Preparation method of micro-powder amoxicillin

Abstract

The invention relates to the technical field of medicine preparation, in particular to a preparation method of micro-powder amoxicillin. The preparation method of the micro-powder amoxicillin, provided by the invention, comprises the following steps: mixing an amoxicillin condensation solution and concentrated hydrochloric acid to obtain an amoxicillin acidizing fluid; ammonia water is added into the amoxicillin acidizing fluid for crystallization and crystal growing in sequence, and micro-powder amoxicillin is obtained; the dripping rate of the ammonia water is 6.5-14 m < 3 > / h; the crystallization is carried out under a stirring condition. The preparation method can be used for preparing the micro-powder amoxicillin with enough small particle size.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a method for preparing micro-powdered amoxicillin. Background Art

[0002] Amoxicillin is a widely used antibiotic used to treat a variety of bacterial infections. Its development history can be traced back to the 1940s, when an Australian scientist named Eric Blom noticed that an antibiotic called penicillin could kill bacteria. The discovery of penicillin triggered a global boom in antibiotic research, and scientists began to look for more antibiotics.

[0003] In the late 1940s, scientist Howard Florey's team successfully discovered a derivative called amoxicillin, which is similar to penicillin but different in chemical structure, making it more resistant to breakdown by enzymes produced by bacteria. In addition, amoxicillin also has a broader antibacterial spectrum and can treat more types of bacterial infections.

[0004] In the following decades, amoxicillin has gradually been widely used and has become a common antibiotic used by doctors and patients. It can be used to treat common infection symptoms such as respiratory tract infections, urinary tract infections, skin infections, etc. Due to its high efficiency and relatively few side effects, amoxicillin is widely recognized as a safe and effective antibiotic.

[0005] Chinese patent CN113133986A discloses that by adjusting the particle size ratio of amoxicillin powder, the amount of amoxicillin light powder is increased, and the minimum particle size of the light powder is no longer limited, but the maximum particle size of the heavy powder is limited, thereby obtaining an amoxicillin capsule with high stability and good solubility. It can be seen that the particle size of amoxicillin has a great influence on the amoxicillin preparation.

[0006] Chinese patent CN115490706A discloses a method for preparing large-particle amoxicillin, which comprises: acidifying the amoxicillin enzymatic condensation solution with concentrated hydrochloric acid to make the pH of the acidified solution less than 0.2, and the molar ratio of amoxicillin to concentrated hydrochloric acid is 1:5.8-7.6, and then dripping ammonia water to the isoelectric point to crystallize amoxicillin. The obtained amoxicillin particle size range is Dv(10)10-15μm, Dv(50)45-60μm, and Dv(90)145-165μm.

[0007] Compared with amoxicillin preparations which require amoxicillin to have a relatively large particle size, veterinary drugs require amoxicillin to have a smaller particle size, which is more conducive to the dissolution of amoxicillin. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing micronized amoxicillin powder, wherein the method can prepare micronized amoxicillin powder with a sufficiently small particle size.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] The present invention provides a method for preparing micro-powdered amoxicillin, comprising the following steps:

[0011] The amoxicillin condensation solution and concentrated hydrochloric acid are mixed to obtain an amoxicillin acidified solution;

[0012] Adding ammonia water to the amoxicillin acidified solution to perform crystallization and crystal cultivation in sequence to obtain micro powder amoxicillin;

[0013] The dripping rate of the ammonia water is 6.5 to 14 m / s. 3 / h; the crystallization is carried out under stirring conditions.

[0014] Preferably, the mass concentration of the concentrated hydrochloric acid is 33% to 35%;

[0015] The concentration of amoxicillin in the amoxicillin condensation solution is 80-220 mg / mL.

[0016] Preferably, the mixing temperature is 15-25°C.

[0017] Preferably, the concentration of amoxicillin in the amoxicillin acidified solution is ≥80 mg / mL;

[0018] The pH value of the amoxicillin acidified solution is 0.8-1.3.

[0019] Preferably, the mass concentration of the ammonia water is 10% to 12%;

[0020] The adding time of the ammonia water is ≤10min.

[0021] Preferably, the pH of the mixed solution obtained after adding the ammonia water is 4-5.

[0022] Preferably, the stirring speed is ≥120 rpm, the stirring time is 10 to 50 min, and the temperature is 15 to 20°C.

[0023] Preferably, the crystal growing temperature is 5-8°C and the time is 20-40 minutes.

[0024] Preferably, after the crystal growing is completed, centrifugation, washing and drying are further performed in sequence.

[0025] Preferably, the particle size range of the micro powder amoxicillin is: Dv (10) <3μm, Dv (50) <8μm, Dv(90) <40μm.

[0026] The invention provides a method for preparing micro powder amoxicillin, comprising the following steps: mixing an amoxicillin condensation liquid and concentrated hydrochloric acid to obtain an amoxicillin acidified liquid; adding ammonia water to the amoxicillin acidified liquid to perform crystallization and crystal cultivation in sequence to obtain micro powder amoxicillin; the ammonia water is dripped at a rate of 6.5 to 14 m / s. 3 / h; the crystallization is carried out under stirring conditions.

[0027] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0028] 1) The preparation method of the present invention can effectively reduce the necessary losses caused by degradation and mother liquor residue in the production process, improve production efficiency, and reduce production costs;

[0029] 2) Acidification with concentrated hydrochloric acid allows the amoxicillin condensate to dissolve more thoroughly, thereby avoiding the generation of impurities due to incomplete dissolution, thereby affecting the quality of the amoxicillin product;

[0030] 3) The present invention controls the acidification (mixing) process to be carried out under stirring conditions, which increases the contact frequency between hydrochloric acid and the material (amoxicillin condensation solution) and accelerates the dissolution rate; on the other hand, it can prevent the material from being partially over-acidified and decomposed, generating other impurities, and further improving the product quality;

[0031] 4) During the crystallization process, controlling the dripping rate of aqueous ammonia can speed up the contact rate between aqueous ammonia and the material (amoxicillin acidified solution), thereby speeding up the reaction speed, making the reaction achieve the purpose of rapid crystallization, and being more conducive to obtaining an amoxicillin product with a sufficiently small particle size;

[0032] 5) During the crystallization process, stirring can accelerate the collision rate between molecules and increase the intensity of the collision, so that the formed amoxicillin crystals break into smaller crystals during the mutual collision to achieve a sufficiently small particle size;

[0033] The particle size range of the micropowder amoxicillin prepared by the preparation method of the present invention is: Dv (10) <3μm, Dv (50) <8μm, Dv (90) <40μm, good quality, and high yield of amoxicillin. DETAILED DESCRIPTION

[0034] The present invention provides a method for preparing micro-powdered amoxicillin, comprising the following steps:

[0035] The amoxicillin condensation solution and concentrated hydrochloric acid are mixed to obtain an amoxicillin acidified solution;

[0036] Adding ammonia water to the amoxicillin acidified solution to perform crystallization and crystal cultivation in sequence to obtain micro powder amoxicillin;

[0037] The dripping rate of the ammonia water is 6.5 to 14 m / s. 3 / h; the crystallization is carried out under stirring conditions.

[0038] In the present invention, unless otherwise specified, all preparation raw materials are commercially available products well known to those skilled in the art.

[0039] The invention mixes the amoxicillin condensation liquid and concentrated hydrochloric acid to obtain the amoxicillin acidified liquid.

[0040] In the present invention, the amoxicillin condensation liquid is preferably a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminogluconic acid under the action of immobilized penicillin acylase. In the present invention, the concentration of amoxicillin in the amoxicillin condensation liquid is preferably 80 to 220 mg / mL. In an embodiment of the present invention, the concentration of amoxicillin in the amoxicillin condensation liquid can be 220 mg / mL, 180 mg / mL or 120 mg / mL.

[0041] In the present invention, the mass concentration of the concentrated hydrochloric acid is preferably 33% to 35%. In an embodiment of the present invention, the mass concentration of the concentrated hydrochloric acid can be 33% or 35%.

[0042] In the present invention, the mixing temperature is preferably 15-25° C., more preferably 18-22° C. In an embodiment of the present invention, the mixing temperature may be 25° C. or 24° C.

[0043] In the present invention, the concentration of amoxicillin in the amoxicillin acidified solution is preferably ≥80 mg / mL. In an embodiment of the present invention, the concentration of amoxicillin in the amoxicillin acidified solution may be 85 mg / mL, 104 mg / mL or 124 mg / mL.

[0044] In the present invention, the mixing process is preferably performed by adding concentrated hydrochloric acid to the amoxicillin condensation solution at a temperature of 15 to 25° C. In the present invention, the addition rate of the concentrated hydrochloric acid is preferably 0.24 to 0.5 m / s. 3 / h, more preferably 0.24 to 0.35 m 3 In an embodiment of the present invention, the addition rate of concentrated hydrochloric acid can be 0.3m 3 / h. In an embodiment of the present invention, the specific process of the mixing may be: injecting the amoxicillin condensation liquid into a buffer tank, controlling the system temperature, and pumping out the feed liquid (amoxicillin condensation liquid) through a delivery pump; when the feed liquid begins to enter the ejector, simultaneously opening the hydrochloric acid discharge valve, injecting hydrochloric acid into the hydrochloric acid inlet of the ejector, and controlling the ejector outlet to make the pH value of the amoxicillin acidified liquid reach the target value.

[0045] After obtaining the amoxicillin acidified liquid, the present invention adds ammonia water to the amoxicillin acidified liquid to sequentially perform crystallization and crystal cultivation to obtain micro-powdered amoxicillin.

[0046] In the present invention, the mass concentration of the ammonia water is preferably 10% to 12%. In an embodiment of the present invention, the mass concentration of the ammonia water may be 12%.

[0047] In the present invention, the addition rate of the ammonia water is preferably 7 to 10 m / s. 3 / h; the addition time of the ammonia water is preferably ≤10min; the addition temperature of the ammonia water is preferably 15-20°C, more preferably 16-19°C, and most preferably 17-18°C. In an embodiment of the present invention, the addition rate of the ammonia water can be 7.67m 3 / h or 7.8m 3 / h; the adding time of the ammonia water can be 9min.

[0048] In the present invention, the pH of the mixed solution obtained after adding the ammonia water is preferably 4 to 5.5, more preferably 4.5 to 5.0. In an embodiment of the present invention, the pH of the mixed solution obtained after adding the ammonia water may be 5.2 or 5.1.

[0049] In the present invention, the crystallization is carried out under stirring, the stirring speed is preferably ≥120 rpm, the time is preferably 10 to 50 min, and the temperature is preferably 15 to 20° C. In an embodiment of the present invention, the stirring speed can be 125 rpm, 130 rpm, the time can be 9 min, and the temperature can be 20° C.

[0050] In the present invention, the crystal growing temperature is preferably 5-8°C, and the time is preferably 20-40 minutes. In an embodiment of the present invention, the crystal growing temperature can be 7°C, 4°C or 5°C, and the time can be 38 minutes, 42 minutes or 40 minutes.

[0051] After the crystal growing is completed, the present invention also preferably includes centrifugation, washing and drying performed sequentially; the present invention does not have any special limitation on the process of centrifugation, washing and drying, and the process well known to those skilled in the art can be used.

[0052] In the present invention, the particle size range of the micro powder amoxicillin is: Dv(10) <3μm, Dv (50) <m8μm,Dv (90) <40μm.

[0053] The preparation method of the micronized amoxicillin provided by the present invention is described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0054] Example 1

[0055] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 120 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 25°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration was 33%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.2 (0.63 m 3 of hydrochloric acid, the rate of addition of hydrochloric acid is 0.3m 3 / h) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 85 mg / mL, a clear solution);

[0056] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and then pumped into a crystallization tank by a delivery pump until all of the liquid was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.2 (under stirring conditions of 125r / min, ammonia water consumption of 1.15m 3 After the ammonia solution was added and the crystallization was completed, the temperature of the crystallization liquid was cooled to 5°C and the crystal was grown for 40 minutes. The obtained crystallization liquid was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0057] Example 2

[0058] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 180 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 24°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration was 33%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.1 (0.63 m 3of hydrochloric acid, the rate of addition of hydrochloric acid is 0.3m 3 / h) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 104 mg / mL, a clear solution);

[0059] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and pumped into a crystallization tank by a delivery pump until all of it was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.1 (under stirring conditions of 130r / min, ammonia water consumption of 1.17m 3 After the ammonia solution was added and the crystallization was completed, the temperature of the crystallization liquid was cooled to 4°C and the crystal was grown for 42 minutes. The obtained crystallization liquid was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0060] Example 3

[0061] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 220 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 25°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration of 35%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.0 (0.67m 3 of hydrochloric acid, the rate of addition of hydrochloric acid is 0.3m 3 / h) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 124 mg / mL, a clear solution);

[0062] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and pumped into a crystallization tank by a delivery pump until all of it was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.0 (under stirring conditions of 130r / min, ammonia water consumption of 1.17m 3 After the ammonia solution was added and the crystallization was completed, the temperature of the crystallization solution was cooled to 7°C and the crystal was grown for 38 minutes. The obtained crystallization solution was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0063] Comparative Example 1

[0064] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 122 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 26°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration was 35%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.1 (0.66 m 3 HCl) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 88 mg / mL, a clear solution);

[0065] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and then pumped into a crystallization tank by a delivery pump until all of the liquid was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.0 (under stirring conditions of 121r / min, ammonia water consumption of 1.10m 3 After the ammonia water was added and the crystallization was completed, the temperature of the crystallization liquid was cooled to 7°C and the crystal was grown for 40 minutes. The obtained crystallization liquid was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0066] Comparative Example 2

[0067] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 179 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 24°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration was 35%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.2 (0.69m 3 HCl) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 99 mg / mL, a clear solution);

[0068] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and then pumped into a crystallization tank by a delivery pump until all of the liquid was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.03 (under stirring conditions of 80r / min, ammonia water consumption of 1.14m 3 After the ammonia solution was added, the temperature was lowered to 5°C and the crystal was grown for 40 minutes. The obtained crystal was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0069] Comparative Example 3

[0070] Amoxicillin condensation liquid (a condensation liquid formed by condensing D-p-hydroxyphenylglycine methyl ester and 6-aminoglycanoic acid under the action of immobilized penicillin acylase, with an amoxicillin concentration of 223 mg / mL) was pumped into a buffer tank, the system temperature was controlled at 25°C, and the feed liquid was pumped out through a delivery pump. When the material began to enter the ejector, the hydrochloric acid (mass concentration was 35%) discharge valve was opened at the same time, and hydrochloric acid was pumped into the hydrochloric acid inlet of the ejector, and the pH of the ejector outlet was controlled to be adjusted to 1.18 (0.72 m 3 HCl) to obtain an amoxicillin acidified solution (the concentration of amoxicillin is 124 mg / mL, a clear solution);

[0071] The amoxicillin acidified liquid was filtered through a 0.45 μm filter element and then pumped into a crystallization tank by a delivery pump until all of the liquid was pumped into the crystallization tank. 3 / h dripping rate of 12% ammonia water to pH 5.1 (under stirring conditions of 97r / min, ammonia water consumption of 1.2m 3 After the ammonia solution was added and the crystallization was completed, the temperature of the crystallization liquid was cooled to 6°C and the crystal was grown for 44 minutes. The obtained crystallization liquid was sent to a centrifuge for material removal. The filter cake was washed twice with 350L purified water and then sent to a drying area for drying to obtain micro powder amoxicillin (the particle size was detected by Malvern laser particle size analyzer with model number Mstersizer3000, and the test results are shown in Table 1).

[0072] Table 1 Particle size distribution of micropowder amoxicillin prepared in Examples 1 to 3 and Comparative Examples 1 to 3

[0073] Example Dv10 / μm Dv10 / μm Dv10 / μm Moisture / wt% Content / wt% Example 1 2.81 7.73 33.04 12.3 99.9 Example 2 2.90 7.69 29.88 12.7 99.8 Example 3 2.80 7.71 20.09 12.6 99.6 Comparative Example 1 5.66 10.45 45.99 12.4 99.7 Comparative Example 2 5.97 10.73 48.22 12.5 99.6 Comparative Example 3 6.82 11.79 60.05 12.3 99.8

[0074] As shown in Table 1, the micropowder amoxicillin prepared by the preparation method of the present invention can meet the Dv (10) <3μm, Dv (50)<8μm, Dv (90) The requirement of <40μm can be well applied to the production of veterinary drugs amoxicillin and amoxicillin sodium, and the amoxicillin obtained has high yield and good quality.

[0075] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing micropowdered amoxicillin, characterized in that: The following steps are involved: The amoxicillin condensation solution and concentrated hydrochloric acid are mixed to obtain an amoxicillin acidified solution; Adding ammonia water to the amoxicillin acidified solution to perform crystallization and crystal cultivation in sequence to obtain micro powder amoxicillin; The dripping rate of the ammonia water is 6.5 to 14 m / s. 3 / h; the crystallization is carried out under stirring conditions.

2. The preparation method according to claim 1, characterized in that The mass concentration of the concentrated hydrochloric acid is 33% to 35%; The concentration of amoxicillin in the amoxicillin condensation solution is 80-220 mg / mL.

3. The preparation method according to claim 2, characterized in that: The mixing temperature is 15-25°C.

4. The preparation method according to claim 3, characterized in that: The concentration of amoxicillin in the amoxicillin acidified solution is ≥80 mg / mL; The pH value of the amoxicillin acidified solution is 0.8-1.

3.

5. The preparation method according to claim 4, characterized in that: The mass concentration of the ammonia water is 10% to 12%; The adding time of the ammonia water is ≤10min.

6. The preparation method according to claim 5, characterized in that: The pH of the mixed solution obtained after adding the ammonia water is 4-5.

7. The preparation method according to claim 1, characterized in that: The stirring speed is ≥120 rpm, the stirring time is 10 to 50 min, and the temperature is 15 to 20°C.

8. The preparation method according to claim 1, characterized in that: The crystal growing process is performed at a temperature of 5 to 8° C. and for a time of 20 to 40 minutes.

9. The preparation method according to claim 1, characterized in that: After the crystal growing is completed, centrifugation, washing and drying are performed in sequence.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The particle size range of the micro powder amoxicillin is: Dv (10) <3μm, Dv (50) <8μm, Dv (90) <40μm.