Preparation method of Aziminib hydrochloride tablet

Abstract

The invention discloses a preparation method of an Azimine hydrochloride tablet, and belongs to the technical field of medicines, the specific preparation method comprises the following steps: mixing Azimine hydrochloride, mannitol, microcrystalline cellulose, polyvinylpolypyrrolidone and fumaric acid at a low speed to obtain premixed dry powder; adding the premixed dry powder into a double-screw hot-melt extruder, adding the standby glyceryl behenate at the same time, extruding to obtain an extrudate, cooling the extrudate, and cutting the extrudate into columnar particles through a screen; transferring the particles into a fluidized bed for cold air curing to obtain cured particles; mechanically finishing the cured particles through a screen, adding colloidal silicon dioxide and magnesium stearate into the cured particles, and mixing to obtain particles to be pressed; and tabletting the to-be-pressed particles by using a rotary tablet press to finally obtain the Azimine hydrochloride tablet. Through an anhydrous melting granulation process and a specific auxiliary material system, the stability, the dissolution performance and the mechanical strength of the medicine are remarkably improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of acsimini hydrochloride tablets. BACKGROUND

[0002] Axicimini hydrochloride is a key tyrosine kinase inhibitor for treating chronic myeloid leukemia (CML). The tablet needs to meet the clinical requirements of high dissolution (15 min >= 85%), dose accuracy (allowable deviation + 5%) and long-term stability (degradation product <= 1.0%). Especially for the characteristics of being sensitive to heat and moisture, the preparation process becomes a core factor affecting the efficacy.

[0003] The existing wet granulation process (such as CN118892460A) uses hydroxypropyl cellulose aqueous solution as a binder, and needs to undergo a drying process above 50℃. Experiments have proved that this process leads to an increase in the degradation product of axicimini hydrochloride to 1.2%~1.5% (accelerated test 40℃ / 75% RH, 3 months), and the lactose carrier is prone to Maillard reaction with primary amine groups under the condition of heat and moisture, further exacerbating drug decomposition.

[0004] The therapeutic window of axicimini hydrochloride is narrow (20~40mg / tablet), and the content decrease caused by degradation may lead to treatment failure or drug resistance. Developing a low-heat-input preparation process has great clinical significance for ensuring patient safety and prolonging the shelf life of the drug. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of axicimini hydrochloride tablets to solve the problem of drug degradation caused by moisture and high temperature in the wet granulation process, while maintaining high dissolution and content uniformity.

[0006] The purpose of the present application can be achieved by the following technical solutions: A preparation method of axicimini hydrochloride tablets, comprising the following steps: S1, mixing axicimini hydrochloride, mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and fumaric acid at a low speed of 20~25 rpm for 10~15 min to obtain a premixed dry powder; S2, adding the premixed dry powder into a twin-screw hot melt extruder, and simultaneously adding standby glyceryl behenate, obtaining an extrudate after extrusion, and cutting the extrudate into cylindrical particles after cooling through a 2.0 mm screen; S3, transferring the particles to a fluidized bed for cold air solidification, and obtaining solidified particles after completion; S4, mechanically granulating the solidified particles through a 1.0 mm screen, and then adding colloidal silicon dioxide and magnesium stearate thereto, and mixing at 36 rpm for 10~15 min, and obtaining particles to be pressed after completion; S5, using a rotary tablet press to compress the granules to be compressed, finally obtaining acimein hydrochloride tablets.

[0007] Further, the setting parameters of the twin-screw hot melt extruder in S2 are as follows: the temperature of the feeding zone is 40-45 DEG C, the temperature of the mixing zone is 65-67 DEG C, the temperature of the die head is 68-70 DEG C, and the screw rotation speed is 200-400 rpm.

[0008] Further, the extrusion pressure control of the twin-screw hot melt extruder in S2 is 8-10 bar.

[0009] Further, the standby glyceryl behenate in S2 is prepared by the following steps: The glyceryl behenate is heated in a water bath to 65-70 DEG C, continuously stirred until completely melted, and kept in a 70 DEG C constant temperature water bath for standby.

[0010] Further, the raw material usage ratio of the acimein hydrochloride tablets is as follows: Acimein hydrochloride: mannitol: microcrystalline cellulose: glyceryl behenate: crosslinked polyvinylpyrrolidone: fumaric acid: colloidal silicon dioxide: magnesium stearate = 20.0g: 160.0g: 60.0g: 15.0g: 12.0g: 1.0g: 1.5g: 2.5g.

[0011] Further, the operating parameters of the fluidized bed in S3 are as follows: the inlet air temperature is 24-25 DEG C, the air speed is 1.5-2.0 m 3 / min, and the solidification time is 8-10 min.

[0012] Further, the die size of the tablet pressing in S5 is 8mm shallow concave round punch.

[0013] Further, the parameter setting of the rotary tablet press in S5 is as follows: the main pressure is 14.5-15.5 kN, and the feeding speed is 30-40 rpm.

[0014] The beneficial effects of the present application are as follows: The present application provides a preparation method of acimein hydrochloride tablets, which significantly improves the drug stability, dissolution performance and mechanical strength through anhydrous melt granulation process and specific excipient system, and the specific analysis is as follows: I. The degradation product is significantly reduced (the stability is improved): the degradation product of examples 1-3 is 0.25%-0.29%, which is much lower than 1.35% of comparative example 1, and meets the standard of ≤1.0%.

[0015] (1) Principle analysis: A. Water-free process is the key. The present application uses glyceryl behenate as a melt binder (S2 step, low-temperature extrusion at 65-70°C), combined with cold air solidification (S3 step, 24-25°C), with a moisture content of <0.5% throughout (core innovation), avoiding degradation caused by moisture and high temperature. The degradation product of Comparative Example 5 (solidification temperature increased to 40°C) increased to 0.42%, proving the necessity of low-temperature solidification to reduce heat exposure.

[0016] B. Synergistic effect of excipients: mannitol replaces lactose to eliminate the risk of Maillard reaction (Comparative Example 2 uses lactose, with a degradation product of 1.10% vs. 0.25% in Example 1); fumaric acid adjusts the microenvironment pH to 4.5-5.0 (added in S1 step), inhibiting alkaline degradation (Comparative Example 3 removes fumaric acid, with a degradation product of 0.42%). The ratio of disintegrants (cross-linked polyvinylpyrrolidone: microcrystalline cellulose = 3:1) indirectly contributes to stability (Comparative Example 4 adjusted to 1:1, with a degradation product of 0.31%).

[0017] (2) Effect: degradation product reduced by more than 70%, shelf life extended, meeting clinical safety requirements.

[0018] II. Dissolution and disintegration performance optimization (efficacy improvement): The 15min dissolution of Examples 1-3 reached 90.3%-92.5% (≥85% standard), with disintegration times of only 43-47 seconds; while Comparative Example 1 had a dissolution of only 80.2%, with a disintegration time of 135 seconds.

[0019] (1) Principle analysis: A. The ratio of disintegrants (3:1) is the core. The high swelling property of cross-linked polyvinylpyrrolidone (Kollidon® CL) and the water absorption property of microcrystalline cellulose (PH-102) synergistically accelerate disintegration (pre-mixed in S1 step). The dissolution of Comparative Example 4 (ratio adjusted to 1:1) decreased to 79.5%, with a disintegration time of 122 seconds, proving the necessity of a ratio of 3:1.

[0020] B. Fumaric acid fine-tunes the pH to optimize the dissolution microenvironment (dissolution decreased to 86.5% in Comparative Example 3 without fumaric acid). The water solubility of mannitol is better than that of lactose (dissolution of 83.7% in Comparative Example 2), promoting drug release.

[0021] C. Water-free process avoids water residue (compared to wet granulation in Comparative Example 1), ensuring rapid dissolution.

[0022] (2) Effect: dissolution increased by more than 10%, disintegration speed increased by 60%, ensuring rapid drug onset.

[0023] III. Mechanical strength and uniformity improvement (production feasibility improvement): The friability of Examples 1-3 is only 0.02%-0.03%, and the content uniformity RSD is 1.2%-1.5% (≤5.0% standard); while the friability of Comparative Example 1 is 0.45%, and the RSD is 3.8%.

[0024] (1) Principle analysis: A. The molten binder (glyceryl behenate) uniformly wraps the drug (hot melt extrusion in step S2), combined with cold air solidification (step S3) to form a dense particle structure, reducing the friability. The friability of Comparative Example 5 (solidification temperature 40°C) rises to 0.08%, proving that low-temperature solidification maintains the integrity of the particles.

[0025] B. Fumaric acid enhances the binding force of the particles (remove fumaric acid in Comparative Example 3, friability rises to 0.32%). Mannitol optimizes the uniformity of mixing (use lactose in Comparative Example 2, RSD rises to 2.9%).

[0026] (2) Effect: The friability is reduced by 90%, the content uniformity is improved (RSD is reduced by more than 50%), ensuring the accuracy of the dose and the production yield.

[0027] In summary, the present application significantly optimizes the prior art through a low-temperature anhydrous process and scientific auxiliary material matching, meets the clinical needs of asimadoline hydrochloride tablets, and has significant progress and industrial applicability. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application. Meanwhile, the raw materials, reagents or devices used in the following embodiments are commercially available or can be obtained by known methods, unless otherwise specified.

[0029] Example 1

[0030] A preparation method of asimadoline hydrochloride tablets, comprising the following steps: S1, raw material preparation (1000 tablets):

[0031] S2, step-by-step operation process: S21, melt granulation: S211, binder melting: place the raw material glyceryl behenate (15.0 g) in a stainless steel container, heat to 65°C in a water bath, continuously stir until completely melted (liquid transparent), and keep in a 70°C constant temperature water bath for standby; S212, dry powder premixing: in a high efficiency mixer (GL-10 type), add the following ingredients in sequence: acipimox hydrochloride (20.0 g), mannitol (160.0 g), microcrystalline cellulose (60.0 g), crospovidone (12.0 g), fumaric acid (1.0 g), and mix at a low speed of 20 rpm for 10 min to obtain a premixed dry powder; S213, hot melt extrusion granulation: add the premixed dry powder into a twin-screw hot melt extruder (Thermo Scientific™ Process 11), wherein the set parameters of the twin-screw hot melt extruder are: feed zone temperature: 40°C, mixing zone temperature: 65°C, die temperature: 68°C, screw rotation speed: 200 rpm. At the same time, glyceryl behenate (70°C) prepared in S211 is injected into the mixing zone through a melt metering pump, and the extrusion pressure of the twin-screw hot melt extruder is controlled at 8 bar. After extrusion, the extrudate is obtained, which is cut into cylindrical granules after cooling through a 2.0 mm screen.

[0032] S22, granule solidification and post-processing: S221, fluidized bed cold air solidification: transfer the granules in S213 to a fluidized bed (GPCG-1 type), and the operating parameters of the fluidized bed are: inlet air temperature: 24°C, air speed: 1.5 m 3 / min, solidification time: 8 min, and the solidified granules are obtained after completion; S222, granulation and lubrication: mechanically granulate the solidified granules in S221 through a 1.0 mm screen, and then add colloidal silicon dioxide (1.5 g) and magnesium stearate (2.5 g) to the granules, and then place them in a V-type mixer and mix at 36 rpm for 10 min, and the final compression granules are obtained after completion.

[0033] S23, tabletting: S231, tabletting operation: use a rotary tablet press (Fette 3090) to tablet the compression granules in S222, and finally obtain acipimox hydrochloride tablets, wherein the die specifications are: 8 mm shallow concave round punches, and the parameter settings of the rotary tablet press are: main pressure: 14.5 kN, feeding speed: 30 rpm.

[0034] Example 2

[0035] A preparation method of acipimox hydrochloride tablets, comprising the following steps: S1, raw material preparation (1000 tablets):

[0036] S2, step-by-step operation process: S21, melt granulation: S211, adhesive melting: put raw material glyceryl behenate (15.0 g) into a stainless steel container, heat to 68℃ in a water bath, continuously stir until completely melted (liquid transparent), and keep in a 70℃ constant temperature water bath for standby; S212, dry powder premixing: in a high-efficiency mixer (GL-10 type), add acipimox hydrochloride (20.0 g), mannitol (160.0 g), microcrystalline cellulose (60.0 g), cross-linked povidone (12.0 g), and fumaric acid (1.0 g) in sequence, mix at 25 rpm for 10 min to obtain a premixed dry powder; S213, hot melt extrusion granulation: add the premixed dry powder into a twin-screw hot melt extruder (Thermo Scientific™ Process 11), and set the parameters of the twin-screw hot melt extruder as follows: feed zone temperature: 42℃, mixing zone temperature: 66℃, die temperature: 68℃, screw speed: 300 rpm. At the same time, inject the glyceryl behenate (70℃) standby in S211 into the mixing zone through a melt metering pump, and control the extrusion pressure of the twin-screw hot melt extruder at 10 bar. After extrusion, the extrudate is obtained, which is cut into cylindrical granules after cooling through a 2.0 mm screen.

[0037] S22, granule solidification and post-processing: S221, fluidized bed cold air solidification: transfer the granules in S213 to a fluidized bed (GPCG-1 type), and set the operating parameters of the fluidized bed as follows: inlet air temperature: 24℃, air speed: 1.8 m 3 / min, solidification time: 10 min, and obtain solidified granules after completion; S222, granulation and lubrication: mechanically granulate the solidified granules in S221 through a 1.0 mm screen, then add colloidal silicon dioxide (1.5 g) and magnesium stearate (2.5 g) to the granules, and mix in a V-type mixer at 36 rpm for 10 min to obtain the granules to be compressed.

[0038] S23, tabletting: S231, tabletting operation: use a rotary tablet press (Fette 3090) to tablet the granules to be compressed in S222, and finally obtain acipimox hydrochloride tablets, wherein the die specifications are 8 mm shallow concave round punches, and the parameters of the rotary tablet press are set as follows: main pressure: 15.0 kN, feeding speed: 35 rpm.

[0039] Example 3

[0040] A preparation method of acipimox hydrochloride tablets, comprising the following steps: S1, raw material preparation (1000 tablets):

[0041] S2, stepwise operation flow: S21, melt granulation: S211, adhesive melting: raw material glyceryl behenate (15.0 g) was placed in a stainless steel container, heated to 70°C in a water bath, and continuously stirred until completely melted (liquid transparent). It was kept in a 70°C constant temperature water bath for standby; S212, dry powder premixing: in a high-efficiency mixer (GL-10 type), add the following ingredients in order: acipimox hydrochloride (20.0 g), mannitol (160.0 g), microcrystalline cellulose (60.0 g), cross-linked polyvinylpyrrolidone (12.0 g), fumaric acid (1.0 g), and mix at 25 rpm for 15 min to obtain a premixed dry powder; S213, hot melt extrusion granulation: the premixed dry powder was added to a twin-screw hot melt extruder (Thermo Scientific™ Process 11), and the set parameters of the twin-screw hot melt extruder were as follows: feed zone temperature: 45°C, mixing zone temperature: 67°C, die temperature: 70°C, screw speed: 400 rpm. Meanwhile, the glyceryl behenate (70°C) standby in S211 was injected into the mixing zone through a melt metering pump, and the extrusion pressure of the twin-screw hot melt extruder was controlled at 10 bar. After extrusion, the extrudate was obtained, and after cooling, the extrudate was cut into cylindrical particles through a 2.0 mm screen.

[0042] S22, particle solidification and post-processing: S221, fluidized bed cold air solidification: the particles in S213 were transferred to a fluidized bed (GPCG-1 type), and the operating parameters of the fluidized bed were as follows: inlet air temperature: 25°C, air speed: 2.0 m 3 / min, solidification time: 10 min, and the solidified particles were obtained after completion; S222, particle sizing and lubrication: the solidified particles in S221 were mechanically sized through a 1.0 mm screen, and then colloidal silicon dioxide (1.5 g) and magnesium stearate (2.5 g) were added, and the mixture was mixed in a V-type mixer at 36 rpm for 15 min, and the resulting particles were obtained.

[0043] S23, tabletting: S231, tabletting operation: the particles in S222 were tabletted using a rotary tablet press (Fette 3090), and the final acipimox hydrochloride tablets were obtained, wherein the die specifications were 8 mm shallow concave round punches, and the parameters of the rotary tablet press were set as follows: main pressure: 15.5 kN, feeding speed: 40 rpm.

[0044] Comparative Example 1 Comparative Example 1 is a wet granulation process in the prior art CN118892460A.

[0045] Comparative Example 2 Comparative Example 2 is a control group of Example 1, in which the mannitol in Example 1 is replaced with an equal amount of lactose (pharmaceutical grade standard (purity ≥ 99.0%), SuperTab® 14SD), and the remaining raw materials, raw material amounts, and preparation steps remain consistent with Example 1, ultimately preparing an asimadoline hydrochloride tablet.

[0046] Comparative Example 3 Comparative Example 3 is a control group of Example 1, in which the raw material fumaric acid in Example 1 is removed, and the remaining raw materials, raw material amounts, and preparation steps remain consistent with Example 1, ultimately preparing an asimadoline hydrochloride tablet.

[0047] Comparative Example 4 Comparative Example 4 is a control group of Example 1, in which the ratio of disintegrants (microcrystalline cellulose and crospovidone) in Example 1 is adjusted to crospovidone: microcrystalline cellulose = 1:1 (total amount unchanged, 36.0g each), and the remaining raw materials, raw material amounts, and preparation steps remain consistent with Example 1, ultimately preparing an asimadoline hydrochloride tablet.

[0048] Comparative Example 5 Comparative Example 5 is a control group of Example 1, in which the inlet air temperature of the fluidized bed in S221 in Example 1 is adjusted to 40°C, and the remaining raw materials, raw material amounts, and preparation steps remain consistent with Example 1, ultimately preparing an asimadoline hydrochloride tablet.

[0049] The asimadoline hydrochloride tablets prepared in Examples 1-3 and Comparative Examples 1-5 were subjected to performance testing, the performance testing process was as follows, and the test results were averaged from ten results, and the specific test results are shown in Table 1 below: (1) Degradation products (accelerated test): Conditions: 40°C ± 2°C / 75% ± 5% RH, aluminum plastic packaging, stored for 3 months; Detection: HPLC method (chromatographic column: C18, mobile phase: acetonitrile-phosphate buffer gradient elution), calculate the total impurity percentage.

[0050] (2) Dissolution: Conditions: 900ml pH 4.5 acetate buffer, 37°C ± 0.5°C, paddle method 75rpm; Detection: Sample at 5 / 10 / 15 / 30min, HPLC to determine the cumulative dissolution rate (n=6).

[0051] (3) Disintegration time: According to the disintegration time limit test method of Chinese Pharmacopoeia 0931 (purified water, 37°C ± 1°C).

[0052] (4) Friability: According to the "China Pharmacopoeia" 0923 tablet friability test method (rotation speed 25 rpm, 100 revolutions).

[0053] (5) Content uniformity: HPLC determination of 10 tablets of the main drug content, calculate RSD% (standard: RSD≤5.0%).

[0054] Table 1 Test results

[0055] Data analysis from Table 1 (1) Degradation products (%): Examples 1-3 (0.25%-0.29%): The anhydrous melt granulation process of the application (S21 step: glyceryl behenate binder is melted at 65-70°C low temperature, combined with fluidized bed cold air solidification S221 step (24-25°C)), the whole process moisture ≤0.5%, avoiding the degradation caused by heat and humidity.

[0056] Comparative Example 1 (1.35%): Wet granulation (CN118892460A) is used, which involves water-soluble binder and drying above 50°C, resulting in a high-temperature and high-humidity environment, which causes the decomposition of asimadoline hydrochloride.

[0057] Comparative Example 2 (1.10%): Mannitol is replaced by lactose, and the degradation product is significantly higher than that of the examples (0.25%). The replacement of mannitol with lactose can eliminate the Maillard reaction (lactose reacts with primary amine groups under heat and humidity to accelerate decomposition), while lactose fails to avoid this risk in this process.

[0058] Comparative Example 3 (0.42%): Remove fumaric acid, degradation product higher than example (0.25%). Fumaric acid is added in the dry powder premix S212 step, which is used to adjust the microenvironment pH to 4.5-5.0 to inhibit alkaline degradation; its absence leads to a weakening of the inhibition effect.

[0059] Comparative Example 4 (0.31%): The ratio of the disintegrant is adjusted to cross-linked polyvinylpyrrolidone: microcrystalline cellulose = 1:1 (originally 3:1), and the degradation product is slightly higher than that of the examples (0.25%). The change of the ratio of the disintegrant does not directly affect the degradation, but indirectly reflects the slightly weaker stability of the excipient system.

[0060] Comparative Example 5 (0.42%): The inlet air temperature of the fluidized bed is adjusted to 40°C (originally 24°C), and the degradation product is significantly higher than that of the examples (0.25%). Cold air solidification (S221 step) reduces heat exposure at low temperature, and the increase in temperature exacerbates the heat sensitivity of the drug.

[0061] Conclusion: The process of the application (water-free operation, mannitol, fumaric acid, low-temperature solidification) is the key to reducing degradation products. Fumaric acid and low-temperature solidification contribute the most, supplemented by mannitol to avoid side reactions.

[0062] (2) 15 min dissolution (%) : Examples 1-3 (90.3-92.5%): Thanks to the synergistic effect of disintegrant system (crospovidone: microcrystalline cellulose = 3:1) and fumaric acid, the short disintegration time (43-47 seconds) promotes rapid dissolution.

[0063] Comparative Example 1 (80.2%): Wet granulation leads to slow disintegration (135 seconds) and insufficient dissolution, due to moisture retention affecting drug release.

[0064] Comparative Example 2 (83.7%): Mannitol is replaced by lactose, the dissolution is lower than the example (92.5%). Lactose can form dense granules in melt granulation, slowing down the dissolution.

[0065] Comparative Example 3 (86.5%): Fumaric acid is removed, the dissolution is lower than the example (92.5%). Fumaric acid adjusts the pH to optimize the dissolution microenvironment, its absence leads to a decrease in dissolution efficiency.

[0066] Comparative Example 4 (79.5%): Disintegrant ratio 1:1 (instead of 3:1), the dissolution is the lowest. The 3:1 ratio of crospovidone to microcrystalline cellulose synergistically disintegrates; the imbalance (reduction of crospovidone) leads to a prolonged disintegration time (122 seconds), directly hindering dissolution.

[0067] Comparative Example 5 (82.1%): Fluidized bed temperature 40°C (instead of 24°C), the dissolution is lower than the example (92.5%). Higher solidification temperature can make the granules harden, slowing down disintegration and dissolution.

[0068] Conclusion: Disintegrant ratio (3:1) and fumaric acid are the core of dissolution improvement, the example process ensures rapid disintegration and high dissolution.

[0069] (3) Disintegration time (seconds) : Examples 1-3 (43-47 seconds): Disintegrant system (crospovidone: microcrystalline cellulose = 3:1, S212 step) synergistic effect and fumaric acid addition, the high swelling of crospovidone combined with the water absorption of microcrystalline cellulose accelerates disintegration.

[0070] Comparative Example 1 (135 seconds): Moisture retention from the wet granulation process causes granule sticking, slow disintegration.

[0071] Comparative Example 2 (125 seconds): Lactose replaces mannitol, disintegration is slower than the example (43 seconds). Mannitol (Pearlitol® 200 SD) has higher water solubility, optimizing disintegration.

[0072] Comparative Example 3 (75 seconds): Fumaric acid is removed, disintegration time is prolonged. Fumaric acid fine-tunes the pH, which can affect the hydration rate of the disintegrant.

[0073] Comparative Example 4 (122 seconds): The disintegrant ratio was 1:1 (originally 3:1), and disintegration was significantly delayed. The proportion of crospovidone was reduced (from 12g to 18g in 36g), which weakened its rapid expansion characteristics.

[0074] Comparative Example 5 (51 seconds): Fluidized bed temperature 40°C (originally 24°C), disintegration time slightly longer than Example 5 (43 seconds). The higher temperature may have solidified the particle surface, slightly delaying disintegration.

[0075] Conclusion: The ratio of disintegrant (3:1) is the main reason for the shortened disintegration time, which can be further optimized by adding fumaric acid and mannitol.

[0076] (4) Friability (%): Examples 1-3 (0.02%-0.03%): Glyceryl behenate (melt binder) and cold air curing (step S221) form a uniform particulate structure to enhance tablet strength.

[0077] Comparative Example 1 (0.45%): Moisture in wet granulation caused uneven particle size and brittle tablets.

[0078] Comparative Example 2 (0.40%): Lactose replaced mannitol, resulting in higher friability than Example 1 (0.02%). Mannitol may have better plasticity than lactose.

[0079] Comparative Example 3 (0.32%): Removal of fumaric acid increased friability (vs. 0.02%). Fumaric acid was added in the premixing step S212, which may enhance particle binding force through microenvironment pH regulation.

[0080] Comparative Example 4 (0.05%): Disintegrant ratio 1:1, friability close to that of Example (0.02%). Adjustment of disintegrant did not significantly affect friability, indicating that glyceryl behenate and process were the dominant factors.

[0081] Comparative Example 5 (0.08%): Fluidized bed temperature 40°C (originally 24°C), brittleness was higher than Example 5 (0.02%). Low-temperature curing (step S221) reduced thermal stress and maintained particle integrity.

[0082] Conclusion: Fumaric acid and low-temperature curing are key to reducing brittleness.

[0083] (5) Content uniformity (RSD, %): Examples 1-3 (1.2%-1.5%): The melt granulation process (S213 hot melt extrusion) ensures uniform drug distribution.

[0084] Comparative Example 1 (3.8%): Moisture in wet granulation caused drug migration and poor uniformity.

[0085] Comparative Example 2 (2.9%): Lactose replaces mannitol, RSD is higher than Example (1.2%). Mannitol (Pearlitol® 200 SD) has better particle size uniformity than lactose, which facilitates uniform mixing.

[0086] Comparative Example 3 (1.8%): Fumaric acid is removed, RSD is slightly higher than Example (1.2%). Fumaric acid fine powder (D 90 ≤20 μm) can enhance the uniformity of dry powder premix (S212 step).

[0087] Comparative Example 4 (1.6%): Disintegrant ratio 1:1, RSD is close to Example (1.2%). Disintegrant adjustment does not significantly affect uniformity.

[0088] Comparative Example 5 (1.4%): Fluid bed temperature 40°C (original 24°C), RSD is slightly higher than Example (1.2%). Low temperature solidification reduces the risk of particle aggregation.

[0089] (6) Conclusion: The melt granulation process and mannitol are the main guarantees of content uniformity.

[0090] Overall analysis conclusion: Process innovation: Anhydrous melt granulation (glyceryl behenate binder) combined with cold air solidification (24-25°C) significantly reduces degradation products (≤0.29% vs. ≥0.31% for comparison).

[0091] Excipient innovation: Mannitol replaces lactose to avoid Maillard reaction (degradation product 1.10% vs. 0.25%).

[0092] Fumaric acid adjusts pH to inhibit degradation and improve friability (friability 0.32% vs. 0.02%).

[0093] Disintegrant ratio (cross-linked polyvinylpyrrolidone: microcrystalline cellulose = 3:1) optimizes disintegration and dissolution (disintegration time 122 seconds vs. 43 seconds).

[0094] Comparative example verification: Comparative Example 2 (lactose replacement) demonstrates the necessity of mannitol.

[0095] Comparative Example 3 (remove fumaric acid) demonstrates the dual role of fumaric acid (degradation inhibition and friability improvement).

[0096] Comparative Example 4 (disintegrant ratio adjustment) demonstrates the criticality of 3:1 ratio for disintegration and dissolution.

[0097] Comparative Example 5 (increased solidification temperature) demonstrates the importance of low temperature operation for degradation control.

[0098] Technical effects: The application solves the degradation problem of wet granulation, improves the dissolution rate, disintegration rate and mechanical properties of tablets, meets the clinical requirements, and has high consistency between examples and stable process.

[0099] It should be noted that in this text, such as the term "includes, contains" or any other variant thereof is intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or also includes the elements inherent to such process, method, article or device.

[0100] Although embodiments of the application have been shown and described, it is to be understood that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for the preparation of asimadoline hydrochloride tablets, characterized in that, Comprising the following steps: S1, mixing acimein hydrochloride, mannitol, microcrystalline cellulose, crosslinked polyvinylpyrrolidone and fumaric acid at 20-25 rpm low speed for 10-15 min to obtain a premixed dry powder; S2, adding the premixed dry powder into a twin-screw hot melt extruder, and adding the standby glyceryl behenate at the same time, obtaining an extrudate after extrusion, and cutting the extrudate into cylindrical particles after cooling through a 2.0 mm screen; S3, transferring the particles to a fluidized bed for cold air solidification, and obtaining solidified particles after completion; S4, mechanically granulating the solidified particles through a 1.0 mm screen, and then adding colloidal silicon dioxide and magnesium stearate, mixing at 36 rpm for 10-15 min, and obtaining particles to be pressed after completion; S5, using a rotary tablet press to press the particles to be pressed, and finally obtaining acimein hydrochloride tablets.

2. A process for the preparation of asimadoline hydrochloride tablets according to claim 1, characterized in that, The setting parameters of the twin-screw hot melt extruder in S2 are as follows: feed zone temperature: 40-45℃, mixing zone temperature: 65-67℃, die temperature: 68-70℃, and screw speed: 200-400 rpm.

3. A process for the preparation of asimadoline hydrochloride tablets according to claim 1, characterized in that, The extrusion pressure control of the twin-screw hot melt extruder in S2 is 8-10 bar.

4. The process for the preparation of asimadoline hydrochloride tablets as claimed in claim 1, wherein, The standby glyceryl behenate in S2 is prepared by the following steps: Heat the glyceryl behenate in a water bath to 65-70℃, continuously stir until completely melted, and keep it in a 70℃ constant temperature water bath for standby.

5. A process for the preparation of asimadoline hydrochloride tablets according to claim 4, characterized in that, The raw material usage ratio of the acimein hydrochloride tablets is as follows: Acimein hydrochloride: mannitol: microcrystalline cellulose: glyceryl behenate: crosslinked polyvinylpyrrolidone: fumaric acid: colloidal silicon dioxide: magnesium stearate = 20.0g: 160.0g: 60.0g: 15.0g: 12.0g: 1.0g: 1.5g: 2.5g.

6. The process for the preparation of asimadoline hydrochloride tablets as claimed in claim 1, wherein, The operating parameters of the fluidized bed in S3 are as follows: inlet air temperature: 24-25℃, air speed: 1.5-2.0 m3 / min, and solidification time: 8-10 min.

7. The process for the preparation of asimadoline hydrochloride tablets as claimed in claim 1, wherein, The punch size of the tablet pressing in S5 is 8mm shallow concave round punch.

8. A process for the preparation of asimadoline hydrochloride tablets according to claim 1, characterized by, The parameter setting of the rotary tablet press in S5 is as follows: main pressure: 14.5-15.5 kN, and feeding speed: 30-40 rpm.

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