Milanserin hydrochloride tablet

Abstract

The invention discloses a mianserin hydrochloride tablet prepared in a wet granulation mode. The mianserin hydrochloride tablet is prepared from mianserin hydrochloride anhydride, calcium hydrogen phosphate, corn starch, hydroxypropyl methylcellulose, colloidal silicon dioxide, magnesium stearate and a film coating agent. According to the mianserin hydrochloride tablet and the preparation method thereof, the stability of the mianserin hydrochloride tablet is improved by using the high-concentration adhesive solution and optimizing the granulation parameter range, the problem that related substances are increased due to crystal transformation of active ingredients in the product preparation process is solved, and the medication safety of patients is better guaranteed.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable mianserin hydrochloride tablet based on a wet granulation process. Background Art

[0002] Mianserin Hydrochloride is a new generation of tetracyclic compounds, which mainly has sedative and antidepressant effects in clinical practice.

[0003]

[0004] Molecular formula: C 18 H 20 N2·HCl.

[0005] Molecular weight: 300.83.

[0006] Chemical name: 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine hydrochloride.

[0007] Mianserin hydrochloride was developed by Organon in the Netherlands and launched on the market in 1985. Its antidepressant effects are similar to those of other currently used antidepressants and also have antianxiety properties. Its chemical structure lacks the essential side chains of tricyclic antidepressants, which are thought to be responsible for their anticholinergic effects. Therefore, mianserin hydrochloride has no anticholinergic adverse effects. Mianserin hydrochloride is well tolerated, particularly in elderly patients and those with cardiovascular disease. It also does not produce significant cardiovascular effects.

[0008] The following table lists the standards for mianserin raw materials and preparations in the European Pharmacopoeia, British Pharmacopoeia, and the draft for public comment. The impurity standards for mianserin preparations are relatively loose, with a single impurity not exceeding 0.5%. Lowering the single impurity limit will help better control product quality and ensure patient safety.

[0009]

[0010] Under the existing technology, people are mostly committed to the development of new crystal forms of mianserin hydrochloride, in order to obtain more stable crystal forms and improve the safety of the preparation.

[0011] RU 2008136656 A discloses a crystal form of mianserin hydrochloride tablets and a method for preparing mianserin hydrochloride tablets by a wet granulation process. 9.68-11.11 wt.% mianserin hydrochloride, 75.5-77.55 wt.% calcium bisphosphate, 60% 8.18-8.38 wt.% potato starch, and 40% 1.61-1.85 wt.% gaseous silicon are mixed in a high-speed rotary mixer at a rotor speed of 60-100 rpm for 10-15 minutes, 1.80-1.96 wt.% methylcellulose is added, which is pre-dissolved in water and heated to a temperature of 45-55°C, and the mixture is stirred at a high speed of 60-100 rpm. The mixture is wetted at high speed for 15-25 minutes, dried to a residual moisture content of 2.5-3.0%, granulated through a sieve with an aperture of 1-1.5 mm, and mixed with the remaining 40% starch and 60% gaseous silica for 15 minutes. 0.97-1.11 wt.% of magnesium stearate is added and mixed for an additional 2-3 minutes. The mixture is calibrated through a sieve with an aperture of 1 mm before tablet compression. After compression, a film coating of hydroxypropyl methylcellulose is applied to the tablet cores at a level of 2.2-3.5% by weight of the tablet. This crystalline form is anhydrous, with characteristic 2θ peaks at 7.48°, 15.03°, and 18.84°.

[0012] CN 117820319 A discloses a new crystalline form of mianserin hydrochloride, designed to address the relatively low dissolution rate of tablets made from this crystalline form of mianserin hydrochloride and improve its dissolution rate. The tablet preparation method is as follows: 30g of mianserin hydrochloride, 48g of starch, 18g of microcrystalline cellulose, and 3g of sodium starch glycolate are weighed, passed through an 80-mesh sieve, and mixed. Then, 28g of 10% povidone K30 in ethanol is added, granulated through a 20-mesh sieve, dried at 60°C to a moisture content of 3.0%, sieved through a 20-mesh sieve, and 1.3g of magnesium stearate is added. The tablets are compressed into 1000 tablets and film-coated. Comparison of the crystal form's PXRD patterns confirms that this crystalline form is consistent with that in RU 2008136656 A.

[0013] CN 117777146 A discloses a new crystalline form I of mianserin hydrochloride monohydrate, with characteristic 2θ diffraction peaks at 8.39°, 12.84°, 13.84°, 14.66°, 16.21°, 17.61°, 19.49°, 21.27°, 22.36°, 25.39°, 25.93°, and 27.73°. The patent discloses a preparation process: 30g of mianserin hydrochloride, 48g of starch, 18g of microcrystalline cellulose, and 3g of sodium starch glycolate are weighed, passed through an 80-mesh sieve, and mixed. Then, 28g of 10% povidone K30 ethanol solution is added, granulated through a 20-mesh sieve, dried at 60°C to a moisture content of 3.0%, sieved through a 20-mesh sieve, and 1.3g of magnesium stearate is added. The tablets are compressed into 1,000 tablets and film-coated to obtain tablets.

[0014] Although the existing technology has studied various crystal forms of mianserin hydrochloride, the presence of water contact and heating in the preparation may cause crystal transformation, resulting in unqualified stability of the final preparation product. Summary of the Invention

[0015] The present invention aims to provide a stable mianserin hydrochloride tablet and a preparation process thereof by studying and optimizing the prescription and preparation process of the mianserin hydrochloride tablet, thereby preventing the product from crystallizing during the preparation process and ensuring good stability during storage.

[0016] Based on the synthesis route of mianserin hydrochloride, the standards included in various pharmacopoeias, and possible degradation pathways, the impurities that may be present in mianserin hydrochloride tablets are as follows:

[0017]

[0018] Since the wet granulation process has the advantages of avoiding separation of active ingredients and excipients and facilitating uniform mixing of active ingredients, and the process is simple, the technology is mature, and it is conducive to large-scale production, the present invention is based on the wet granulation process and solves the problem of active ingredient crystallization during the granulation process through a specific prescription composition and process optimization.

[0019] The specific technical solution of the present invention is as follows: A mianserin hydrochloride tablet is prepared by wet granulation and tableting. The tablet comprises anhydrous mianserin hydrochloride, calcium hydrogen phosphate, corn starch, hypromellose, colloidal silicon dioxide, and magnesium stearate, and is prepared by the following method:

[0020] Calcium hydrogen phosphate and mianserin hydrochloride are added to a wet mixing granulator, the cutter speed is set to 500-1500 rpm, the stirring speed is set to 80-200 rpm, and premixing is carried out for 5-10 minutes. A 10%-18% (w / v) aqueous solution of hypromellose is added as a binder, the cutter speed is kept constant, the stirring speed is adjusted to 100-125 rpm, and a soft material is prepared for 2-8 minutes. The soft material is dried using a fluidized bed to obtain dry granules. The dry granules, colloidal silicon dioxide, magnesium stearate and corn starch are added to a granulator for granulation, and the mixture is mixed and then compressed into tablets.

[0021] Preferably, in the mianserin hydrochloride tablets, the model of the hypromellose is selected from E3, E5 or E15.

[0022] Preferably, in the mianserin hydrochloride tablets, the calcium hydrogen phosphate includes anhydrous calcium hydrogen phosphate and / or calcium hydrogen phosphate dihydrate.

[0023] Preferably, the mianserin hydrochloride tablets further include a step of coating the tablets after tableting.

[0024] Preferably, the mianserin hydrochloride tablets have the following components in parts by weight: 10-100 parts of mianserin hydrochloride, 150-300 parts of calcium hydrogen phosphate, 10-80 parts of corn starch, 3-10 parts of hypromellose, 2-10 parts of colloidal silicon dioxide, and 0.1-10 parts of magnesium stearate.

[0025] Preferably, the mianserin hydrochloride tablet further comprises 2 to 10 parts of a film coating agent.

[0026] The advantages and positive effects of the present invention are:

[0027] The present invention studied the existing anhydrate and hydrate crystal forms of mianserin hydrochloride. The results showed that the hydrate crystal form has poor stability and exhibits significant growth of related substances under conditions such as light, high temperature, and high humidity. Although the anhydrate has good stability, it easily transforms into the hydrate crystal form during preparation and storage, resulting in poor stability.

[0028] Through extensive research, the present invention unexpectedly discovered that the use of a high-concentration binder solution and specific granulation process parameters can prevent the transformation of mianserin hydrochloride from an anhydrous crystal form to a hydrate crystal form with poor stability. At the same time, the problem of impurity growth during the storage process of the product is solved, thereby improving product stability.

[0029] The preparation method of the present invention has good process feasibility, the product dissolution is highly similar to that of the original research, and the in vitro dissolution is similar, thereby providing patients with a safe, effective and quality-controlled mianserin hydrochloride tablet. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 : Comparison of characteristic peaks of PXRD patterns of anhydrous and hydrated forms of mianserin hydrochloride. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0032] Example 1 Stability Study of Anhydrate Crystalline Form and Hydrate Crystalline Form of API

[0033] Mianserin hydrochloride anhydrate crystalline form was prepared according to RU 2008136656 A, and mianserin hydrochloride monohydrate crystalline form was prepared according to CN 117777146 A. PXRD of both crystalline forms was tested, and stability was investigated.

[0034] The PXRD detection method is as follows:

[0035] Instrument parameters:

[0036] Light source: Cu-Kα radiation, wavelength bbhd crystal module

[0037] Light tube voltage: 40kV Light tube current 40mA

[0038] Scanning angle: 5-50°

[0039] Step size: 0.026° Step time: 50s

[0040] Incident light module: Divergence slit 1 / 4° Anti-scattering slit 1° Light shield 10mm

[0041] Diffraction light module: anti-scattering slit 7.5mm

[0042] Sample stage: rotating sample stage (rotating speed 1spr)

[0043] Sample holder: PW1811 / 16 sample cup

[0044] Sample preparation: Grind an appropriate amount of mianserin hydrochloride for 3 minutes to form a powder. Spread it evenly into the sample cup, flush with the edge of the sample tank, and scrape off the excess sample around it.

[0045] 1 Crystal form and characteristic peaks

[0046] The PXRD patterns of the hydrate crystal form and the anhydrate crystal form prepared by the present invention are as follows: Figure 1 The characteristic peak data of the patent documents RU2008136656A, CN117820319A and CN117777146A are shown in Table 1. In order to facilitate the subsequent comparative study of the crystal forms, the 2θ diffraction peaks of 8.39°, 12.84°, and 17.61° were selected as the comparative characteristic peaks of the hydrate crystal form, and 7.48°, 15.03°, and 18.84° were selected as the comparative characteristic peaks of the anhydrate crystal form.

[0047] Table 1: Comparison of characteristic peaks 2θ of crystal forms

[0048]

[0049] 2. Stability investigation

[0050] The anhydrate and hydrate crystal forms of mianserin hydrochloride were placed under high temperature, high humidity, light, long-term and accelerated conditions, respectively, to investigate the stability of the crystal forms of mianserin hydrochloride and related substances.

[0051] Table 2: Stability test conditions

[0052]

[0053] 2.1 Detection methods for related substances

[0054] The inspection method is determined according to the high performance liquid chromatography method (General Chapter 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0055] Take about 10 mg of the product and place it in a 10 ml volumetric flask. Dissolve it in methanol and dilute to the mark. Shake well.

[0056] Control solution: Accurately measure 1 ml of the test solution, place it in a 50 ml volumetric flask, dilute it to the mark with methanol, and shake well. Accurately measure 1 ml of the test solution, place it in a 20 ml volumetric flask, dilute it to the mark with methanol, and shake well.

[0057] Sensitivity solution: Take about 9 mg of mianserin reference substance, place it in a 10 ml volumetric flask, add methanol to dissolve and dilute to the scale, shake well, accurately measure 1 ml, place it in a 100 ml volumetric flask, dilute to the scale with methanol, shake well, accurately measure 1 ml, place it in a 20 ml volumetric flask, dilute to the scale with methanol, and shake well.

[0058] Chromatographic conditions: Use octadecylsilane bonded silica gel as the packing (Agilent Infinity Lab Poroshell 120 EC-C18, 4.6 mm × 250 mm, 4 μm or equivalent columns are recommended); mobile phase A consists of 0.05 mol / L diammonium hydrogen phosphate buffer (pH adjusted to 7.5 with phosphoric acid)-methanol (90:10), and mobile phase B consists of water-methanol (5:95), with a linear gradient elution as shown in the table below. The flow rate is 1 ml / min; the column temperature is 45°C; the detection wavelength is 230 nm; the injection plate temperature is 6°C; and the injection volume is 10 μl. If gradient peaks interfere with the detection of impurities, it is recommended to install a ghost peak trapping cartridge (4.0 mm × 30 mm) between the mixer and injector of the liquid chromatograph pump.

[0059]

[0060] System suitability requires that the theoretical plate number calculated based on the Mianserin peak in the control solution chromatogram should be no less than 2000. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0061] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0062] If there are impurity peaks in the chromatogram of the limit test solution, the impurity content is calculated by the main component self-reference method with the correction factor, and all meet the corresponding limit requirements in the following table. Chromatographic peaks in the chromatogram of the test solution with a corrected peak area less than the main peak area of ​​the sensitivity solution are ignored (0.05%).

[0063] Impurity name Relative retention time Correction Factor limit(%) Impurity A 0.70 2.4 ≤0.15 Impurity B 0.50 1.0 ≤0.3 Impurity E 0.82 1.0 ≤0.15 Other single impurities — 1.0 ≤0.10 Total impurities — — ≤0.5

[0064] Calculation formula:

[0065]

[0066] Total impurities (%) = ∑ unknown impurities (%) + ∑ known impurities (%)

[0067] Where A 杂质 is the peak area of ​​the impurity peak in the chromatogram of the test solution;

[0068] A 对照 is the peak area of ​​the main peak in the chromatogram of the reference solution;

[0069] f is the correction factor for impurities, and other unknown impurities are calculated as 1.0.

[0070] 2.2 Crystal stability

[0071] The X-ray powder diffraction results of the anhydrate crystal form and the hydrate crystal form under different stability conditions are shown in Tables 3 and 4. The results show that the anhydrate crystal form and the hydrate crystal form are stable under high temperature, high humidity and light conditions and will not undergo crystal transformation.

[0072] Table 3: Crystalline stability of anhydrate of mianserin hydrochloride

[0073]

[0074] Table 4: Crystalline stability of mianserin hydrochloride hydrate

[0075]

[0076] 2.3 Stability of Related Substances in APIs

[0077] The results of related substances of the anhydrous crystal form and the hydrated crystal form under different stability conditions are shown in Table 5. The results show that the anhydrous crystal form has a smaller impurity growth trend under various conditions, the hydrate has poor stability, and the growth of related substances under various stability conditions, especially under light conditions, is higher than that of the anhydrous crystal form.

[0078] Table 5: Comparison of the stability of the crystalline forms of mianserin hydrochloride hydrate and anhydrate - related substances

[0079]

[0080]

[0081] Preparation process research of Examples 2 to 7

[0082] Using a 12% aqueous solution of hydropropyl methylcellulose as a binder and anhydrous mianserin hydrochloride as the API, granulation was conducted to investigate the factors affecting the crystal transformation, such as granulation time, soft material placement time, soft material drying temperature, and drying time. The results showed that granulation time and stirring speed had a significant impact on crystal transformation. The details are as follows: 1. Prescription

[0083] Material Name Single tablet dosage (mg) Mianserin hydrochloride anhydrate crystal form 30 Calcium hydrogen phosphate 222.5 corn starch 30 Hydroxypropyl methylcellulose 4.5 Colloidal silica 6 magnesium stearate 3 Purified water (granulation) 33

[0084] 2 Process

[0085] Add calcium hydrogen phosphate and mianserin hydrochloride to a wet granulator, set the blade speed to 1500 rpm and the stirring speed to 200 rpm, and premix for 5 minutes. After adding the aqueous solution of hypromellose, granulate and dry according to the parameters in the table below. The wet granules are oven-dried. After tableting, the crystal form is tested and the tablets are stored under accelerated conditions (temperature 40°C ± 2°C, relative humidity 75% ± 5%) for one month to observe changes in the crystal form and related substances.

[0086] Table 6: Parameters for studying crystal transformation factors

[0087]

[0088] 3. Detection methods for related substances in preparations

[0089] Inspection method: High performance liquid chromatography method according to 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0090] Specific operations:

[0091] Solution preparation:

[0092] Solvent: Acetonitrile-water (50:50)

[0093] Test solution: Take 20 tablets of this product, accurately weigh them, grind them into powder, accurately weigh about 201 mg of fine powder (equivalent to 20 mg of mianserin hydrochloride), place it in a 20 ml volumetric flask, add 15 ml of solvent, sonicate for 10 minutes to dissolve the mianserin hydrochloride, dilute to the scale with solvent, shake well, filter, and take the filtrate.

[0094] Control solution: Accurately measure 1 ml of the test solution, place it in a 200 ml volumetric flask, dilute to the scale with solvent, and shake well.

[0095] System suitability solution: Take about 201 mg of the fine powder under the content determination item (equivalent to about 20 mg of mianserin hydrochloride), place it in a 20 ml volumetric flask, add 2 ml of 3% hydrogen peroxide solution, shake well to allow the fine powder to fully contact the 3% hydrogen peroxide solution, heat in a 40°C water bath for 1 hour, take out, cool, dilute to the scale with solvent, shake well, filter, and take the filtrate.

[0096] Sensitivity solution: Take an appropriate amount of mianserin reference substance, weigh accurately, dissolve it in solvent and quantitatively dilute it to make a solution containing approximately 0.5 μg of mianserin hydrochloride per 1 ml.

[0097] Chromatographic conditions and system suitability requirements:

[0098] Chromatographic column: Octadecylsilane bonded silica gel as filler (YMC Triart C18, 4.6 mm × 150 mm, 3 μm or equivalent performance column is recommended);

[0099] Trap column: If the gradient peak affects the detection of related substances, it is recommended to install a ghost peak trapping column (Panhe cph3040, 4.0 mm × 30 mm) between the mixer and the injector of the liquid chromatography pump, and a guard column (Yuexu Ultimate XB-C18, 4.6 mm × 10 mm, 5 μm) in front of the chromatographic column;

[0100] Mobile phase A: 0.02 mol / L diammonium phosphate buffer (adjust pH to 8.0 with phosphoric acid or ammonia)-acetonitrile (90:10);

[0101] Specific preparation steps: weigh 2.64g of diammonium hydrogen phosphate, add 1000ml of water and stir to dissolve, adjust the pH value to 8.0 with phosphoric acid or ammonia water, filter, measure 900ml, add 100ml of acetonitrile, mix well, and sonicate.

[0102] Mobile phase B: water-acetonitrile (30:70);

[0103] Specific preparation steps: Take 700 ml of acetonitrile after filtration and 300 ml of water, mix well, and sonicate.

[0104] Flow rate: 1.0 ml / min;

[0105] Column temperature: 30°C;

[0106] Detection wavelength: 250nm;

[0107] Injector temperature: 10°C;

[0108] Injection volume: 10 μl;

[0109] Gradient program:

[0110]

[0111] System suitability requirements: In the system suitability solution chromatogram, impurity G and mianserin should elute sequentially, and the theoretical plate number calculated based on the mianserin peak should be no less than 5000; in the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0112] Assay method and limits

[0113] Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0114] Limits: If there are impurity peaks in the chromatogram of the test solution, except for the excipient peaks and solvent peaks with relative retention times less than 0.07, if there is a chromatographic peak with a retention time consistent with that of impurity G in the system suitability solution, the corrected peak area (multiplied by the correction factor 1.2) shall not be greater than the main peak area of ​​the control solution (0.5%), the peak area of ​​impurity E (relative retention time of approximately 0.67) shall not be greater than the main peak area of ​​the control solution (0.5%), the peak area of ​​other individual impurities shall not be greater than the main peak area of ​​the control solution (0.5%), the total amount of impurities shall not exceed 1.0%, and chromatographic peaks with an area less than the main peak area of ​​the sensitivity solution shall be ignored (0.05%).

[0115] Calculation formula:

[0116]

[0117] Total impurities (%) = ∑ known impurities % + ∑ unknown impurities %

[0118] Where A i is the peak area of ​​the impurity in the chromatogram of the test solution;

[0119] A r is the peak area of ​​mianserin in the chromatogram of the control solution;

[0120] f is the correction factor for impurities, and unknown impurities are calculated as 1.0.

[0121] 4 Results

[0122] Table 7: Results of research on crystal transformation factors

[0123]

[0124] Table 8: Crystal form test results

[0125]

[0126]

[0127] 5 Conclusion

[0128] Comparative studies of Examples 2-7 revealed that while cutter speed, soft material placement time, and drying time had minimal impact on crystal form changes, granulation time and stirring speed had a greater impact on crystal transformation. Within the stirring speed range of 100-125 rpm and a granulation time of 2-8 minutes, crystal transformation did not occur within 60 minutes of soft material placement and drying time. Furthermore, even after one month under accelerated stability conditions, crystal transformation did not occur. Samples that experienced crystal transformation showed significant increases in related substances.

[0129] Examples 8-17 Adhesive Studies

[0130] The effects of different binder types, concentrations, and dosages on dissolution, compressibility, and crystal form were investigated. Changes in related substances and crystal forms of the self-made and reference preparations under different stability conditions were also investigated.

[0131] Table 9: Mianserin Hydrochloride Tablets Reference Preparation Information

[0132]

[0133] 1 prescription

[0134] Table 10: Adhesive Study Unit Dose Prescription Amount (mg)

[0135]

[0136]

[0137] 2 Process

[0138] Calcium hydrogen phosphate and mianserin hydrochloride were added to a wet mixer granulator, with the blade speed set at 1500 rpm and the stirring speed at 200 rpm. Premixing was performed for 5 minutes. After the addition of the hydropropyl methylcellulose aqueous solution, the blade speed was maintained constant and the stirring speed was 125 rpm. Granulation was continued for 4 minutes. The wet granules were dried in a fluidized bed and granulated. The granulated material was added to a mixer, mixed, and compressed into tablets. Finally, a film coating agent was used for coating.

[0139] 3 Dissolution test method

[0140] Inspection method: General Chapter 0931 Dissolution and Release Determination Method 1 and 0401 Ultraviolet-Visible Spectrophotometry of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0141] Specific operations:

[0142] Dissolution conditions: Use 500 ml of pH 4.5 acetate buffer (2.99 g sodium acetate, 14 ml of 2 mol / L acetic acid solution, dissolve in water, dilute to 1000 ml, and shake well) as the dissolution medium. Rotate at 100 rpm. Sampling should be performed according to the procedure described above, with samples collected at 5, 10, and 15 minutes. Temperature should be 37°C ± 0.5°C. Basket method.

[0143] Solution preparation

[0144] Test solution: Take the eluate, filter it, and take the filtrate.

[0145] Reference solution: Take an appropriate amount of mianserin hydrochloride reference substance, accurately weigh it, dissolve it in methanol and quantitatively dilute it to make a solution containing approximately 1.5 mg per 1 ml. Accurately measure an appropriate amount and quantitatively dilute it with dissolution medium to make a solution containing approximately 60 μg per 1 ml.

[0146] Determination method: Take the test sample solution and the reference sample solution, measure the absorbance at a wavelength of 279 nm according to the UV-visible spectrophotometry method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0401), and calculate the solubility.

[0147] Calculation formula:

[0148]

[0149] Where A 样 is the absorbance of mianserin hydrochloride in the test solution;

[0150] A 对 is the absorbance of mianserin hydrochloride in the reference solution;

[0151] W 对 is the sample weight of mianserin hydrochloride reference substance, mg;

[0152] P is the content of mianserin hydrochloride reference substance;

[0153] V 对 is the dilution volume of the reference solution, ml;

[0154] 500 is the volume of dissolution medium, ml;

[0155] 30 is the specification of Mianserin Hydrochloride Tablets, mg.

[0156] 4 Results

[0157] Table 11: Adhesive Study Results

[0158]

[0159] Table 12: Crystal form detection results at 0

[0160]

[0161]

[0162] 5. Conclusion

[0163] Based on the above results, through investigation of the binder, it was unexpectedly discovered that increasing the binder concentration significantly accelerated dissolution. However, excessive concentrations resulted in poor compressibility, and lower concentrations and other types of binders could cause changes in the crystal form during the preparation process. Therefore, this process requires controlling the concentration of the HPMC solution to 10% to 18%, and the dosage to 3 to 6 mg per tablet.

[0164] Comparative study on the stability of self-made and reference preparations

[0165] Stability comparisons were performed using Examples 8, 16, and 17 with a reference formulation to examine changes in related substances and crystal forms under different stability conditions.

[0166] Table 13: Stability test conditions

[0167] Inspection conditions specific conditions Inspection time accelerate Temperature 40℃±2℃ Relative humidity 75%±5% March, June long Temperature 30℃±2℃ Relative humidity 65%±5% March, June

[0168] Table 14: Comparison of stability between different self-made products and reference preparations - Crystal form

[0169]

[0170]

[0171] Table 15: Comparative results of stability of different homemade preparations and reference preparations - related substances

[0172]

[0173] According to the following results, the crystal form of the self-made products prepared with different prescriptions did not change during the stability study. The reference preparation maintained a mixed crystal state during the study and its stability was significantly worse than that of the self-made product, indicating that the self-made product has better stability.

Claims

1. A mianserin hydrochloride tablet, characterized in that The tablets are prepared by wet granulation and tableting. The tablets comprise mianserin hydrochloride anhydrate, calcium hydrogen phosphate, corn starch, hypromellose, colloidal silicon dioxide, and magnesium stearate. The tablets are prepared by the following method: adding calcium hydrogen phosphate and mianserin hydrochloride to a wet mixing granulator, setting a cutter speed of 500 rpm to 1500 rpm and a stirring speed of 80 rpm to 200 rpm, premixing for 5 to 10 minutes, adding a 10% to 18% (w / v) aqueous solution of hypromellose as a binder, keeping the cutter speed constant, adjusting the stirring speed to 100 rpm to 125 rpm, preparing a soft material for 2 to 8 minutes, drying the soft material in a fluidized bed to obtain dry granules, adding the dry granules, colloidal silicon dioxide, magnesium stearate, and corn starch to a granulator for granulation, mixing, and tableting to obtain the tablets.

2. The mianserin hydrochloride tablet according to claim 1, characterized in that The type of Hydroxypropyl Methylcellulose is selected from one or more of E3, E5 and E15.

3. The mianserin hydrochloride tablet according to claim 1, characterized in that The calcium hydrogen phosphate includes anhydrous calcium hydrogen phosphate and / or calcium hydrogen phosphate dihydrate.

4. The mianserin hydrochloride tablet according to claim 1, characterized in that It includes the step of coating the tablets after tableting.

5. The mianserin hydrochloride tablet according to claim 1, characterized in that The weight parts of the components of the tablet are as follows: 10-100 parts of mianserin hydrochloride, 150-300 parts of calcium hydrogen phosphate, 10-80 parts of corn starch, 3-10 parts of hypromellose, 2-10 parts of colloidal silicon dioxide, and 0.1-10 parts of magnesium stearate.

6. The mianserin hydrochloride tablet according to claim 5, characterized in that The tablet further comprises 2 to 10 parts of a film coating agent.

7. The mianserin hydrochloride tablet according to any one of claims 1 to 6, characterized in that The PXRD spectrum of mianserin hydrochloride anhydrate has characteristic peaks at 2θ diffraction angles of 7.48±0.2°, 15.03±0.2°, and 18.84±0.2°, and has one or more of the following characteristic peaks: 9.53±0.2°, 11.89±0.2°, 15.91±0.2°, 19.32±0.2°, 20.54±0.2°, 21.35±0.2°, 23.49±0.2°, and 25.04±0.2°.

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