A process for the preparation of oral antibiotic granules

Abstract

The application discloses a preparation method of oral antibiotic granules, which comprises the following steps: 1) raw material treatment: preparing a binder solution; screening the rest of raw materials; 2) granulation: mixing the prescription amount of raw materials in a mixer; using a one-step granulator, setting the air inlet temperature, adding the binder solution prepared in step 1) in a top spraying mode to carry out granulation, and controlling the moisture content of the granules to be less than 2.1%; 3) whole granulation: arranging the granules through a screen; 4) mixing: mixing the whole granules again; 5) packaging: packaging according to the specified specifications, and the obtained oral antibiotic granules have good stability and dissolution rate.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of oral antibiotic granules. BACKGROUND

[0002] Faropenem sodium is an oral antibiotic with a penicillin ring as a basic skeleton. It has excellent antibacterial effect on gram-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus. In addition, it also has antibacterial activity on gram-negative bacteria such as Escherichia coli and Haemophilus influenzae. It also has antibacterial activity on penicillin-resistant Streptococcus pneumoniae. It can also be used for infections of the ear, nose and throat such as pharyngolaryngitis, tonsillitis and otitis media, skin infections such as contagious pustular disease, and respiratory tract infections such as scarlet fever and whooping cough.

[0003] Patent CN106309382A discloses faropenem sodium granules and a preparation method thereof. By strictly controlling the use of water in the wet granulation process, strictly controlling the drying temperature and drying time, and finally controlling the moisture content of the final product at 1.4-2.2%, the impurity content of the faropenem sodium granules is controlled. However, ethanol is used in the preparation process to avoid the generation of polymers, and the influence factors investigated are less, and the finally set impurity standard is too high, and the impurity content is not well controlled. SUMMARY

[0004] To solve the problems in the prior art, the application provides a preparation method of oral antibiotic granules, comprising the following steps:

[0005] 1) Preparation of the adhesive solution; the rest of the raw and auxiliary materials are sieved;

[0006] 2) Granulation: the prescription amount of raw and auxiliary materials is added to the mixer for mixing; a one-step granulator is used, the inlet air temperature is set, the adhesive solution prepared in step 1) is added in the form of top spraying for granulation, and the moisture content of the granules is controlled to be below 2.1%;

[0007] 3) Granule screening: the granules are screened;

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

[0009] 5) Packaging: packaging according to the specified specifications;

[0010] The oral antibiotic granules comprise faropenem sodium 12-13%, filler 80-90%, adhesive 1-5%, stabilizer 0.1-0.5%, flavoring agent 0.05-1.0% and coloring agent 0.05-1.0% by weight percentage.

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

[0012] Further, the atomization pressure in the granulation process in step 2) is 0.5-1.5 bar.

[0013] Further, the material temperature in the granulation process in step 2) is 30-50℃.

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

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

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

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

[0018] Further, when the filler is sucrose, the sucrose is first mechanically pulverized and then treated with a 40-mesh sieve together with the remaining excipients in step 1).

[0019] In another aspect, the present application provides two oral antibiotic granules prepared according to the above method, which are preferably faropenem sodium granules.

[0020] Compared with the prior art, the present application improves the stability of oral antibiotic granules (hereinafter referred to as "faropenem sodium granules") by a specific granulation technique, effectively controls the content of impurities, polymers and S-isomer in the granules, ensures higher safety of the drug, 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 application exhibit excellent dissolution rate and solubility, and the dissolution rate is comparable to that of 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 application avoids the use of organic solvents such as ethanol, reduces production costs and environmental pollution, and the alcohol-free preparation process improves the safety of the drug and reduces the potential risk of organic solvent residues to the health of patients. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly described below. Obviously, the described embodiments are only some, but not all, of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art belong to the scope of protection of the present application.

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

[0025] The present inventors have found that a specific granulation technique, fine control of parameters in the granulation process, can significantly improve the stability of faropena sodium granules, while effectively ensuring the dissolution of faropena sodium granules. The entire process includes the following main steps:

[0026] 1) Preparation of the binder solution; the rest of the raw and auxiliary materials are sieved;

[0027] In an embodiment of the present application, the composition of faropena sodium granules includes, by weight percentage: faropena sodium 12-13%, filler 80-90%, binder 1-5%, stabilizer 0.1-0.5%, flavoring agent 0.05-1.0%, coloring agent 0.05-1.0%.

[0028] In an embodiment of the present application, 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 coloring agent is yellow pigment.

[0029] In a specific embodiment of the present application, hydroxypropyl cellulose is dissolved in purified water to prepare a 5% hydroxypropyl cellulose solution, and yellow pigment is added to the solution and dissolved, stirred evenly, to obtain a hydroxypropyl cellulose pigment solution, ready for use.

[0030] The sucrose is mechanically pulverized and passed through a 40-mesh sieve, and the rest of the raw and auxiliary materials are passed through a 40-mesh sieve.

[0031] 2) Granulation: the prescription amount of raw and auxiliary materials are mixed in a mixer; a one-step granulator is used, the inlet air temperature is set, the binder solution prepared in step 1) is added in a top spraying manner for granulation, and the water content of the granules is controlled to be less than 2.1%;

[0032] In an embodiment of the present application, an appropriate amount of wetting agent can also be added during the granulation process. The wetting agent is preferably purified water.

[0033] In a specific embodiment of the present application, the materials are weighed according to the prescription amount, and the prescription amount of sucrose, faropenal sodium, aspartame, calcium sodium edetate, orange flavor and mannitol are sequentially added into a hopper mixer, the rotation speed is set to 15 rpm, and mixed for 10 min to obtain a premix powder. The present application does not set specific limitations on the mixing parameters, and any parameter combination that can achieve the purpose of uniform mixing can be used.

[0034] In a specific embodiment of the present application, the premix powder is added into a one-step granulator, the inlet air temperature is set to 60-80℃, the prepared 5% hydroxypropyl cellulose solution is top-sprayed for granulation, and an appropriate amount of water is continuously sprayed according to the granule state. The water as a wetting agent aims to improve the flowability of the granules, facilitating the subsequent granulation and dispensing process. Too little water may result in too much fine powder and poor flowability; too much water may result in too hard granules, affecting tabletting and dissolution. Those skilled in the art can add an appropriate amount of water according to the granule state. 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 not limited to the listed values. Other values not listed in this range are also applicable. The air volume is 10-27 m 3 / h, and the material temperature is maintained at 30-50℃, for example, 50℃, 45℃, 40℃, 35℃ or 30℃, but not limited to the listed values. Other values not listed in this range are also applicable. After granulation, drying is continued until the water 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 in this range are also applicable.

[0035] The granule state described in the present application covers multiple key aspects, including uniformity of granule size, roundness and smoothness of granule shape, appropriateness of granule hardness, degree of excellent flowability of granules, moderate control of granule adhesion (not too much adhesion), and good presentation of granule color and appearance. These aspects are from the perspective of conventional examination in the art, aiming to ensure the quality and performance of the granules to meet the needs of subsequent formulation processes and ensure the quality of the final product.

[0036] The top spraying refers to spraying the binder solution vertically downward from the top of the device to the powder material to achieve wetting and binding of the material, thereby forming granules.

[0037] The atomization pressure alone directly affects the size and distribution of the binder droplets sprayed from the nozzle; higher atomization pressure will form smaller droplets, which may lead to excessively fine drug particles. Lower atomization pressure will cause the binder droplets sprayed from the nozzle to become larger and the distribution may be relatively uneven, and larger droplets may not fully cover the powder surface, leading to increased unevenness in the granule formation process.

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

[0039] Controlling the moisture content of the granules is also important to ensure product quality. Proper moisture content helps maintain the physical, chemical and microbiological stability of the granules, while also ensuring smooth processing.

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

[0041] 3) Sizing: sizing the granules through a screen;

[0042] In a specific embodiment of the present application, a swing sizer is used to size the granules through a 30-mesh screen.

[0043] 4) Mixing: remixing the sized granules;

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

[0045] 5) Packaging: packaging according to the specified specifications.

[0046] The examples and comparative examples of the present application are specifically listed as follows, but the present application 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 source of raw and auxiliary materials

[0050]

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

[0052] 1) Raw and auxiliary material treatment:

[0053] Dissolve hydroxypropyl cellulose (20 g) in purified water to make a 5% hydroxypropyl cellulose solution, and add the prescribed amount of yellow pigment to the solution and dissolve, stir evenly, to obtain a hydroxypropyl cellulose pigment solution, ready for use.

[0054] Grind the prescribed amount of sucrose by machine and pass through a 40 mesh sieve, and pass the rest of the raw and auxiliary materials through a 40 mesh sieve.

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

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

[0057] Add the premix powder into the one-step granulator, set the inlet air temperature to 60-80°C, top-spray granulation with the 5% hydroxypropyl cellulose pigment solution prepared in step 1), and continue to spray an appropriate amount of water (not more than 0.72 ml / g) according to the granule state, atomization pressure 1.5 bar, air volume 10-27 m 3 / h, keep the material temperature at 50°C, after granulation, continue to dry until the granule moisture is 1.3% (fast moisture meter 105°C / 5min to measure the moisture content).

[0058] 3) Granulation: use a swing granulator to pass through a 30 mesh sieve.

[0059] 4) Mixing: add the granulated particles after granulation into the hopper mixer, set the rotation speed to 15 rpm, mix for 5 min.

[0060] 5) Packaging: use a granule packaging machine to package the granules obtained in step 4), packaging specification 0.5 g / bag.

[0061] Example 2

[0062] Adjust the atomization pressure in step 2) granulation to 1.0 bar, the prescription composition and other process steps and conditions are the same as in Example 1.

[0063] Example 3

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

[0065] Example 4

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

[0067] Example 5

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

[0069] Example 6

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

[0071] Example 7

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

[0073] Comparative Example 1

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

[0075] Comparative Example 2

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

[0077] Comparative Example 3

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

[0079] Comparative Example 4

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

[0081] Comparative Example 5

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

[0083] Comparative Example 6

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

[0085] Comparative Example 7

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

[0087] Comparative Example 8

[0088] In step 2), the atomization pressure during 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 in Example 1.

[0089] Comparative Example 9

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

[0091] Dissolution and related substances were determined in faropenem sodium granules obtained in Examples 1-7 and Comparative Examples 1-9, as well as commercially available faropenem sodium granules (batch number 9P02H, Maruhiro Co., Ltd.).

[0092] Dissolution test method

[0093] Method II of Dissolution and Release Determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931).

[0094] Dissolution medium: water.

[0095] Dissolution conditions: paddle method, 50 rpm, 37.0 ± 0.5℃, 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 to the dissolution vessel.

[0097] Detection method: High performance liquid chromatography (HPLC) was used for determination.

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

[0099] Table 2 Dissolution test results

[0100]

[0101]

[0102] Related substance test method

[0103] Determine by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part 4 General 0512).

[0104] Take the test product solution. Take an appropriate amount of the product (about equivalent to 25 mg of faropenem), accurately weigh, place in a 50 ml volumetric flask, dissolve and dilute to the mark with water, shake well, filter, and take the filtrate as the test product solution.

[0105] Accurately take 1 ml of the test product solution into a 100 ml volumetric flask, dilute to the mark with water, and shake well.

[0106] Take the blank excipient solution. Take an appropriate amount of the blank excipient, prepare a solution containing the same concentration of excipient as the test product solution, and use the same method as the test product solution. The solution is used as the excipient solution.

[0107] Take the impurity positioning solution. Take an appropriate amount of the impurity TFTA reference substance, dissolve and dilute with water to prepare a solution containing about 0.02 mg per 1 ml, and use it as the impurity positioning solution.

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

[0109] Chromatographic conditions. Use octadecylsilane-bonded silica gel as the filler; use phosphate buffer (weigh 6.12 g of potassium dihydrogen phosphate, 1.79 g of sodium hydrogen phosphate dodecahydrate, and 1.61 g of tetrabutylammonium bromide, dissolve and dilute to 1000 ml with water) as mobile phase A; use mobile phase A-acetonitrile (1:1) as mobile phase B. Gradient elution is performed according to the following Table 3; the flow rate is 1.0 ml per minute; the column temperature is 40°C; the detection wavelength is 240 nm; the injection volume is 20 μl.

[0110] System suitability requirements. The separation between the faropenem peak and the m-hydroxyacetophenone peak in the system suitability solution chromatogram should be greater than 11.

[0111] Determination method. Accurately take the test product solution, positioning solution, blank excipient solution, and control solution, respectively, into the liquid chromatograph, and record the chromatogram.

[0112] Limits. If there are impurity peaks in the test product solution chromatogram, deduct the solvent peak and the excipient peak, the TFTA peak area should not be greater than 1.0% of the main peak area of the control solution, and the area of other single impurity peaks should not be greater than 0.2% of the main peak area of the control solution (0.2%), and the sum of the areas of all impurity peaks should not be greater than 1.5% of the main peak area of the control solution (1.5%).

[0113] Table 3: Gradient elution program

[0114]

[0115]

[0116] S-isomer was determined by high performance liquid chromatography (ChP 2020 edition four general rules 0512).

[0117] The test solution was prepared by accurately weighing an appropriate amount of the product (about equivalent to 50 mg of faropenem) from 10 bags, finely grinding, and dissolving in a 50 ml volumetric flask with about 10 ml of water. The solution was diluted to the mark with water, shaken well, and used as the test solution.

[0118] The system suitability solution was prepared by accurately weighing an appropriate amount of faropenem reference substance and faropenem S-isomer reference substance, dissolving and diluting with water to contain 0.3 mg per 1 ml of each, and used as the system suitability solution.

[0119] The sensitivity solution was prepared by accurately measuring an appropriate amount of the system suitability solution, diluting with water to contain 0.6 μg per 1 ml of each, and used as the sensitivity solution.

[0120] The chromatographic conditions were as follows: octadecylsilane-bonded silica gel as the filler (Welch Ultimate XB-C18 4.6 x 150 mm, 5 μm or a chromatographic column with equivalent performance); phosphate buffer (take potassium dihydrogen phosphate 4.8 g, sodium phosphate dibasic dodecahydrate 5.4 g and tetrabutylammonium bromide 1.0 g, dissolve and dilute with water to 1000 ml)-acetonitrile (900:100) as mobile phase A; phosphate buffer (take potassium dihydrogen phosphate 4.8 g, sodium phosphate dibasic dodecahydrate 5.4 g and tetrabutylammonium bromide 1.0 g, dissolve and dilute with water to 1000 ml)-acetonitrile (500:500) as mobile phase B; linear gradient elution was carried out according to Table 4; the flow rate was 2.5 ml per minute; the column temperature was 40°C; the detection wavelength was 240 nm; the injection volume was 20 μl.

[0121] Table 4: Gradient elution program

[0122]

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

[0124] The test solution was accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded.

[0125] If there is a chromatographic peak in the chromatogram of the test solution which has the same retention time as the S-isomer, calculate the area of this peak as a percentage of the total area of the peaks. The area of this peak shall not exceed 0.3% of the total area.

[0126] Determine by size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition Part 4 General Test 0514).

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

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

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

[0130] Determine by size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition Part 4 General Test 0514).

[0131] The limit is calculated by peak area by external standard method, and the faropenem polymer content is calculated as faropenem, which shall not exceed 0.5%.

[0132] Table 5 Impurity information of faropenem sodium granules

[0133]

[0134] The related substance test results of the examples and comparative examples are shown in Table 6:

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

[0136]

[0137] From the dissolution test results of Table 2, it can be seen that the faropenem sodium granules obtained in Examples 1 to 7 are all fast-dissolving (85% or more at 15 min) and have similar dissolution to the commercially available product. Faropenem sodium granules, as an oral antibiotic, can be used for respiratory infection-related conditions, which requires that faropenem sodium granules can be rapidly dissolved after oral administration and can be absorbed in the respiratory tract. The faropenem sodium granules obtained in Comparative Examples 1 to 9 do not reach 85% at 15 min, and have a large difference from the commercially available product.

[0138] From the results of related substances, s-isomer and faropenem polymer in Table 6, it can be seen that the faropenem sodium granules obtained in Examples 1 to 7 all meet the limit requirements of related substances, and the content is lower than that of the commercially available product. The faropenem sodium granules obtained in Comparative Examples 1 to 9 have not successfully achieved the dual goals of fast dissolution and low related substance content.

[0139] The atomization pressure of Examples 1 to 7 is 0.5 to 1.5 bar. When other conditions are the same, the atomization pressure of Comparative Example 1 is adjusted to 1.7 bar, and the faropenem sodium granules obtained thereby meet the requirements of related substances, but the dissolution at 15 min does not reach 85%. The atomization pressure of Comparative Example 2 is adjusted to 0.4 bar, and the faropenem sodium granules obtained thereby still meet the limit of related substances, but the impurities TFTA, total impurities and polymer are all increased to different degrees compared with Examples 1 to 7, and the dissolution at 15 min does not reach 85%.

[0140] The material temperature of Examples 1-7 was 30-50°C, and the material temperature of Comparative Example 3 was too high (55°C) under the same conditions, which not only failed to achieve the fast dissolution effect, but also increased the TFTA, total impurities and polymers in the faropenem sodium particles obtained in Comparative Example 3 compared with Examples 1-7, and the polymers exceeded the limit requirement. The material temperature of Comparative Example 4 was too low (25°C), and the related substance content of the faropenem sodium particles obtained in Comparative Example 4 was still within the limit, but the impurities TFTA, total impurities and polymers increased compared with Examples 1-7, and the fast dissolution effect was not achieved.

[0141] The moisture content of the particles after drying in Examples 1-7 was 1.3-2.1%, and the moisture content of the particles in Comparative Example 5 was too low (1.1%) and the moisture content of the particles in Comparative Example 6 was too high (2.3%) under the same conditions, and the related substance content of the faropenem sodium particles obtained in Comparative Examples 5 and 6 met the requirements, but the impurities TFTA, total impurities and polymers increased compared with Examples 1-7, and the content of the polymers was very close to the limit value. Moreover, the dissolution degree at 15 min did not reach 85%, and the fast dissolution effect was not achieved. It can also be seen that the control of the moisture content of the particles alone can increase the impurity content, but the related substance content, including the content of the polymers and S isomers, in the final product has not exceeded the limit.

[0142] Under the same conditions, two or three conditions of Comparative Examples 7-9 were not within the range of Examples 1-7, and the dissolution effect showed that the dissolution degree at 15 min of the faropenem sodium particles obtained in Comparative Examples 7-9 did not reach 85%, and the fast dissolution effect was not achieved. The material temperature (55°C) and the moisture content (2.1%) of the particles of Comparative Example 7 exceeded the range of Examples 1-7, and the faropenem sodium particles obtained in Comparative Example 7 not only increased the impurities TFTA, total impurities and polymers compared with Examples 1-7, but also exceeded the limit requirement of the polymers; the atomization pressure (1.7 bar) and the material temperature (55°C) of Comparative Example 8 exceeded the range of Examples 1-7, and the atomization pressure (1.7 bar), the material temperature (55°C) and the moisture content (1.1%) of the particles of Comparative Example 9 all exceeded the range of Examples 1-7, and the faropenem sodium particles obtained in Comparative Examples 8 and 9 increased the TFTA, total impurities and polymers compared with Examples 1-7, and the polymers exceeded the limit requirement.

[0143] Although the relationship between the atomization pressure, the material temperature and the moisture content of the particles and the dissolution degree and the related substance of the faropenem sodium particles is not clear, the three can cooperate with each other within a certain range to achieve the dual goals of fast dissolution and low related substance content of the faropenem sodium particles.

[0144] The above describes the embodiments of the present application, but the present application is not limited to the above-described specific embodiments, which are merely illustrative but not restrictive, and a person of ordinary skill in the art can make many forms under the inspiration of the present application without departing from the purpose of the present application and the scope protected by the claims, which all belong to the protection of the present application.

Claims

1. A process for the preparation of oral antibiotic granules, characterized in that, It comprises the following steps: 1) raw material processing: preparing adhesive solution; sieving the rest of raw materials; 2) granulation: mixing the prescription amount of raw materials in a mixer; using a one-step granulator, setting the inlet air temperature, adding the adhesive solution prepared in step 1) in the form of top spraying to perform granulation, and controlling the moisture content of the granules below 2.1%; 3) granulating: arranging the granules through a screen; 4) mixing: mixing the granules after granulating again; 5) packaging: packaging according to the specified specifications; The oral antibiotic granules comprise, by weight percentage: faropenem sodium 12-13%, filler 80-90%, adhesive 1-5%, stabilizer 0.1-0.5%, flavoring agent 0.05-1.0%, and coloring agent 0.05-1.0%; The preparation of the adhesive solution in step 1) is as follows: adding the prescription amount of adhesive to purified water to prepare a 5% adhesive solution, and adding the prescription amount of coloring agent; The atomization pressure during the granulation process in step 2) is 0.5-1.5 bar, and the material temperature is 30-50℃; The filler is sucrose and mannitol, the adhesive is hydroxypropyl cellulose, the stabilizer is calcium sodium edetate, the flavoring agent is aspartame and / or orange flavor, and the coloring agent is yellow pigment.

2. The process for preparing oral antibiotic granules according to claim 1, characterized in that, The moisture content during the granulation process in step 2) is 1.3-2.1%.

3. The process for the preparation of oral antibiotic granules according to claim 2, characterized in that, The inlet air temperature during the granulation process in step 2) is 60-80℃, and the air volume is 10-27m³ / h.

4. The process for the preparation of oral antibiotic granules as claimed in claim 3 wherein, In step 2), a wetting agent can also be added during the granulation process.

5. The process for the preparation of oral antibiotic granules as claimed in claim 4 wherein, The wetting agent is water.

6. The process for preparing oral antibiotic granules according to claim 5, characterized in that, In step 1), the sucrose is first mechanically crushed, and then sieved with the rest of the raw materials through a 40-mesh screen.

7. The oral antibiotic granules prepared by the method of any one of claims 1-6, wherein the oral antibiotic granules are faropenem sodium granules.

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