CN109908104B

CN109908104B - Amoxicillin capsule and preparation method thereof

Info

Publication number: CN109908104B
Application number: CN201910326279.5A
Authority: CN
Inventors: 马慧丽; 杨婷婷; 王晨光
Original assignee: Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Current assignee: Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Priority date: 2019-04-23
Filing date: 2019-04-23
Publication date: 2021-07-27
Anticipated expiration: 2039-04-23
Also published as: CN109908104A

Abstract

The invention relates to an amoxicillin capsule and a preparation method thereof, belonging to the technical field of medicines. In the amoxicillin capsule test of 6 months, the amount of impurity X is less than or equal to 0.2 percent; the chemical name of the impurity X is 2-hydroxyamino-2- (4-hydroxyphenyl) -N- [2- (5- (4-hydroxyphenyl) pyrazinyl) ethyl]Acetamide with molecular formula C₂₀H₂₀N₄O₄. The invention realizes the effect of reducing the impurity X in the amoxicillin capsule by changing the prescription, and meanwhile, the micropowder silica gel in the prescription is loose in texture and filled among particles after being used, and the particles are isolated from being embedded with each other, so that the invention has the protection effect of isolating air and resisting oxidation, plays an important role in reducing the impurity X, and the product of the invention has better impurity control than the original product and the product in the prior art.

Description

Amoxicillin capsule and preparation method thereof

Technical Field

The invention relates to an amoxicillin capsule and a preparation method thereof, belonging to the technical field of medicines.

Background

Amoxicillin, which is the most commonly used broad-spectrum antibiotic of semi-synthetic penicillins, has strong bactericidal effect and strong ability of penetrating cell membranes, and can be prepared into capsules, tablets, granules, dispersible tablets and the like. Because the amoxicillin oral liquid has good absorbability and curative effect and is not easy to relapse after treatment, the world health organization recommends amoxicillin as the preferred beta-lactam oral antibiotic, and the amoxicillin oral liquid still occupies an important position in the oral antibiotic so far.

Amoxicillin was developed by Beecham corporation (now GSK corporation) in the united kingdom in 1968, and its capsules were first marketed in the united kingdom before 1972 in 4/19, and later in france, usa, spain, greece, etc. For the treatment of the following infections in adults and children: acute bacterial sinusitis, acute otitis media, acute streptococcal tonsillitis and pharyngitis, exacerbation of chronic bronchitis, community-acquired pneumonia, acute cystitis, asymptomatic bacteriuria during pregnancy, acute pyelonephritis, typhoid and paratyphoid fever, dental abscess with spread of cellulitis, prosthetic joint infection, helicobacter pylori eradication, Lyme disease, and Amoxil is also used for preventing endocarditis.

Chinese patent CN201510141461.5 discloses an amoxicillin capsule and a preparation method thereof. The amoxicillin capsule comprises the following components in parts by mass: 100 parts of amoxicillin, 0.1-1 part of sodium dodecyl sulfate, 0.1-3 parts of talcum powder and 0.25-2.0 parts of magnesium stearate. According to the invention, the higher dissolution rate of the amoxicillin is ensured by adjusting the particle size of the amoxicillin granules as the raw material and adjusting the proportion of the auxiliary materials, so that the use of disintegrants such as sodium carboxymethyl starch and crospovidone is avoided, and the volume of the amoxicillin capsule is reduced; the preparation method simplifies the production and preparation steps of the amoxicillin capsule, reduces the production cost, reduces the content of high molecular impurities in the amoxicillin capsule, and improves the production efficiency.

Chinese patent CN201711441039.7 discloses an amoxicillin medicinal preparation and a preparation method thereof. The amoxicillin preparation comprises the following components in parts by mass: 90.0-99.9 parts of amoxicillin and 0.1-10.0 parts of magnesium stearate; the preparation method is a dry pressing method. The invention can ensure good dissolution and stability of the amoxicillin preparation by controlling the amoxicillin particle size distribution, the magnesium stearate particle size distribution and the pressure of a dry press.

Chinese patent CN201811255007.2 discloses an amoxicillin capsule and a production method and application thereof. The dry granulation is adopted to control the granularity range of the raw materials, and the dissolution rate of the capsule is improved by adjusting the dosage of magnesium stearate under the condition of not using a disintegrating agent, so that the aim of achieving the dissolution behavior of the product similar to that of the original preparation is fulfilled. On the premise of meeting the quality requirement of the medicine, compared with the prior art, the invention is simpler, the volume of the capsule is reduced, and the compliance of clinical use is improved.

The research on the impurities with novel structures generated in the degradation process of the amoxicillin preparation is a dynamic development and continuous promotion process, the new impurities are determined and controlled, the quality standard of the amoxicillin preparation can be further improved, and the medication safety is improved.

Disclosure of Invention

In the process of intensive research and development on the amoxicillin preparation, the applicant finds that the amoxicillin capsule generates a new degradation impurity under the condition of high oxidation temperature, which is named as impurity X. The chemical name of the impurity X is 2-hydroxyamino-2- (4-hydroxyphenyl) -N- [2- (5- (4-hydroxyphenyl) pyrazinyl) ethyl]Acetamide with molecular formula C₂₀H₂₀N₄O₄Having the chemical structure shown in formula I below:

the generation of the new impurity X is completed by the following method: 4 amoxicillin capsules produced by Shijiazhuang Zhongnuo pharmaceutical industry (Shijiazhuang) Co.Ltd, batch No. 254150852, specification 0.25g, capsule shell removal, pouring into a 50mL three-necked bottle, adding 5mL 30% hydrogen peroxide, heating the system to 60 ℃ and keeping the temperature overnight. Directly controlling the temperature not to exceed 60 ℃, concentrating under reduced pressure until the temperature is dry to obtain a damaged product, and finding out an impurity X through liquid phase detection. Separating the destroyed product by preparing liquid phase, flowing out from mobile phase to no mobile phase, collecting solution by stages, mixing the solutions containing impurity X by liquid phase detection, controlling temperature not more than 60 deg.C, concentrating under reduced pressure to dryness to obtain impurity X sample 30mg with chromatographic purity of 90.17%.

Wherein, the liquid phase detection method adopts a method of checking related substances in the quality standard of amoxicillin capsules in the second part of Chinese pharmacopoeia 2015 edition;

the liquid phase conditions were prepared as follows:

a chromatographic column: shim-pack GIS C18(250mm 20mm, 5 μm)

Wavelength: 254nm

Sample introduction amount: 0.8ml

Flow rate: 15ml/min

Mobile phase A: 0.05% glacial acetic acid water solution

Mobile phase B: acetonitrile

Isocratic elution: a, B is 80: 20.

the chemical structure of the above new impurity X is confirmed by the following map data:

LC-MS of the novel impurity X is shown in FIG. 1, and the molecular weight is 381.0 [ M + H [ ]]⁺(ii) a Molecular weight 760.9 is [2M + H]⁺The molecular weight of the new impurity X is deduced to be 380.1. The high resolution MS of the new impurity X is shown in figure 2, the molecular weight of the high resolution mass spectrum is 381.15544 and is consistent with the LC-MS spectrum, and the given molecular formula is C₂₀H₂₀N₄O₄。

The NMR spectrum (BRUKER 400 NMR, deuterated DMSO) of the new impurity X is shown in FIG. 3,¹H-NMRδ(ppm)：2.58(m，2H，-CH₂-)，3.40(m，2H，-CH₂-)，4.51(s，1H，-CH-)，6.71-6.73(dd，2H，ArH)，7.16-7.18(dd，2H，ArH)，6.79-6.82(dd，2H，ArH)，8.22-8.25(dd，2H，ArH)，7.08(s，1H，-CH-)，8.34(s，1H，-CH-)。

the NMR spectrum (BRUKER 400 NMR, deuterated DMSO) of the new impurity X is shown in FIG. 4,¹³C-NMRδ(ppm)：30.07，37.71，56.36，115.13，115.74，122.78，126.63，127.71，130.26，137.28，148.98，156.37，158.33，159.20，165.02，169.73。

the analysis and detection method of the new impurity X is as follows:

1. chromatographic conditions

High performance liquid chromatograph: waters e2695

A chromatographic column: phellomena Luna C184.6mm × 250cm,5 μm

Detection wavelength: 254nm

Flow rate: 1.0mL/min

Column temperature: 35 deg.C

Sample introduction volume: 20 μ L

Mobile phase:

mobile phase A: separately measuring 1980ml of 0.05mol/L phosphate buffer solution (pH 5.0) and 20ml of acetonitrile (the ratio of the two is 99: 1) by using a measuring cylinder, putting the mixture into a 2000ml beaker, uniformly mixing, filtering by a 0.45 mu m mixed microporous membrane, and degassing by ultrasound for 2-3 minutes.

Mobile phase B: 800ml of 0.05mol/L phosphate buffer solution (pH 5.0) and 200ml of acetonitrile (the ratio of the two is 80: 20) are respectively measured by a measuring cylinder, placed in a 1000ml beaker, uniformly mixed, filtered by a 0.45 mu m organic microporous filter membrane, and degassed by ultrasound for 2-3 minutes.

Eluting with mobile phase A-mobile phase B (92: 8) at equal rate, and immediately eluting with the following linear gradient after amoxicillin peak is completely eluted, wherein the gradient elution procedure is as follows:

time (minutes)	Mobile phase A (%)	Mobile phase B (%)
			0	92	8
25	0	100
			40	0	100
41	92	8
			55	92	8

2. Solution preparation

Diluting liquid: mobile phase A

Marker solution of impurity X: the impurity X prepared in example 1 was precisely weighed, dissolved in the mobile phase A and diluted to prepare a solution containing about 20. mu.g of the impurity X per 1ml, as a marker solution of the impurity X.

Amoxicillin system applicability solution: weighing an appropriate amount of amoxicillin system applicability reference substance, adding the mobile phase A into a measuring flask to dissolve and dilute the mobile phase A to scale to prepare amoxicillin system applicability solution of 2mg/ml, and shaking up to obtain the amoxicillin system applicability reference substance.

Control solution: precisely weighing about 23mg of amoxicillin reference substance (calculated according to C16H19N3O5S, containing about 20mg of amoxicillin) in a 100ml measuring flask, adding mobile phase A to dissolve and dilute to scale, shaking up, precisely weighing 5ml of the solution, placing in a 50ml measuring flask, diluting to scale with mobile phase A, and shaking up to obtain a solution containing about 20 μ g of amoxicillin in each 1 ml. In particular, the amoxicillin control herein refers to an amoxicillin trihydrate control.

Test solution: precisely weighing about 0.12g of amoxicillin capsule content (calculated according to C16H19N3O5S, containing about 100mg of amoxicillin), placing in a 50ml measuring flask, dissolving and diluting to scale with mobile phase A, shaking up to prepare solution containing 2.0mg of amoxicillin (calculated according to C16H19N3O 5S) in each 1ml, filtering, and taking the subsequent filtrate.

3. Measurement of

And precisely measuring the diluent, the marker solution of the impurity X, the amoxicillin system applicability solution, the reference solution and the test solution by 20 mu l respectively, injecting the solutions into a liquid chromatograph, and recording the chromatogram.

And (3) testing the applicability of the system: and (3) taking 20 mu l of amoxicillin system applicability solution, injecting into a liquid chromatograph, and recording the chromatogram map which is consistent with the standard chromatogram map.

4. Characterization of impurities

Description of the test: and (3) sample introduction detection is carried out on the test sample solution and the marker solution of the impurity X, and a chromatogram is recorded, so that the peak retention time of more than 0.2% of unknown impurities in the test sample solution and the peak retention time of the marker of the impurity X are consistent, and the quality can be determined. The HPLC profile of the impurity X marker solution is shown in FIG. 5, and the HPLC profile of the test sample solution is shown in FIG. 6.

5. Content calculation

The amount of impurities is calculated from the principal component to which the correction factor is added by a self-control method.

Description of the test:

preparing solutions with concentration ranges of 5% -150% of the concentration of an amoxicillin control solution and 150% of the report limit concentration-specified limit of impurity X, respectively preparing at least 5 solutions with different levels of concentration, measuring and recording peak areas of amoxicillin and impurity X in the solutions with different concentrations by HPLC, giving a function curve of the peak areas of amoxicillin and impurity X and the concentration (unit: mu g/mL) of a corresponding substance, and calculating slope, intercept and correlation coefficient.

Test data:

preparing amoxicillin reference substance solutions with different concentrations: precisely weighing amoxicillin trihydrate reference substance about 13.77mg (as per C)₁₆H₁₉N₃O₅And (S) measuring to obtain a solution containing about 12.00744mg of amoxicillin), placing the solution into a 10ml measuring flask, adding the mobile phase A to dissolve and dilute the solution to scale, shaking up, precisely measuring 5ml of the solution, placing the solution into a 100ml measuring flask, diluting the solution to scale with the mobile phase A, and shaking up to obtain a mother solution containing about 60 mu g of amoxicillin in each 1 ml. And precisely measuring the mother liquor of 5ml, 4ml, 3ml, 2ml, 1ml and 1ml respectively, placing the mother liquor in measuring bottles of 10ml, 25ml and 50ml respectively, diluting the mother liquor to scales by using the mobile phase A, shaking the mother liquor uniformly, and preparing the serial concentration solutions with the amoxicillin concentration shown in the table below.

Preparing impurity X solutions with different concentrations: precisely weighing about 7.44mg (as C) of impurity X₂₀H₂₀N₄O₄About 12.00744mg of impurity X), placing in a 100ml measuring flask, adding mobile phase A to dissolve and dilute toGraduating and shaking up to obtain mother liquor solution containing 67 μ g of the total weight of the mother liquor per 1 ml. Then precisely measuring the mother liquor of 5ml, 4ml, 3ml, 2ml, 1ml and 1ml respectively, placing the mother liquor in measuring bottles of 10ml, 25ml and 50ml respectively, diluting the mother liquor to a scale by using the mobile phase A, shaking the mother liquor uniformly, and preparing the serial concentration solutions with the impurity X concentration as shown in the table below.

The content calculation method comprises the following steps:

the slope of the amoxicillin standard curve was divided by the slope of the impurity X standard curve to obtain the correction factor for impurity X, which was calculated from the above test data to be 3021745/15091874-0.20. Then, the content of the impurity X in the test solution is calculated according to the following formula:

the HPLC profile of the test solution is shown in FIG. 6, and the HPLC profile of the control solution is shown in FIG. 7.

Furthermore, through comparative research, the prior art products such as the original research products and the like all generate impurities X in an acceleration test, and the content of the impurities X is high. Therefore, the amoxicillin capsule with more reliable quality needs to be developed, the product quality is improved, and the safety of clinical medication is ensured.

The invention aims to provide an amoxicillin capsule with more reliable quality aiming at the defects of the prior art, and the amoxicillin capsule is prepared by controlling the particle size distribution of an amoxicillin raw material and preferably selecting magnesium stearate and aerosil as auxiliary materials in a specific ratio. The product of the invention greatly reduces the content of impurity X, remarkably improves the long-term stability of the preparation, and has good dissolution effect, thereby ensuring the safety and effectiveness of medication.

In order to realize the purpose of the invention, the following technical scheme is adopted:

the invention provides an amoxicillin capsule, which consists of a capsule shell and a content, wherein the content comprises a medicinal component amoxicillin and an auxiliary material, and the auxiliary material selects magnesium stearate and aerosil, and is characterized in that the weight ratio of amoxicillin to magnesium stearate to aerosil is 250: 0.78-1.26: 0.26-0.38.

According to the amoxicillin capsule, the amoxicillin raw material serving as the medicinal component is granulated by a dry-process granulator, and the particle size distribution of the obtained amoxicillin dry-process granules is required to meet the requirements that the particle size distribution is larger than 24 meshes and less than or equal to 5%, the particle size distribution is larger than 24-80 meshes and more than or equal to 65%, and the particle size distribution is smaller than 80 meshes and less than or equal to 30%.

The amoxicillin capsule comprises the capsule shell without sodium dodecyl sulfate, and further comprises gelatin, erythrosine, indigo, yellow iron oxide and titanium dioxide.

The amoxicillin capsule has the impurity X content less than or equal to 0.2 percent in the accelerated 6-month test.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	250g
Magnesium stearate	0.78g
		Silica gel micropowder	0.26g
Capsule shell size	2# Capsule Shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: more than 24 meshes account for 1 percent, 24-80 meshes account for 70 percent, and less than 80 meshes account for 29 percent.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	500g
Magnesium stearate	2.11g
		Silica gel micropowder	0.63g
Capsule shell size	0# lengthened capsule shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: 2 percent of more than 24 meshes, 76 percent of 24-80 meshes and 22 percent of less than 80 meshes.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	250g
Magnesium stearate	0.91g
		Silica gel micropowder	0.31g
Capsule shell size	2# Capsule Shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: the content of more than 24 meshes accounts for 4 percent, the content of 24-80 meshes accounts for 75 percent, and the content of less than 80 meshes accounts for 21 percent.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	500g
Magnesium stearate	2.35g
		Silica gel micropowder	0.75g
Capsule shell size	0# lengthened capsule shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: the content of the active ingredients is 4 percent larger than 24 meshes, 68 percent between 24 and 80 meshes and 28 percent smaller than 80 meshes.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	250g
Magnesium stearate	0.96g
		Silica gel micropowder	0.28g
Capsule shell size	2# Capsule Shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: 2 percent of more than 24 meshes, 78 percent of 24-80 meshes and 20 percent of less than 80 meshes.

The amoxicillin capsule comprises the following components in parts by weight:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	500g
Magnesium stearate	2.53g
		Silica gel micropowder	0.71g
Capsule shell size	0# lengthened capsule shell
		Capsule shell composition	Gelatin, erythrosine, indigo blue, yellow iron oxide and titanium dioxide

Wherein, the particle size distribution of the amoxicillin dry-process particles is as follows: more than 24 meshes account for 3 percent, 24-80 meshes account for 81 percent, and less than 80 meshes account for 16 percent.

The invention also provides a preparation method of the amoxicillin capsule, which comprises the following steps:

1. dispensing: pulverizing the adjuvants, and sieving with 80 mesh sieve respectively; respectively weighing raw materials and auxiliary materials according to a prescription;

2. and (3) dry granulation: granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting parameters of the dry granulator. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing speed to be 8rpm, mixing for 5 minutes, sampling, and screening through an electric oscillating screen to detect the particle size distribution of the amoxicillin dry particles;

3. mixing: putting the prepared dry-process granules into a mixing barrel, adding the sieved additional auxiliary materials of magnesium stearate and aerosil according to the prescription amount, and mixing for 5 minutes at the mixing speed of 10 rpm;

4. filling: detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by the amoxicillin capsules with the specified specification, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into capsule shells with reasonable sizes by using the capsule filling machine to obtain the amoxicillin capsules with the required specification;

5. packaging: and (4) carrying out aluminum-plastic packaging on the filled capsules by an aluminum-plastic packaging machine, and finally boxing and boxing.

In the step 2, the particle size distribution of the amoxicillin dry-process particles prepared by the method meets the following requirements: more than 24 meshes and less than or equal to 5 percent, 24-80 meshes and more than or equal to 65 percent, and less than 80 meshes and less than or equal to 30 percent. More preferred dry particle size distribution: more than 24 meshes account for 1 percent, 24-80 meshes account for 79 percent, and less than 80 meshes account for 20 percent; more than 24 meshes account for 1 percent, 24-80 meshes account for 70 percent, and less than 80 meshes account for 29 percent; 2 percent of more than 24 meshes, 76 percent of 24-80 meshes and 22 percent of less than 80 meshes; more than 24 meshes account for 4%, 24-80 meshes account for 75%, and less than 80 meshes account for 21%; more than 24 meshes account for 4%, 24-80 meshes account for 68%, and less than 80 meshes account for 28%; 2 percent of more than 24 meshes, 78 percent of 24-80 meshes and 20 percent of less than 80 meshes; more than 24 meshes account for 3 percent, 24-80 meshes account for 81 percent, and less than 80 meshes account for 16 percent.

In step 2, setting parameters of a dry granulator: the pressure of the press roll is 90-100bar, the rotating speed of the press roll is 8-13rpm, the feeding rotating speed is 90-98rpm, the whole grain rotating speed is 250-300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes respectively. More preferred dry granulator parameters: the press roll pressure is 90bar, the press roll rotating speed is 12rpm, the feeding rotating speed is 95rpm, the whole grain rotating speed is 300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 90bar, the press roll rotating speed is 13rpm, the feeding rotating speed is 98rpm, the whole grain rotating speed is 250rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 100bar, the press roll rotating speed is 12rpm, the feeding rotating speed is 90rpm, the whole grain rotating speed is 300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 90bar, the press roll rotating speed is 12rpm, the feeding rotating speed is 90rpm, the whole grain rotating speed is 300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 100bar, the press roll rotating speed is 8rpm, the feeding rotating speed is 98rpm, the whole grain rotating speed is 300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 100bar, the press roll rotating speed is 11rpm, the feeding rotating speed is 90rpm, the whole grain rotating speed is 250rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes; the press roll pressure is 100bar, the press roll rotating speed is 11rpm, the feeding rotating speed is 90rpm, the whole grain rotating speed is 250rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes.

In the step 4, the capsule shell with the reasonable size is formed by filling 0.25g of amoxicillin capsule into a No. 2 capsule shell, and filling 0.5g of amoxicillin capsule into a No. 0 lengthened capsule shell.

By changing the prescription, auxiliary materials such as sodium dodecyl sulfate and the like in the existing prescription are removed, the effect of reducing the impurity X in the amoxicillin capsule is realized, meanwhile, the micropowder silica gel in the prescription is loose in texture and filled among particles after being used, mutual embedding among the particles is isolated, the protective effect of isolating air and resisting oxidation is realized, the vital effect of reducing the generation of the impurity X is also realized, the limit of the impurity X in the amoxicillin capsule is determined to be 0.2%, and the product disclosed by the invention is superior to the original product and the product in the prior art in the control of the impurity. In addition, although the magnesium stearate in the formula has a lubricating effect and is beneficial to filling of amoxicillin capsules, the magnesium stearate has a dissolution retarding effect to a certain extent due to hydrophobicity, the aerosil adopted in the formula has a dissolution promoting effect, is used in combination with the magnesium stearate and has a specific proportion of 0.3-0.5% of magnesium stearate and 0.1-0.15% of aerosil, and the optimal raw material granularity distribution range preferred by the invention is combined, so that the amoxicillin capsules are stable in filling amount and achieve a good dissolution effect at the same time, and are dissolved for 99-103% in 120min under the synergistic effect of various factors, and finally, the dissolution behavior of the amoxicillin capsules is kept consistent with that of the original grinding products, and the in-vitro and in-vivo equivalence is achieved.

Drawings

FIG. 1 LC-MS spectrogram of new impurity X degraded by amoxicillin capsule of the invention

FIG. 2 is a high-resolution MS spectrogram of the amoxicillin capsule degrading new impurity X

FIG. 3 is a hydrogen spectrum diagram of new impurity X for amoxicillin capsule degradation according to the invention

FIG. 4 is a carbon spectrum chart of the new impurity X for amoxicillin capsule degradation of the invention

FIG. 5 HPLC chromatogram of an impurity X marker solution for analytical detection of an impurity X according to the invention

FIG. 6 HPLC chromatogram of a test solution for analysis and detection of the impurity X according to the present invention

FIG. 7 HPLC chromatogram of a control solution for the analytical detection of impurities X according to the invention

FIG. 8 dissolution curves of the Amoxicillin capsules of formula 1 to formula 9 of Experimental example 1 of the present invention

FIG. 9 dissolution curves of prescription 10 to prescription 14 amoxicillin capsules of experimental example 2 of the present invention

FIG. 10 dissolution curves in Water of Amoxicillin capsules of examples 1 to 6 and comparative examples 1 to 5 of test example 4 of the present invention

Detailed Description

The following detailed description of the invention is provided to facilitate an understanding of the invention and to enable any person skilled in the art to make or use the invention without limiting it.

COMPARATIVE EXAMPLE 1 preparation of Amoxicillin Capsule (0.25g) of the existing prescription technology

Prescription:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	250g
Magnesium stearate	1.5g
		Croscarmellose sodium	6.531g
Sodium dodecyl sulfate	1.435g
		Capsule shell size	No. 1 capsule shell
Capsule shell composition	Gelatin, sodium dodecyl sulfate, brilliant blue, lemon yellow and titanium dioxide

The preparation method comprises the following steps:

1. dispensing of drugs

Pulverizing adjuvants including sodium dodecyl sulfate, croscarmellose sodium and magnesium stearate, and sieving with 80 mesh sieve; the raw materials and the auxiliary materials are respectively weighed according to the prescription. It should be noted that the actual dosage of amoxicillin is amoxicillin (as C)₁₆H₁₉N₃O₅S) the dosage/content/(1-moisture) of the prescription, wherein the content and the moisture are detected according to a detection method in the amoxicillin quality standard of the second part of the Chinese pharmacopoeia 2015 edition, and the detected content of the raw material exceeds 100 percent and is calculated according to 100 percent.

2. Dry granulation

Adding the amoxicillin raw material and the croscarmellose sodium into a hopper mixer according to the prescription amount, uniformly mixing, granulating by using a dry granulator, and setting the parameters of the dry granulator: the pressure of a press roll is 110bar, the rotating speed of the press roll is 10rpm, and the feeding rotating speed is 80 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 16 meshes; the screen mesh number of the oscillating screen is as follows: 20 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: 7 percent of more than 20 meshes, 66 percent of 20-80 meshes and 27 percent of less than 80 meshes.

3. Mixing

And (3) putting the prepared dry-process granules into a mixing barrel, adding the sieved additional auxiliary materials of sodium dodecyl sulfate and magnesium stearate according to the prescription amount, mixing, setting the mixing rotation speed to be 8rpm, and mixing for 10 minutes.

4. Filling in

Detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by 0.25g amoxicillin, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into a No. 1 capsule by using the capsule filling machine to obtain the amoxicillin capsule with 0.25 g.

5. Package (I)

And (4) carrying out aluminum-plastic packaging on the filled capsules by an aluminum-plastic packaging machine, and finally boxing and boxing.

COMPARATIVE EXAMPLE 2 preparation of Amoxicillin Capsule (0.5g) of the existing prescription technology

Prescription:

	prescription
		Amoxicillin (according to C)₁₆H₁₉N₃O₅S meter	500g
Magnesium stearate	3g
		Croscarmellose sodium	13.062g
Sodium dodecyl sulfate	2.87g
		Capsule shell size	0# Capsule Shell
Capsule shell composition	Gelatin, sodium dodecyl sulfate, brilliant blue, lemon yellow and titanium dioxide

The preparation method comprises the following steps:

1. dispensing of drugs

2. Dry granulation

Adding the amoxicillin raw material and the croscarmellose sodium into a hopper mixer according to the prescription amount, uniformly mixing, granulating by using a dry granulator, and setting the parameters of the dry granulator: the pressure of a press roll is 110bar, the rotating speed of the press roll is 10rpm, and the feeding rotating speed is 80 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 16 meshes; the screen mesh number of the oscillating screen is as follows: 20 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: 7 percent of more than 20 meshes, 68 percent of 20-80 meshes and 25 percent of less than 80 meshes.

3. Mixing

4. Filling in

Detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by 0.5g amoxicillin, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into a No. 0 capsule by using the capsule filling machine to obtain the 0.5g amoxicillin capsule.

5. Package (I)

COMPARATIVE EXAMPLE 3 Amoxicillin Capsule (0.25g) of patent CN104856972B was prepared

According to the formula and the preparation method disclosed in embodiment 1 of the invention patent CN104856972B, 0.25g of amoxicillin capsules are prepared, wherein the capsule shell adopts a No. 1 capsule, and the capsule shell comprises the components of gelatin, sodium dodecyl sulfate, brilliant blue, lemon yellow and titanium dioxide.

COMPARATIVE EXAMPLE 4 Amoxicillin Capsule (0.25g) of patent CN109172539A was prepared

According to the formula and the preparation method disclosed in embodiment 1 of the invention patent CN109172539A, 0.25g of amoxicillin capsules are prepared, wherein the capsule shell adopts a No. 1 capsule, and the capsule shell comprises the components of gelatin, erythrosine, indigo, yellow iron oxide and titanium dioxide.

Comparative example 5 Amoxicillin capsules from original research corporation

Commercial products: amoxicillin capsules from GlaxoSmithKline, uk (trade name:

) Specification: 0.5 g/pellet, batch number: 2051.

EXAMPLE 1 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

Pulverizing magnesium stearate and silica gel micropowder, and sieving with 80 mesh sieve; the raw materials and the auxiliary materials are respectively weighed according to the prescription. It should be noted that the actual dosage of amoxicillin is amoxicillin (as C)₁₆H₁₉N₃O₅S) the dosage/content/(1-moisture) of the prescription, wherein the content and the moisture are detected according to a detection method in the amoxicillin quality standard of the second part of the Chinese pharmacopoeia 2015 edition, and the detected content of the raw material exceeds 100 percent and is calculated according to 100 percent. The amoxicillin uses the same batch of raw material medicines as the comparative examples 1 and 2.

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 90bar, the rotating speed of the press roll is 12rpm, and the feeding rotating speed is 95 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: more than 24 meshes account for 1 percent, 24-80 meshes account for 70 percent, and less than 80 meshes account for 29 percent.

3. Mixing

And (3) putting the prepared dry-process granules into a mixing barrel, adding the sieved additional auxiliary materials of magnesium stearate and aerosil according to the prescription amount, mixing, setting the mixing rotation speed to be 10rpm, and mixing for 5 minutes.

4. Filling in

Detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by 0.25g amoxicillin, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into a No. 2 capsule by using the capsule filling machine to obtain the amoxicillin capsule with 0.25 g.

5. Package (I)

Example 2 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 90bar, the rotating speed of the press roll is 13rpm, and the feeding rotating speed is 98 rpm; the whole grain rotating speed is 250rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: 2 percent of more than 24 meshes, 76 percent of 24-80 meshes and 22 percent of less than 80 meshes.

3. Mixing

4. Filling in

Detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by 0.5g amoxicillin, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into a 0# lengthened capsule by using the capsule filling machine to obtain the 0.5g amoxicillin capsule.

5. Package (I)

Example 3 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 100bar, the rotating speed of the press roll is 12rpm, and the feeding rotating speed is 90 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: the content of more than 24 meshes accounts for 4 percent, the content of 24-80 meshes accounts for 75 percent, and the content of less than 80 meshes accounts for 21 percent.

3. Mixing

4. Filling in

5. Package (I)

Example 4 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 90bar, the rotating speed of the press roll is 12rpm, and the feeding rotating speed is 90 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: the content of the active ingredients is 4 percent larger than 24 meshes, 68 percent between 24 and 80 meshes and 28 percent smaller than 80 meshes.

3. Mixing

4. Filling in

5. Package (I)

Example 5 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

Pulverizing magnesium stearate and silica gel micropowder, and sieving with 80 mesh sieve; the raw materials and the auxiliary materials are respectively weighed according to the prescription. It should be noted that the actual dosage of amoxicillin is amoxicillin (as C)₁₆H₁₉N₃O₅S) dosage/content/(1-moisture) of the prescription, wherein the content and the moisture are detected according to a detection method in the second amoxicillin quality standard of Chinese pharmacopoeia 2015 editionAnd (4) detecting, wherein the content of the detected raw materials exceeds 100% and is calculated according to 100%. The amoxicillin uses the same batch of raw material medicines as the comparative examples 1 and 2.

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 100bar, the rotating speed of the press roll is 8rpm, and the feeding rotating speed is 98 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: 2 percent of more than 24 meshes, 78 percent of 24-80 meshes and 20 percent of less than 80 meshes.

3. Mixing

4. Filling in

5. Package (I)

Example 6 preparation of Amoxicillin capsules according to the invention

Prescription:

The preparation method comprises the following steps:

1. dispensing of drugs

2. Dry granulation

Granulating the amoxicillin raw material with the prescription amount by using a dry granulator, and setting the parameters of the dry granulator: the pressure of the press roll is 100bar, the rotating speed of the press roll is 11rpm, and the feeding rotating speed is 90 rpm; the whole grain rotating speed is 250rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes. Carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing rotation speed to be 8rpm, mixing for 5 minutes, sampling, and screening and detecting the particle size distribution of the dry particles through an electric oscillating screen: more than 24 meshes account for 3 percent, 24-80 meshes account for 81 percent, and less than 80 meshes account for 16 percent.

3. Mixing

4. Filling in

5. Package (I)

Test example 1 particle size distribution screening test of raw Material

Because the raw material granules can generate obvious adverse effect on the dissolution of the amoxicillin capsules after being sieved greatly and the dissolution of the capsules at the end point is incomplete, the invention changes the sieving of a 20-mesh sieve in the existing prescription into a 24-mesh sieve, and controls the whole particle size of the granules to be smaller, thereby improving the dissolution effect.

Small trials explored the effect of different raw material particle sizes on capsule dissolution: screening raw materials prepared by a dry method into formulas with different particle sizes (shown in table 1), adding 0.5% of magnesium stearate and 0.1% of aerosil, uniformly mixing, and manually filling 0.5g of amoxicillin capsules with specifications. And the dissolution curve of the amoxicillin capsules with the prescriptions 1-9 is measured according to the first basket method of 0931 in the four parts of the Chinese pharmacopoeia 2015 year edition, 900ml of water is used as a dissolution medium, the rotating speed is 100 r/min, and the results are shown in the table 2 and the figure 8 through high performance liquid detection.

Table 1 raw material prescription with different particle sizes

	Is larger than 24 meshes	24-80 mesh	Less than 80 mesh
				Prescription
1	40％	60％	0％
				Prescription
2	25％	75％	0％
				Prescription 3	20％	50％	30％
Prescription 4	10％	70％	20％
				Prescription 5	5％	75％	20％
Prescription 6	0％	75％	25％
				Prescription 7	5％	65％	30％
Prescription 8	5％	60％	35％
				Prescription 9	0％	65％	35％

TABLE 2 dissolution curves of prescription 1-prescription 9 amoxicillin capsules

Through the exploration of the prescription on the particle size, the particle size distribution has influence on the capsule dissolution curve from the aqueous medium dissolution curve. If large particles are more (formula 1 and formula 2), the dissolution curve is slow, and the large particles cannot be dissolved in the later period; if both large particles and fine particles are more (formula 3 and formula 4), the dissolution is fast in the early stage, but the large particles are too much and the complete dissolution cannot be realized in the later stage; the dissolution curve is moderate when the particle size distribution is moderate (formula 5, formula 6 and formula 7), and the end-point dissolution can be completely dissolved. If the amount of large particles is proper, and the amount of medium particles is slightly less, or the amount of small particles is slightly more (formula 8, formula 9), the particle size distribution will result in fast dissolution, but the dissolution is complete, but the dissolution curve is not consistent with the original dissolution curve, and biological inequality will result.

Thus, the dry particle size distribution is ultimately defined as: more than 24 meshes and less than or equal to 5 percent, 24-80 meshes and more than or equal to 65 percent, and less than 80 meshes and less than or equal to 30 percent. Test example 2 screening test for the amounts of magnesium stearate and aerosil

Prescription 10-prescription 14 are designed according to different dosages of magnesium stearate and aerosil, and are shown in table 3.

TABLE 3 prescription for different dosages of magnesium stearate and aerosil

Amoxicillin capsules of formula 10-formula 14 were prepared according to the preparation method of example 2. Wherein, the dry granulator parameters are as follows: the pressure of the press roll is 100bar, the rotating speed of the press roll is 9rpm, and the feeding rotating speed is 98 rpm; the whole grain rotating speed is 300rpm, and the mesh number of the whole grain screen is 18 meshes; the screen mesh number of the oscillating screen is as follows: 24 meshes and 80 meshes; the particle size distribution of the obtained dry-process particles is as follows: more than 24 meshes account for 1 percent, 24-80 meshes account for 79 percent, and less than 80 meshes account for 20 percent.

Examining the influence of different dosages of magnesium stearate and aerosil on the dissolution of the amoxicillin capsules, determining the dissolution curve of the amoxicillin capsules with the prescriptions 10 to 14 according to the first basket method of the four 0931 parts of the Chinese pharmacopoeia 2015 year edition, taking 900ml of water as a dissolution medium, rotating at 100 r/min, and performing high performance liquid detection, wherein the results are shown in table 4 and fig. 9.

TABLE 4 dissolution curves for prescription 10-prescription 14 amoxicillin capsules

The dosage of magnesium stearate and aerosil is groped, and the dissolution curve is moderate when the dosage of magnesium stearate is 0.3 percent, the dosage of aerosil is 0.12 percent (prescription 10), the dosage of magnesium stearate is 0.5 percent, the dosage of aerosil is 0.10 percent (prescription 11), the dosage of magnesium stearate is 0.5 percent and the dosage of aerosil is 0.15 percent (prescription 12), the end-point dissolution can be completely dissolved, and the filling amount of the capsule is qualified; when the dosage of magnesium stearate is 1.0 percent and the dosage of aerosil is 0.15 percent (prescription 13), the filling quantity of the capsule is qualified, but the dissolution curve becomes slow and the end point can not be completely dissolved; when the dosage of magnesium stearate is reduced to 0.8 percent and the dosage of aerosil is increased to 0.2 percent (formula 14), the dissolution effect is not improved, the capsule filling is difficult, the filling amount is unqualified, and the dissolution is slow and incomplete.

Tests show that the dosage of magnesium stearate is less than 0.3%, the fluidity of the mixed material is poor, the filling stability of the filled capsule is affected, and the dissolution effect is poor when the dosage of magnesium stearate is more than 0.5%; the using amount of the micro silica gel powder is too small, the materials are not easy to mix uniformly, the using amount of the micro silica gel powder cannot be too large at the same time and is more than 0.15 percent, and the filling amount of the capsule cannot be reached because the micro silica gel powder is loose and is not easy to fill during capsule filling. Therefore, in order to achieve better dissolution effect and meet the requirement of capsule filling amount, the dosage of magnesium stearate is finally determined to be 0.3-0.5 percent, and the dosage of aerosil is finally determined to be 0.1-0.15 percent.

Test example 3 stability examination

The amoxicillin capsule samples prepared in examples 1-6 of the invention and the samples in comparative examples 1-5 are subjected to accelerated test under the conditions of temperature 40 +/-2 ℃ and relative humidity 75 +/-5% for 6 months. The detection methods of the dissolution rate, the content, related substances and the amoxicillin polymer (polymer for short) are all pharmacopeia methods (Chinese pharmacopeia 2015 year edition two), the detection method of the impurity X is according to the detection method of the invention part, and the results are shown in Table 5.

The quality standard of the amoxicillin capsules is clearly recorded in the second part of the Chinese pharmacopoeia 2015 year edition, and the required content is 90.0-110.0%, the single impurity content of related substances is not more than 1.0%, the total impurity content of related substances is not more than 5.0%, the amoxicillin polymer (polymer for short) is not more than 0.2%, and the dissolution limit is 80%.

TABLE 5 accelerated test results

As can be seen from table 5: the amoxicillin capsule samples prepared in examples 1-6 of the present invention were higher in content and lower in related substances than in comparative examples 1-5, and impurity X was not detected in the amoxicillin capsule samples prepared in examples 1-6 at 0 month, whereas impurity X was detected in the samples of comparative examples 1-5. After 6 months of accelerated tests, the amoxicillin capsules prepared in examples 1-6 have slower content reduction, the content is all over 101%, the related substances increase more slowly, the single impurity content of the related substances is all below 0.25%, the total impurity content of the related substances is all below 2.1%, the polymer is all 0.01%, the impurity X is all below 0.15%, and the dissolution rate is qualified; comparative examples 1 to 5 also meet the quality standards, but comparative examples 1, 2 and 3 both decrease the content and increase the related substances rapidly due to the inclusion of sodium dodecyl sulfate and other excipients in the formulation, wherein the impurity X is more than 1% after 6 months of acceleration, while comparative examples 4 and 5 do not include sodium dodecyl sulfate and other excipients, and decrease the content and increase the related substances slightly more slowly than comparative examples 1, 2 and 3, but the impurity X also increases to about 0.7% after 6 months of acceleration.

The results show that the amoxicillin capsules prepared in the embodiments 1 to 6 of the present invention do not contain auxiliary materials such as sodium dodecyl sulfate and the like in the prescription, and the micropowder silica gel having a protective effect is added, so that the prepared samples have low impurity content and better stability, and the generation of the impurity X is significantly reduced. Therefore, the limit of the impurity X is set to be 0.2%, the quality control is stricter, the product quality is further improved, and the method is a better driving protection navigation for clinical medication.

Test example 4 dissolution Curve comparison

The dissolution curves in water of the amoxicillin capsule samples prepared in examples 1-6 of the invention and the samples of comparative examples 1-5 are determined under the conditions that the dissolution curve is determined according to the first basket method of 0931 in the four parts of the 2015 edition of Chinese pharmacopoeia, 900ml of water is used as a dissolution medium, the rotating speed is 100 r/min, and the results are shown in table 6 and fig. 10 through high performance liquid detection.

TABLE 6 dissolution profiles in water for Amoxicillin capsules of examples 1-6 and comparative examples 1-5

In the examples 1-6 of the invention, by adjusting the particle size distribution of the raw materials and adopting magnesium stearate and aerosil in a specific ratio, the prepared sample has a good dissolution curve in an aqueous medium, and the dissolution curve is 101.7-103.5% in 120min, and the dissolution curve of the samples in the examples 1-6 of the invention is consistent with that of the original ground product.

Auxiliary materials such as a disintegrating agent and sodium dodecyl sulfate are added into the formulas of the comparative examples 1 and 2, the dissolution of the sample is too fast, 90% is already achieved within 30min, the subsequent dissolution release is too slow, the dissolution rate is about 99% within 120min, and the dissolution curve is far different from that of the original product; compared with the formulas of the comparative example 1 and the comparative example 2, the formula of the comparative example 3 does not contain the disintegrating agent and is added with the talcum powder, the sample is slowly dissolved and incompletely dissolved, the dissolution rate is about 93 percent at 120min, and the dissolution curve is inconsistent with that of the original product; comparative example 4 by controlling the particle size of the raw materials and only adding the lubricant in the prescription, the dissolution curve of the sample is good, 102.1% of the dissolution is carried out at 120min, and the dissolution curve is consistent with that of the original product.

Test example 5 bioequivalence study

From the original grinding product

(Amoxicillin capsule developed by GlaxoSmithKline company in British) as a reference preparation, and the invention develops a single-center, open and random preparation with scientific and reasonable design for the productThe mechanical and double-cycle cross human body bioequivalence test research is carried out, the in-vivo metabolic process of the drug after the amoxicillin capsule is orally taken by a single dose of a healthy subject is observed, corresponding pharmacokinetic parameters are estimated, and the bioavailability and bioequivalence are evaluated.

1. Research method

The study was a single-center, open, randomized, two-cycle crossover experimental study design with an elution period of 7 days. 26 subjects were selected in the fasting/postprandial test, and 0.5g (sample prepared in example 2) of amoxicillin capsule (1 capsule) or 1 reference preparation (1 capsule) was orally administered in different periods

0.5g (sample of comparative example 5), plasma samples were taken before and within 12h after dosing and the amoxicillin concentration of the plasma samples was determined by LC-MS/MS.

2. Pharmacokinetic calculation results

Pharmacokinetic calculation results: oral test preparation amoxicillin capsule 0.5g and reference preparation calculated by WinNonlin 6.4 or above version software

The main pharmacokinetic parameters of 0.5g are as follows:

open web test t_1/21.42 plus or minus 0.18h and 1.36 plus or minus 0.16h respectively; t is_max2.00(1.50,2.58) h and 1.75(1.50,2.33) h respectively; c_max8589.58 +/-1877.66 ng/mL and 8450.83 +/-2099.86 ng/mL respectively; AUC_0-t25847.96 ± 3516.41h ng/mL and 24397.98 ± 3350.27h ng/mL, respectively; AUC_0-∞26956.98 ± 3532.51h ng/mL and 25493.33 ± 3354.35h ng/mL, respectively.

Postprandial test t_1/21.42 plus or minus 0.36h and 1.33 plus or minus 0.16h respectively; t is_max3.00(2.67,3.50) h and 3.00(2.50,4.25) h respectively; c_max7960.80 +/-1490.85 ng/mL and 7956.40 +/-1932.84 ng/mL respectively; AUC_0-t25931.28 ± 5381.17h ng/mL and 24900.18 ± 6575.55h ng/mL, respectively; AUC_0-∞27206.33 ± 5661.63h ng/mL and 26053.10 ± 6553.84h ng/mL, respectively.

3. Determination result of bioequivalence

C of fasting test preparation and reference preparation_max、AUC_0-tAnd AUC_0-∞After logarithmic conversion, the ratio of the geometric mean values is 102.01 percent, 106.13 percent and 106.16 percent respectively, and the 90 percent confidence intervals corresponding to the ratio are 93.16-110.78 percent respectively (C)_max)，103.00～109.32％(AUC_0-t)，103.05～109.32％(AUC_0-∞)。

C of postprandial test and reference preparations_max、AUC_0-tAnd AUC_0-∞After logarithmic conversion, the ratio of the geometric mean values is 101.24%, 105.28% and 105.63%, and the 90% confidence intervals corresponding to the ratio are 94.48-108.71% (C)_max)，101.22～109.55％(AUC_0-t)，102.05～109.37％(AUC_0-∞)。

According to the bioequivalence determination criteria, fasting/postprandial bioequivalence of the two preparations can be determined. By nonparametric examination, T_maxThere was no significant difference (P) between the test and reference formulations>0.05)。

4. Conclusion

The fasting and postprandial test results prove that the amoxicillin capsule sample in the embodiment 2 and the original product in the comparative example 5 are bioequivalent preparations, and the curative effect in vivo is consistent.

Therefore, the amoxicillin capsule product provided by the invention has good dissolution behavior under the condition of well controlling the impurity X, achieves in-vivo biological equivalence with the original product, has high preparation stability, has obvious effect compared with the existing product, and provides a better choice for clinical application.

The above is only a preferred embodiment of the present invention, and it should be understood that the present invention is not limited thereto, and those skilled in the art can make various modifications, decorations and equivalents without departing from the principle of the present invention, and therefore, the present invention is to be covered within the protection scope of the present invention.

Claims

1. An amoxicillin capsule is characterized by comprising a capsule shell and contents, wherein the contents comprise a medicinal component amoxicillin and auxiliary materials, and the auxiliary materials comprise magnesium stearate and aerosil; the weight ratio of the amoxicillin to the magnesium stearate to the aerosil is 250: 0.78-1.26: 0.26-0.38;

in the amoxicillin capsule test of 6 months, the amount of impurity X is less than or equal to 0.2 percent; the chemical name of the impurity X is 2-hydroxyamino-2- (4-hydroxyphenyl) -N- [2- (5- (4-hydroxyphenyl) pyrazinyl) ethyl]Acetamide with molecular formula C₂₀H₂₀N₄O₄Having the chemical structure shown in formula I below:

the preparation method of the amoxicillin capsule comprises the following steps:

(1) and dispensing: pulverizing the adjuvants, and sieving with 80 mesh sieve respectively; respectively weighing amoxicillin and auxiliary materials according to a prescription;

(2) and dry granulation: granulating the amoxicillin with the prescription amount by using a dry granulator, and setting parameters of the dry granulator; carrying out secondary granulation on particles which do not meet the requirements in the production process through a dry granulation machine, putting the finally obtained dry particles into a mixing barrel for mixing, setting the mixing speed to be 8rpm, mixing for 5 minutes, sampling, and screening through an electric oscillating screen to detect the particle size distribution of the amoxicillin dry particles;

(3) and mixing: putting the prepared dry-process granules into a mixing barrel, adding the sieved additional auxiliary materials of magnesium stearate and aerosil according to the prescription amount, and mixing for 5 minutes at the mixing speed of 10 rpm;

(4) filling: detecting the content of amoxicillin in the mixed materials, converting the amount of the mixed materials required by the amoxicillin capsules with the specified specification, setting the speed of a capsule filling machine to be less than or equal to 140 r/min, and accurately and quantitatively filling the mixed materials into capsule shells with reasonable sizes by using the capsule filling machine to obtain the amoxicillin capsules with the required specification;

(5) and packaging: carrying out aluminum-plastic packaging on the filled capsules by an aluminum-plastic packaging machine, and finally boxing and boxing;

wherein, in the step (2), the particle size distribution of the amoxicillin dry-process particles is as follows: more than 24 meshes and less than or equal to 5 percent, 24-80 meshes and more than or equal to 65 percent, less than 80 meshes and less than or equal to 30 percent; the setting of the parameters of the dry granulating machine comprises the following steps: the pressure of the press roll is 90-100bar, the rotating speed of the press roll is 8-13rpm, the feeding rotating speed is 90-98rpm, the whole grain rotating speed is 250-300rpm, the mesh number of the whole grain screen is 18 meshes, and the mesh number of the oscillating screen is 24 meshes and 80 meshes respectively; in the step (4), the capsule shell with the reasonable size is formed by filling 0.25g of amoxicillin capsule into a No. 2 capsule shell, and filling 0.5g of amoxicillin capsule into a No. 0 lengthened capsule shell.

2. An amoxicillin capsule according to claim 1, characterized in that the pharmaceutical ingredient amoxicillin raw material is first granulated with a dry granulator, and the obtained amoxicillin dry granules have a particle size distribution of greater than 24 mesh and less than or equal to 5%, 24-80 mesh and greater than or equal to 65%, and less than 80 mesh and less than or equal to 30%.

3. An amoxicillin capsule according to claim 1 or 2, characterized in that the capsule shell ingredients are gelatin, erythrosine, indigo, yellow iron oxide and titanium dioxide.

4. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight:

5. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight:

6. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight:

7. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight:

8. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight:

9. An amoxicillin capsule according to claim 3, characterized in that it consists of the following components in parts by weight: