtain penicillin V potassium; e) Store in a dry place.

2. A new process for preparing penicillin V potassium according to claim 1, characterized in that: In the step a), the flocculant used in the flocculation treatment of the penicillin fermentation broth is polyacrylamide, the concentration is 0.1-1.0%, the usage is controlled at 5-10% (v / v), the flocculation treatment temperature is 10-30° C., and the time is 15-45 minutes.

3. A new process for preparing penicillin V potassium according to claim 1, characterized in that: The specific method of step b) is: taking the drum filtrate through a roll-type ultrafiltration membrane device, cyclically concentrating the drum filtrate to obtain a dialysate before water addition, gradually adding water to the dialysate before water addition to obtain a dialysate after water addition, and then concentrating the dialysate after water addition through a nanofiltration membrane to obtain a nanofiltration concentrated solution, respectively taking the dialysate before water addition and the nanofiltration concentrated solution for acidification and crystallization, and mixing them to obtain penicillin V acid crystals I; or mixing the dialysate before water addition, the dialysate after water addition and the nanofiltration concentrated solution in a certain proportion, acidifying and crystallizing to obtain penicillin V acid crystals I.

4. A new process for preparing penicillin V potassium according to claim 3, characterized in that: The pore size of the ultrafiltration membrane is 3-30K, the ultrafiltration operating pressure is controlled at 8-10 bar, the average membrane flux is 20-45 LMH, and the operating temperature is 8-15°C.

5. A new process for preparing penicillin V potassium according to claim 3, characterized in that: The dialysate is obtained after adding water as follows: the drum filtrate is first circulated and concentrated 5 to 15 times, and then 0.5 to 1.0 times of water is gradually added to increase the yield.

6. A new process for preparing penicillin V potassium according to claim 3, characterized in that: The acid used in the acidification crystallization process is one of sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.

7. A new process for preparing penicillin V potassium according to claim 1, characterized in that: The recrystallization process in step c) is as follows: dissolving penicillin V acid crystals I in an organic solvent and adding water for dissolution, wherein the organic solvent is one of methanol, ethanol, isopropanol or acetone, wherein the ratio of penicillin V acid crystals I (g): organic solvent (mL): water (mL) = 1:3-6:20-90, the recrystallization temperature is 10-30°C, the crystal growing time is 10-45min, the peristaltic pump addition time is 45-90min, and the amount of water used for washing the filter cake (mL): penicillin V acid crystals II (g) = 4-10:

1.

8. A new process for preparing penicillin V potassium according to claim 1, characterized in that: The specific steps of step d) are: 1) Base solution preparation, penicillin V acid crystals: organic solvent I (one of methanol, butyl ester, butanol, acetone or isopropanol): cosolvent = 1:5-20:0.1-1.0, dissolve, filter membrane, rinse the bottle with organic solvent I (one of methanol, butyl ester, butanol, acetone or isopropanol), and transfer to the base solution; 2) Feeding liquid preparation, penicillin V acid crystal: potassium isooctanoate = 1:0.5-1.0, potassium isooctanoate: organic solvent II (one of methanol, butyl ester, butanol, acetone or isopropanol) = 1:5-10, dissolve, filter membrane, rinse the bottle with organic solvent II (one of methanol, butyl ester, butanol, acetone or isopropanol), and transfer to the feeding liquid; 3) Start the reaction crystallization, slowly add the feeding liquid into the base liquid, the speed is 200-500 rpm, the reaction temperature is 10-30°C, the reaction time is 1-3h, and the crystal is grown for 1-2h.

9. A new process for preparing penicillin V potassium according to claim 1, characterized in that: In the step e), the drying temperature is 50-65° C., the drying time is 6-12 hours, and the product is stored in a drying container after drying.

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