Preparation process of anti-top-cracking and anti-sticking tamoxifen citrate tablet

Abstract

The invention relates to a preparation process of anti-top-cracking and anti-sticking tamoxifen citrate tablets, and belongs to the technical field of pharmaceutical preparations. The tamoxifen citrate tablet comprises the following components in percentage by weight: 8%-9% of tamoxifen citrate, 85%-88% of a diluent, 1%-3% of a disintegrating agent, 1%-2% of a lubricant, 1%-2% of an adhesive and the balance of coating powder. According to the preparation process, raw material medicines are treated by adopting air jet pulverization, one-step granulation is performed through a fluidized bed, cross-linking sodium carboxymethyl cellulose and magnesium stearate are mixed step by step, and tabletting parameters are optimized, so that the problems of sticking, top cracking, insufficient lubrication and poor dissolution behavior in a traditional process are effectively solved; the quality, the production efficiency and the stability of the tablet are remarkably improved, the rapid dissolution and the effective absorption of the medicine are ensured, and a new solution thought is provided for the preparation of the tamoxifen citrate tablet.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a preparation process of anti-capping and anti-sticking tamoxifen citrate tablets. Background Art

[0002] Tamoxifen citrate is a commonly used anti-tumor drug widely used in the treatment of breast cancer. However, its API suffers from poor compressibility, which makes it difficult for the particles to bind tightly during tableting, thus affecting the hardness and stability of the tablets. Traditionally, high-shear wet granulation has been widely used in the preparation of oral solid dosage forms. However, this process has certain drawbacks when dealing with APIs with poor compressibility, such as tamoxifen citrate. During tableting, due to the poor compressibility of the API and the limitations of traditional processes, granule sticking and capping are common. Sticking not only affects the appearance quality of the tablets, but can also lead to excessive tablet weight variation, thereby affecting the accuracy of the drug dosage. Capping can easily cause tablets to break during storage or transportation, reducing the product's qualified rate.

[0003] Magnesium stearate, a commonly used lubricant, plays a crucial role in tablet preparation. However, insufficient dosage can lead to poor lubrication and increase the risk of sticking, while excessive dosage can affect drug dissolution and release characteristics. Therefore, precisely controlling the dosage of magnesium stearate to ensure tablet quality and stability is a major challenge facing traditional processes.

[0004] Furthermore, excessive API particle size is a key factor influencing dissolution behavior. Excessive particle size can slow drug release in the body, thereby impacting drug efficacy. Therefore, effectively controlling API particle size to ensure rapid dissolution and effective drug absorption is a crucial issue that needs to be addressed in the formulation process.

[0005] Therefore, it is urgent to develop a preparation process for anti-capping and anti-sticking tamoxifen citrate tablets to ensure the quality and stability of the tablets and improve the efficacy of the drug. Summary of the Invention

[0006] The object of the present invention is to provide a preparation process for anti-capping and anti-sticking tamoxifen citrate tablets, which solves the problem of tablet capping by increasing the compressibility of the material through a one-step granulation process.

[0007] The purpose of the present invention can be achieved through the following technical solutions:

[0008] Disclosed are anti-capping and anti-sticking tamoxifen citrate tablets, which comprise the following ingredients, calculated by weight: 8% to 9% of tamoxifen citrate, 85% to 88% of a diluent, 1% to 3% of a disintegrant, 1% to 2% of a lubricant, 1% to 2% of a binder, and the remainder being a coating powder.

[0009] As a preferred technical solution of the present invention, the diluent is lactose, corn starch or a combination thereof.

[0010] As a preferred technical solution of the present invention, the adhesive is gelatin.

[0011] As a preferred technical solution of the present invention, the disintegrant is cross-linked sodium carboxymethylcellulose.

[0012] As a preferred technical solution of the present invention, the lubricant is magnesium stearate.

[0013] As a preferred technical solution of the present invention, the coating powder is a mixed powder of hypromellose 2910, polyethylene glycol 300 and titanium dioxide.

[0014] A preparation process for anti-capping and anti-sticking tamoxifen citrate tablets, the specific steps of the preparation process are as follows:

[0015] The raw materials were subjected to air flow pulverization according to the ratio, and then granulated using a fluidized bed. Cross-linked sodium carboxymethyl cellulose was added for mixing at a mixing speed of 10 rpm and a mixing time of 10 minutes. Magnesium stearate was then added for mixing at a mixing speed of 10 rpm and a mixing time of 5 minutes. Finally, tableting and coating were performed to obtain the anti-capping and anti-sticking tamoxifen citrate tablets.

[0016] As a preferred technical solution of the present invention, the air flow pulverization process controls the particle size of the raw material to be within the range of D90≤24μm.

[0017] As a preferred technical solution of the present invention, the frequency of the fan in the premixing and preheating step of granulation in the fluidized bed is 15 Hz, the inlet air temperature is set at 65°C, and the liquid spraying is started after the material temperature reaches 40°C. The premixing and preheating are performed for 5 to 10 minutes. The inlet air frequency of the liquid spraying step is 17 Hz, the actual inlet air temperature is 62.1 to 70.6°C, the atomization pressure is 0.1 MPa, the liquid supply rate is 12.5 mL / min, the liquid spraying time is 37 minutes, the fan frequency of the drying step is 15 to 17 Hz, the inlet air temperature is 65°C, and the particles are discharged after the moisture content is ≤3.0%.

[0018] As a preferred technical solution of the present invention, the tableting hardness is 3 to 7 kg.

[0019] The present invention significantly enhances the binding force between particles by optimizing the formulation composition and combining the fluidized bed one-step granulation process. The premixing and preheating and precise spray drying steps in the fluidized bed granulation process ensure that the particles reach a suitable humidity and temperature before tableting, further reducing the sticking phenomenon and improving the tableting quality. The present invention adopts a step-by-step mixing method, first adding cross-linked carboxymethyl cellulose sodium for mixing, and then adding magnesium stearate, which helps to ensure the uniform distribution of magnesium stearate in the particles and avoid local excess or deficiency. By accurately controlling the mixing speed and time, the present invention can ensure that the amount of magnesium stearate is within the optimal range, ensuring the lubrication effect while avoiding adverse effects on drug dissolution and release characteristics.

[0020] The present invention uses airflow milling to process the API, effectively controlling the API particle size within the range of D90 ≤ 24 μm. This particle size range helps increase the API's surface area, speeding up its dissolution rate and improving its dissolution behavior. Optimized particle size control also helps ensure rapid release and effective absorption of the drug in the body, improving its bioavailability.

[0021] The fluidized bed one-step granulation process integrates mixing, granulation, and drying into a single device, simplifying the production process and improving efficiency. This process also produces granules with uniform particle size and excellent flowability, facilitating subsequent tableting and coating processes, thereby improving overall product quality.

[0022] The coating powder used in this invention is a mixed powder of hypromellose 2910, polyethylene glycol 300, and titanium dioxide. This coating formula has excellent film-forming and light-shielding properties, effectively protecting the tablets from external environmental influences such as light and humidity, thereby improving tablet stability. The coating layer also improves the tablet's appearance, making it smoother and more aesthetically pleasing, enhancing the user experience.

[0023] By precisely controlling the tablet hardness within the range of 3 to 7 kg, the present invention ensures that the tablets are not easily broken during storage and transportation, while also ensuring that the drug release rate in the body meets the expected rate. Furthermore, the appropriate tablet hardness helps reduce tablet capping during the tableting process, thereby improving the product qualification rate.

[0024] Beneficial effects of the present invention:

[0025] The invention significantly enhances particle binding force, reduces sticking, and improves tableting quality by optimizing the prescription and fluidized bed granulation process; adopts step-by-step mixing to ensure uniform distribution of magnesium stearate and accurately controls the amount of magnesium stearate, thereby ensuring lubrication effect and avoiding affecting drug dissolution; air flow milling controls the particle size of the raw material drug and improves the dissolution rate; and accurately controls the tableting hardness, ensures tablet stability and drug release rate, and improves the product qualification rate. DETAILED DESCRIPTION

[0026] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined purpose of the invention, the specific implementation methods, structures, features and effects of the present invention are described in detail below in combination with the embodiments.

[0027] Example 1

[0028] Preparation of tamoxifen citrate tablets by one-step granulation

[0029] The prescription of the tamoxifen citrate tablets is:

[0030]

[0031] The preparation process of the tamoxifen citrate tablets is as follows:

[0032]

[0033] The relevant data of the tamoxifen citrate tablets prepared by the above prescription and preparation process were measured, and the test results are summarized in the following table.

[0034]

[0035]

[0036] The above experimental data show that the present invention optimizes the process parameters to make the one-step granulation process, tableting, and coating process smooth, and has good process feasibility.

[0037] Example 2

[0038] Preparation of tamoxifen citrate tablets by high shear wet granulation

[0039] The prescription of the tamoxifen citrate tablets is:

[0040]

[0041]

[0042] The preparation process of the tamoxifen citrate tablets is as follows:

[0043]

[0044] The relevant data of the tamoxifen citrate tablets prepared by the above prescription and preparation process were measured, and the experimental results are shown in the following table.

[0045]

[0046]

[0047] The above experimental data show that the granulation process using the wet high shear granulation process is smooth, but the granules have poor compressibility and unqualified friability, and cannot be compressed into tablets normally.

[0048] Example 3

[0049] Effect of different addition ratios of magnesium stearate

[0050] To address the sticking issue that occurs during tableting after wet high-shear granulation, which occurs at the deepest point of the shallow concave punch, the magnesium stearate dosage in the formulation was increased to reduce the risk of sticking. Granulates from batch 2021090801 were mixed with 1%, 1.5%, and 2% magnesium stearate, respectively. The mixtures were then compressed and coated, and the dissolution profiles were compared.

[0051] (1) Tablet compression comparison

[0052]

[0053] (2) Characterization

[0054] batch number 2021090801 2021111101 2021090801-02 Average tablet weight mg 182 183 189 Average thickness (mm) 3.41 3.35 3.59 Average hardness kg 6.02 4.10 3.00 Disintegration time (24 mesh) 2m50s~3m44s 2m29s-2m53s There are small particles at 5m, 7m

[0055] The above characterization data show that as the amount of magnesium stearate increases, the compressibility decreases and the disintegration time increases.

[0056] (3) Dissolution curve

[0057]

[0058]

[0059] (4) Conclusion

[0060] The above data show that increasing the magnesium stearate dosage improves sticking, but excessive dosage can significantly affect compressibility and dissolution profiles. Increasing magnesium stearate dosage slows tablet dissolution. Therefore, using a 1.5% magnesium stearate dosage to prepare the formulation effectively avoids sticking while maintaining compressibility and dissolution.

[0061] Example 4

[0062] Effect of API Particle Size

[0063] The prescription of the tamoxifen citrate tablets is:

[0064]

[0065] The preparation process of the tamoxifen citrate tablets is as follows:

[0066]

[0067]

[0068] Different API particle size ranges were studied, and the dissolution data in 0.02 mol / L hydrochloric acid solution (100 rpm) are summarized in the following table.

[0069]

[0070] From the above experimental data, we can see that using D 90 The preparation process of the API samples with a particle size range of 3.454-24.406 μm was smooth, with no sticking or capping. The tablets dissolve more than 85% in 0.02 mol / L hydrochloric acid solution at 15 min, indicating rapid dissolution. The dissolution behavior was similar to that of the reference preparation. Therefore, the API particle size was set to D 90 The best effect is ≤24μm.

[0071] Example 5

[0072] Effect of tablet hardness

[0073] A scale-up study was conducted in the workshop to test the effects of the tableting parameters of the workshop's high-speed tablet press on the finished product of tamoxifen citrate tablets. The specific parameter settings and related experimental data are summarized in the following table.

[0074]

[0075] The above experimental data show that tablets can be pressed smoothly when the average hardness is 3 to 7 kg, and the weight difference and friability are both qualified, and the plain tablets disintegrate within 5 minutes.

[0076] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to equivalent embodiments using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A tamoxifen citrate tablet that is anti-cracking and anti-sticking, characterized in that: The anti-capping and anti-sticking tamoxifen citrate tablets include the following ingredients, calculated by weight percentage: 8% to 9% of tamoxifen citrate, 85% to 88% of a diluent, 1% to 3% of a disintegrant, 1% to 2% of a lubricant, 1% to 2% of a binder, and the remainder being a coating powder.

2. The anti-capping and anti-sticking tamoxifen citrate tablet according to claim 1, wherein: The diluent is lactose, corn starch or a combination thereof.

3. The anti-capping and anti-sticking tamoxifen citrate tablet according to claim 1, characterized in that: The binder is gelatin.

4. The anti-capping and anti-sticking tamoxifen citrate tablet according to claim 1, characterized in that: The disintegrant is croscarmellose sodium.

5. The anti-capping and anti-sticking tamoxifen citrate tablet according to claim 1, characterized in that: The lubricant is magnesium stearate.

6. The anti-capping and anti-sticking tamoxifen citrate tablet according to claim 1, characterized in that: The coating powder is a mixed powder of hypromellose 2910, polyethylene glycol 300 and titanium dioxide.

7. A process for preparing the anti-capping and anti-sticking tamoxifen citrate tablets according to any one of claims 1 to 6, characterized in that: The specific steps of the preparation process are as follows: The raw materials were subjected to air flow pulverization according to the ratio, and then granulated using a fluidized bed. Cross-linked sodium carboxymethyl cellulose was added for mixing at a mixing speed of 10 rpm and a mixing time of 10 minutes. Magnesium stearate was then added for mixing at a mixing speed of 10 rpm and a mixing time of 5 minutes. Finally, tableting and coating were performed to obtain the anti-capping and anti-sticking tamoxifen citrate tablets.

8. The process for preparing the anti-capping and anti-sticking tamoxifen citrate tablet according to claim 7, wherein: The air flow pulverization process controls the particle size of the raw materials to be within the range of D90≤24μm.

9. The process for preparing a tamoxifen citrate tablet having anti-capping and anti-sticking properties according to claim 7, wherein: The fan frequency of the premixing and preheating step in the fluidized bed granulation is 15 Hz, the inlet air temperature is set at 65°C, and the spraying is started after the material temperature reaches 40°C. The premixing and preheating are performed for 5 to 10 minutes. The inlet air frequency of the spraying step is 17 Hz, the actual inlet air temperature is 62.1 to 70.6°C, the atomization pressure is 0.1 MPa, the liquid supply rate is 12.5 mL / min, and the spraying time is 37 minutes. The fan frequency of the drying step is 15 to 17 Hz, the inlet air temperature is 65°C, and the granules are discharged after the moisture content is ≤3.0%.

10. The process for preparing a tamoxifen citrate tablet with anti-capping and anti-sticking properties according to claim 7, wherein: The tableting hardness is 3-7 kg.

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