A method for preparing penicillin V potassium by a spray drying method

Abstract

The application provides a method for preparing penicillin V potassium by a spray drying method, and belongs to the technical field of drug synthesis. In the method, potassium hydroxide and a mixed solution of strong alkali and weak acid potassium salt are salted at a specific temperature, and then negative pressure spray drying is performed at a low temperature. The method has the advantages of simple process flow, no need to use a large amount of solvent, no solid waste and waste liquid, and environmental protection. In addition, high-purity penicillin V potassium can be obtained. The results of examples show that, according to the method, the penicillin V potassium obtained has the purity of C 16 H 18 N2O5S is not less than 87%, the maximum single impurity is not more than 0.8%, the total impurity is not more than 2.1%, and the polymer is not more than 0.1%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing penicillin V potassium by spray drying. Background Technology

[0002] Penicillin V potassium (also known as phenoxymethylpenicillin potassium) is a natural penicillin. Compared with penicillin G, it has advantages such as acid stability, better oral absorption, and better enzyme resistance. It is suitable for treating upper and lower respiratory tract infections, skin and soft tissue infections, otitis media, purulent meningitis, pneumonia, gonorrhea, etc., caused by penicillin-sensitive bacteria. It can also be used to prevent rheumatic diseases and bacterial endocarditis. Currently, the main method for preparing penicillin V potassium is the solvent method, which includes three stages: fermentation, extraction, and purification. The fermentation stage includes spore preparation, seed preparation, fermentation process, and filtration of fermentation broth. This stage is characterized by a long cycle, high energy consumption, and large waste liquid production. The extraction and purification process utilizes the difference in solubility of penicillin V in water and organic solvents under different pH conditions. Through extraction, transfer, and separation processes, the purpose of concentration and purification is achieved. This process is not only long but also produces a large amount of waste liquid and requires the use of activated carbon, which easily generates a large amount of solid waste. Another route involves synthesizing penicillin V via a chemical process using 6-APA and phenoxyacetyl chloride. This route is highly polluting and produces 4-hydropenicillin V derivatives, which cannot be separated from penicillin V, resulting in impurities. The most advanced method is the enzymatic synthesis of penicillin V using 6-APA, which produces less pollution and no impurities or derivatives. Penicillin V is also synthesized via a solvent crystallization process, where it forms a salt with an organic acid potassium salt, crystallizes in an organic solvent, and is then separated from the solid state and dried under vacuum to obtain penicillin V potassium. While this method produces a high-quality product, it results in significant organic solvent pollution, with residual organic solvents easily remaining in the product, and the production cost is high, making it unsuitable for veterinary use.

[0003] Spray drying is a method that instantly disperses liquid materials into extremely fine droplets, which evaporate moisture in a very short time upon contact with hot air, directly transforming the liquid into a solid powder. It boasts advantages of high efficiency and environmental friendliness. Currently, research has explored its application in preparing sourdough powder, traditional Chinese medicine, lactoferrin powder, and highly aromatic tea powder. While spray drying offers these advantages, it requires relatively high temperatures. Penicillin V potassium contains a core component called the β-lactam ring, a crucial structure for its antibacterial activity. However, the β-lactam ring is a four-membered ring with significant ring strain. At higher temperatures, the molecule gains sufficient energy, making this inherently high-energy and unstable β-lactam ring more susceptible to ring-opening reactions, potentially destroying the drug's active structure. Therefore, due to the temperature sensitivity of penicillin V potassium, direct spray drying is insufficient to obtain high-purity penicillin V potassium.

[0004] Therefore, how to prepare high-purity penicillin V potassium using spray drying is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing high-purity penicillin V potassium using spray drying.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing potassium penicillin V by spray drying, comprising the following steps: (1) Spray the mixed alkaline solution into the stirred penicillin V acid suspension to carry out the salt formation reaction and obtain penicillin V potassium solution; The solute in the mixed alkaline solution consists of potassium hydroxide and potassium strong base weak acid salt; The pH value of the salt formation reaction is 5.0~7.5; (2) Spray dry the penicillin V potassium solution obtained in step (1) to obtain penicillin V potassium; The inlet temperature of the spray dryer is 130~160℃, and the outlet temperature of the spray dryer is 90~98℃.

[0007] Preferably, in step (1), the mass ratio of potassium hydroxide to potassium strong base weak acid salt is 1:(1.2~4.0).

[0008] Preferably, the potassium strong base weak acid salt in step (1) includes one or more of potassium carbonate, potassium bicarbonate and potassium acetate.

[0009] Preferably, in step (1), the molar ratio of penicillin V acid to the total alkali in the mixed alkaline solution is 1:1.0~1.1.

[0010] Preferably, in step (1), the mass ratio of solute to solvent in the mixed alkaline solution is 5~12:100.

[0011] Preferably, in step (1), the mass ratio of penicillin V acid to solvent in the penicillin V acid suspension is 10~35:100.

[0012] Preferably, the spraying rate in step (1) is 6~8 min / 100L.

[0013] Preferably, the temperature of the salt formation reaction in step (1) is 0~15℃ and the time of the salt formation reaction is 5~15min.

[0014] Preferably, the stirring rate in step (1) is 200~300 rpm.

[0015] Preferably, the vacuum degree of spray drying in step (2) is -100~-600Pa.

[0016] This invention provides a method for preparing penicillin V potassium by spray drying, comprising the following steps: spraying a mixed alkaline solution into a stirred penicillin V acid suspension to carry out a salt formation reaction to obtain a penicillin V potassium solution; the solute in the mixed alkaline solution is composed of potassium hydroxide and a strong base weak acid salt of potassium; the pH value of the salt formation reaction is 5.0~7.5; spray drying the penicillin V potassium solution to obtain penicillin V potassium; the inlet temperature of the spray drying is 130~160℃, and the outlet temperature of the spray drying is 90~98℃.

[0017] This invention utilizes a mixed alkali and penicillin V acid to prepare penicillin V potassium via a salt-forming reaction. Spraying the mixed alkali solution into a stirred penicillin V acid suspension prevents excessively high local alkali concentrations and the generation of byproducts. This invention uses potassium hydroxide and a strong-base-weak acid salt of potassium as the mixed alkali. During the salt-forming reaction, the strong alkali enhances the salt-forming property of penicillin V acid, ensuring complete salt formation. Simultaneously, the strong-base-weak acid salt of potassium stabilizes the pH value of the salt-forming reaction within a smaller range, preventing problems such as low salt yield or high impurity content caused by excessive pH fluctuations. Therefore, this invention, by controlling the pH value of the salt-forming reaction with a mixed alkali composed of potassium hydroxide and a strong-base-weak acid salt of potassium, can suppress impurity formation and improve the yield and purity of penicillin V potassium. This invention controls the pH of the salt-forming reaction to be 5.0–7.5, and the pH of the resulting penicillin V potassium solution is also stable within this range. Within this range, penicillin V potassium exhibits good stability. When spray-drying the penicillin V potassium solution, controlling the inlet temperature to 130–160°C results in good drying performance. During spray drying, the water on the surface of the penicillin V potassium droplets evaporates rapidly, carrying away a large amount of heat. Under negative pressure, water evaporation is even faster and more thorough. This provides a brief "protective period" for the heat-sensitive penicillin V potassium, inhibiting its decomposition into impurities. This invention also controls the outlet temperature of the spray dryer to 90–98°C, preventing prolonged exposure of the completely dried penicillin V potassium particles from causing ring-opening or degradation and the formation of byproducts, thus obtaining high-purity penicillin V potassium. This invention first increases the yield and purity of penicillin V potassium in the solution during the salt-forming reaction, while simultaneously controlling the pH range of the resulting penicillin V potassium solution and the spray drying parameters to prevent the decomposition of penicillin V potassium into byproducts. The method provided by this invention involves selecting a mixed solution of potassium hydroxide and potassium (a strong base and weak acid salt) to form a salt at a specific temperature, followed by low-temperature negative pressure spray drying. This process is not only simple but also eliminates the need for large amounts of solvent, generating no solid waste or waste liquid, thus offering environmental advantages. Furthermore, it yields high-purity penicillin V potassium. Example results show that the penicillin V potassium obtained using the method provided by this invention, calculated based on anhydrous purity, contains C... 16 H 18 The content of N2O5S shall not be less than 87%, the maximum single impurity shall not exceed 0.8%, the total impurities shall not exceed 2.1%, and the polymer shall not exceed 0.1%. Detailed Implementation

[0018] This invention provides a method for preparing potassium penicillin V by spray drying, comprising the following steps: (1) Spray the mixed alkaline solution into the stirred penicillin V acid suspension to carry out the salt formation reaction and obtain penicillin V potassium solution; The solute in the mixed alkaline solution consists of potassium hydroxide and potassium strong base weak acid salt; The pH value of the salt formation reaction is 5.0~7.5; (2) Spray dry the penicillin V potassium solution obtained in step (1) to obtain penicillin V potassium; The inlet temperature of the spray dryer is 130~160℃, and the outlet temperature of the spray dryer is 90~98℃.

[0019] Unless otherwise specified, all raw materials used in this invention are commercially available products well-known in the art.

[0020] In this invention, a mixed alkaline solution is sprayed into a stirred penicillin V acid suspension to carry out a salt formation reaction, thereby obtaining a penicillin V potassium solution.

[0021] In this invention, the preferred mass ratio of solute to solvent in the mixed alkaline solution is 5-12:100. As an embodiment of this invention, the mass ratio of solute to solvent in the mixed alkaline solution can be 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 10.5:100, 11:100, or 12:100. This invention controls the mass ratio of solute to solvent in the mixed alkaline solution within the above range, achieving a suitable concentration, which is more conducive to controlling the reaction rate and making the salt formation reaction more complete.

[0022] The present invention does not impose any particular limitation on the preparation method of the mixed alkaline solution, as long as the solute is completely dissolved in the solvent to form a solution.

[0023] In this invention, the solvent in the mixed alkaline solution is preferably purified water.

[0024] In this invention, the solute in the mixed alkaline solution consists of potassium hydroxide and a strong-base-weak-acid salt of potassium. By using potassium hydroxide and a strong-base-weak-acid salt of potassium as a mixed alkali, this invention can enhance the salt-forming property of penicillin V acid during the salt-forming reaction, ensuring complete salt formation of penicillin V acid. Simultaneously, the strong-base-weak-acid salt of potassium stabilizes the pH value of the salt-forming reaction within a smaller range, preventing problems such as low salt formation or high impurity content caused by excessive pH fluctuations during the salt-forming reaction.

[0025] In this invention, the potassium strong-base weak acid salt preferably includes one or more of potassium carbonate, potassium bicarbonate, and potassium acetate. The use of the aforementioned potassium strong-base weak acid salt in this invention helps to stabilize the pH value of the salt-forming reaction.

[0026] In this invention, the mass ratio of potassium hydroxide to potassium strong base weak acid salt is preferably 1:1.2 to 4.0, more preferably 1:1.5 to 2.5. By controlling the mass ratio of potassium hydroxide to potassium strong base weak acid salt within the above range, this invention can control the pH value of the salt formation reaction within a suitable range.

[0027] In this invention, the preferred mass ratio of penicillin V acid to solvent in the penicillin V acid suspension is 10-35:100. As an embodiment of this invention, the mass ratio of penicillin V acid to solvent in the penicillin V acid suspension can be 10:100, 15:100, 20:100, 25:100, 30:100, or 35:100. This invention controls the mass ratio of penicillin V acid to solvent within the above range, achieving a suitable concentration, which is more conducive to controlling the reaction rate and making the salt formation reaction more complete.

[0028] The present invention does not specify the preparation method of the penicillin V acid suspension; penicillin V acid can be uniformly dispersed in a solvent.

[0029] In this invention, the solvent for the penicillin V acid suspension is preferably purified water.

[0030] In this invention, the preferred molar ratio of penicillin V acid to the total alkali in the mixed alkaline solution is 1:1.0~1.1. By controlling the molar ratio of penicillin V acid to the total alkali in the mixed alkaline solution within the above range, this invention enables more complete salt formation.

[0031] In this invention, the spraying rate is preferably 6-8 min / 100L, more preferably 7-8 min / 100L. By controlling the spraying rate within this range, the mixed alkaline solution and penicillin V acid suspension are mixed more thoroughly, preventing excessively high local concentrations of the mixed alkaline solution. This invention does not impose any particular limitation on the spraying device; any conventional spraying device can be used.

[0032] In this invention, the stirring speed is preferably 200-300 rpm, more preferably 250-280 rpm. This invention, by spraying the mixed alkaline solution into the stirred penicillin V acid suspension, enables the mixed alkaline solution to disperse rapidly after being sprayed into the penicillin V acid suspension, preventing excessively high local concentrations of the mixed alkaline solution from forming byproducts.

[0033] In this invention, the preferred temperature for the salt-forming reaction is 0-15°C, and the preferred reaction time is 5-15 min. As an embodiment of this invention, the temperature for the salt-forming reaction can be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, or 15°C; and the reaction time can be 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, or 15 min. By conducting the salt-forming reaction at the above temperatures, this invention can promote the complete salt formation of penicillin V acid, thereby improving the yield and purity of penicillin V potassium.

[0034] In this invention, the pH value of the salt-forming reaction is 5.0~7.5. As an embodiment of this invention, the pH value of the salt-forming reaction can be 5.0, 6.0, 6.1, 6.2, 6.3, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, or 7.5. By controlling the pH value of the salt-forming reaction to 5.0~7.5, this invention ensures complete salt formation of penicillin V acid. In this invention, the pH fluctuation value during the salt-forming reaction does not exceed 0.5. Controlling the pH fluctuation value to not exceed 0.5 reduces the formation of byproducts.

[0035] After obtaining the penicillin V potassium solution, the present invention spray-dries the penicillin V potassium solution to obtain penicillin V potassium.

[0036] In this invention, the inlet temperature of the spray dryer is 130~160℃. As an embodiment of this invention, the inlet temperature of the spray dryer can be 130℃, 135℃, 140℃, 145℃, 150℃, 155℃, 158℃, or 160℃. This invention controls the inlet temperature to be 130~160℃, resulting in a better drying effect. During the instantaneous spray drying process, the water on the surface of the penicillin V potassium droplets evaporates rapidly, carrying away a large amount of heat. This provides a brief "protective period" for the heat-sensitive penicillin V potassium, preventing it from decomposing into impurities.

[0037] In this invention, the outlet temperature of the spray dryer is 90~98℃. As an embodiment of this invention, the outlet temperature of the spray dryer can be 96℃. This invention controls the outlet temperature of the spray dryer to 90~98℃ to prevent the fully dried penicillin V potassium particles from being exposed for extended periods, which could lead to ring-opening or degradation and the generation of byproducts, thereby obtaining high-purity penicillin V potassium.

[0038] In this invention, the vacuum degree of the spray drying is preferably -100 to -600 Pa. As an embodiment of this invention, the vacuum degree of the spray drying can be -100 Pa, -200 Pa, -300 Pa, -400 Pa, -480 Pa, or -600 Pa. By controlling the vacuum degree of the spray drying within the above range, this invention helps to improve drying efficiency.

[0039] The method provided by this invention first increases the yield and purity of penicillin V potassium in the penicillin V potassium solution during the salt formation reaction, while controlling the pH range of the formed penicillin V potassium solution and the parameters of spray drying, which can prevent the decomposition of penicillin V potassium to form byproducts, thereby improving the purity of penicillin V potassium.

[0040] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0041] Example 1 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 35 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 3.5 kg of base A and 7.0 kg of base B in 100 kg of purified water to obtain a mixed alkaline solution; wherein base A is potassium hydroxide and base B is potassium bicarbonate. 84 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 6.8 for 10 min to obtain a penicillin V potassium solution. The pH fluctuation should not exceed 0.5. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 158°C, the outlet temperature to 96°C, and the vacuum degree to -480Pa, to obtain white penicillin V potassium powder. The test results of penicillin V potassium prepared in this embodiment are shown in Table 1; test report number CJ05320250901.

[0042] Example 2 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 15 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 2.0 kg of base A and 4.0 kg of base B in 100 kg of purified water to obtain a mixed alkaline solution; wherein base A is potassium hydroxide and base B is potassium bicarbonate. 63 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 6.6 for 15 min to obtain a penicillin V potassium solution. The pH fluctuation should not exceed 0.5. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 158°C, the outlet temperature to 96°C, and the vacuum degree to -480Pa, to obtain white penicillin V potassium powder. The test results of penicillin V potassium prepared in this embodiment are shown in Table 1; test report number CJ05320250701.

[0043] Example 3 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 35 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 3.5 kg of base A and 7.0 kg of base B in 100 kg of purified water to obtain a mixed alkaline solution; wherein base A is potassium hydroxide and base B is potassium bicarbonate. 84 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 7.2 for 10 min to obtain a penicillin V potassium solution. The pH fluctuation should not exceed 0.5. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 152°C, the outlet temperature to 96°C, and the vacuum degree to -540Pa, to obtain white penicillin V potassium powder. The test results of the penicillin V potassium prepared in this embodiment are shown in Table 1; test report number CJ05320251203.

[0044] Comparative Example 1 This comparative example uses penicillin V potassium prepared by the commonly used solvent method, which is a commercially available product sourced from Sinopharm Vicda Pharmaceutical Co., Ltd. The test results of penicillin V potassium in this comparative example are shown in Table 1.

[0045] Comparative Example 2 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 15 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 6.0 kg of base A in 100 kg of purified water to obtain a mixed alkaline solution; wherein base A is potassium hydroxide. 63 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 7.0 for 6 min to obtain a penicillin V potassium solution. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 158°C, the outlet temperature to 96°C, and the vacuum degree to -480Pa, to obtain a light yellow powder of penicillin V potassium. The test results of the penicillin V potassium prepared in this comparative example are shown in Table 1.

[0046] Comparative Example 3 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 15 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 6.0 kg of potassium bicarbonate in 100 kg of purified water to obtain a mixed alkaline solution; 63L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280rpm) at a rate of 8min / 100L. The salt formation reaction was carried out at a temperature of 5℃ and a pH of 6.8 for 15min. The resulting penicillin V potassium solution was not clear and the salt formation was incomplete. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 158°C, the outlet temperature to 96°C, and the vacuum degree to -480Pa, to obtain white penicillin V potassium powder. The test results of the penicillin V potassium prepared in this comparative example are shown in Table 1.

[0047] Comparative Example 4 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 15 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 2.0 kg of potassium hydroxide and 4.0 kg of potassium bicarbonate in 100 kg of purified water to obtain a mixed alkaline solution; 63 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 6.6 for 12 min to obtain a penicillin V potassium solution. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 180°C, the outlet temperature to 120°C, and the vacuum degree to -480Pa, to obtain yellow penicillin V potassium powder. The test results of the penicillin V potassium prepared in this comparative example are shown in Table 1.

[0048] Comparative Example 5 A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Mix 15 kg of penicillin V acid with 100 kg of purified water to obtain a penicillin V acid suspension; Dissolve 2.0 kg of potassium hydroxide and 4.0 kg of potassium bicarbonate in 100 kg of purified water to obtain a mixed alkaline solution; 63 L of mixed alkaline solution was sprayed into a penicillin V acid suspension being stirred (280 rpm) at a rate of 8 min / 100 L. The salt formation reaction was carried out at a temperature of 5 °C and a pH of 6.6 for 12 h to obtain a penicillin V potassium solution. (2) Spray dry the penicillin V potassium solution obtained in step (1), control the inlet temperature of the spray dryer to 100°C, the outlet temperature to 70°C, and the vacuum degree to -480Pa, and do not obtain white powder penicillin V potassium. The test results of the penicillin V potassium prepared in this comparative example are shown in Table 1.

[0049] Table 1. Detection results of penicillin V potassium prepared in Examples 1-3 and Comparative Examples 1-5

[0050] In Table 1, the test results are based on the 2020 edition of the Pharmacopoeia of the People's Republic of China. Content refers to the content of penicillin V in the penicillin V potassium product. The standard requires a penicillin V content of not less than 85.7%, a maximum single impurity content of not more than 1.5%, a total impurity content of not more than 3.0%, and a polymer content of not more than 0.6%. As can be seen from Table 1, the penicillin V potassium content in the product obtained using the method provided by this invention can reach over 87%, and the maximum single impurity, total impurity, and polymer content all meet the standard requirements.

[0051] The comparison between Comparative Example 1 and Example 2 shows that the quality of the penicillin V potassium product prepared by this spray drying method fully meets the pharmacopoeia requirements and is similar to the quality indicators of the product prepared by the solvent crystallization method.

[0052] The comparison between Comparative Example 2 and Example 2 shows that the product quality made entirely from potassium hydroxide does not meet the pharmacopoeia requirements.

[0053] The comparison between Comparative Example 3 and Example 2 shows that the salt formation of the strong base weak acid salt using potassium is incomplete, the water solubility is poor, and other quality indicators do not meet the pharmacopoeia requirements.

[0054] The comparison between Comparative Example 4 and Example 2 shows that excessively high spray drying temperature has a destructive effect on the quality of penicillin V potassium product.

[0055] The comparison between Comparative Example 5 and Example 2 shows that if the spray drying temperature is too low, penicillin V potassium dry powder cannot be obtained.

[0056] The method provided by this invention does not generate solid waste or waste liquid, thus solving the environmental problems associated with solvent methods. Furthermore, the method is simple, has a short production cycle, and reduces production costs. Therefore, the method provided by this invention not only has the advantages of being fast, environmentally friendly, simple, and capable of large-scale production, but also yields high-purity penicillin V potassium.

[0057] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing penicillin V potassium by spray drying, comprising the following steps: (1) Spray the mixed alkaline solution into the stirred penicillin V acid suspension to carry out the salt formation reaction and obtain penicillin V potassium solution; The solute in the mixed alkaline solution consists of potassium hydroxide and potassium strong base weak acid salt; The pH value of the salt formation reaction is 5.0~7.5; (2) Spray dry the penicillin V potassium solution obtained in step (1) to obtain penicillin V potassium; The inlet temperature of the spray dryer is 130~160℃, and the outlet temperature of the spray dryer is 90~98℃.

2. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of potassium hydroxide to potassium strong base weak acid salt is 1:(1.2~4.0).

3. The preparation method according to claim 1 or 2, characterized in that, In step (1), the strong base weak acid salt of potassium includes one or more of potassium carbonate, potassium bicarbonate and potassium acetate.

4. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of penicillin V acid to the total alkali in the mixed alkaline solution is 1:1.0~1.

1.

5. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of solute to solvent in the mixed alkaline solution is 5~12:

100.

6. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of penicillin V acid to solvent in the penicillin V acid suspension is 10~35:

100.

7. The preparation method according to claim 1, characterized in that, The spraying rate in step (1) is 6~8 min / 100L.

8. The preparation method according to claim 1, characterized in that, The temperature of the salt formation reaction in step (1) is 0~15℃ and the time of the salt formation reaction is 5~15min.

9. The preparation method according to claim 1, characterized in that, The stirring speed in step (1) is 200~300 rpm.

10. The preparation method according to claim 1, characterized in that, The vacuum degree of spray drying in step (2) is -100~-600Pa.

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