A method for preparing norfloxacin capsules

Abstract

This invention provides a method for preparing norfloxacin capsules. By weight percentage, the capsule contents are 35%-45% norfloxacin and 55%-65% starch. The preparation method includes steps such as excipient pretreatment, premixing, wet granulation, drying, sizing, and filling. The prepared norfloxacin capsules have small weight differences, high and stable dissolution, and stable quality even after 6 months of accelerated storage.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a method for preparing norfloxacin capsules. Background Technology

[0002] Norfloxacin, also known as norfloxacin, has the chemical name 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, as shown in the structural formula below. It is a third-generation quinolone antibacterial drug that inhibits the action of DNA gyrase in pathogenic bacteria in the digestive tract, thereby preventing bacterial DNA replication. It is suitable for urinary tract infections, gonorrhea, prostatitis, intestinal infections, typhoid fever, and other Salmonella infections caused by susceptible bacteria.

[0003]

[0004] In China, norfloxacin preparations mainly include norfloxacin injection, norfloxacin capsules, norfloxacin tablets, norfloxacin eye drops, and norfloxacin ointment. Among these, 100mg norfloxacin capsules are the most commonly used, with the most manufacturers and the greatest quality variation. The Zhuhai Municipal Institute for Food and Drug Control analyzed 37 batches of norfloxacin capsules sampled from various areas of Zhuhai between 2016 and 2021. The analysis showed that one batch of norfloxacin capsules failed the dissolution test, while the others met the limits. However, there are significant differences in the quality of norfloxacin capsules produced by different manufacturers, and even within the same batch from the same manufacturer, mainly in dissolution behavior. Norfloxacin tends to clump together when dissolved in a pH 6.8 dissolution medium and water, resulting in a slow dissolution rate. This means that the clinical efficacy of norfloxacin capsules used clinically cannot match that of norfloxacin tablets (reference preparation) from Kyorin Pharmaceutical Industries Co., Ltd. of Japan.

[0005] Therefore, it is necessary to conduct further research on the formulation and preparation process of norfloxacin capsules to improve the dissolution rate of norfloxacin, so as to achieve product quality consistent with the reference formulation and ensure safe and effective medication. Summary of the Invention

[0006] The inventors of this invention unexpectedly discovered during their research on norfloxacin capsules that by controlling the particle size of norfloxacin and optimizing the preparation method, the prepared norfloxacin capsules exhibited smaller weight variations, higher and more stable dissolution rates, and stable quality even after 6 months of accelerated storage.

[0007] First, this invention provides a method for preparing norfloxacin capsules, wherein the capsule contents, by weight percentage, are 35%-45% norfloxacin and 55%-65% starch; the preparation method includes the following steps:

[0008] (1) Pretreatment of auxiliary materials;

[0009] Dry the starch in an oven at 50-60℃ for 4-6 hours, then pass it through a 120-mesh sieve for later use.

[0010] (2) Premixing and wet granulation:

[0011] Norfloxacin and starch are added to a wet granulation machine for stirring and premixing. Then, under stirring conditions, binder water is added and wet granulation is performed. The water spraying speed is controlled to spray the aqueous solution evenly, so that the spraying process lasts for 120-160 seconds and the granulation time is 60-110 seconds after spraying.

[0012] (3) Drying and granulation:

[0013] Dry at 55-65℃, and the loss on drying should not exceed 1.2%; the dried granules are then added to a granulator with a 2.0mm mesh size.

[0014] (4) Filling: Fill the granules into capsules.

[0015] Preferably, the capsule contents, by weight percentage, consist of 38%-42% norfloxacin and 58%-62% starch.

[0016] More preferably, the capsule contents, by weight percentage, are 40% norfloxacin and 60% starch.

[0017] In step (1), the temperature is preferably 54-57°C, and more preferably vacuum drying is performed.

[0018] In step (2), the aqueous solution is added at a temperature of 32-35℃, and the weight ratio of the aqueous solution to norfloxacin is (0.05-0.08):1. In step (2), the particle size D of norfloxacin... 90 20-30μm, D 50 It is 12-15μm.

[0019] In step (2), the parameters for premixing, spraying the adhesive solution, and granulation are as follows:

[0020]

[0021] Where rpm is the number of revolutions per minute.

[0022] Furthermore, in step (4), each capsule contains 0.1g of norfloxacin and the contents of each capsule weigh 0.25g.

[0023] This invention controls the particle size of norfloxacin and optimizes the preparation method, especially optimizing the temperature of the adhesive aqueous solution, the addition time, and the granulation time. The resulting norfloxacin capsules have small weight differences, high and stable dissolution, and stable quality even after 6 months of accelerated storage. Detailed Implementation

[0024] This invention discloses a method for preparing norfloxacin capsules. Those skilled in the art can refer to the content of this invention and, in conjunction with the relevant principles of pharmaceutical formulation, appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention. The application of this invention has been described through preferred embodiments, and those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0025] To better understand the invention and not to limit its scope, all figures indicating amounts, percentages, and other numerical values ​​used in this application should, in all cases, be understood to be modified by the word "approximately." Each numerical parameter should at least be considered as obtained based on reported significant figures and through conventional rounding methods.

[0026] The present invention will be further illustrated by the following examples, but the examples do not limit the present invention in any way.

[0027] The particle size of norfloxacin used in the embodiments of the present invention is shown in the table below:

[0028] Components <![CDATA[D 50 ]]> <![CDATA[D 90 ]]> Norfloxacin 1 14.3μm 26.9μm Norfloxacin 2 12.8μm 22.7μm Norfloxacin 3 12.6μm 37.1μm Norfloxacin 4 9.5μm 20.6μm Norfloxacin 5 21.4μm 39.1μm

[0029] Weight difference:

[0030] Take 20 capsules, weigh them precisely, pour out the contents, and clean the capsule shells with a small brush; then weigh the hard capsule shells precisely again, and calculate the content of each capsule and the average content. The difference between the content of each capsule and the theoretical content should be ±10%.

[0031] Determination of dissolution profile

[0032] Dissolution medium: pH 6.8 buffer solution, water; 1000ml

[0033] Rotation speed: 50 rpm

[0034] Sampling times: 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min

[0035] Example 1: Norfloxacin Capsules

[0036] I. Prescription Composition:

[0037]

[0038] Norfloxacin capsules were prepared by adding raw materials according to the prescription of 10,000 capsules. The same applies below.

[0039] II. Preparation method:

[0040] (1) Pretreatment of auxiliary materials;

[0041] Place the starch in an oven at 54-57℃ and dry under reduced pressure for 5 hours. Then pass it through a 120-mesh sieve for later use.

[0042] (2) Premixing and wet granulation:

[0043] Norfloxacin and starch were added to a wet granulation machine for premixing and stirring. Then, water was added as a binder under stirring conditions at a temperature of 34°C. Wet granulation was performed, and the water spraying speed was controlled to ensure uniform spraying of the aqueous solution. Granulation was then carried out after the aqueous solution was sprayed.

[0044] The parameters for premixing, spraying into the aqueous solution, and granulation are as follows:

[0045]

[0046] (3) Drying and granulation:

[0047] Dry at 60℃, and the loss on drying is not higher than 0.8%; the dried granules are added to a granulator with a sieve aperture of 2.0 mm.

[0048] (4) Filling: Fill the granules into capsules, each capsule containing 250mg of contents, including 100mg of norfloxacin.

[0049] III. Test Results:

[0050] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 1.

[0051] Table 1: Weight variation of norfloxacin capsules prepared in Example 1

[0052] sample Weight difference in conclusion Example 1 -2.78％～3.44％ Compliant

[0053] 2. The dissolution curves of the prepared norfloxacin capsules were determined in water at pH 6.8, and the results are shown in Table 2-3.

[0054] Table 2: Dissolution curves of norfloxacin capsules prepared in Example 1 in pH 6.8 buffer solution.

[0055]

[0056] Table 3: Dissolution curves of norfloxacin capsules prepared in Example 1 in aqueous solution

[0057]

[0058] Example 2: Norfloxacin Capsules

[0059] I. Prescription Composition:

[0060]

[0061] II. Preparation method: Same as in Example 1.

[0062] III. Test Results:

[0063] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 4.

[0064] Table 4: Weight variation of norfloxacin capsules prepared in Example 2

[0065] sample Weight difference in conclusion Example 2 -2.77％～3.56％ Compliant

[0066] 2. The dissolution curves of the prepared norfloxacin capsules were determined in water at pH 6.8, and the results are shown in Table 5-6.

[0067] Table 5: Dissolution curves of norfloxacin capsules prepared in Example 2 in pH 6.8 buffer solution.

[0068]

[0069] Table 6: Dissolution curves of norfloxacin capsules prepared in Example 2 in aqueous solution

[0070]

[0071] As can be seen from Examples 1-2, the present invention uses only starch as an excipient, the process is simple, and the prepared norfloxacin capsules not only meet the requirements for filler content, but also have stable dissolution (the RSD of the dissolution result at the first time point of 10 min is less than 20%; the RSD of the dissolution result from 10 min to 120 min is less than 10%), which is equivalent to the original drug and can effectively replace the original drug product.

[0072] Comparative Examples 1-3: Effect of Norfloxacin Particle Size

[0073] I. Prescription Composition: Norfloxacin used is shown in the table below, and the rest is the same as in Example 1.

[0074] Comparative Example Norfloxacin Comparative Example 1 Norfloxacin 3 Comparative Example 2 Norfloxacin 4 Comparative Example 3 Norfloxacin 5

[0075] II. Preparation method: Same as in Example 1.

[0076] III. Test Results:

[0077] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 7.

[0078] Table 7: Weight differences of norfloxacin capsules prepared in Comparative Examples 1-3

[0079] sample Weight difference in conclusion Comparative Example 1 -2.33％～2.48％ Compliant Comparative Example 2 -2.72％～2.15％ Compliant Comparative Example 3 -3.09％～3.14％ Compliant

[0080] 2. The dissolution curves of the prepared norfloxacin capsules were determined in water at pH 6.8, and the results are shown in Table 8-9.

[0081] Table 8: Dissolution curves of norfloxacin capsules prepared in Comparative Examples 1-3 in pH 6.8 buffer solution.

[0082]

[0083] Table 9: Dissolution curves of norfloxacin capsules prepared in aqueous solution in Comparative Examples 1-3

[0084]

[0085] Comparative analysis of Example 1 and Comparative Examples 1-3 revealed that the particle size of norfloxacin affects the dissolution of norfloxacin capsules; only norfloxacin within a specific particle size range (D...) can dissolve. 90 20-30μm, D 50 Norfloxacin capsules prepared with a particle size of 12-15 μm are equivalent to the original drug (similarity factor not less than 50) and exhibit stable dissolution (RSD of less than 20% for the first time point at 10 min; RSD of less than 10% for dissolution from 10 min to 120 min). When using norfloxacin with other particle sizes, the prepared norfloxacin capsules dissolve too quickly or too slowly, are not equivalent to the original drug (similarity factor less than 50), and exhibit unstable dissolution (RSD of more than 20% for the first time point at 10 min; RSD of more than 10% for the second time point at 20 min).

[0086] Comparative Examples 4-7: Effects of Starch Pretreatment on Auxiliary Materials

[0087] I. Prescription composition: Same as in Example 1.

[0088] II. Preparation method: Step (1) is shown in the table below, and steps (2)-(4) are the same as in Example 1.

[0089] Comparative Example Step (1) Comparative Example 4 Pass the starch through a 120-mesh sieve and set aside. Comparative Example 5 Place the starch in an oven at 42-45℃ and dry under reduced pressure for 5 hours. Then pass it through a 120-mesh sieve for later use. Comparative Example 6 Place the starch in an oven at 54-57℃ and dry under reduced pressure for 2 hours. Then pass it through a 120-mesh sieve and set aside. Comparative Example 7 Place the starch in an oven at 54-57℃ and dry under reduced pressure for 8 hours. Then pass it through a 120-mesh sieve for later use.

[0090] III. Test Results:

[0091] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 10.

[0092] Table 10: Weight variation of norfloxacin capsules prepared in Comparative Examples 4-7

[0093] sample Weight difference in conclusion Comparative Example 4 -12.36％～10.58％ Non-compliant Comparative Example 5 -10.12％～9.26％ Non-compliant Comparative Example 6 -7.31％～5.13％ Compliant Comparative Example 7 -5.65％～7.12％ Compliant

[0094] 2. The dissolution curves of the prepared norfloxacin capsules were determined in water at pH 6.8, and the results are shown in Table 11-12.

[0095] Table 11: Dissolution curves of norfloxacin capsules prepared in Comparative Examples 6-7 in pH 6.8 buffer solution.

[0096]

[0097] Table 12: Dissolution curves of norfloxacin capsules prepared in comparative examples 6-7 in aqueous solution

[0098]

[0099] Comparative analysis of Example 1 and Comparative Examples 4-7 revealed that the pretreatment of the excipient starch affected the fill weight variation and dissolution behavior of norfloxacin capsules. Only norfloxacin capsules prepared with excipient starch treated using a specific method (starch dried in an oven at 50-60℃ for 4-6 hours) were equivalent to the original drug (similarity factor not less than 50) and exhibited stable dissolution (RSD of dissolution results at the first time point of 10 min was less than 20%; RSD of dissolution results from 10 min to 120 min was less than 10%). When starch was not pretreated or was pretreated using other methods, the prepared norfloxacin capsules exhibited problems such as unacceptable fill weight variation or unstable dissolution (RSD of dissolution results at the first time point of 10 min was greater than 20%; RSD of dissolution results at the second time point of 20 min was greater than 10%), resulting in significant differences in product quality.

[0100] Comparative Examples 8-9: Effect of temperature on adhesive aqueous solution

[0101] I. Prescription composition: Same as in Example 1.

[0102] II. Preparation method: The temperature of the aqueous solution in step (2) is shown in the table below. The remaining steps are the same as in Example 1.

[0103] Comparative Example The temperature of the aqueous solution in step (2) Comparative Example 8 The water temperature is 20℃ Comparative Example 9 The water temperature is 40℃

[0104] III. Test Results:

[0105] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 13.

[0106] Table 13: Weight differences of norfloxacin capsules prepared in Comparative Examples 8-9

[0107] sample Weight difference in conclusion Comparative Example 8 -5.42％～6.59％ Compliant Comparative Example 9 -6.70％～4.16％ Compliant

[0108] 2. The dissolution curves of the prepared norfloxacin capsules were determined in water at pH 6.8, and the results are shown in Table 14-15.

[0109] Table 14: Dissolution curves of norfloxacin capsules prepared in Comparative Examples 8-9 in pH 6.8 buffer solution.

[0110]

[0111] Table 15: Dissolution curves of norfloxacin capsules prepared in comparative examples 8-9 in aqueous solution

[0112]

[0113] Comparative analysis of Example 1 and Comparative Examples 8-9 revealed that the temperature of the binder aqueous solution during wet granulation affects the dissolution behavior of norfloxacin capsules. Only norfloxacin capsules prepared using an aqueous solution at a specific temperature (32-35℃) as the binder were equivalent to the original drug (similarity factor not less than 50) and exhibited stable dissolution (RSD of dissolution results at the first time point of 10 min was less than 20%; RSD of dissolution results from 10 min to 120 min was less than 10%). When aqueous solutions at other temperatures were used as the binder, the dissolution of the prepared norfloxacin capsules was unstable (RSD of dissolution results at the first time point of 10 min was greater than 20%; RSD of dissolution results at the second time point of 20 min was greater than 10%), indicating significant differences in product quality.

[0114] Comparative Examples 10-14: Effects of premixing, spraying into aqueous solution, and granulation time

[0115] I. Prescription composition: Same as in Example 1.

[0116] II. Preparation method: The premixing, spraying into the aqueous solution, and granulation time in step (2) are shown in the table below. The remaining steps and parameters are the same as in the actual experiment.

[0117] Example 1

[0118]

[0119] III. Test Results:

[0120] 1. The weight difference of the prepared norfloxacin capsules was measured, and the results are shown in Table 16.

[0121] Table 16: Weight variation of norfloxacin capsules prepared in Comparative Examples 10-14

[0122] sample Weight difference in conclusion Comparative Example 10 -6.55％～5.37％ Compliant Comparative Example 11 -11.37％～9.80％ Non-compliant Comparative Example 12 -9.79％～12.12％ Non-compliant Comparative Example 13 -12.54％～10.16％ Non-compliant Comparative Example 14 -13.25％～11.41％ Non-compliant

[0123] 2. The dissolution curves of norfloxacin capsules prepared in Comparative Example 10 were determined in water at pH 6.8, and the results are shown in Tables 17-18.

[0124] Table 17: Dissolution curves of norfloxacin capsules prepared in Comparative Example 10 in pH 6.8 buffer solution.

[0125]

[0126] Table 18: Dissolution curves of norfloxacin capsules prepared in Comparative Example 10 in aqueous solution

[0127]

[0128] Comparative analysis of Example 1 and Comparative Examples 10-14 revealed that parameters such as premixing, aqueous solution spraying, and granulation time during wet granulation affected the fill weight variation and dissolution behavior of norfloxacin capsules. Only norfloxacin capsules prepared with specific premixing, aqueous solution spraying, and granulation times (premixing time 160-200s, aqueous solution spraying time 120-160s, granulation time 60-110s) were equivalent to the original drug (similarity factor not less than 50) and exhibited stable dissolution (RSD of dissolution results at the first time point of 10 min was less than 20%; RSD of dissolution results from 10 min to 120 min was less than 10%). When other ranges were used for premixing, aqueous solution spraying, and granulation time, the prepared norfloxacin capsules exhibited problems such as unqualified fill weight variation or unstable dissolution (RSD of dissolution results at the first time point of 10 min was greater than 20%; RSD of dissolution results at the second time point of 20 min was greater than 10%), resulting in significant differences in product quality.

[0129] Example 3: Stability Test

[0130] Norfloxacin capsules prepared in Examples 1-2 and Comparative Example 1 were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% (accelerated) for 6 months. Samples were taken at the end of the 6th month, and dissolution curves were determined in water at pH 6.8. The results are shown in Tables 19-20.

[0131] Table 19: Dissolution curves of norfloxacin capsules in pH 6.8 buffer solution after 6 months of accelerated dissolution in Examples 1-2 and Comparative Example 1

[0132]

[0133] Table 20: Dissolution curves of norfloxacin capsules in aqueous solution after 6 months of accelerated dissolution in Examples 1-2 and Comparative Example 1

[0134]

[0135] The norfloxacin capsules prepared in Examples 1 and 2 of this invention showed no significant change in dissolution behavior after being placed under accelerated conditions for 6 months, indicating that the norfloxacin capsules prepared in this invention have stable dissolution.

[0136] The norfloxacin capsule composition prepared in Comparative Example 1 showed unstable dissolution after being placed for 6 months with accelerated storage.

Claims

1. A method for preparing norfloxacin capsules, wherein the capsule contents, by weight percentage, are 35%-45% norfloxacin and 55%-65% starch; the preparation method includes the following steps: (1) Pretreatment of auxiliary materials; Place the starch in a 50-60℃ oven and dry it under reduced pressure for 4-6 hours. Then, pass it through a 120-mesh sieve and set it aside. (2) Premixing and wet granulation: Norfloxacin and starch are added to a wet granulation machine for stirring and premixing. Then, under stirring conditions, binder water is sprayed in for wet granulation. The water spraying speed is controlled to ensure uniform spraying of the aqueous solution. The spraying process lasts for 120-160 seconds, and the granulation time after spraying is 60-110 seconds. (3) Drying and granulation: Dry at 55-65℃, and the loss on drying should not exceed 1.2%; the dried granules are then added to a granulator with a 2.0mm mesh size. (4) Filling: Fill the granules into capsules; In step (2), the particle size D of norfloxacin 90 20-30μm, D 50 The particle size is 12-15 μm; the aqueous solution is added at a temperature of 32-35℃; the parameters for premixing, spraying the binder solution, and granulation are as follows: 。 2. The preparation method according to claim 1, characterized in that, The capsule contents consist of 38%-42% norfloxacin and 58%-62% starch.

3. The preparation method according to claim 1, characterized in that, The capsule contents consist of 40% norfloxacin and 60% starch.

4. The preparation method according to claim 1, characterized in that, In step (1), the product is dried under reduced pressure at 54-57℃.

5. The preparation method according to claim 1, characterized in that, In step (4), each capsule contains 0.1g of norfloxacin.

6. The preparation method according to claim 1, characterized in that, In step (4), the contents of each capsule weigh 0.25g.

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