Preparation method of oral antibiotic granules

Abstract

The invention discloses a preparation method of oral antibiotic granules. The preparation method comprises the following steps: 1) treating raw materials and auxiliary materials: preparing an adhesive solution; sieving other raw and auxiliary materials; 2) granulating: adding the raw and auxiliary materials according to the prescription amount into a mixer for mixing; a one-step granulator is used, the air inlet temperature is set, the adhesive solution prepared in the step 1) is added in a top spraying mode for granulation, and the water content of granules is controlled to be 2.1% or below; (3) finishing granules: finishing the granules through a screen; (4) mixing: mixing the whole granules again; and 5) packaging: packaging according to set specifications. The oral antibiotic granules obtained by the invention have good stability and dissolution rate.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing oral antibiotic granules. Background Art

[0002] Faropenem Sodium is an oral antibiotic with penicillin ring as the basic skeleton. It has excellent antibacterial effect on Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus, etc. In addition, it also has antibacterial activity against Gram-negative bacteria such as Escherichia coli and Haemophilus influenzae. It has antibacterial activity against penicillin-resistant Streptococcus pneumoniae. It can also be used for ENT infections such as pharyngitis / laryngitis, tonsillitis, otitis media, skin infections such as impetigo, and respiratory infections such as scarlet fever and whooping cough.

[0003] Patent CN106309382A discloses faropenem sodium granules and a preparation method thereof, which controls the impurity content of faropenem sodium granules by strictly controlling the use of water in the wet granulation process, strictly controlling the drying temperature and drying time, and ultimately controlling the moisture content of the final product to 1.4-2.2%. However, ethanol is used in the preparation process to avoid the formation of polymers, and the influencing factors investigated are relatively few. The impurity standard finally set is too high, and the impurity content is not well controlled. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the present invention provides a method for preparing oral antibiotic granules, comprising the following steps:

[0005] 1) Raw material processing: prepare adhesive solution; sieve the remaining raw materials;

[0006] 2) Granulation: Add the prescribed amount of raw materials and auxiliary materials into a mixer and mix; use a one-step granulator, set the air inlet temperature, add the binder solution prepared in step 1) by top spraying for granulation, and control the moisture content of the granules to be below 2.1%;

[0007] 3) Granulation: sieve to sort the granules;

[0008] 4) Mixing: Mix the granules again after granulation;

[0009] 5) Packaging: Packaging according to established specifications;

[0010] The oral antibiotic granules include, by weight percentage, 12-13% of faropenem sodium, 80-90% of a filler, 1-5% of a binder, 0.1-0.5% of a stabilizer, 0.05-1.0% of a flavoring agent, and 0.05-1.0% of a colorant.

[0011] Furthermore, the binder solution in step 1) is prepared by adding a prescribed amount of binder into purified water to prepare a 5% binder solution, and then adding a prescribed amount of colorant.

[0012] Furthermore, the atomization pressure in the granulation process of step 2) is 0.5 to 1.5 bar.

[0013] Furthermore, the material temperature during the granulation process of step 2) is 30-50°C.

[0014] Furthermore, in step 2), the moisture content during the granulation process is 1.3-2.1%.

[0015] Furthermore, in step 2), the air inlet temperature during the granulation process is 60-80°C, and the air volume is 10-27m 3 / h.

[0016] Furthermore, in step 2) the granulation process, a wetting agent may be added.

[0017] Furthermore, the filler is sucrose and / or mannitol, the binder is hydroxypropyl cellulose, the stabilizer is calcium sodium edetate, the flavoring agent is aspartame and / or orange flavor, the colorant is yellow pigment, and the wetting agent is water.

[0018] Furthermore, when the filler is sucrose, in the step 1), the sucrose is firstly mechanically crushed, and then sieved through a 40-mesh sieve together with the remaining raw materials and auxiliary materials.

[0019] On the other hand, the present invention provides two oral antibiotic granules prepared according to the above method, wherein the oral antibiotic granules are preferably faropenem sodium granules.

[0020] Compared with the prior art, the present invention improves the stability of oral antibiotic granules (hereinafter referred to as "faropenem sodium granules") through a specific granulation technology, effectively controls the content of impurities, polymers and S isomers in the granules, ensures that the drug has higher safety, and reduces the risk of adverse reactions and side effects.

[0021] In addition, the faropenem sodium granules obtained by the preparation method of the present invention exhibit excellent dissolution rate and solubility, and their dissolution is comparable to similar products on the market. This advantage ensures that the drug can be rapidly absorbed and widely distributed in the human body, thereby effectively ensuring the bioavailability of the drug and significantly improving the therapeutic effect.

[0022] The method of the present invention avoids the use of organic solvents such as ethanol, thereby reducing production costs and environmental pollution. The alcohol-free preparation process improves the safety of the drug and reduces the potential risk of organic solvent residues to patient health. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be described clearly below. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of the present application.

[0024] The terms "first", "second", etc. in the specification and claims of this application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated before and after are in an "or" relationship.

[0025] The inventors of the present application have found that a specific granulation technology can significantly improve the stability of faropenem sodium granules by finely controlling the parameters during the granulation process, while effectively ensuring the dissolution rate of faropenem sodium granules. The entire process includes the following main steps:

[0026] 1) Raw material processing: prepare adhesive solution; sieve the remaining raw materials;

[0027] In one embodiment of the present invention, the composition of the faropenem sodium granules in terms of weight percentage includes: 12-13% faropenem sodium, 80-90% filler, 1-5% binder, 0.1-0.5% stabilizer, 0.05-1.0% flavoring agent, and 0.05-1.0% colorant.

[0028] In one embodiment of the present invention, the filler is sucrose and / or mannitol, the binder is hydroxypropyl cellulose, the stabilizer is calcium sodium edetate, the flavoring agent is aspartame and / or orange flavor, and the colorant is yellow pigment.

[0029] In a specific embodiment of the present invention, hydroxypropyl cellulose is dissolved in purified water to prepare a 5% hydroxypropyl cellulose solution, and yellow pigment is added to the solution to dissolve and stir to obtain a hydroxypropyl cellulose pigment solution for later use.

[0030] The sucrose was mechanically crushed and passed through a 40-mesh sieve, and the other raw materials and auxiliary materials were all passed through a 40-mesh sieve.

[0031] 2) Granulation: Add the prescribed amount of raw materials and auxiliary materials into a mixer and mix; use a one-step granulator, set the air inlet temperature, add the binder solution prepared in step 1) by top spraying for granulation, and control the moisture content of the granules to be below 2.1%;

[0032] In one embodiment of the present invention, an appropriate amount of wetting agent may be added during the granulation process, and the wetting agent is preferably purified water.

[0033] In a specific embodiment of the present invention, the materials are weighed according to the prescribed amount, and the prescribed amount of sucrose, faropenem sodium, aspartame, edetate calcium sodium, orange flavor and mannitol are added to the hopper mixer in sequence, the speed is set to 15 rpm, and the mixture is mixed for 10 minutes to obtain a premixed powder. The present invention does not set specific restrictions on the mixing parameters, and any combination of parameters that can achieve the purpose of uniform mixing can be used.

[0034] In a specific embodiment of the present invention, the premixed powder is added to a one-step granulator, the air inlet temperature is set to 60-80°C, the prepared 5% hydroxypropyl cellulose solution is top-sprayed for granulation, and an appropriate amount of water is continuously sprayed according to the state of the particles. Water is used as a wetting agent to improve the fluidity of the particles, which is convenient for the subsequent granulation and packaging process. Too little addition may result in too much fine powder and poor fluidity; too much addition may result in too hard particles, affecting tableting and dissolution. Those skilled in the art may add an appropriate amount of water according to the state of the particles; the atomization pressure is 0.5-1.5 bar, for example, 1.5 bar, 1.4 bar, 1.3 bar, 1.2 bar, 1.1 bar, 1.0 bar, 0.9 bar, 0.8 bar, 0.7 bar, 0.6 bar or 0.5 bar, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; the air volume is 10-27 m 3 / h, maintaining the material temperature at 30-50°C, for example, 50°C, 45°C, 40°C, 35°C or 30°C, but not limited to the listed values, other values ​​not listed within the numerical range are also applicable; after the granulation is completed, continue to dry until the moisture content is 1.3-2.1%, preferably 1.3-1.9%, for example, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% or 1.9%, but not limited to the listed values, other values ​​not listed within the numerical range are also applicable.

[0035] The particle state described in the present invention covers a number of key aspects, including uniformity of particle size, roundness and smoothness of particle shape, suitability of particle hardness, excellent degree of particle fluidity, moderate control of particle adhesion (not too much adhesion), and good presentation of particle color and appearance. These aspects are based on the conventional observation of the field, aiming to ensure the quality and performance of the particles, so as to meet the requirements of the subsequent formulation process and ensure the quality of the final product.

[0036] The top spraying described in the present invention refers to spraying the binder solution vertically downward from the top of the equipment onto the powder material to achieve wetting and bonding of the material, thereby forming particles.

[0037] Atomization pressure alone directly affects the size and distribution of the adhesive droplets sprayed from the nozzle; higher atomization pressure will form finer droplets, which may result in over-fine drug particles. Lower atomization pressure will cause the adhesive droplets sprayed from the nozzle to become larger and the distribution may be relatively uneven. Larger droplets may not fully cover the powder surface, resulting in increased non-uniformity in the particle formation process.

[0038] Although drying time and temperature are important, in the preparation process of faropenem sodium granules, controlling the material temperature during granulation is crucial to the formation of granules and the stability of the final product. Higher temperatures can accelerate solvent evaporation and shorten drying time, but may also cause degradation of heat-sensitive ingredients. Too low a temperature may result in poor granule hardness and poor water solubility, thereby affecting the release rate and efficacy of the drug. The appropriate temperature range helps maintain the stability of the active ingredient and the integrity of the granule structure.

[0039] Controlling the moisture content of the pellets is also important for ensuring product quality. The appropriate moisture content helps maintain the physical, chemical and microbiological stability of the pellets, while ensuring smooth processing.

[0040] The inventors have found through a large number of experiments that when the atomization pressure, material temperature and particle moisture content are all within a specific range, the final dissolution performance and stability of the faropenem sodium particles can be effectively guaranteed.

[0041] 3) Granulation: granulation is sorted through a sieve;

[0042] In a specific embodiment of the present invention, a swing granulator is used to granulate the particles through a 30-mesh screen.

[0043] 4) Mixing: remixing the granules after granulation;

[0044] In a specific embodiment of the present invention, the granules after granulation are added into a hopper mixer, the rotation speed is set to 15 rpm, and mixing is performed for 5 minutes.

[0045] 5) Packaging: Packaging shall be carried out according to the established specifications.

[0046] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0047] Example 1

[0048] 1. The prescription composition is shown in Table 1:

[0049] Table 1 Prescription composition and sources of raw and excipients

[0050]

[0051] 2. Process description: (2000 bags, 1kg)

[0052] 1) Raw material processing:

[0053] Hydroxypropyl cellulose (20 g) was dissolved in purified water to prepare a 5% hydroxypropyl cellulose solution, and the prescribed amount of yellow pigment was added to the solution to dissolve and stirred to obtain a hydroxypropyl cellulose pigment solution for later use.

[0054] The prescribed amount of sucrose was mechanically crushed and passed through a 40-mesh sieve, and the remaining raw and auxiliary materials were all passed through a 40-mesh sieve.

[0055] 2) Granulation (fluidized bed: FLZB-3.0):

[0056] Weigh the materials according to the prescription amount, add the prescription amount of sucrose, faropenem sodium, aspartame, edetate calcium sodium, orange flavor and mannitol into the hopper mixer in turn, set the speed to 15 rpm, mix for 10 minutes, and obtain a premixed powder.

[0057] Add the premixed powder into the one-step granulator, set the air inlet temperature to 60-80°C, top-spray the 5% hydroxypropyl cellulose pigment solution prepared in step 1) for granulation, and continue to spray an appropriate amount of water (not exceeding 0.72 ml / g) according to the state of the particles, the atomization pressure is 1.5 bar, and the air volume is 10-27 m 3 / h, maintaining the material temperature at 50°C, and continuing to dry until the moisture content of the granules is 1.3% (moisture content is measured by a rapid moisture meter at 105°C / 5min).

[0058] 3) Granulation: Use a swing granulator to granulate through a 30-mesh sieve.

[0059] 4) Mixing: Add the granules after granulation into the hopper mixer, set the speed to 15 rpm, and mix for 5 minutes.

[0060] 5) Packaging: The granules obtained in step 4) are packaged using a granule packaging machine, with a packaging specification of 0.5 g / bag.

[0061] Example 2

[0062] The atomization pressure in step 2) granulation was adjusted to 1.0 bar, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0063] Example 3

[0064] The atomization pressure in step 2) granulation was adjusted to 0.5 bar, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0065] Example 4

[0066] The material temperature in step 2) granulation was adjusted to 46°C, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0067] Example 5

[0068] The material temperature in step 2) granulation was adjusted to 30°C, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0069] Example 6

[0070] The moisture content in the granulation of step 2) was adjusted to 1.7%, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0071] Example 7

[0072] The moisture content in the granulation of step 2) was adjusted to 2.1%, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0073] Comparative Example 1

[0074] The atomization pressure in step 2) granulation was adjusted to 1.7 bar, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0075] Comparative Example 2

[0076] The atomization pressure in step 2) granulation was adjusted to 0.4 bar, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0077] Comparative Example 3

[0078] The material temperature in step 2) granulation was adjusted to 55°C, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0079] Comparative Example 4

[0080] The material temperature in step 2) granulation was adjusted to 25°C, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0081] Comparative Example 5

[0082] The moisture content in the granulation of step 2) was adjusted to 1.1%, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0083] Comparative Example 6

[0084] The moisture content in the granulation of step 2) was adjusted to 2.3%, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0085] Comparative Example 7

[0086] The material temperature in step 2) granulation was adjusted to 55° C. and the moisture content was 2.2%. The formulation composition and other process steps and conditions were the same as those in Example 1.

[0087] Comparative Example 8

[0088] The atomization pressure in step 2) granulation was adjusted to 1.7 bar, the material temperature was 55° C., and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0089] Comparative Example 9

[0090] The atomization pressure in step 2) granulation was adjusted to 1.7 bar, the material temperature was 55° C., the moisture content was 1.1%, and the formulation composition and other process steps and conditions were the same as those in Example 1.

[0091] The dissolution rates and related substances of the faropenem sodium granules obtained in Examples 1 to 7 and Comparative Examples 1 to 9 and the commercially available faropenem sodium granules (lot number 9P02H, Maruhiro Co., Ltd.) were measured.

[0092] Dissolution test method

[0093] According to the second method of dissolution and release determination (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931).

[0094] Dissolution medium: aqueous medium.

[0095] Dissolution conditions: paddle method, 50 rpm, 37.0 ± 0.5 °C, 900 ml.

[0096] Sampling points: After 5, 10, 15, 20, 30, and 45 minutes respectively, take 10 ml of the dissolution solution, filter it through a 0.45 μm filter membrane, discard the initial filtrate and use it as the test solution; at the same time, add an equal amount of medium into the dissolution cup.

[0097] Detection method: Determined by high performance liquid chromatography.

[0098] The dissolution test results of the embodiments and comparative examples are shown in Table 2:

[0099] Table 2 Dissolution test results

[0100]

[0101]

[0102] Related substance detection methods

[0103] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0104] Test solution Take an appropriate amount of this product (equivalent to 25 mg of faropenem), accurately weigh it, put it in a 50 ml volumetric flask, add water to dissolve and dilute to the scale, shake well, filter, and take the filtrate as the test solution.

[0105] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with water, and shake well.

[0106] Blank excipient solution Take an appropriate amount of blank excipient and prepare a solution containing the same concentration of excipient as the test solution in the same way as the excipient solution.

[0107] Impurity localization solution: Take an appropriate amount of impurity TFTA reference substance, dissolve it in water and dilute it to make a solution containing about 0.02 mg per 1 ml, which is used as the impurity localization solution.

[0108] System suitability solution: Accurately weigh an appropriate amount of this product (approximately equivalent to 25 mg of faropenem), place it in a 50 ml volumetric flask, add 10 ml of internal standard solution (weigh 0.5 g of m-hydroxyacetophenone, place it in a 200 ml volumetric flask, add 20 ml of acetonitrile to dissolve, dilute with water to the scale, shake well), dilute with water to the scale, shake well, filter, and take the filtrate as the system suitability solution.

[0109] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; phosphate buffer (6.12 g potassium dihydrogen phosphate, 1.79 g disodium hydrogen phosphate dodecahydrate and 1.61 g tetrabutylammonium bromide were weighed, dissolved in water and diluted to 1000 ml) was used as mobile phase A; mobile phase A-acetonitrile (1:1) was used as mobile phase B. Gradient elution was performed according to Table 3; flow rate was 1.0 ml per minute; column temperature was 40°C; detection wavelength was 240 nm; injection volume was 20 μl.

[0110] System suitability requirements: In the system suitability solution chromatogram, the resolution between the faropenem peak and the m-hydroxyacetophenone peak should be greater than 11.

[0111] Determination method: Accurately measure the test solution, positioning solution, blank excipient solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0112] If there are impurity peaks in the chromatogram of the limit test solution, after deducting the solvent peak and the excipient peak, the TFTA peak area shall not be greater than the main peak area of ​​the control solution (1.0%), the other individual impurity peak areas shall not be greater than 0.2 times (0.2%) the main peak area of ​​the control solution, and the sum of the impurity peak areas shall not be greater than 1.5 times (1.5%) the main peak area of ​​the control solution.

[0113] Table 3: Gradient elution program

[0114]

[0115]

[0116] The S-isomer was determined by high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0117] Test solution Take 10 bags of this product, grind it into powder, accurately weigh an appropriate amount (equivalent to 50 mg of faropenem), put it in a 50 ml volumetric flask, add about 10 ml of water to dissolve it, dilute it to the scale with water, shake well, and use it as the test solution.

[0118] System use solution: Accurately weigh appropriate amount of faropenem reference substance and faropenem S-isomer reference substance, dissolve in water and dilute to make a mixed solution containing 0.3 mg of each in 1 ml, which is used as the system suitability solution.

[0119] Sensitivity solution: Accurately measure an appropriate amount of system suitability solution, dilute with water to make a mixed solution containing 0.6 μg of each component per 1 ml, which is used as the sensitivity solution.

[0120] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (Welch Ultimate XB-C18 4.6×150mm, 5μm or chromatographic column of equivalent performance); phosphate buffer (4.8g of potassium dihydrogen phosphate, 5.4g of disodium hydrogen phosphate dodecahydrate and 1.0g of tetrabutylammonium bromide were dissolved in water and diluted to 1000ml)-acetonitrile (900:100) was used as mobile phase A; phosphate buffer (4.8g of potassium dihydrogen phosphate, 5.4g of disodium hydrogen phosphate dodecahydrate and 1.0g of tetrabutylammonium bromide were dissolved in water and diluted to 1000ml)-acetonitrile (500:500) was used as mobile phase B; linear gradient elution was performed according to Table 4; the flow rate was 2.5ml per minute; the column temperature was 40°C; the detection wavelength was 240nm; the injection volume was 20μl.

[0121] Table 4: Gradient elution program

[0122]

[0123] System suitability requirements: In the chromatogram of the system solution, the separation between the faropenem peak and the S-isomer peak should meet the requirements, and the tailing factor of the faropenem peak should be 0.9 to 1.5. In the sensitivity solution spectrum, the signal-to-noise ratio of the main component chromatographic peak height should be greater than 10.

[0124] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0125] If there is a chromatographic peak with the same retention time as the S-isomer in the chromatogram of the limit test solution, its peak area shall not be greater than 0.3% of the total peak area calculated by the peak area normalization method.

[0126] Faropenem polymer was determined by size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0514).

[0127] Test solution Take an appropriate amount of this product (equivalent to about 0.2 g of faropenem), weigh accurately, place in a 10 ml volumetric flask, add water to dissolve and dilute to the scale, shake well, filter, and take the filtrate as the test solution.

[0128] Reference solution: Take an appropriate amount of faropenem reference substance, weigh it accurately, dissolve it in water and quantitatively dilute it to make a solution containing about 0.1 mg of faropenem per 1 ml.

[0129] Chromatographic conditions and system suitability test: Sephadex G-10 (40-120 μm) was used as filler, the inner diameter of the column was 1.0-1.5 cm, and the length of the column was 30-40 cm; mobile phase A was 0.015 mol / L phosphate buffer at pH 7.0 [0.015 mol / L disodium hydrogen phosphate solution and 0.015 mol / L sodium dihydrogen phosphate solution (61:39)], and mobile phase B was water; the flow rate was 1.5 ml / min; the detection wavelength was 254 nm. 100 μl of 0.5 mg / ml blue dextran 2000 solution was injected into the liquid chromatograph, and the mobile phases A and B were used as the mobile phases for determination, and the chromatograms were recorded. The theoretical plate number calculated based on the blue dextran 2000 peak should not be less than 700, and the tailing factor should be less than 2.0. The ratio of the retention time of the blue dextran 2000 peak in the two mobile phase systems should be between 0.93 and 1.07. The retention time ratio of the main peak of the control solution and the polymer peak in the test solution to the blue dextran 2000 peak in the corresponding chromatographic system should be between 0.93 and 1.07. Weigh 0.2g of faropenem sodium, place it in a 10ml volumetric flask, dissolve it with 0.5mg / ml blue dextran 2000 solution and dilute to the scale, shake well. Take 100μl and inject it into the liquid chromatograph, measure it with mobile phase A, and record the chromatogram. The peak height of the polymer and the valley height ratio between the monomer and the polymer should be greater than 2.0. Use mobile phase B as the mobile phase, accurately measure 100μl of the control solution, inject it continuously 5 times, and the relative standard deviation of the peak area should not be greater than 5.0%.

[0130] Determination method: Accurately measure 100 μl of the test solution, use mobile phase A as the mobile phase for determination, and record the chromatogram. Accurately measure 100 μl of the control solution and inject it into the liquid chromatograph, use mobile phase B as the mobile phase, and record the chromatogram.

[0131] The limit is calculated by peak area using the external standard method, and the content of faropenem-containing polymers, calculated as faropenem, shall not exceed 0.5%.

[0132] Table 5 Impurity information in faropenem sodium granules

[0133]

[0134] The test results of the relevant substances in the embodiments and comparative examples are shown in Table 6:

[0135] Table 6 Test results of related substances, s-isomer and faropenem polymer

[0136]

[0137] From the dissolution test results in Table 2, it can be seen that the faropenem sodium granules obtained in Examples 1 to 7 all dissolve rapidly (reaching more than 85% at 15 minutes) and are similar to the dissolution of commercially available products. As an oral antibiotic, faropenem sodium granules can be used for respiratory infection-related diseases, which requires that faropenem sodium granules can be rapidly dissolved after oral administration and can be absorbed in the respiratory tract. However, the faropenem sodium granules obtained in Comparative Examples 1 to 9 did not reach 85% in dissolution at 15 minutes, and the gap with commercially available products was large.

[0138] From the test results of related substances, s-isomers and faropenem polymers in Table 6, it can be seen that the contents of related substances in the faropenem sodium granules obtained in Examples 1 to 7 all meet the limit requirements and are lower than those of commercially available products. However, the faropenem sodium granules obtained in Comparative Examples 1 to 9 failed to successfully achieve the dual goals of rapid dissolution and maintaining a low content of related substances.

[0139] The atomization pressure of Examples 1 to 7 was 0.5 to 1.5 bar. When other conditions were the same, the atomization pressure of Comparative Example 1 was adjusted to 1.7 bar, and the contents of related substances in the obtained faropenem sodium granules met the requirements, but the solubility did not reach 85% at 15 min. The atomization pressure of Comparative Example 2 was adjusted to 0.4 bar, and the contents of related substances in the obtained faropenem sodium granules were still within the limit, but the impurities TFTA, total impurities and polymers were increased to varying degrees compared with Examples 1 to 7, and the solubility did not reach 85% at 15 min.

[0140] The material temperature of Examples 1 to 7 is 30 to 50°C. When other conditions are the same, the material temperature of Comparative Example 3 is too high (55°C), which not only fails to achieve the effect of rapid dissolution, but also, from the perspective of related substances, the TFTA, total impurities and polymers in the faropenem sodium granules obtained in Comparative Example 3 are increased to varying degrees compared with Examples 1 to 7, and the polymer has exceeded the limit requirements. The material temperature of Comparative Example 4 is too low (25°C). From the perspective of related material data, the content of related substances in the faropenem sodium granules obtained in Comparative Example 4 is still within the limit, but the impurities TFTA, total impurities and polymers are increased to varying degrees compared with Examples 1 to 7, and the effect of rapid dissolution is not achieved.

[0141] In Examples 1 to 7, the moisture content of the particles after drying is controlled to be 1.3 to 2.1%. When other conditions are the same, the moisture content of the particles in Comparative Example 5 is too low (1.1%), and the moisture content of the particles in Comparative Example 6 is too high (2.3%). The contents of related substances in the faropenem sodium particles obtained by both meet the requirements, but the impurities TFTA, total impurities and polymers are increased to varying degrees compared with Examples 1 to 7, especially the content of polymers is very close to the limit value. And its solubility did not reach 85% at 15 minutes, and the effect of rapid dissolution was not achieved. It can also be seen from this that although the control of the moisture content of the particles alone will increase the impurity content, the content of related substances including polymers and S isomers in the final product has not exceeded the limit.

[0142] When other conditions are the same, two or three conditions of Comparative Examples 7 to 9 are not within the range of Examples 1 to 7. From the dissolution effect, it can be seen that the solubility of the faropenem sodium granules obtained in these three comparative examples did not reach 85% at 15 minutes, and the effect of rapid dissolution was not achieved. The material temperature (55°C) and the granule moisture content (2.1%) of Comparative Example 7 exceeded the range of Examples 1 to 7, and the faropenem sodium granules obtained not only had impurities TFTA, total impurities and polymers increased to varying degrees compared with Examples 1 to 7, but also the polymer exceeded the limit requirements; the atomization pressure (1.7 bar) and material temperature (55°C) of Comparative Example 8 exceeded the range of Examples 1 to 7, and the atomization pressure (1.7 bar), material temperature (55°C) and granule moisture content (1.1%) of Comparative Example 9 exceeded the range of Examples 1 to 7. The TFTA, total impurities and polymers in the faropenem sodium granules obtained in Comparative Examples 8 and Comparative Examples 9 increased to varying degrees compared with Examples 1 to 7, and the polymer exceeded the limit requirements.

[0143] Although the relationship between atomization pressure, material temperature and particle moisture content and the dissolution rate and related substances of faropenem sodium granules is unclear, the three factors cooperate with each other within a specific range to achieve the dual goals of rapid dissolution of faropenem sodium granules while maintaining a low content of related substances.

[0144] The embodiments of the present application are described above, but the present application is not limited to the above-mentioned specific implementation modes. The above-mentioned specific implementation modes are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing oral antibiotic granules, It is characterized in that The steps include: 1) Raw material processing: prepare adhesive solution; sieve the remaining raw materials; 2) Granulation: Add the prescribed amount of raw materials and auxiliary materials into a mixer and mix; use a one-step granulator, set the air inlet temperature, add the binder solution prepared in step 1) by top spraying for granulation, and control the moisture content of the granules to be below 2.1%; 3) Granulation: granulation is sorted through a sieve; 4) Mixing: Mix the granules again after granulation; 5) Packaging: Packaging according to established specifications; The oral antibiotic granules include, by weight percentage, 12-13% of faropenem sodium, 80-90% of a filler, 1-5% of a binder, 0.1-0.5% of a stabilizer, 0.05-1.0% of a flavoring agent, and 0.05-1.0% of a colorant.

2. The method for preparing the oral antibiotic granules according to claim 1, It is characterized in that Step 1) The binder solution is prepared by adding a prescribed amount of binder into purified water to prepare a 5% binder solution, and then adding a prescribed amount of colorant.

3. The method for preparing the oral antibiotic granules according to claim 2, It is characterized in that The atomization pressure during step 2) granulation is 0.5 to 1.5 bar.

4. The method for preparing the oral antibiotic granules according to claim 3, It is characterized in that The material temperature during step 2) granulation is 30-50°C.

5. The method for preparing the oral antibiotic granules according to claim 4, It is characterized in that Step 2) The moisture content during the granulation process is 1.3-2.1%.

6. The method for preparing the oral antibiotic granules according to claim 5, It is characterized in that Step 2) During the granulation process, the air inlet temperature is 60-80°C and the air volume is 10-27m 3 / h.

7. The method for preparing the oral antibiotic granules according to claim 6, It is characterized in that In step 2), a wetting agent may also be added during the granulation process.

8. The method for preparing oral antibiotic granules according to claim 7, It is characterized in that The filler is sucrose and / or mannitol, the binder is hydroxypropyl cellulose, the stabilizer is calcium sodium edetate, the flavoring agent is aspartame and / or orange flavor, the colorant is yellow pigment, and the wetting agent is water.

9. The method for preparing oral antibiotic granules according to claim 8, It is characterized in that When the filler is sucrose, in step 1), the sucrose is firstly mechanically crushed, and then sieved through a 40-mesh sieve together with the remaining raw materials.

10. The oral antibiotic granules prepared by the method according to any one of claims 1 to 9, wherein the oral antibiotic granules are preferably faropenem sodium granules.

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