A drug substance, pharmaceutical composition, and preparation method and application thereof

Abstract

The application discloses a bulk drug, a pharmaceutical composition, a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. 24 H 32 ClNO6, has the following characteristics: D50 is 20-75 microns, and the particle size distribution span is 1≤(D90-D10) / D50≤2.5. The bulk drug has good process stability, dissolution stability and chemical stability. The pharmaceutical composition and the pharmaceutical preparation adopting the bulk drug have good process stability, dissolution stability and chemical stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and relates to an active pharmaceutical ingredient, a pharmaceutical composition, its preparation method and application. Background Technology

[0002] Sapogrelate is a highly selective 5-hydroxytryptamine (5-HT) receptor antagonist (hereinafter referred to as compound A), with the following chemical structural formula: .

[0003] Compound A specifically binds to 5-HT2 receptors on platelets, exerting an antagonistic effect and inhibiting the increase in intraplatelet calcium ion levels caused by receptor activation, platelet aggregation, and the vasoconstrictive response associated with platelet activation and aggregation. Due to its significant antithrombotic effect and ability to improve collateral circulation, compound A is widely used clinically as an antiplatelet drug for the treatment of peripheral vascular diseases.

[0004] Compound A is a highly variable drug, and marketed Compound A tablets exhibit dissolution instability. For example, in a pH 4.5 acetate solution, the relative standard deviation (RSD) of dissolution at 5 and 10 minutes is excessively large. Therefore, it is necessary to improve dissolution stability, reduce variability caused by formulation factors, and ensure stable efficacy.

[0005] Patent document CN105769800A discloses a saxagrel ester hydrochloride tablet, composed of the following raw and excipient materials in parts by weight: 100 parts of compound A, 60-100 parts of PH302 microcrystalline cellulose, 4-8 parts of citric acid, 2-6 parts of magnesium stearate, 8-12 parts of micronized silica gel, and 105-6 parts of 295F6800. This invention pre-mixes and pulverizes compound A with citric acid to a specific particle size, and after mixing with a specific type of microcrystalline cellulose, it satisfies both the flowability requirements of the mixed particles during direct compression and the dissolution behavior of the formulation. Stability test results also show that its stability is superior to that of commercially available formulations. However, this invention does not address the issue of dissolution instability.

[0006] Patent document CN108524462A discloses a preparation process for sarpogrelate hydrochloride tablets. To improve the impact of wet granulation on the stability of compound A, the preparation process was adjusted by mixing light anhydrous silica with compound A, crystalline cellulose, and carboxymethyl cellulose and granulating them in a single step. This improved the flow-aiding effect of light anhydrous silica during granulation, resulting in more uniform mixing of raw materials, easier molding, and higher granulation efficiency. Based on the change in the preparation process, the amounts of raw materials used in tablet preparation were adjusted accordingly, reducing the amount of filler and increasing the amounts of stabilizer, flow aid, and disintegrant. Through the combination of adjustments to the preparation process and the amount of raw material components, compound A tablets with good stability, dissolution, and compressibility were obtained. However, this invention also failed to address the issue of dissolution instability, posing a quality risk.

[0007] Although there are many studies on the stability of Compound A tablets, there are few studies on the dissolution stability of Compound A tablets. Therefore, developing a Compound A drug composition with good dissolution stability remains challenging. Summary of the Invention

[0008] To address the aforementioned technical problems, this invention provides a raw material, a pharmaceutical composition, a method for preparing the same, and its application.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] This invention provides a pharmaceutical ingredient, the structural formula of which is as follows:

[0011] ,

[0012] It has the following characteristics: D50 is 20-75 micrometers, and the particle size distribution range is 1≤(D90-D10) / D50≤2.5.

[0013] Experiments have shown that when the D50 of the active pharmaceutical ingredient and the particle size distribution span (D90-D10) / D50 are within the specific protection range of this invention, the tablets prepared by wet granulation exhibit good process stability and dissolution stability. When either D50 or the particle size distribution span (D90-D10) / D50 is outside the above range, both process stability and dissolution stability cannot be simultaneously achieved.

[0014] In some embodiments, the D50 of the active pharmaceutical ingredient is selected from 20 micrometers, 20 micrometers, 21 micrometers, 22 micrometers, 23 micrometers, 24 micrometers, 25 micrometers, 26 micrometers, 27 micrometers, 28 micrometers, 29 micrometers, 30 micrometers, 31 micrometers, 32 micrometers, 33 micrometers, 34 micrometers, 35 micrometers, 36 micrometers, 37 micrometers, 38 micrometers, 39 micrometers, 40 micrometers, 41 micrometers, 42 micrometers, 43 micrometers, 44 micrometers, 45 micrometers, 46 micrometers, 47 micrometers, 48 ​​micrometers, 49 micrometers, 50 micrometers, 51 micrometers, 52 micrometers, 53 micrometers, 54 micrometers, and 55 micrometers. The particle size distribution range is 56 micrometers, 57 micrometers, 58 micrometers, 59 micrometers, 60 micrometers, 61 micrometers, 62 micrometers, 63 micrometers, 64 micrometers, 65 micrometers, 66 micrometers, 67 micrometers, 68 micrometers, 69 micrometers, 70 micrometers, 71 micrometers, 72 micrometers, 73 micrometers, 74 micrometers, 75 micrometers, or any range derived thereof, and the particle size distribution span (D90-D10) / D50 is selected from 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, or any range derived thereof. Preferably, D50 is 21-74 micrometers, and the particle size distribution span 1.1 ≤ (D90-D10) / D50 ≤ 2.2.

[0015] In some embodiments, the D10 of the active pharmaceutical ingredient is 3-25 micrometers, for example, 3 micrometers, 4 micrometers, 5 micrometers, 6 micrometers, 7 micrometers, 8 micrometers, 9 micrometers, 10 micrometers, 11 micrometers, 12 micrometers, 13 micrometers, 14 micrometers, 15 micrometers, 16 micrometers, 17 micrometers, 18 micrometers, 19 micrometers, 20 micrometers, 21 micrometers, 22 micrometers, 23 micrometers, 24 micrometers, 25 micrometers, or any range derived thereof. Preferably, it is 6-17 micrometers.

[0016] Based on the above-mentioned active pharmaceutical ingredient, the present invention provides the application of the active pharmaceutical ingredient in the preparation of pharmaceutical formulations.

[0017] The pharmaceutical preparations described in this invention are tablets, granules, or capsules. Tablets are preferred.

[0018] In some embodiments, the application is in the preparation of pharmaceutical formulations using wet granulation.

[0019] Based on the above-mentioned active pharmaceutical ingredient, the present invention provides a pharmaceutical composition comprising the active pharmaceutical ingredient and pharmaceutically acceptable excipients.

[0020] In some embodiments, the porosity of the pharmaceutical composition is <5%, for example, selectable from 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, or any range derived therefrom. Preferably, it is 0.5%-5%.

[0021] In some implementations, the porosity detection method adopts the porosity detection method of Zhejiang Jieheng Technology Co., Ltd. The sample preparation steps of the detection process refer to the sample preparation steps described in patent document CN119757315A. The sample preparation is carried out by SEM to collect sample data. The image acquisition, processing and analysis process is integrated into image analysis software (JIT software: JIT-QMA), and the porosity data is calculated by the software.

[0022] In some embodiments, preferably, the excipients include at least one of fillers, disintegrants, flow aids, stabilizers, binders, and lubricants.

[0023] The filler is at least one of microcrystalline cellulose, mannitol, corn starch and lactose.

[0024] The disintegrant is at least one of carboxymethyl cellulose and calcium carboxymethyl cellulose.

[0025] The flow aid is at least one of light anhydrous silica and talc.

[0026] The stabilizer is at least one of citric acid hydrate and citric acid.

[0027] Preferably, the adhesive is at least one of hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.

[0028] Preferably, the lubricant is at least one of calcium stearate, magnesium stearate, and talc.

[0029] In some embodiments, the pharmaceutical composition comprises, by weight percentage, the following components: 46%-68% active pharmaceutical ingredient, 15%-35% filler, 0%-25% disintegrant, 0%-2% flow aid, 0%-2% stabilizer, 1%-4% binder, and 1%-4% lubricant.

[0030] In some embodiments, the pharmaceutical composition comprises, by weight percentage, the following components: 55%-60% active pharmaceutical ingredient, 15%-35% filler, 0%-17% disintegrant, 0%-2% flow aid, 1%-1.2% stabilizer, 1%-2.5% binder, and 2%-3% lubricant.

[0031] In some embodiments, the pharmaceutical composition has a weight variation of less than 7.5%; preferably, the weight variation of the pharmaceutical composition is less than 5.0%; and more preferably, the weight variation of the pharmaceutical composition is less than 2.0%.

[0032] In some embodiments, the pharmaceutical composition is a tablet with a friability of less than 1%; preferably, the friability of the tablet does not exceed 0.5%; more preferably, the friability of the tablet is less than 0.2%.

[0033] In some embodiments, the pharmaceutical composition is a tablet, the tablet is a plain tablet, and the hardness of the plain tablet is greater than 25N; preferably, the hardness of the plain tablet is greater than 30N.

[0034] Based on the above-described pharmaceutical composition, the present invention also provides a method for preparing the pharmaceutical composition, wherein the pharmaceutical composition is prepared by a wet granulation process.

[0035] In some embodiments, the wet granulation process includes the following steps:

[0036] S1. Dissolve the adhesive and stabilizer in water to obtain the adhesive solution;

[0037] S2. The active pharmaceutical ingredient is mixed with fillers, disintegrants, and glidants, and then granulated using a wet granulation process with a binder, followed by drying and granulation.

[0038] S3. After granulation, the granules are mixed with lubricant and compressed into tablets to obtain plain tablets.

[0039] In some embodiments, the wet granulation process includes the following steps:

[0040] S1. Dissolve the adhesive in water to obtain an adhesive solution;

[0041] S2. The active pharmaceutical ingredient is mixed with stabilizers, fillers, disintegrants, and glidants, and then granulated using a wet granulation process with a binder, followed by drying and granulation.

[0042] S3. After granulation, the granules are mixed with lubricant and compressed into tablets to obtain plain tablets.

[0043] In some embodiments, at least 75% of the granulated particles can pass through a 65-mesh sieve; preferably, 75%-100% of the granulated particles can pass through a 65-mesh sieve.

[0044] In some implementations, the tableting process uses a tablet press with a main pressure greater than 500 kg; preferably, the tablet press uses a main pressure of 525-1200 kg.

[0045] In some embodiments, the tableting qualification rate in the preparation method is greater than 80%; preferably, the tableting qualification rate is greater than 85%, more preferably, the tableting qualification rate is greater than 90%; most preferably, in a preparation scale of more than 100,000 tablets / batch, the tableting qualification rate is greater than 95%.

[0046] In some embodiments, the raw film prepared by the method does not include a light-blocking agent.

[0047] In some embodiments, the preparation method further includes coating the uncoated tablets.

[0048] In some implementations, the coating process involves spraying a coating liquid at 30-34°C until the coating weight gain reaches 20%, drying until the loss on drying is <1.5%, and then granulating the material after discharge.

[0049] The present invention also provides a method for treating peripheral vascular disease, comprising administering the aforementioned active pharmaceutical ingredient or the aforementioned pharmaceutical composition to a subject.

[0050] In some implementations, the peripheral vascular disease includes peripheral artery disease, diabetic peripheral vascular disease, or thromboangiitis obliterans.

[0051] The active pharmaceutical ingredient or pharmaceutical composition of the present invention may be administered via any route suitable for the condition being treated. In some embodiments, suitable routes include oral, rectal, nasal, pulmonary, local (including oral and sublingual), and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition.

[0052] The specific dosage and method of administration of the active pharmaceutical ingredient or pharmaceutical composition of this invention for different subjects are determined by many factors, including the patient's age, weight, sex, natural health condition, nutritional status, the potency of the drug, the time of administration, the metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. The effective dosage of the active ingredient depends at least on the nature of the condition to be treated, its toxicity, the method of delivery, and the pharmaceutical formulation, and will be determined through clinician dose escalation studies using conventional methods. A daily dose of approximately 0.0001 to approximately 100 mg / kg body weight can be anticipated, for example, 0.0001 mg / kg, 0.0005 mg / kg body weight, 0.001 mg / kg body weight, 0.005 mg / kg body weight, 0.01 mg / kg body weight, 0.05 mg / kg body weight, 0.1 mg / kg body weight, 0.5 mg / kg body weight, 1 mg / kg body weight, 2 mg / kg body weight, 3 mg / kg body weight, 4 mg / kg body weight, 5 mg / kg body weight, 6 mg / kg body weight, 7 mg / kg body weight, 8 mg / kg body weight, 9 mg / kg body weight, etc. 10 mg / kg body weight, 11 mg / kg body weight, 12 mg / kg body weight, 13 mg / kg body weight, 14 mg / kg body weight, 15 mg / kg body weight, 16 mg / kg body weight, 17 mg / kg body weight, 18 mg / kg body weight, 19 mg / kg body weight, 20 mg / kg body weight, 21 mg / kg body weight, 22 mg / kg body weight, 23 mg / kg body weight, 24 mg / kg body weight, 25 mg / kg body weight, 26 mg / kg body weight, 27 mg / kg body weight, 28 mg / kg body weight, 29 mg / kg body weight, 30 mg / kg body weight, 31mg / kg body weight, 32mg / kg body weight, 33mg / kg body weight, 34mg / kg body weight, 35mg / kg body weight, 36mg / kg body weight, 37mg / kg body weight, 38mg / kg body weight, 39mg / kg body weight, 40mg / kg body weight, 41mg / kg body weight, 42 mg / kg body weight, 43 mg / kg body weight, 44 mg / kg body weight, 45 mg / kg body weight, 46 mg / kg body weight, 47 mg / kg body weight, 48 mg / kg body weight, 49 mg / kg body weight, 50 mg / kg body weight, 51 mg / kg body weight, 52mg / kg body weight, 53mg / kg body weight, 54mg / kg body weight, 55mg / kg body weight, 56mg / kg body weight, 57mg / kg body weight, 58mg / kg body weight, 59mg / kg body weight, 60mg / kg body weight, 61mg / kg body weight, 62mg / kg body weight, 63 mg / kg body weight, 64 mg / kg body weight, 65 mg / kg body weight, 66 mg / kg body weight, 67 mg / kg body weight, 68 mg / kg body weight, 69 mg / kg body weight, 70 mg / kg body weight, 71 mg / kg body weight, 72 mg / kg body weight,73 mg / kg body weight, 74 mg / kg body weight, 75 mg / kg body weight, 76 mg / kg body weight, 77 mg / kg body weight, 78 mg / kg body weight, 79 mg / kg body weight, 80 mg / kg body weight, 81 mg / kg body weight, 82 mg / kg body weight, 83 mg / kg body weight, 84 mg / kg body weight, 85 mg / kg body weight, 86 mg / kg body weight, 87 mg / kg body weight, 88 mg / kg body weight, 89 mg / kg body weight, 90 mg / kg body weight, 91 mg / kg body weight, 92 mg / kg body weight, 93 mg / kg body weight, 94 mg / kg body weight, 95 mg / kg body weight, 96 mg / kg body weight, 97 mg / kg body weight, 98 mg / kg body weight, 99 mg / kg body weight, 100 mg / kg body weight, or any range derived thereof. The stated dosage may be in the form of a single dose or multiple doses.

[0053] The beneficial effects of this invention are as follows:

[0054] (1) Active pharmaceutical ingredients with D50 of 20-75 μm and particle size distribution range K value of 1-2.5 have good process stability, dissolution stability and chemical stability during wet granulation, and are suitable for large-scale production.

[0055] (2) Comparative Example 1 revealed that when the D50 of the active pharmaceutical ingredient and the particle size distribution span (D90-D10) / D50 are both outside the specific protection range of this invention, the compressibility and dissolution stability of the pharmaceutical composition are significantly deteriorated. Comparative Examples 2 and 3 revealed that when either the D50 of the active pharmaceutical ingredient or the particle size distribution span (D90-D10) / D50 is outside the specific protection range of this invention, dissolution stability and tablet weight variation are affected, resulting in varying degrees of deterioration. In summary, D50 and the particle size distribution span (D90-D10) / D50 have a substantial impact on the dissolution stability and tablet weight variation of the pharmaceutical composition. When either the D50 of the active pharmaceutical ingredient or the particle size distribution span (D90-D10) / D50 is outside the above range, it is impossible to simultaneously meet the requirements of process stability, dissolution stability, and large-scale production.

[0056] (3) Experiments showed that when the porosity of the drug composition was <5%, the dissolution rate was greater than 85% at 15 min and the RSD of the dissolution rate at each time point did not exceed 10%; it also had good compressibility, small difference in tablet weight, and friability of less than 0.5%; after 30 days of high-temperature storage, the growth of impurities was small, and it had good process stability, dissolution stability and chemical stability.

[0057] (4) Compared with the reference formulation, the tablets prepared by the present invention have better dissolution stability and reduce the potential risk of inconsistent dissolution behavior in vivo. Attached Figure Description

[0058] Figure 1 During the porosity detection process, the pharmaceutical composition prepared for this invention was processed and sliced ​​to obtain a cross-sectional image of the tablet.

[0059] Figure 2 This is the coating sheet of the present invention. Detailed Implementation

[0060] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0061] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention.

[0062] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0063] The "pharmaceuticalally acceptable" ingredients described in this invention are substances that are suitable for humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., have a reasonable benefit / risk ratio.

[0064] The “pharmaceutical composition” and “pharmaceutical formulation” described in this invention can be prepared by any method known in pharmaceutical science. Generally, these preparation methods involve associating the pharmaceutical composition with one or more other auxiliary ingredients, and then, if desired and / or expected, shaping and / or packaging the product into desired single-dose or multi-dose units.

[0065] The "pharmaceutical composition" and "pharmaceutical formulation" of this invention can be prepared according to known methods, such as those described in the General Rules for Preparation of Pharmaceuticals in the Chinese Pharmacopoeia 2025, the Japanese Pharmacopoeia 18th Edition, the United States Pharmacopoeia 39th Edition, and the European Pharmacopoeia 11th Edition. The specific method depends on the dosage form.

[0066] In this invention, the term "porosity" refers to the proportion of pore volume in the total volume of a sample.

[0067] The term "particle size D90" refers to the particle size at which the cumulative particle size distribution number of a sample reaches 90%.

[0068] The term "particle size D50" refers to the particle size at which the cumulative particle size distribution number of a sample reaches 50%.

[0069] The term "particle size D10" refers to the particle size at which the cumulative particle size distribution number of a sample reaches 10%.

[0070] Particle size distribution span (K value), also known as particle size distribution, refers to the value obtained by dividing the particle size (D90-D10) by D50. The size of the K value represents the width or narrowness of the particle size distribution. The smaller the K value, the more concentrated the particle size distribution; the larger the K value, the more dispersed the particle size distribution.

[0071] In this invention, the term "relative standard deviation (RSD)" refers to a core statistical indicator that measures the dispersion of test data and is used to quantify the uniformity and reliability of a set of parallel test results. According to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms," ​​the RSD of dissolution of oral solid dosage forms (tablets, capsules, etc.) must meet the following requirements: "The relative standard deviation of dissolution at the first sampling time point shall not exceed 20%, and the relative standard deviation of dissolution at other sampling time points shall not exceed 10%."

[0072] In this invention, the terms "subject" or "patient" are well known in the art and are used interchangeably to refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, and camels, with humans being the most preferred. This term does not imply a specific age or sex. Therefore, adult and neonatal subjects, whether male or female, are included.

[0073] In this invention, "water" refers to water with a temperature above 0°C, for example, the temperature can be selected as 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, or any range derived therefrom.

[0074] All numerical values ​​or expressions relating to component amounts, process conditions, etc., used in this invention shall be understood to be modified by the word "about" in all cases. When referring to a quantity or range of values, the quantity or range is an approximation within experimental variability (or within statistical experimental error). In this invention, the term "about" shall have the meaning of being within 10%, preferably within 5%, of the specified value or range.

[0075] This invention does not limit the source of the raw and auxiliary materials used. Unless otherwise specified, all raw and auxiliary materials used in this invention are commercially available pharmaceutical-grade products commonly used in this technical field. For example, the specific material information used in the embodiments of this invention is as follows: reference formulation (compound A tablets, purchased from Mitsubishi Tanabe Pharmaceutical Co., Ltd., Japan, batch number J787), crystalline cellulose (Asahi Kasei Corporation), mannitol (Roquette Freres; ROQUETTE AMERICA, INC.), corn starch (Anhui Shanhe Pharmaceutical Excipients Co., Ltd.), lactose (Megir, Germany), carboxymethyl cellulose (NICHIRIN CHEMICALINDUSTRIES, LTD), calcium carboxymethyl cellulose (Bolak company limited), light anhydrous silica (Evonik Operations GmbH), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), and hydroxypropyl methylcellulose.

[0076] [Detection Indicators and Methods]

[0077] 1. Porosity

[0078] Detection Method: The porosity detection method of Zhejiang Jieheng Technology Co., Ltd. was adopted. The sample preparation process followed the steps described in patent document CN119757315A. Sample preparation and data acquisition were performed using SEM. The specific imaging principle is as follows: During the imaging process of scanning electron microscopy (SEM), pores typically appear as nearly black dark areas in secondary electron or backscattered electron images. This is because when the electron beam scans to the pore area on the sample surface, the absence of solid material in this area leads to a sharp decrease in the intensity of detectable secondary electron or backscattered electron signals, resulting in very little signal received by the detector. Therefore, this corresponds to extremely low pixel brightness values ​​in the grayscale image. The complete image acquisition, processing, and analysis process described above is automated by integrating it into image analysis software (JIT software: JIT-QMA). This software system realizes the statistical analysis of pore features from SEM images. The cross-section of the tablet was detected during the testing process as shown in the image. Figure 1 As shown.

[0079] 2. Friability

[0080] Testing method: For tablets weighing 0.65g or less, take several tablets to make the total weight approximately 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Blow away the powder that has fallen off the tablets, accurately weigh (W1), place in a cylinder, and rotate 100 times. Remove, blow away the powder in the same way, and accurately weigh (W2). Friability (%) = [(W1-W2) / W1]×100%.

[0081] 3. Hardness

[0082] Testing method: Automatic measurement using a tablet hardness tester.

[0083] 4. Tablet weight difference

[0084] Detection and calculation method: Take 20 tablets of the test sample, accurately weigh the total weight, and calculate the average tablet weight W. 平均 Then, the weight W of each piece is precisely measured. t Compare the weight of each tablet to the average tablet weight. Tablet weight difference = (W t -W 平均 ) / W 平均 .

[0085] 5. Dissolution rate

[0086] Detection Method: Following the dissolution and release ratio assay (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II), dissolution media were prepared using pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and 900 mL of water, respectively. The dissolution speed was 50 rpm. Samples (5 mL each) were taken at 5, 10, 15, and 30 min (with an equal volume of replenished solution immediately). The sample was filtered through a 0.45 μm PES filter, and the filtrate was used as the test solution. The absorbance was measured at 270 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0401), and the dissolution rate was calculated. The dissolution results were obtained from six parallel tests of the formulation. The average dissolution rate of the six tablets was calculated as the dissolution rate of the formulation at different time points.

[0087] The standard deviation and relative standard deviation are obtained using the following formulas:

[0088]

[0089]

[0090] In the above formula, S represents the standard deviation; RSD represents the relative standard deviation; Dissolution values ​​for individual test samples are expressed as a percentage of the labeled drug content in each sample. It is the average dissolution rate of the test samples; n is the number of test samples, which is 6 in the dissolution test.

[0091] 6. Stability

[0092] Detection method:

[0093] Chromatographic conditions and system suitability: Octadecylsilane-bonded silica gel was used as the stationary phase (Waters Symmetry C18, 4.6). A 150 mm, 5 μm or equivalent column was used, with water-acetonitrile-trifluoroacetic acid (1300:700:1) as the mobile phase, column temperature 40 °C, flow rate 0.8 mL / min, detection wavelength 272 nm, injection volume 10 μL, and isocratic run for 12 min. The reference solution was injected six times consecutively, and the relative standard deviation of the peak area of ​​compound A should not exceed 2.0%.

[0094] Test solution: Take 10 tablets (100mg) of the sample to be tested, place them in a 200ml volumetric flask, add an appropriate amount of diluent (water-acetonitrile-trifluoroacetic acid (1300:700:1)), sonicate for 10min, cool, dilute to the mark, and shake well. Take an appropriate amount and centrifuge at 8000rpm for 5min, accurately transfer 2mL of the supernatant to a 100mL volumetric flask, dilute to the mark with diluent, and shake well to obtain the test solution.

[0095] Reference solution: Weigh an appropriate amount of compound A reference standard accurately, dissolve it in diluent and dilute quantitatively to a solution containing approximately 0.1 mg of compound A per 1 mL.

[0096] Related substances determination methods:

[0097] After the baseline stabilizes, inject 1-2 injections of blank solution, 3 consecutive injections of reference solution, 1 injection of system suitability solution, 1 injection of sensitivity solution, 1 injection of test solution, and 1 injection of accompanying reference solution into the liquid chromatograph sequentially, and record the chromatogram. Calculate the content of each impurity in the test sample by peak area using the principal component external standard method with correction factors.

[0098] The system suitability requirements are as follows: In the system suitability solution chromatogram, the resolution between compound A and impurity A should be no less than 3; in the reference solution chromatogram, the RSD of the peak area of ​​compound A in three consecutive reference solutions and a total of four reference solutions should be ≤5.0%; in the sensitivity solution, the signal-to-noise ratio of the peak of compound A should be no less than 10.

[0099] 7. Tableting pass rate

[0100] Tableting pass rate = Number of qualified tablets after compression / Total number of tablets compressed

[0101] Qualified tablets are those with a weight within ±10% of the standard tablet weight (170mg for unprocessed tablets) and a hardness greater than 30N. Unqualified tablets mainly include those with cracks, tablets with top cracks, adhesion, tablet weight difference greater than ±10%, loose tablets, and those that fail to meet appearance or hardness standards.

[0102] [Preparation of active pharmaceutical ingredients]

[0103] The active pharmaceutical ingredient with a larger initial particle size was pulverized to prepare active pharmaceutical ingredients with different particle sizes, and the corresponding particle size distribution was detected using a Malvern laser particle size analyzer for later use.

[0104] The preparation method of active pharmaceutical ingredient a is as follows: crude compound A is prepared according to the method of Example 2 of patent document JP1983032847A. 2 kg of crude compound A and 2.5 L of methanol are added to a reaction bottle, the temperature is raised to 60°C, the mixture is clarified, and after naturally cooling to room temperature, it is stirred to precipitate crystals, filtered, and dried to obtain compound A, which is used as active pharmaceutical ingredient a.

[0105] Specifically, the preparation method of the active pharmaceutical ingredient is as follows:

[0106] Preparation of active pharmaceutical ingredient 1: Weigh an appropriate amount of active pharmaceutical ingredient a, and pulverize it using a high-speed pulverizer 2wrpn for 25-30 seconds to obtain active pharmaceutical ingredient 1.

[0107] Preparation of active pharmaceutical ingredient 2: Weigh an appropriate amount of active pharmaceutical ingredient a, and pulverize it for 15-20 seconds using a high-speed pulverizer 2wrpn to obtain active pharmaceutical ingredient 2.

[0108] Preparation of active pharmaceutical ingredient 3: Weigh an appropriate amount of active pharmaceutical ingredient 2 and pulverize it for 5-10 seconds using a high-speed pulverizer 2wrpn to obtain active pharmaceutical ingredient 3.

[0109] Preparation of active pharmaceutical ingredient 4: Weigh an appropriate amount of active pharmaceutical ingredient a, and pulverize it for 5-10 seconds using a high-speed pulverizer 2wrpn to obtain active pharmaceutical ingredient 4.

[0110] Preparation of active pharmaceutical ingredient 5: Weigh an appropriate amount of active pharmaceutical ingredient 1 and pulverize it for 5-10 seconds using a high-speed pulverizer 2wrpn to obtain active pharmaceutical ingredient 5.

[0111] Preparation of active pharmaceutical ingredient 6: Take an appropriate amount of active pharmaceutical ingredient a to obtain active pharmaceutical ingredient 6.

[0112] Preparation of active pharmaceutical ingredient 7: Following the method in Example 5 of patent document CN1824647B, 1 kg of crude compound A, 8.8 L of acetone, and 0.55 L of water were mixed. The mixture was heated to dissolve, and then the internal temperature was cooled to 50°C. A suspension prepared by adding 0.05 kg of type II crystals and 0.7 L of acetone was added to the solution, followed by the addition of 0.5 L of acetone. The mixture was cooled to 10°C, the crystals were filtered off, washed with 1 L of acetone, and dried under reduced pressure to obtain active pharmaceutical ingredient 7.

[0113] Preparation of active pharmaceutical ingredient 8: Weigh an appropriate amount of active pharmaceutical ingredient a and pulverize it using a GMP02 air jet mill at 0.8 MPa, a classifier speed of 8500-9500 rpm, and a feed rate of 400 g / h to obtain active pharmaceutical ingredient 8.

[0114] Specifically, the particle size detection method is as follows:

[0115] Take approximately 0.5 g of the active pharmaceutical ingredient, add 20 mL of ethyl acetate, then add 1 drop of Span 80, sonicate for 30 seconds and stir until uniformly dispersed. Set up the method according to the conditions listed below, and determine the particle size and particle size distribution according to Method III (General Chapter 0982, Particle Size and Particle Size Distribution Determination, Part IV, Chinese Pharmacopoeia 2020 Edition). Measuring instrument: Malvern MASTERESIZER 3000 laser particle size analyzer. The particle size results are shown in Table 1 below.

[0116] Table 1. Active pharmaceutical ingredients with different particle size distributions

[0117]

[0118] As can be seen from Table 1, for compound A, the K value of the active pharmaceutical ingredient prepared by recrystallization is often relatively large, usually greater than 2.5. By pulverizing, the K value of the active pharmaceutical ingredient can be reduced and the particle size uniformity of the active pharmaceutical ingredient can be improved.

[0119] [Analysis of the properties of the active pharmaceutical ingredient]

[0120] The effects of the active pharmaceutical ingredient with a specific particle size distribution on the stability and dissolution stability of tablets are described in detail below with reference to Examples 1-3 and Comparative Examples 1-3.

[0121] Basic Example Pharmaceutical Composition

[0122] Table 2 Formulation table of pharmaceutical compositions

[0123]

[0124] The preparation method of the pharmaceutical composition is as follows:

[0125] 1. Weigh the main ingredients, fillers, disintegrants, glidants, stabilizers, binders, and lubricants according to the prescription.

[0126] 2. Granulation and sizing:

[0127] (1) Adhesive preparation: Dissolve the adhesive and stabilizer in water and use it as an adhesive solution.

[0128] (2) Granulation: Add the main material, filler, disintegrant and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a 1.0 mm aperture pulverizer for crushing (80% passes through a 65 mesh sieve).

[0129] 3. Mixing and tableting:

[0130] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tableted using a tablet press to obtain unprocessed tablets.

[0131] Pharmaceutical compositions of Examples 1-3 and Comparative Examples 1-3

[0132] Using active pharmaceutical ingredients with different particle size distributions, and following the formulations and preparation methods of the above-mentioned basic embodiments, pharmaceutical compositions of Examples 1-3 and Comparative Examples 1-3 were prepared. In Example 1, the main ingredient was active pharmaceutical ingredient 1; in Example 2, the main ingredient was active pharmaceutical ingredient 4; in Example 3, the main ingredient was active pharmaceutical ingredient 5; and in Comparative Examples 1-3, the main ingredients were active pharmaceutical ingredients 6-8, respectively.

[0133] The properties of the pharmaceutical compositions prepared in Examples 1-3 and Comparative Examples 1-2 are shown in Table 3.

[0134] Table 3. Effects of different active pharmaceutical ingredients on the properties of the drug composition

[0135]

[0136] In the table, " / " indicates that the item was not detected.

[0137] The results show:

[0138] As shown in Examples 1-3, the pharmaceutical composition prepared by wet granulation using a raw material with a D50 of 20-75 μm and a K value of 1-2.5 exhibits a tablet hardness of over 45 N, a porosity of 1.3%-2.0%, good compressibility, small tablet weight variation (±0.9%~±1.2%), and extremely low friability of approximately 0.03%-0.08%. The 15-minute dissolution rate is ≥91.8%, and the RSD of dissolution at each time point does not exceed 10%. Furthermore, after 30 days of high-temperature storage, the tablet color of the pharmaceutical composition prepared by this invention remains unchanged and is still white. Although the content of impurity A and total impurities increases to some extent, the content does not exceed 1.0%, indicating that the raw material with a D50 of 20-75 μm and a K value of 1-2.5 has good process stability, dissolution stability, and chemical stability during wet granulation.

[0139] As shown in Comparative Example 1, the active pharmaceutical ingredient (API) has a large D50 and a K value exceeding 2.5. For example, with a D50 of 97.1 μm and a K value of 2.97, the particle size obtained after wet granulation is relatively large, resulting in poor compressibility of the formulation during tableting. Even increasing the tableting pressure does not improve the hardness of the tablets. This may be because the API has poor water absorption properties when the particle size is too large, making it difficult for the API to absorb water during wet granulation. Furthermore, the high moisture content in the excipients leads to over-granulation, which adversely affects the compressibility of the tablets. Simultaneously, the prepared tablets showed a 5-minute dissolution RSD of 19.2%, indicating significantly deteriorated dissolution stability.

[0140] As shown in Comparative Example 2, the D50 of the active pharmaceutical ingredient (API) is 20-75 μm, but the K value exceeds 2.5. For example, if the D50 is 42.4 μm but the K value is greater than 2.5, the fragility of the tablets after wet granulation increases significantly, and the RSD of the 5-minute dissolution rate is high, reaching 23.2%, indicating deteriorated dissolution stability. Since compound A is a highly variable drug, an excessively high RSD of dissolution rate poses a potential risk of inconsistent dissolution behavior in vivo.

[0141] According to Comparative Example 3, the active pharmaceutical ingredient (API) with a smaller D50 and a K value between 1 and 2.5 μm, for example, with a D50 of 6.9 μm and a K value of 2.41, the tablets obtained by wet granulation of this API showed a significantly increased difference in tablet weight (±5.5%) compared to the API with a larger particle size of 20-75 μm.

[0142] Meanwhile, experimental studies have found that when the D50 of the active pharmaceutical ingredient is too small, there is also a problem of low tableting qualification rate. The tablets prepared in Comparative Example 3 have a tableting qualification rate of less than 80%, while the tablets prepared in Examples 1-3 have a tableting qualification rate of more than 90%.

[0143] [Performance Evaluation of Pharmaceutical Compositions]

[0144] The properties of the pharmaceutical compositions containing the active pharmaceutical ingredient claimed in this invention are described in detail below with reference to Examples 4-7 and Comparative Example 4.

[0145] Example 4 Pharmaceutical Composition

[0146] Table 4 Prescription Table for Example 4

[0147]

[0148] The preparation method is as follows:

[0149] 1. Weigh the main ingredients, fillers, disintegrants, glidants, stabilizers, binders, and lubricants according to the prescription.

[0150] 2. Granulation and sizing:

[0151] (1) Adhesive preparation: Dissolve the adhesive and stabilizer in water and use it as an adhesive solution.

[0152] (2) Granulation: Add the main material, filler, disintegrant and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a 1.0 mm aperture pulverizer for crushing (85% passes through a 65 mesh sieve).

[0153] 3. Mixing and tableting:

[0154] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tablets are compressed using a tablet press.

[0155] Example 5 Pharmaceutical Composition

[0156] Table 5. Prescription Table for Example 5

[0157]

[0158] The preparation method is the same as in Example 4.

[0159] Example 6 Pharmaceutical Composition

[0160] Table 6 Prescription Table for Example 6

[0161]

[0162] The preparation method is as follows:

[0163] 1. Weigh the main ingredients, fillers, flow aids, stabilizers, binders, and lubricants according to the prescription.

[0164] 2. Granulation and sizing:

[0165] (1) Adhesive preparation: Dissolve the adhesive in water at 0-30℃ and use it as an adhesive solution.

[0166] (2) Granulation: Add the main material, stabilizer, filler and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a 1.0 mm aperture pulverizer for crushing (90% passes through a 65 mesh sieve).

[0167] 3. Mixing and tableting:

[0168] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tablets are compressed using a tablet press.

[0169] Example 7 Pharmaceutical Composition

[0170] Table 7 Prescription Table for Example 7

[0171]

[0172] The preparation method is as follows:

[0173] 1. Weigh the main ingredients, fillers, disintegrants, stabilizers, binders, and lubricants according to the prescription.

[0174] 2. Granulation and sizing:

[0175] (1) Adhesive preparation: Dissolve the adhesive in water at 0-30℃ and use it as an adhesive solution.

[0176] (2) Granulation: Add the main material, stabilizer, filler and disintegrant into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a 1.0 mm aperture pulverizer for crushing (95% passes through a 65 mesh sieve).

[0177] 3. Mixing and tableting:

[0178] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tablets are compressed using a tablet press.

[0179] Comparative Example 4: Pharmaceutical Composition

[0180] Table 8. Prescription Table for Comparative Example 4

[0181]

[0182] The preparation method is as follows:

[0183] Using active pharmaceutical ingredient 1, a tablet was prepared according to the method of Example 1 in patent JP2009209137A.

[0184] The properties of the pharmaceutical compositions prepared in Examples 4-7 and Comparative Example 4 are shown in Table 9.

[0185] Table 9. Effects of different drug compositions on their properties

[0186]

[0187] The " / " indicates that the item was not detected.

[0188] The results show:

[0189] The pharmaceutical composition obtained by wet granulation of the present invention has a tablet hardness of ≥32N, a porosity of ≤5%, good compressibility, small tablet weight variation (±1.1%~±1.6%), a friability of ≥0.4%, and a dissolution rate of ≥88.6% at 15 min, with a dissolution RSD of ≥8% at each time point. After high-temperature storage for 30 days, the tablet color remains unchanged and is still white. Although the content of impurity A and total impurities increases to some extent, the content does not exceed 1.0%, indicating that the pharmaceutical composition prepared using the active pharmaceutical ingredient of the present invention has good process stability, dissolution stability and chemical stability.

[0190] Regarding the tableting pass rate, Examples 4, 5, and 7 showed fewer instances of loose, cracked, and adhered tablets during the tableting process, with a pass rate greater than 90%. However, Example 6 exhibited some adhesion and cracking during the tableting process, resulting in a lower pass rate of approximately 85%. Comparative Example 4 showed significant adhesion and cracking during the tableting process, leading to a higher number of defective tablets and a pass rate below 80%.

[0191] [Evaluation of the effect of porosity on the performance of pharmaceutical compositions]

[0192] The following specific embodiments and comparative examples will further help those skilled in the art to understand the technical effects achieved by porosity in this invention.

[0193] Pharmaceutical compositions of Examples 8-9 and Comparative Example 5

[0194] Small-scale tests were conducted using the formulation of Example 1 and raw material 1, respectively. By controlling the particle size after granulation, the prepared tablets had different porosities.

[0195] The specific preparation method is as follows:

[0196] 1. Weigh the main ingredients, fillers, disintegrants, glidants, stabilizers, binders, and lubricants according to the prescription.

[0197] 2. Granulation and sizing:

[0198] (1) Adhesive preparation: Dissolve the adhesive and stabilizer in warm water and use it as an adhesive solution.

[0199] (2) Granulation: Add the main material, filler, disintegrant and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a blower of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. After drying, crush and sieve the material to obtain materials of different granulation sizes.

[0200] 3. Mixing and tableting:

[0201] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tablets are compressed using a tablet press.

[0202] Pharmaceutical compositions of Examples 10-13 and Comparative Example 6

[0203] Pilot-scale tests were conducted using the formulation of Example 1 and raw material 1, respectively. By controlling the pressure of the tablet press, the prepared tablets were made to have different porosities.

[0204] The specific preparation method is as follows:

[0205] 1. Weigh the main ingredients, fillers, disintegrants, glidants, stabilizers, binders, and lubricants according to the prescription.

[0206] 2. Granulation and sizing:

[0207] (1) Adhesive preparation: Dissolve the adhesive and stabilizer in warm water and use it as an adhesive solution.

[0208] (2) Granulation: Add the main material, filler, disintegrant and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a pulverizer with a 1.0 mm aperture for pulverization.

[0209] 3. Mixing and tableting:

[0210] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and pressure is applied using a tablet press. By controlling the main pressure, a drug composition with the corresponding porosity is obtained.

[0211] The properties of the pharmaceutical compositions prepared in Examples 8-13 and Comparative Examples 5-6 are shown in Table 10.

[0212] Table 10. Effect of porosity on the properties of pharmaceutical compositions

[0213]

[0214] Note:

[0215] (1) In the table, M1 indicates that all the granules after granulation pass through the 65-mesh sieve, M2 indicates that 75% of the granules after granulation pass through the 65-mesh sieve, and M3 indicates that the granules after granulation are the material on the 65-mesh sieve.

[0216] (2) In the table, “NA” means not detected and “ / ” means not detected.

[0217] The results show:

[0218] As can be seen from Examples 8-13, when the porosity of the pharmaceutical composition is less than 5%, it has good compressibility, small tablet weight difference, and friability not exceeding 0.2%; the prepared unprocessed tablets have a dissolution rate of greater than 85% after 15 minutes, and the RSD of dissolution rate at each time point does not exceed 10%; after high-temperature storage for 30 days, the increase in impurities is small, and it has good process performance, dissolution stability and chemical stability.

[0219] Comparing Comparative Example 5 and Comparative Example 6, it can be seen that when the porosity of the drug composition is greater than 5%, its brittleness will increase to 0.56%-0.79%, and the dissolution stability of the prepared tablets is poor, with a 5-minute dissolution RSD of more than 20%. After being stored at high temperature for 30 days, there are problems such as a significant increase in impurity A and total impurities (more than 1%) or tablet discoloration.

[0220] Example 14 Tablets

[0221] Table 11 Tablet Prescription List (140,000 tablets)

[0222]

[0223] The preparation method is as follows:

[0224] 1. Weigh the main ingredients, fillers, disintegrants, glidants, stabilizers, binders, and lubricants according to the prescription.

[0225] 2. Granulation and sizing:

[0226] (1) Adhesive preparation: Dissolve the adhesive and stabilizer in water and use it as an adhesive solution.

[0227] (2) Granulation: Add the main material, filler, disintegrant and flow aid into the mixing granulator and stir for 5 minutes. Add the binder and stir to granulate; use a fluidized bed for drying, with an air inlet temperature of 60℃ and a fan speed of 30 Hz, until the material temperature reaches 40℃ and the machine is stopped. The dried material is then put into a pulverizer with a 1.0 mm aperture for pulverization.

[0228] 3. Mixing and tableting:

[0229] After granulation, the granules are fed into a mixer, lubricant is added and mixed, and then tableted using a tablet press at a pressure of 765 kg.

[0230] 4. Coating:

[0231] The coating solution is used for coating in a coating machine. The exhaust temperature during the coating process is 42±2℃, and the weight gain of the coating is controlled at 3wt%, resulting in coated tablets.

[0232] The coated tablets prepared in Example 14 are as follows Figure 2 As shown in Table 12, its performance is as follows.

[0233] Table 12 Performance of the uncoated and coated tablets prepared in Example 14

[0234]

[0235] The results showed that the tablets prepared using the active pharmaceutical ingredient of the present invention have high hardness, good compressibility, a tableting qualification rate of more than 95% during large-scale production, small tablet weight difference, and low brittleness; the dissolution rate at 15 min is greater than 90%, and the RSD of dissolution rate at each time point does not exceed 10%, indicating good process performance, dissolution stability and chemical stability.

[0236] Compared with the reference formulation, the dissolution rate of the reference formulation was 27.6% at 5 min and the RSD reached 29.4%. Therefore, compared with the reference formulation, the tablets prepared by this invention have better dissolution stability and reduce the potential risk of inconsistent dissolution behavior in vivo.

[0237] The above description, in conjunction with specific embodiments, further illustrates the present invention. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of the present invention can be made without departing from the spirit and scope of the invention, and all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. The use of a pharmaceutical composition in improving the dissolution stability of an active pharmaceutical ingredient in the pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an active pharmaceutical ingredient and pharmaceutically acceptable excipients. The structural formula of the active pharmaceutical ingredient is as follows: ， The active pharmaceutical ingredient has the following characteristics: D10 is 3-25 micrometers, D50 is 20-75 micrometers, and the particle size distribution range is 1≤(D90-D10) / D50≤2.5; The pharmaceutical composition is in the form of a tablet; The excipients include at least one of fillers, disintegrants, flow aids, stabilizers, binders, and lubricants.

2. The application according to claim 1, characterized in that, The porosity of the pharmaceutical composition is <5%.

3. The application according to claim 1, characterized in that, The filler is at least one of microcrystalline cellulose, mannitol, corn starch, and lactose; The disintegrant is at least one of carboxymethyl cellulose and calcium carboxymethyl cellulose; The flow aid is at least one of light anhydrous silica and talc. The stabilizer is at least one of citric acid hydrate and citric acid; The adhesive is at least one of hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose; The lubricant is at least one of calcium stearate, magnesium stearate, and talc.

4. The application according to any one of claims 1-3, characterized in that, The pharmaceutical composition comprises, by mass percentage, the following components: 46%-68% active pharmaceutical ingredient, 15%-35% filler, 0%-25% disintegrant, 0%-2% flow aid, 0%-2% stabilizer, 1%-4% binder, and 1%-4% lubricant.

5. The application according to claim 4, characterized in that, The pharmaceutical composition is prepared by a wet granulation process.

6. The application according to claim 5, characterized in that, The wet granulation process includes the following steps: S1. Dissolve the adhesive and stabilizer in water to obtain the adhesive solution; S2. The active pharmaceutical ingredient is mixed with fillers, disintegrants, and glidants, and then granulated using a wet granulation process with a binder, followed by drying and granulation. S3. After granulation, the granules are mixed with lubricant and compressed into tablets to obtain plain tablets; Or it may include the following steps: S1. Dissolve the adhesive in water to obtain an adhesive solution; S2. The active pharmaceutical ingredient is mixed with stabilizers, fillers, disintegrants, and glidants, and then granulated using a wet granulation process with a binder, followed by drying and granulation. S3. After granulation, the granules are mixed with lubricant and compressed into tablets to obtain plain tablets.

7. The application according to claim 6, characterized in that, It also includes coating the raw film.

8. The application according to claim 1, characterized in that, The RSD of the dissolution rate of the pharmaceutical composition at each time point does not exceed 10%.

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