Preparation method of high-purity nicardipine hydrochloride tablet

Abstract

The invention provides a preparation method of a high-purity nicardipine hydrochloride tablet, which specifically comprises the following steps: crushing a nicardipine hydrochloride raw material, adding the crushed nicardipine hydrochloride raw material, a disintegrating agent 1, a filling agent and an adhesive into a fluidized bed, adding dextrin slurry for boiling granulation, adding a lubricating agent and a disintegrating agent 2 after granulation is finished, and carrying out size stabilization, mixing and tabletting to obtain the high-purity nicardipine hydrochloride tablet. According to the invention, the process design of internally adding the disintegrating agent 1 and externally adding the disintegrating agent 2 is combined with the specific filler and adhesive, so that the production process is simplified, the stable effect that the disintegration time limit of the tablet core is less than or equal to 7 minutes is realized, the production complexity is reduced, and the conventional coating process is avoided. By designing process parameters matched with the formula, the problems of purity reduction and the like caused by excessive heating or non-uniform mixing of materials in the granulating process are effectively avoided, and the remarkable effect that the product purity is 99.94% or above is achieved. Moreover, the dextrin slurry is prepared by taking purified water as a solvent, the hidden danger of organic solvent residue is avoided, and the process flow is safe and environment-friendly.

Description

Technical Field

[0001] This invention belongs to the field of nicardipine hydrochloride tablet technology, specifically relating to a method for preparing high-purity nicardipine hydrochloride tablets. Background Technology

[0002] Nicardipine hydrochloride, a commonly used calcium channel blocker, is widely used to treat cardiovascular diseases such as hypertension and angina pectoris. Currently, nicardipine hydrochloride is mostly available in injection or oral solution dosage forms, while tablet products and their preparation methods face several limitations: some tablet manufacturing processes rely on complex coating procedures to ensure stability, which not only increases production processes and costs but also affects drug dissolution efficiency; some process parameters are incompatible with excipients, or the addition of key components such as disintegrants is limited, resulting in poor dissolution and insufficient stability of the prepared nicardipine hydrochloride tablets, thus affecting bioavailability; furthermore, some manufacturing processes use organic solvents as solvents, which not only causes environmental pollution and increases subsequent recycling costs but also poses a risk of organic solvent residue, affecting product quality.

[0003] In summary, in order to overcome the shortcomings of existing nicardipine hydrochloride tablet products and preparation processes, it is of great practical significance to develop a simple, environmentally friendly preparation method for nicardipine hydrochloride tablets that can simultaneously achieve high purity, high stability, and rapid disintegration. This is also a technical problem that urgently needs to be solved by those skilled in the art.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing nicardipine hydrochloride tablets. In this invention, the raw material is nicardipine hydrochloride, and the excipients are only dextrin slurry, fillers, binders, lubricants, and disintegrants, resulting in a simplified and low-cost formulation. By combining internally added disintegrant 1 and externally added disintegrant 2 with specific fillers and binders, the production process is simplified while achieving a stable tablet core disintegration time of ≤7 minutes. This reduces production complexity and avoids conventional coating processes. By designing process parameters compatible with the formulation, problems such as decreased purity due to overheating or uneven mixing during granulation are effectively avoided, achieving a product purity of over 99.94%. Furthermore, this invention uses purified water as a solvent to prepare the dextrin slurry, eliminating the risk of organic solvent residue and ensuring a safe and environmentally friendly process.

[0006] To achieve the above objectives, the present invention provides a method for preparing nicardipine hydrochloride tablets and a method for preparing the same, comprising the following steps:

[0007] (1) After crushing the nicardipine hydrochloride raw material, add it together with disintegrant 1, filler and binder into the boiling pot, set the fan frequency to 30-50Hz, mix at room temperature for 5-15 minutes;

[0008] Turn on the heating. When the material temperature reaches 30-50℃, set the following settings to maintain the atomization pressure of 0.20-0.35MPa and the peristaltic pump speed of 30-120rpm throughout the production process: spray in the dextrin slurry for granulation and drying, then pull out the material chamber.

[0009] (2) Add disintegrant 2 and lubricant to the material chamber and granulate using a V-type screen at a frequency of 8-12Hz;

[0010] (3) After mixing the granules, compress them into tablets to obtain high-purity nicardipine hydrochloride tablets.

[0011] In a preferred embodiment, in step (1), the particle size of the nicardipine hydrochloride raw material after pulverization is below 200 micrometers.

[0012] In a preferred embodiment, in step (1), the disintegrant 1 includes at least one of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, and sodium carboxymethyl starch.

[0013] In a preferred embodiment, in step (1), the filler includes at least one of mannitol, corn starch, microcrystalline cellulose, lactose, and pregelatinized starch.

[0014] In a preferred embodiment, in step (1), the adhesive includes at least one of dextrin, hydroxypropyl methylcellulose, corn starch, and pregelatinized starch.

[0015] In a preferred embodiment, in step (1), the mass ratio of the disintegrant 1, nicardipine hydrochloride, filler, binder and dextrin slurry is (20-40): (9.5-12): (15-16.2): ​​(10-12): (45-55).

[0016] In a preferred embodiment, in step (1), the dextrin slurry is prepared by mixing dextrin and purified water and stirring until homogeneous; preferably, the temperature of the purified water is 80-200℃, and the mass ratio of the purified water to dextrin is (8-10):1.

[0017] In a preferred embodiment, in step (2), the disintegrant 2 includes at least one of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, silica, and cross-linked sodium carboxymethyl cellulose.

[0018] In a preferred embodiment, in step (2), the lubricant includes at least one of magnesium stearate, stearic acid, and polyethylene glycol.

[0019] In a preferred embodiment, in step (2), the mass ratio of the disintegrant 2, the lubricant and the nicardipine hydrochloride in step (1) is (4-6):(0.1-1):(9.5-12).

[0020] In a preferred embodiment, in step (2), the aperture of the V-shaped screen is 1.0-2.0 mm.

[0021] In a preferred embodiment, in step (3), the mixing speed is 6-12 rpm and the mixing time is 10-30 min.

[0022] In a preferred embodiment, in step (3), the tableting mold is a 5.5mm shallow concave die.

[0023] In a preferred embodiment, in step (3), the tablet core hardness of the prepared nicardipine hydrochloride tablet is 3.0-8.0 kg, the disintegration time is ≤7 min, the weight difference is ±2.1%, and the product purity is ≥99.94%.

[0024] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0025] 1. In terms of the formulation design of this invention, the raw material is nicardipine hydrochloride, and the excipients are only dextrin slurry, filler, binder, lubricant, and disintegrants 1 and 2. The formulation is simple and low-cost. Disintegrant 1 is selected from at least one of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, and sodium carboxymethyl starch. All designed components have good hydrophilicity and swelling properties, forming a loose structure inside the particles, providing the basic driving force for subsequent disintegration. Disintegrant 2 is selected from at least one of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, silica, and crospovidone carboxymethyl cellulose. These components have highly efficient disintegration characteristics, accelerating tablet dispersion outside the particles and forming a synergistic effect with disintegrant 1. The filler is selected from components with good flowability and compressibility, such as microcrystalline cellulose and lactose, ensuring tableting effect. The lubricant is selected from common pharmaceutical components such as magnesium stearate and talc, which can reduce inter-particle friction and improve tableting smoothness.

[0026] 2. Regarding the preparation method, this invention obtains nicardipine hydrochloride powder with a particle size of less than 200 micrometers by pulverizing raw materials, increasing the contact area between the drug and the dissolution medium and providing a basis for rapid dissolution. Through the process design of adding internal disintegrant 1 and external disintegrant 2, combined with specific fillers and binders, disintegrant 1 is uniformly dispersed inside the particles during the boiling granulation process. After contact with water, it quickly absorbs water and swells, forming pores and cracks inside the particles and destroying the integrity of the particle structure. Disintegrant 2 is dispersed outside the particles during the total mixing stage. After contact with water, it quickly swells and generates mechanical force, accelerating the overall dispersion of the tablets and synergistically improving disintegration efficiency and dissolution uniformity. Thus, a stable effect of tablet core disintegration time ≤7min can be achieved without relying on the coating process. By designing process parameters that are compatible with the formulation, problems such as decreased purity caused by excessive heating or uneven mixing of materials during granulation are effectively avoided. By using purified water as a solvent to prepare dextrin slurry, the interaction between organic solvents and drugs is avoided, reducing the generation of impurities and lowering the risk of solvent residue.

[0027] 3. This invention improves product purity and disintegration effect through formula design and process optimization. The resulting product has a purity of over 99.94%, a single impurity content of less than 0.02%, a disintegration time of ≤7min, a weight difference of ±2.1%, and stable and reliable product quality. Moreover, the process is simple, safe and environmentally friendly, and is especially suitable for large-scale industrial production. Detailed Implementation

[0028] To enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below with reference to specific embodiments. However, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0029] This invention provides a method for preparing high-purity nicardipine hydrochloride tablets, which solves the problems of complex preparation methods, low production efficiency, and poor quality of nicardipine hydrochloride tablets in the prior art.

[0030] Unless otherwise specified, the technical means used in this invention are conventional means well known to those skilled in the art. All raw materials, reagents, instruments, and equipment used in this invention can be purchased commercially or prepared using existing methods. Unless otherwise specified, all reagents used in this invention are of analytical grade.

[0031] In this invention, the weight parts can be weight units known in the art such as µg, mg, g, kg, or multiples thereof, such as 1 / 10, 1 / 100, 10 times, 100 times, etc.

[0032] Example 1: Preparation of Nicardipine Hydrochloride Tablets

[0033] (1) Add 50g of dextrin to 450g of purified water and stir for 20min to obtain dextrin slurry.

[0034] (2) 110g of nicardipine hydrochloride raw material was crushed using a pulverizer, and the particle size after crushing was 50 micrometers. 270g of pregelatinized starch (disintegrant 1), the crushed material, 150g of microcrystalline cellulose (filler), and 111g of dextrin (binder) were added to the boiling pot. Then the fan frequency was set to 30-50Hz, and the mixture was boiled and mixed for 10 minutes without heating. Then the heating was turned on. When the material temperature reached 45℃, the atomization pressure was set to 0.3MPa and the peristaltic pump speed was set to 70rpm. The dextrin slurry prepared in step (1) was sprayed for granulation. After spraying, it was dried. After drying, it was dropped into the pot and pulled out of the material chamber.

[0035] (3) Add 30g sodium carboxymethyl starch (disintegrant 2), 23g silica (disintegrant 2), and 7g magnesium stearate (lubricant) to the material chamber. Use a 1.0mm V-shaped sieve for granulation at a frequency of 9Hz. Mix the granulated particles at a speed of 9rpm for 20min. Use a 5.5mm shallow concave die to compress the mixed particles into tablets. The tablet core hardness should be 3.0-8.0kg, the disintegration time should be less than or equal to 15min, and the weight difference should be ±3.0%.

[0036] Example 2: Preparation of Nicardipine Hydrochloride Tablets

[0037] (1) Add 50g of dextrin to 450g of purified water and stir for 20min to obtain dextrin slurry.

[0038] (2) 110g of nicardipine hydrochloride raw material was crushed using a pulverizer, and the particle size after crushing was 55 micrometers. 270g of pregelatinized starch (disintegrant 1), the crushed material, 150g of lactose (filler), and 111g of corn starch (binder) were added to the boiling pot. Then the fan frequency was set to 30-50Hz, the air inlet temperature was not more than 80℃, and the mixture was boiled and mixed for 10 minutes without heating. Then the heating was turned on. When the material temperature reached 30-50℃, the atomization pressure was set to 0.20MPa and the peristaltic pump speed was set to 70rpm. The dextrin slurry prepared in step (1) was sprayed for granulation. After spraying, it was dried. After drying, it was dropped into the pot and pulled out of the material chamber.

[0039] (3) Add 30g sodium carboxymethyl starch (disintegrant 2), 23g silica (disintegrant 2), and 7g magnesium stearate (lubricant) to the material chamber. Use a 1.0mm V-shaped sieve for granulation at a frequency of 8-12Hz. Mix the granulated particles at a speed of 9rpm for 20min. Use a 5.5mm shallow concave die to compress the mixed particles into tablets. The tablet core hardness should be 3.0-8.0kg, the disintegration time should be less than or equal to 15min, and the weight difference should be ±3.0%.

[0040] Example 3: Preparation of Nicardipine Hydrochloride Tablets

[0041] (1) Add 50g of dextrin to 450g of purified water and stir for 20min to obtain dextrin slurry.

[0042] (2) Nicardipine hydrochloride raw material 110 was crushed using a pulverizer, and the particle size after crushing was 43 micrometers. 270g of pregelatinized starch (disintegrant 1), crushed material, 150g of microcrystalline cellulose (filler), and 111g of dextrin (binder) were added to the boiling pot. Then the fan frequency was set to 45Hz and the air inlet temperature was not more than 80℃. The mixture was boiled and mixed for 10 minutes without heating. Then the heating was turned on. When the material temperature reached 45℃, the atomization pressure was set to 0.30MPa and the peristaltic pump speed was set to 75rpm. The dextrin slurry prepared in step (1) was sprayed for granulation. After spraying, it was dried. After drying, it was dropped into the pot and pulled out of the material chamber.

[0043] (3) Add 53g sodium carboxymethyl starch (disintegrant 2) and 7g magnesium stearate (lubricant) to the material chamber, and granulate using a 1.0mm V-shaped sieve at a granulation frequency of 11Hz. Mix the granulated particles at a mixing speed of 9rpm for 20min. Compress the mixed particles into tablets using a 5.5mm shallow concave die, requiring a core hardness of 3.0-8.0kg, a disintegration time of less than or equal to 15min, and a weight difference of ±3.0%.

[0044] Example 4: Preparation of Nicardipine Hydrochloride Tablets

[0045] (1) Add 50g of dextrin to 450g of purified water and stir for 20min to obtain dextrin slurry.

[0046] (2) 110g of nicardipine hydrochloride raw material was crushed using a pulverizer, and the particle size after crushing was 60 micrometers. 265g of corn starch (disintegrant 1), the crushed material, 155g of lactose (filler), and 111g of dextrin (binder) were added to the boiling pot. Then the fan frequency was set to 30-50Hz, the air inlet temperature was not more than 80℃, and the mixture was boiled and mixed for 10 minutes without heating. Then the heating was turned on. When the material temperature reached 30-50℃, the atomization pressure was set to 0.30MPa and the peristaltic pump speed was set to 75rpm. The dextrin slurry prepared in step (1) was sprayed for granulation. After spraying, it was dried. After drying, it was dropped into the pot and pulled out of the material chamber.

[0047] (3) Add 30g sodium carboxymethyl starch (disintegrant 2), 23g silica (disintegrant 2), and 7g magnesium stearate (lubricant) to the material chamber. Use a 1.0mm V-shaped sieve for granulation at a frequency of 8-12Hz. Mix the granulated particles at a speed of 9rpm for 20min. Use a 5.5mm shallow concave die to compress the mixed particles into tablets. The tablet core hardness should be 3.0-8.0kg, the disintegration time should be less than or equal to 15min, and the weight difference should be ±3.0%.

[0048] Example of effect

[0049] The nicardipine hydrochloride tablets of this invention underwent identification and other tests, and the results are as follows:

[0050] I. Identification

[0051] (1) Take an appropriate amount of the fine powder of this product (20 mg of nicardipine hydrochloride), add 8 ml of methanol to dissolve the nicardipine hydrochloride, filter, and divide the filtrate into two portions. Add a few drops of chromium ammonium thiocyanate test solution to one portion, and a pink precipitate will be formed. The other portion of the solution should show the identification reaction of chloride.

[0052] (2) In the chromatogram under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

[0053] (3) Take 1 ml of the test solution under the content determination section, add methanol to 5 ml, and determine by ultraviolet-visible spectrophotometry. The maximum absorption is at a wavelength of 236 nm and the minimum absorption is at a wavelength of 219 nm. The specific test results are shown in Table 1.

[0054] Table 1

[0055]

[0056] II. Related Substances

[0057] Test method: Refer to the requirements of the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 2.

[0058] Table 2

[0059]

[0060] III. Weight Difference

[0061] Test method: Take 20 tablets of the test sample, accurately weigh the total weight, calculate the average tablet weight, and then accurately weigh each tablet separately. Compare the weight of each tablet with the average tablet weight (for tablets without content determination or for traditional Chinese medicine tablets with labeled tablet weight, the weight of each tablet should be compared with the labeled tablet weight). The test results are shown in Table 2.

[0062] Table 3

[0063]

[0064] IV. Disintegration Time Limit

[0065] Test method: Refer to the requirements of the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 4.

[0066] Table 4

[0067]

[0068] V. Microbial Limits

[0069] Test method: Refer to the requirements of the 2020 edition of the Chinese Pharmacopoeia. The test results are shown in Table 5.

[0070] Table 5

[0071]

[0072] VI. Conclusion

[0073] Examples 1-4 show that the substances are homogeneous and stable, with rapid disintegration time, stable components, and small weight differences, indicating that the nicardipine hydrochloride tablets prepared by the technical solution of the present invention have excellent drug dissolution performance.

[0074] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing nicardipine hydrochloride tablets, characterized in that, Includes the following steps: (1) After crushing the nicardipine hydrochloride raw material, add it together with disintegrant 1, filler and binder into the boiling pot, set the fan frequency to 30-50Hz, mix at room temperature for 5-15 minutes; Turn on the heating. When the material temperature reaches 30-50℃, set the following settings to maintain the atomization pressure of 0.20-0.35MPa and the peristaltic pump speed of 30-120rpm throughout the production process: spray in the dextrin slurry for granulation and drying, then pull out the material chamber. (2) Add disintegrant 2 and lubricant to the material chamber and granulate using a V-type screen at a frequency of 8-12Hz; (3) After mixing the granules, compress them into tablets to obtain high-purity nicardipine hydrochloride tablets.

2. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (1), the particle size of the nicardipine hydrochloride raw material after pulverization is below 200 micrometers.

3. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (1), the disintegrant 1 includes at least one of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, and sodium carboxymethyl starch.

4. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (1), the disintegrant 1 includes at least one of corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, and sodium carboxymethyl starch; The filler includes at least one of mannitol, corn starch, microcrystalline cellulose, lactose, and pregelatinized starch; The adhesive includes at least one of dextrin, hydroxypropyl methylcellulose, corn starch, and pregelatinized starch.

5. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (1), the mass ratio of the disintegrant 1, nicardipine hydrochloride, filler, binder and dextrin slurry is (20-40): (9.5-12): (15-16.2): ​​(10-12): (45-55).

6. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (1), the dextrin slurry is prepared by mixing dextrin and purified water and stirring until homogeneous.

7. The method for preparing nicardipine hydrochloride tablets as described in claim 6, characterized in that, The purified water temperature is 80-200℃, and the mass ratio of purified water to dextrin is (8-10):

1.

8. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (2), the disintegrant 2 includes at least one of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, silica, and croscarmellose sodium; The lubricant includes at least one of magnesium stearate, stearic acid, and polyethylene glycol.

9. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (2), the mass ratio of the disintegrant 2, the lubricant and the nicardipine hydrochloride in step (1) is (4-6):(0.1-1):(9.5-12).

10. The method for preparing nicardipine hydrochloride tablets as described in claim 1, characterized in that, In step (3), the tablet core hardness of the prepared nicardipine hydrochloride tablets is 3.0-8.0 kg, the disintegration time is ≤7 min, the weight difference is ±2.1%, and the product purity is ≥99.94%.

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