A penicillin V potassium capsule and a preparation method thereof

Abstract

This invention discloses a penicillin V potassium capsule and its preparation method. The preparation method includes: preparing modified polylactic acid glycolic acid copolymer microspheres; mixing penicillin V potassium micropowder with the modified polylactic acid glycolic acid copolymer microspheres, adding fumed silica and anhydrous calcium hydrogen phosphate for further mixing to obtain a blend; granulating the blend using a dry granulation method; filling the obtained granules into capsules, polishing, and packaging; and modifying the polylactic acid glycolic acid copolymer with povidone and ethyl cellulose to obtain the modified polylactic acid glycolic acid copolymer microspheres. This invention designs polylactic acid glycolic acid copolymer microspheres that are double-modified with povidone and ethyl cellulose, resulting in better drug loading flowability, more stable mixing uniformity, and significantly improved flowability compared to penicillin V potassium powder. The addition of fumed silica and anhydrous calcium phosphate further enhances antistatic properties and reduces the powder return rate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a penicillin V potassium capsule and its preparation method. Background Technology

[0002] Penicillin V potassium belongs to the β-lactam antibiotic class. Its antibacterial spectrum is similar to that of penicillin G. It can destroy bacterial cell walls and has bactericidal effects. It is suitable for mild to moderate infections caused by penicillin-sensitive strains, including tonsillitis, pharyngitis, scarlet fever, and erysipelas caused by streptococci; bronchitis, pneumonia, otitis media, and sinusitis caused by pneumococci; and skin and soft tissue infections caused by susceptible staphylococci. Penicillin V potassium is also used as a prophylactic agent for recurrent rheumatic fever and infective endocarditis, and can also be used for spirochetal infections.

[0003] The β-lactam ring of penicillin V potassium is the core of its efficacy, but it is easily hydrolyzed and ring-opened under conditions of high temperature, high humidity, acidity, alkalinity, and metal ions, leading to a decrease in content within its shelf life, the appearance of degradation impurities, and an increased risk of inactivation and allergic reactions. Because penicillin V potassium is highly hygroscopic, it degrades rapidly upon contact with water, requiring high levels of moisture, pH, and metal ions in the capsule shell and filler. Traditional wet granulation methods are clearly insufficient for these requirements and have therefore been gradually replaced by dry granulation and direct powder filling methods.

[0004] Patent document CN104146985A discloses a method for preparing penicillin V potassium capsules, which employs a direct powder filling method. The method involves mixing penicillin V potassium technical material and magnesium stearate, filling the resulting powder using a fully automated capsule filling machine, followed by thermal bonding and packaging. However, this method still requires further improvement. Because penicillin V potassium micropowder is highly electrostatic and prone to agglomeration, direct filling can lead to unstable feeding, stratification, and the need for remixing after mixing. Furthermore, the drug powder easily adheres to the hopper, mixer, and filling machine, resulting in a lower actual penicillin V potassium content in the capsules. Additionally, a subsequent thermal bonding process is required for aluminum-plastic packaging. The process conditions are: compressed air 0.4–0.7 MPa, upper plate temperature 130–150°C, lower plate temperature 130–150°C, heat sealing temperature 200–230°C, and imprinting temperature 190–210°C. The temperatures in this process pose a significant risk of ring-opening degradation to penicillin V potassium.

[0005] Penicillin V potassium capsules are prepared using a dry granulation and filling method. This process eliminates the need for water addition and heating, which is more beneficial to drug stability. However, it still has the following technical drawbacks: First, stratification and drug agglomeration still occur during mixing; second, electrostatic adsorption and adhesion to the capsule walls need further improvement, and further reducing the moisture content in the system can still enhance drug stability; third, the poor flowability of penicillin V potassium makes it prone to powder return issues when using dry granulation and filling. Therefore, how to solve the technical drawbacks of preparing penicillin V potassium capsules using dry granulation and filling and reduce the difficulty of process control are problems that need to be addressed. In view of this, this patent application is filed. Summary of the Invention

[0006] To address the above issues, the purpose of this patent application is to provide a penicillin V potassium capsule that exhibits excellent quality stability in high-temperature and high-humidity environments, as well as good mixing uniformity, hygroscopicity, and flowability, thus solving the technical challenges currently faced in preparing penicillin V potassium capsules using dry granulation and filling methods.

[0007] This invention is achieved through the following technical solution: The first objective of this invention is to provide a method for preparing penicillin V potassium capsules, comprising the following steps: (1) Preparation of modified polylactic acid-glycolic acid copolymer microspheres; (2) After mixing the potassium penicillin V micro powder with the modified polylactic acid glycolic acid copolymer microspheres, fumed silica and anhydrous calcium hydrogen phosphate were added and mixed again to obtain a blend; (3) The blend is granulated using a dry granulation method; (4) Fill the obtained particles into capsules, polish and package them; The modified polylactic acid glycolic acid copolymer microspheres were obtained by modifying the polylactic acid glycolic acid copolymer with polyvinyl ketone and ethyl cellulose.

[0008] This invention designs polylactic acid-glycolic acid copolymer microspheres modified with povidone and ethyl cellulose. These microspheres possess the structural properties of latex microspheres, exhibiting elasticity that disperses shear pressure during dry granulation, protecting the drug crystal form. They also offer more uniform thermal conductivity, reducing localized friction hotspots during shearing, resulting in better drug flowability and more stable mixing uniformity. The flowability of these microspheres is significantly improved compared to penicillin V potassium powder. Furthermore, the hydrophobic modification of the polylactic acid-glycolic acid copolymer with ethyl cellulose prevents moisture from contacting the drug crystals, significantly enhancing stability. Modification with povidone further strengthens the interfacial bonding between the microspheres and the drug, allowing the drug powder to be better anchored on the microsphere surface, preventing physical desorption and resolving issues of layering, agglomeration, and electrostatic desorption during transport. Fumed silica and anhydrous calcium phosphate are also added to the raw materials. The synergistic effect between anhydrous calcium phosphate and latex microspheres forms a composite of elastic regulation and rigid framework, which stabilizes the return powder rate at ≤6%. Fumed silica can not only act as a water absorbent to absorb moisture from the environment, but also form an antistatic system with the microspheres, further eliminating the phenomenon of static clinging to the wall.

[0009] As a preferred technical solution, in step (1), the preparation process of the modified polylactic acid-glycolic acid copolymer microspheres is as follows: Preparation of the oil phase: Polylactic acid glycolic acid copolymer, polyvinyl ketone, and ethyl cellulose are added to an organic solvent and stirred at room temperature until completely dissolved to obtain the oil phase; Preparation of the aqueous phase: Add polyvinyl alcohol to an aqueous solution and control the temperature to 8~15℃ to obtain the aqueous phase; The oil phase is slowly dripped into the aqueous phase and sheared at 6000~10000 rpm for 3~5 min to form a uniform emulsion; After stirring the emulsion at 300-500 rpm for a certain period of time at room temperature, let it stand and allow it to evaporate in a ventilated environment for 4-6 hours. The resulting product is then centrifuged, washed, and vacuum dried.

[0010] In this invention, a one-step in-situ dual modification method is used to prepare modified polylactic acid-glycolic acid copolymer microspheres. Ethyl cellulose, as a hydrophobic component, tends to remain on the surface of the microspheres, forming a low-absorption surface, while povidone tends to migrate to the aqueous interface, resulting in a richer array of polar groups on the microsphere surface. This ultimately forms a hydrophobic structure that anchors the drug. This ensures the quality stability of penicillin V potassium during both the production and storage of the capsules.

[0011] As a preferred technical solution, the weight ratio of the polylactic acid glycolic acid copolymer to povidone and ethyl cellulose is 1:(0.08~0.15):(0.06~0.15), and the molecular weight of the polylactic acid glycolic acid copolymer is 10000~30000.

[0012] As a preferred technical solution, the organic solvent is a mixture of dichloromethane and ethanol, with a volume ratio of 2:(1~2). And / or, the mass fraction of polyvinyl alcohol in the aqueous phase is 1-2%; And / or, vacuum drying is drying at 25°C or below for 12-24 hours.

[0013] As a preferred technical solution, in step (2), the weight ratio of the penicillin V potassium micro powder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica, and anhydrous dicalcium phosphate is 250:(30~50):(1~3):(10~18).

[0014] In this invention, the weight ratio of penicillin V potassium micropowder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica, and anhydrous dicalcium phosphate is rationally designed: If the weight of the modified polylactic acid-glycolic acid copolymer microspheres is too small, they cannot completely encapsulate the penicillin V potassium micropowder, and delamination and desorption problems will still exist, resulting in insufficient protection of the drug crystal form. If the weight is too large, it will increase costs and be detrimental to the return rate of powder. If the weight of fumed silica is too small, it will be insufficient in terms of antistatic properties and assisting action, and its water absorption capacity will also be reduced. If it is too large, it will lead to unstable packing and silica floating and delamination. If the amount of anhydrous dicalcium phosphate is too small, it will lack rigidity and the particles will be brittle. If the amount is too large, it will reduce the elastic buffer, making the drug crystal form easily crushed and slowing down dissolution.

[0015] As a preferred technical solution, the D90 of the penicillin V potassium micropowder is 50-80 micrometers, and the specific surface area of ​​the fumed silica is greater than or equal to 250 m². 2 / g.

[0016] As a preferred technical solution, in step (3), a dry granulation machine is used for granulation. The pressure of the roller in the dry granulation machine is 3~5 MPa, the feeding speed is 80~120 r / min, and the roller speed is 20~30 r / min.

[0017] In the dry granulation process, this invention rationally adjusts the pressure of the pressure rollers and uses low-pressure extrusion to avoid shear friction and heating. The extrusion forms thin sheet-like particles, ensuring that the particles are free from adhesion and clumping. It also fully utilizes the elastic buffering effect of the modified polylactic acid-glycolic acid copolymer microspheres to protect the drug's crystal form from change and prevent the β-lactam ring in penicillin V potassium from opening and degrading, thus ensuring drug quality.

[0018] As a preferred technical solution, in the granulation process, coarse granulation is performed first, followed by fine granulation; For coarse granulation, pass through a 20-30 mesh sieve; for fine granulation, pass through a 40-50 mesh sieve.

[0019] As a preferred technical solution, in step (4), the filling temperature is controlled at 20~24℃ and the ambient humidity is controlled at 40~45%; Polish the filled capsules for 3-5 minutes.

[0020] The second objective of this invention is to provide a penicillin V potassium capsule, which is prepared using any of the methods described above.

[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects: 1. This invention designs polylactic acid-glycolic acid copolymer microspheres that are modified with polyvinylpyrrolidone and ethyl cellulose. These microspheres have the structural properties of latex microspheres, have a certain elasticity, can disperse shear pressure during dry granulation using a pressure roller, have better drug loading flowability, more stable mixing uniformity, and the flowability of the microspheres is significantly improved compared to penicillin V potassium powder.

[0022] 2. This invention utilizes ethyl cellulose to hydrophobically modify polylactic acid-glycolic acid copolymer, improving its hygroscopic properties. Furthermore, using povidone to modify the copolymer further enhances the interfacial bonding between the microspheres and the drug, allowing the drug powder to be better anchored on the microsphere surface, preventing physical desorption and solving the problems of layering, agglomeration, and electrostatic desorption during transport. Fumed silica and anhydrous calcium phosphate are also added to the raw materials. The synergistic effect between anhydrous calcium phosphate and latex microspheres forms a composite of elastic regulation and rigid framework, reducing the return powder rate. Fumed silica not only acts as a desiccant to absorb moisture from the environment but also forms an antistatic system with the microspheres, further eliminating electrostatic adhesion. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0024] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0025] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0026] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0027] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. The process is performed sequentially. For example, the method includes steps (a) and (b), indicating that the method may include step (a) performed sequentially. (b) may also include steps (b) and (a) performed sequentially. For example, the method may also include step (c). This indicates that step (c) can be added to the method in any order; for example, the method may include steps (a), (b), and (c). It may also include steps (a), (c) and (b), or steps (c), (a) and (b), etc.

[0028] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included. Example 1:

[0029] The preparation of a penicillin V potassium capsule includes the following steps: 1. Preparation of modified polylactic acid-glycolic acid copolymer microspheres (1) Preparation of oil phase: Polylactic acid glycolic acid copolymer, polyvinyl ketone, and ethyl cellulose are added to a mixture of dichloromethane and ethanol in a weight ratio of 1:0.08:0.06. The volume ratio of dichloromethane to ethanol is 2:1. Stir at room temperature until completely dissolved and clear to obtain the oil phase. The molecular weight of polylactic acid glycolic acid copolymer is 10,000. (2) Preparation of aqueous phase: Polyvinyl alcohol is added to an aqueous solution to prepare a polyvinyl alcohol solution with a mass fraction of 2%, and the temperature is controlled to 8°C under water bath conditions to obtain the aqueous phase; (3) The oil phase is slowly dripped into the aqueous phase and sheared at 6000 rpm for 5 min to form a uniform emulsion; (4) After stirring the emulsion at 300 rpm for a certain time at room temperature, let it stand and ventilate for 4 hours to evaporate. Then, centrifuge the obtained product and discard the supernatant. Wash it twice with deionized water and vacuum dry it at 23°C for 15 hours to obtain the modified microspheres.

[0030] 2. Preparation of Penicillin V Potassium Capsules (1) After mixing the potassium penicillin V micropowder with the modified polylactic acid glycolic acid copolymer microspheres at 250 rpm for 15 min, fumed silica and anhydrous dicalcium phosphate were added and the mixture was further mixed at 350 rpm for 30 min to obtain a blend. The weight ratio of potassium penicillin V micropowder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica, and anhydrous dicalcium phosphate was 250:45:1:12. The D90 of the potassium penicillin V micropowder was 50 micrometers, and the specific surface area of ​​the fumed silica was 250 m². 2 / g.

[0031] (3) The blend is granulated using a dry granulation method; Specifically, the uniformly mixed material is fed into a dry granulator and extruded to form granules. At the same time, coarse granulation and fine granulation are carried out. A 20-mesh sieve is used for coarse granulation and a 40-mesh sieve is used for fine granulation.

[0032] The pressure of the pressure roller is 3 MPa, the feeding speed is 100 r / min, and the rotation speed of the pressure roller is 20 r / min. (4) Fill the obtained particles into capsules. The filling temperature is controlled at 20°C and the ambient humidity is controlled at 40%. After polishing for 3 minutes, the capsules are packaged. Example 2:

[0033] The preparation of a penicillin V potassium capsule includes the following steps: 1. Preparation of modified polylactic acid-glycolic acid copolymer microspheres (1) Preparation of oil phase: Polylactic acid glycolic acid copolymer, polyvinyl ketone, and ethyl cellulose are added to a mixture of dichloromethane and ethanol in a weight ratio of 1:0.15:0.15. The volume ratio of dichloromethane to ethanol is 2:2. Stir at room temperature until completely dissolved and clear to obtain the oil phase. The molecular weight of polylactic acid glycolic acid copolymer is 30,000. (2) Preparation of aqueous phase: Polyvinyl alcohol is added to an aqueous solution to prepare a polyvinyl alcohol solution with a mass fraction of 1%, and the temperature is controlled at 15°C under water bath conditions to obtain the aqueous phase; (3) The oil phase is slowly dripped into the aqueous phase and sheared at 10,000 rpm for 3 min to form a uniform emulsion; (4) After stirring the emulsion at 500 rpm for a certain time at room temperature, let it stand and ventilate for 6 hours to evaporate. Then, centrifuge the obtained product and discard the supernatant. Wash it twice with deionized water and vacuum dry it at 23°C for 24 hours to obtain the modified microspheres.

[0034] 2. Preparation of Penicillin V Potassium Capsules (1) After mixing the potassium penicillin V micropowder with the modified polylactic acid glycolic acid copolymer microspheres at 250 rpm for 15 min, fumed silica and anhydrous dicalcium phosphate were added and the mixture was continued to be mixed at 350 rpm for 30 min to obtain a blend; wherein the weight ratio of potassium penicillin V micropowder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica and anhydrous dicalcium phosphate was 250:30:3:10; the D90 of potassium penicillin V micropowder was 80 micrometers and the specific surface area of ​​fumed silica was 300 m². 2 / g.

[0035] (3) The blend is granulated using a dry granulation method; Specifically, the uniformly mixed material is fed into a dry granulator and extruded to form granules. At the same time, coarse granulation and fine granulation are carried out. A 30-mesh sieve is used for coarse granulation and a 50-mesh sieve is used for fine granulation.

[0036] The pressure of the pressure roller is 5 MPa, the feeding speed is 120 r / min, and the rotation speed of the pressure roller is 30 r / min. (4) Fill the obtained particles into capsules. The filling temperature is controlled at 24℃ and the ambient humidity is controlled at 42%. After polishing for 5 minutes, the capsules are packaged. Example 3:

[0037] The preparation of a penicillin V potassium capsule includes the following steps: 1. Preparation of modified polylactic acid-glycolic acid copolymer microspheres (1) Preparation of oil phase: Polylactic acid glycolic acid copolymer, polyvinyl ketone, and ethyl cellulose are added to a mixture of dichloromethane and ethanol in a weight ratio of 1:0.10:0.10. The volume ratio of dichloromethane to ethanol is 2:1. Stir at room temperature until completely dissolved and clear to obtain the oil phase; wherein the molecular weight of polylactic acid glycolic acid copolymer is 20000. (2) Preparation of aqueous phase: Polyvinyl alcohol is added to an aqueous solution to prepare a polyvinyl alcohol solution with a mass fraction of 1.5%, and the temperature is controlled to 10°C under water bath conditions to obtain the aqueous phase; (3) The oil phase is slowly dripped into the aqueous phase and sheared at 8000 rpm for 4 min to form a uniform emulsion; (4) After stirring the emulsion at 400 rpm for a certain time at room temperature, let it stand and ventilate for 5 hours to evaporate. Then, centrifuge the obtained product and discard the supernatant. Wash it twice with deionized water and vacuum dry it at 20°C for 18 hours to obtain the modified microspheres.

[0038] 2. Preparation of Penicillin V Potassium Capsules (1) After mixing the potassium penicillin V micropowder with the modified polylactic acid glycolic acid copolymer microspheres at 250 rpm for 15 min, fumed silica and anhydrous dicalcium phosphate were added and the mixture was continued to be mixed at 350 rpm for 30 min to obtain a blend; wherein the weight ratio of potassium penicillin V micropowder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica and anhydrous dicalcium phosphate was 250:40:2:15; the D90 of potassium penicillin V micropowder was 60 micrometers and the specific surface area of ​​fumed silica was 300 m². 2 / g.

[0039] (3) The blend is granulated using a dry granulation method; Specifically, the uniformly mixed material is fed into a dry granulator and extruded to form granules. At the same time, coarse granulation and fine granulation are carried out. A 20-mesh sieve is used for coarse granulation and a 40-mesh sieve is used for fine granulation.

[0040] The pressure of the pressure roller is 4 MPa, the feeding speed is 100 r / min, and the rotation speed of the pressure roller is 30 r / min. (4) Fill the obtained particles into capsules. The filling temperature is controlled at 22℃ and the ambient humidity is controlled at 40%. After polishing for 5 minutes, package the capsules.

[0041] Comparative Example 1: The difference from Example 1 is that only polyvinylpyrrolidone was used to modify the polylactic acid-glycolic acid copolymer. Everything else is the same as in Example 1.

[0042] Comparative Example 2: The difference from Example 1 is that only ethyl cellulose was used to modify the polylactic acid-glycolic acid copolymer. Everything else is the same as in Example 1.

[0043] Comparative Example 3: The difference from Example 1 is that, in the preparation of the blend, only potassium penicillin V micro powder, modified polylactic acid glycolic acid copolymer microspheres and anhydrous calcium hydrogen phosphate are added, and fumed silica is not added.

[0044] Comparative Example 4: The difference from Example 1 is that, in the preparation of the blend, only potassium penicillin V micropowder, modified polylactic acid glycolic acid copolymer microspheres and fumed silica are added, and anhydrous calcium hydrogen phosphate is not added.

[0045] Comparative Example 5: The difference from Example 1 is that the anhydrous calcium hydrogen phosphate in the formula is replaced with anhydrous sodium dihydrogen phosphate.

[0046] test: 1. The contents, moisture content, and stability of each example and comparative example were determined. For instance, the capsules were continuously placed at 50±2℃ and RH 75%±5% for 6 months to determine the contents of the maximum single impurity and total impurities, in order to determine the stability of the capsules. The specific test results are shown in Table 1.

[0047] Table 1

[0048] As shown in Table 1, the penicillin V potassium capsules obtained in each embodiment of the present invention exhibit good stability during long-term storage and accelerated testing. In Comparative Example 1, the lack of modification of the polylactic acid-glycolic acid copolymer with povidone led to more severe electrostatic desorption and adhesion during the production process compared to the other embodiments, resulting in a significant decrease in the content of penicillin V potassium. In Comparative Example 2, the lack of modification with ethyl cellulose reduced hydrophobicity, resulting in increased moisture content and a significant increase in the content of other impurities in the prepared drug. In Comparative Example 3, the absence of fumed silica made electrostatic adhesion more likely, leading to a significant decrease in the content of penicillin V potassium in the capsules. In Comparative Example 4, the lack of anhydrous calcium dihydrogen phosphate prevented elastic adjustment, resulting in powder return and repeated granulation, which introduced impurities into the drug. In Comparative Example 5, the use of anhydrous sodium dihydrogen phosphate, which has a certain degree of acidity, may cause hydrolysis of penicillin V potassium under long-term storage. Furthermore, its hygroscopicity is higher than that of anhydrous calcium phosphate, significantly impacting the stability of the drug.

[0049] In summary, the products obtained in Examples 1 to 3 of this invention all have excellent stability, maintaining a high content of active ingredients even under high temperature and humidity and long-term storage, and with very little generation of impurities.

[0050] 2. The inventors further measured the mixing uniformity, flowability, static electricity and hygroscopicity of the products obtained in each embodiment and comparative example.

[0051] Mixing uniformity determination: Refer to the content uniformity test method in Section 4, General Chapter 0941 of the 2025 edition of the Chinese Pharmacopoeia. A+2.2S should not exceed 15.0. The smaller the value, the better the content uniformity.

[0052] The hygroscopicity test was conducted according to the "Guiding Principles for Hygroscopicity Test" in Part IV of the 2025 edition of the Chinese Pharmacopoeia. The weight gain of the particles after 24 hours under conditions of 25℃±1℃ and relative humidity of 80%±2% was used as the evaluation index. Deliquescence: Absorbs sufficient moisture to form a liquid; Highly hygroscopic: Increases weight by at least 15% due to moisture absorption; Hygroscopic: Increases weight by at least 2% due to moisture absorption, less than 15%; Slightly hygroscopic: Increases weight by at least 0.2% due to moisture absorption, less than 2%; No or almost no hygroscopicity: Increases weight by at least 0.2% due to moisture absorption.

[0053] Flowability determination: Using a BEP2 powder flowability tester, fix the bottom disk with a diameter of 100 mm. Slowly pour the contents of each capsule to be tested into the funnel above the nozzle with a diameter of 10 mm and a height of 75 mm from the bottom of the nozzle to the bottom disk. When the height of the cone formed by the contents on the bottom disk no longer increases, read the cone height h and the radius r of the bottom disk. Perform three parallel measurements and calculate the R2 angle of repose. The formula is R2 angle of repose = arctan(h / r).

[0054] The electrostatic charge is measured using a powder particle electrostatic tester (such as a Faraday cup electrostatic measurement system).

[0055] The measurement results are shown in Table 2.

[0056] Table 2

[0057] As shown in Table 2, the pharmaceutical products obtained in each embodiment of the present invention exhibit good mixing uniformity, flowability, and hygroscopicity, meeting the standard requirements. In Comparative Example 1, the absence of povidone resulted in poor bonding between the penicillin V potassium micropowder and the microspheres, leading to stratification, agglomeration, and reduced flowability. In Comparative Example 2, the absence of ethyl cellulose resulted in a slight decrease in mixing uniformity, a significant decrease in hygroscopicity, and poorer flowability compared to the embodiments. In Comparative Example 3, the absence of fumed silica significantly reduced both flowability and uniformity, while increasing water absorption. In Comparative Example 4, the absence of anhydrous calcium phosphate had some impact on uniformity, flowability, and hygroscopicity, but it was not significant. In Comparative Example 5, anhydrous sodium dihydrogen phosphate was used, resulting in slightly poorer flowability and a greater density difference between sodium phosphate and the microspheres. This led to slight sedimentation and stratification during long-term mixing and transportation, resulting in a significant decrease in uniformity.

[0058] The above specific embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing penicillin V potassium capsules, characterized in that, Includes the following steps: (1) Preparation of modified polylactic acid-glycolic acid copolymer microspheres; (2) After mixing the potassium penicillin V micro powder with the modified polylactic acid glycolic acid copolymer microspheres, fumed silica and anhydrous calcium hydrogen phosphate were added and mixed again to obtain a blend; (3) The blend is granulated using a dry granulation method; (4) Fill the obtained particles into capsules, polish and package them; The modified polylactic acid glycolic acid copolymer microspheres were obtained by modifying the polylactic acid glycolic acid copolymer with polyvinyl ketone and ethyl cellulose.

2. The method for preparing a penicillin V potassium capsule according to claim 1, characterized in that, In step (1), the preparation process of the modified polylactic acid-glycolic acid copolymer microspheres is as follows: Preparation of the oil phase: Polylactic acid glycolic acid copolymer, polyvinyl ketone, and ethyl cellulose are added to an organic solvent and stirred at room temperature until completely dissolved to obtain the oil phase; Preparation of the aqueous phase: Add polyvinyl alcohol to an aqueous solution and control the temperature to 8~15℃ to obtain the aqueous phase; The oil phase is slowly dripped into the aqueous phase and sheared at 6000~10000 rpm for 3~5 min to form a uniform emulsion; After stirring the emulsion at 300-500 rpm for a certain period of time at room temperature, let it stand and allow it to evaporate in a ventilated environment for 4-6 hours. The resulting product is then centrifuged, washed, and vacuum dried.

3. The method for preparing a penicillin V potassium capsule according to claim 2, characterized in that, The weight ratio of the polylactic acid glycolate copolymer to povidone and ethyl cellulose is 1:(0.08~0.15):(0.06~0.15), and the molecular weight of the polylactic acid glycolate copolymer is 10000~30000.

4. The method for preparing a penicillin V potassium capsule according to claim 2, characterized in that, The organic solvent is a mixture of dichloromethane and ethanol, with a volume ratio of 2:(1~2). And / or, the mass fraction of polyvinyl alcohol in the aqueous phase is 1-2%; And / or, vacuum drying is drying at 25°C or below for 12-24 hours.

5. The method for preparing a penicillin V potassium capsule according to claim 1, characterized in that, In step (2), the weight ratio of the potassium penicillin V micro powder, modified polylactic acid glycolic acid copolymer microspheres, fumed silica, and anhydrous dicalcium phosphate is 250:(30~50):(1~3):(10~18).

6. The method for preparing a penicillin V potassium capsule according to claim 1, characterized in that, The D90 of the penicillin V potassium micropowder is 50-80 micrometers, and the specific surface area of ​​the fumed silica is greater than or equal to 250 m². 2 / g.

7. The method for preparing a penicillin V potassium capsule according to claim 1, characterized in that, In step (3), a dry pellet mill is used for pelleting. The pressure of the roller in the dry pellet mill is 3~5 MPa, the feeding speed is 80~120 r / min, and the roller speed is 20~30 r / min.

8. The method for preparing a penicillin V potassium capsule according to claim 7, characterized in that, During the granulation process, coarse granulation is performed first, followed by fine granulation. For coarse granulation, pass through a 20-30 mesh sieve; for fine granulation, pass through a 40-50 mesh sieve.

9. The method for preparing a penicillin V potassium capsule according to claim 1, characterized in that, In step (4), the filling temperature is controlled at 20~24℃, and the ambient humidity is controlled at 40~45%; Polish the filled capsules for 3-5 minutes.

10. A penicillin V potassium capsule, characterized in that, It is obtained by the preparation method described in any one of claims 1 to 9.

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