Terbinafine hydrochloride tablets and preparation method thereof

Abstract

The present invention provides terbinafine hydrochloride tablets, comprising terbinafine hydrochloride, a disintegrant, a binder, a polymethacrylic acid resin, glycolic acid, a glidant, and a lubricant. Compared with the prior art, the present invention uses glycolic acid, an organic acid, as a pH regulator to maintain an acidic pH environment throughout the tablet, thereby ensuring product stability throughout its storage cycle. Furthermore, polymethacrylic acid resin is used as a filler to improve the compressibility of the material, ensuring that the product meets hardness requirements throughout its storage cycle, with quality comparable to that of a tablet at day 0.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a terbinafine hydrochloride tablet and a preparation method thereof. Background Art

[0002] Terbinafine hydrochloride is an allylamine antifungal drug that can treat infections of the skin, hair and nails caused by Trichophyton, Microsporum canis and Epidermophyton floccosum. It can also treat various ringworms, skin yeast infections caused by Candida and onychomycosis caused by mold.

[0003] Terbinafine hydrochloride tablets are generally prepared by wet granulation, but the raw material of terbinafine hydrochloride accounts for more than 70% of the prescription. Terbinafine hydrochloride is a crystalline powder, resulting in poor compressibility of the material. It is difficult to achieve the established hardness during the tableting process, and the product has obvious pressure release after accelerated testing, resulting in faster dissolution of the product. At the same time, the raw material terbinafine hydrochloride has slightly poor stability. After accelerated testing, the product has a significant increase in related substances, which cannot guarantee the stability of the product throughout the storage period. Summary of the Invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide a terbinafine hydrochloride tablet with good stability and a preparation method thereof.

[0005] The invention provides a terbinafine hydrochloride tablet comprising terbinafine hydrochloride, a disintegrant, a binder, a polymethacrylic acid resin, glycolic acid, a glidant and a lubricant.

[0006] Preferably, including:

[0007]

[0008] Preferably, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch;

[0009] The binder is selected from one or more of hydroxypropyl cellulose, hypromellose, povidone, gelatin and polyethylene glycol;

[0010] The glidant is selected from colloidal silicon dioxide;

[0011] The lubricant is selected from one or more of magnesium stearate, micropowder silica gel and talc.

[0012] Preferably, the terbinafine hydrochloride tablets are detected for related substances by high performance liquid chromatography; the stationary phase of the high performance liquid chromatography is octadecylsilane bonded silica gel; the mobile phase of the high performance liquid chromatography includes mobile phase A and mobile phase B; the mobile phase A is a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 40:20:40; the mobile phase B is a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 10:50:40.

[0013] Preferably, the high performance liquid chromatography adopts linear gradient elution, and the elution procedure is as follows in terms of volume fraction:

[0014] Time (min) A％ B％ 0 100 0 10 80 20 25 0 100 30 0 100 31 70 30 38 100 0

[0015] The present invention also provides a method for preparing terbinafine hydrochloride tablets, comprising:

[0016] Terbinafine hydrochloride, a disintegrant, a binder and a polymethacrylic acid resin are mixed, and a glycolic acid aqueous solution is added for wet granulation. After drying and granulation, a flow aid and a lubricant are added for total mixing, and tableting is performed to obtain terbinafine hydrochloride tablets.

[0017] Preferably, the terbinafine hydrochloride, disintegrant, binder and polymethacrylic acid resin are mixed for 5 to 10 minutes before adding the glycolic acid aqueous solution.

[0018] Preferably, the mass concentration of the glycolic acid aqueous solution is 3% to 8%; the glycolic acid aqueous solution is added within 1 minute.

[0019] Preferably, the flow aid is added and mixed for 3 to 5 minutes, and then the lubricant is added and mixed for a total of 3 to 5 minutes.

[0020] Preferably, the hardness of the tablet is 80-100N.

[0021] The present invention provides terbinafine hydrochloride tablets, comprising terbinafine hydrochloride, a disintegrant, a binder, a polymethacrylic acid resin, glycolic acid, a glidant, and a lubricant. Compared with the prior art, the present invention uses glycolic acid, an organic acid, as a pH regulator to maintain an acidic pH environment throughout the tablet, thereby ensuring product stability throughout its storage cycle. Furthermore, polymethacrylic acid resin is used as a filler to improve the compressibility of the material, ensuring that the product meets hardness requirements throughout its storage cycle, with quality comparable to that of a tablet at day 0. DETAILED DESCRIPTION

[0022] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0023] The invention provides a terbinafine hydrochloride tablet comprising terbinafine hydrochloride, a disintegrant, a binder, a polymethacrylic acid resin, glycolic acid, a glidant and a lubricant.

[0024] Further preferably, the terbinafine hydrochloride tablets provided by the present invention include:

[0025]

[0026] In the present invention, the content of the disintegrant in the terbinafine hydrochloride tablets is preferably 45 to 15 parts by weight, more preferably 4 to 12 parts by weight, and even more preferably 4 to 10 parts by weight; in the embodiments provided by the present invention, the content of the disintegrant in the terbinafine hydrochloride tablets is specifically 8 parts by weight, 10 parts by weight, 6 parts by weight, 4 parts by weight or 7.7 parts by weight; the type of the disintegrant is preferably one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch.

[0027] In the present invention, the content of the binder in the terbinafine hydrochloride tablets is preferably 0.5 to 8 parts by weight, more preferably 0.5 to 6 parts by weight, further preferably 0.8 to 5 parts by weight, and most preferably 0.8 to 3 parts by weight; in the embodiments provided by the present invention, the content of the binder in the terbinafine hydrochloride tablets is specifically 1.6 parts by weight, 0.8 parts by weight, 2.4 parts by weight or 1.55 parts by weight; the type of the binder is preferably one or more of hydroxypropyl cellulose, hypromellose, povidone, gelatin and polyethylene glycol.

[0028] The terbinafine hydrochloride tablets provided by the present invention use polymethacrylic acid resin as a filler; the content of the polymethacrylic acid resin in the terbinafine hydrochloride tablets is preferably 5 to 25 parts by weight, more preferably 5 to 20 parts by weight, and most preferably 5 to 15 parts by weight; in the embodiments provided by the present invention, the content of the polymethacrylic acid resin in the terbinafine hydrochloride tablets is specifically 6 parts by weight, 8 parts by weight, 12 parts by weight, 14 parts by weight, 10 parts by weight, or 10.75 parts by weight.

[0029] The terbinafine hydrochloride tablets provided by the present invention use glycolic acid as a pH regulator; the content of the glycolic acid in the terbinafine hydrochloride tablets is preferably 0.1 to 5 parts by weight, more preferably 0.1 to 3 parts by weight, further preferably 0.2 to 2 parts by weight, and most preferably 0.2 to 1 part by weight; in the embodiments provided by the present invention, the content of the glycolic acid in the terbinafine hydrochloride tablets is specifically 0.2 parts by weight, 0.6 parts by weight, 1 part by weight, or 0.7 parts by weight.

[0030] In the present invention, the content of the glidant in the terbinafine hydrochloride tablets is preferably 0.5 to 5 parts by weight, more preferably 0.5 to 3 parts by weight, further preferably 0.5 to 2 parts by weight, and most preferably 0.5 to 1 part by weight; in the embodiments provided by the present invention, the content of the lubricant in the terbinafine hydrochloride tablets is specifically 0.5 parts by weight; the glidant is preferably colloidal silicon dioxide.

[0031] In the present invention, the content of the lubricant in the terbinafine hydrochloride tablets is preferably 0.3 to 5 parts by weight, more preferably 0.3 to 3 parts by weight, further preferably 0.3 to 2 parts by weight, and most preferably 0.4 to 1 part by weight; in the embodiments provided by the present invention, the content of the lubricant in the terbinafine hydrochloride tablets is specifically 0.4 parts by weight or 0.6 parts by weight; the type of the lubricant is preferably one or more of magnesium stearate, micropowdered silica gel and talc.

[0032] The present invention uses the organic acid glycolic acid as a pH regulator to maintain the pH environment of the entire tablet at an acidic state, thereby ensuring the stability of the product throughout the entire storage period. At the same time, polymethacrylic acid resin is selected as a filler to improve the compressibility of the material, ensuring that the hardness of the product meets the requirements throughout the entire storage period and the quality is equivalent to that of the tablet at day 0.

[0033] The present invention also provides a method for detecting related substances in the above-mentioned terbinafine hydrochloride tablets. The present invention preferably detects related substances by high performance liquid chromatography; the stationary phase of the high performance liquid chromatography is octadecylsilane bonded silica gel; the mobile phase of the high performance liquid chromatography includes mobile phase A and mobile phase B; the mobile phase A is preferably a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 40:20:40; the mobile phase B is preferably a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 10:50:40; the concentration of the triethylamine buffer is preferably 0.1% to 0.5%, more preferably 0.2% to 0.3%; the pH value of the triethylamine buffer is 6 to 7, more preferably 6.5; in the present invention, glacial acetic acid is preferably used to adjust the pH value of the triethylamine buffer; the high performance liquid chromatography adopts linear gradient elution, and the elution procedure is as follows in terms of volume fraction:

[0034] Time (min) A％ B％ 0 100 0 10 80 20 25 0 100 30 0 100 31 70 30 38 100 0

[0035] The flow rate of the mobile phase in the high performance liquid chromatography is preferably 0.5 mL / min; the detection wavelength of the high performance liquid chromatography is preferably 280 nm; the injection temperature is preferably 2°C to 6°C, more preferably 4°C; in the present invention, the terbinafine hydrochloride tablets are preferably first dissolved in a solvent before detecting related substances; the solvent is preferably an acetonitrile aqueous solution; and the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is preferably 2:1.

[0036] The present invention also provides a preparation method of the terbinafine hydrochloride tablets, comprising: mixing terbinafine hydrochloride, a disintegrant, a binder and a polymethacrylic acid resin, adding a glycolic acid aqueous solution for wet granulation, drying and granulating, adding a flow aid and a lubricant for total mixing, and tableting to obtain the terbinafine hydrochloride tablets.

[0037] The present invention has no particular limitation on the sources of all raw materials, and any raw materials available on the market can be used. The types and contents of the terbinafine hydrochloride, disintegrant, binder, polymethacrylic acid resin, glycolic acid, glidant, and lubricant are the same as those described above and will not be described in detail here.

[0038] In the present invention, the terbinafine hydrochloride, binder, flow aid and polymethacrylic acid resin are preferably all sieved first; the mesh number of the sieve is preferably 50-100 mesh, more preferably 80 mesh.

[0039] Terbinafine hydrochloride, a disintegrant, a binder and polymethacrylic acid resin are mixed; the mixing is preferably carried out in a wet granulation mixer; and the mixing time is preferably 5 to 10 minutes.

[0040] After mixing, a glycolic acid aqueous solution is added for wet granulation; the mass concentration of the glycolic acid aqueous solution is preferably 3% to 8%, more preferably 5%; the glycolic acid aqueous solution is preferably added within 1 minute; the stirring speed of the wet granulation is preferably 300 to 400 rpm, and the shear rate is preferably 1500 to 2000 rpm; the time of the wet granulation is preferably 5 to 7 minutes; the wet granulation is preferably carried out using an oscillating granulator; the mesh size of the granulation screen for the wet granulation is preferably 24 to 30 meshes.

[0041] After wet granulation, the granules are dried; the drying is preferably carried out in a fluidized bed dryer; the moisture content is preferably controlled to be less than 3%.

[0042] After drying, the granules are sized; the granulation is preferably performed using an oscillating granulator; the mesh size of the granules is preferably 24 to 30 meshes.

[0043] After granulation, a glidant and a lubricant are added for total mixing; the total mixing is preferably carried out in a three-dimensional motion mixer; in the present invention, it is preferred to add the glidant and mix for 3 to 5 minutes before adding the lubricant for total mixing; the total mixing time is preferably 3 to 5 minutes.

[0044] After the total mixing, tableting is performed to obtain terbinafine hydrochloride tablets; the hardness of the tablets is preferably 80-100N.

[0045] The present invention adopts the method of adding glycolic acid, an organic acid, to a wetting agent for granulation, thereby maintaining the pH value environment of the entire tablet at an acidic state, thereby ensuring the stability of the product throughout the entire storage period. Secondly, polymethacrylic acid resin is used as a filler to improve the compressibility of the material, ensuring that the hardness of the product throughout the entire storage period meets the requirements and the quality is equivalent to that of the tablet on day 0. In addition, the process provided by the present invention has good reproducibility, controllable quality, and meets the requirements of consistency evaluation. The preparation process is simple and suitable for industrial production.

[0046] To further illustrate the present invention, the following describes in detail a terbinafine hydrochloride tablet and a preparation method thereof in conjunction with examples.

[0047] The reagents used in the following examples are all commercially available.

[0048] Terbinafine hydrochloride: produced by Zhejiang Dongya Pharmaceutical Co., Ltd.; glycolic acid: Shanghai Bilai Chemical Technology Co., Ltd.; polymethacrylate resin: Lianyungang Hengyang Pharmaceutical Co., Ltd.; microcrystalline cellulose: Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Model 101; hydropropyl methylcellulose: Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Model E5; cross-linked polyvinylpyrrolidone: BASF (China) Co., Ltd. Model XL-10; colloidal silicon dioxide: Cabot Corporation; magnesium stearate: Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; terbinafine hydrochloride reference substance: China National Institute for Food and Drug Control; pH 1.2 dissolution medium: preparation method according to the "Guidelines for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Preparations".

[0049] The products obtained in the embodiments, test examples and comparative examples were tested according to the following method:

[0050] Test method:

[0051] Related substance determination test:

[0052] Related substances: Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0053] Solvent: acetonitrile-water (2:1).

[0054] Test solution: Take an appropriate amount of fine powder of this product, dissolve it in solvent and dilute it into a solution containing approximately 0.3 mg of terbinafine per 1 ml, shake well, centrifuge and take the supernatant as the test solution.

[0055] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with solvent to make a solution containing approximately 0.3 μg of terbinafine per 1 ml.

[0056] System suitability solution: Take an appropriate amount of terbinafine hydrochloride, dissolve it in solvent and dilute it to a solution containing 2 mg per 1 ml, and irradiate it under a UV lamp at 254 nm for 0.5 hour.

[0057] Sensitivity solution: Accurately measure an appropriate amount of control solution and quantitatively dilute it with solvent to make a solution containing approximately 0.03 μg of terbinafine per 1 ml.

[0058] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; triethylamine buffer (0.2% triethylamine solution, adjusted to pH 6.5 with glacial acetic acid)-methanol-acetonitrile (40:20:40) was used as mobile phase A, and triethylamine buffer-methanol-acetonitrile (10:50:40) was used as mobile phase B. Linear gradient elution was performed according to the table below at a flow rate of 0.5 ml per minute; the detection wavelength was 280 nm; the injection volume was 10 μL.

[0059] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 10 80 20 25 0 100 30 0 100 31 70 30 38 100 0

[0060] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0061] Content determination test:

[0062] Content determination: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0512).

[0063] Test solution: Take 20 tablets of this product, grind them into powder, accurately weigh an appropriate amount of fine powder, add solvent to dissolve and quantitatively dilute to a solution containing approximately 0.1 mg of terbinafine per 1 ml, filter, and take the filtrate as the test solution.

[0064] Reference solution: Take an appropriate amount of terbinafine hydrochloride reference substance, accurately weigh it, dissolve it in solvent and quantitatively dilute it to make a solution containing approximately 0.1 mg of terbinafine per 1 ml.

[0065] Solvents, system suitability solutions, and chromatographic conditions are listed under Related Substances.

[0066] Determination: Accurately measure the test solution and reference solution, inject them separately into a liquid chromatograph, and record the chromatogram. Calculate the terbinafine content in the test sample based on the peak area using the external standard method.

[0067] Dissolution test:

[0068] Samples were taken and tested according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2). 900 ml of pH 1.2 dissolution medium was used as the dissolution medium at a speed of 50 rpm. After 10, 15, 30, 45, and 60 minutes, 15 ml of the sample was taken, and 10 ml was discarded to prepare the test sample. Separately, approximately 20 mg of terbinafine hydrochloride reference substance was accurately weighed and placed in a 100 ml volumetric flask. Dissolved in a solvent (methanol: water = 1:1) and quantitatively diluted to the mark, then shaken. Accurately measure 5 ml and place it in a 25 ml volumetric flask. Add pH 1.2 medium and quantitatively dilute to the mark, then shaken. The test and reference solutions were then measured for absorbance at a wavelength of 283 nm using UV-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0401). The cumulative dissolution amount per tablet was calculated.

[0069] Test Example 1: Prescription Screening Test

[0070] Prescription composition:

[0071]

[0072] 186.7 g of terbinafine hydrochloride (content 98.7%, total impurities 0.05%) were taken and tablets containing terbinafine hydrochloride were prepared according to the above table. The dissolution and related substances were tested, and the tableting was also tested. The concentration of the glycolic acid aqueous solution was 5%.

[0073] Preparation process:

[0074] (1) Raw material and auxiliary material processing: Terbinafine hydrochloride raw material, hypromellose and colloidal silicon dioxide are all passed through an 80-mesh sieve; polymethacrylic acid resin is passed through an 80-mesh sieve and set aside;

[0075] (2) Premixing and granulation: Terbinafine hydrochloride, cross-linked polyvinylpyrrolidone, hypromellose, and polymethacrylic acid resin (added according to the prescription requirements) were added to a wet granulation mixer and mixed for 10 minutes. A glycolic acid aqueous solution (added according to the prescription requirements) was added for granulation. The stirring speed of the granulation was 400 rpm and the shear rate was 1500 rpm. The slurry addition was completed within 1 minute. The granulation was continued for 6 minutes. The material was discharged and the soft material was granulated using a swing granulator with a 24-mesh steel mesh.

[0076] (3) Drying: The granules obtained in step (2) are dried in a fluidized bed dryer with an inlet air temperature of 60°C and a moisture content of less than 3%;

[0077] (4) Granulation: The dried granules obtained in step (3) are granulated using an oscillating granulator, and the granulation screen is a 24-mesh steel mesh;

[0078] (5) Total mixing: Add the granules obtained in step (4) into a three-dimensional motion mixer, add the converted amount of colloidal silicon dioxide and mix for 5 minutes, then add magnesium stearate and mix for 5 minutes;

[0079] (6) Tablet pressing: Use a φ11mm punch for tablet pressing, and the hardness is controlled at 100N.

[0080] Quality control results:

[0081] The homemade tablets were subjected to accelerated testing (40°C / 75%) for 1 month together with the reference preparation (produced by Novartis, Portugal, the same below) and packaged as commercially available packaging to monitor product quality changes. The results are shown in Tables 1 to 3.

[0082] Table 1 Hardness change monitoring results

[0083] prescription 0-day hardness results Accelerated 1-month hardness results Prescription 1 100N 50N Prescription 2 100N 80N Prescription 3 100N 100N Prescription 4 100N 100N Prescription 5 100N 100N

[0084] The test results show that the hardness of the terbinafine hydrochloride tablets prepared by the present invention does not decrease significantly during the stability study and is comparable to that of the reference preparation, which is superior to other prescription examples. In addition, for the terbinafine hydrochloride tablets prepared by the present invention, as the amount of polymethacrylic acid resin increases, the compressibility of the material increases, and the tablet hardness is comparable to that of the reference preparation.

[0085] Table 2 Monitoring results of related substances

[0086]

[0087] The test results show that: in the terbinafine hydrochloride tablets prepared by the present invention, as polymethacrylic acid resin and glycolic acid are added, the change trend of related substances during the stability study is relatively slow, which is comparable to the reference preparation and better than other prescription examples.

[0088] Table 3 Dissolution monitoring results

[0089]

[0090] The test results show that the dissolution of the terbinafine hydrochloride tablets prepared by the present invention is equivalent to that of the reference preparation and is better than other prescription examples; the greater the amount of polymethacrylic acid resin added, the closer the dissolution of the product is to the reference preparation.

[0091] Test Example 2: Influencing Factor Test

[0092] The terbinafine hydrochloride tablets obtained in Example 1 were compared with Comparative Examples 1, 2, and 3, and the results were as described in Table 4.

[0093] Table 4 Stability test results of Terbinafine Hydrochloride Tablets

[0094]

[0095]

[0096] The test results show that, in the terbinafine hydrochloride tablets prepared by the present invention, the polymethacrylic acid resin and glycolic acid act together, and the product-related substances are optimal after high temperature, high humidity and light inspection. Under the condition of the presence of polymethacrylic acid resin, the hardness of the product changes little and has little effect on dissolution. The quality of the product produced by the combined action of the two is better than that of the comparative example.

[0097] Test Example 3: Accelerated Test

[0098] The products of Examples 1, 2, 3, and 4 and the products of Comparative Examples 1 and 2 were subjected to accelerated testing (40° C. / 75% RH) using aluminum-plastic packaging. The results are shown in Table 5.

[0099] Table 5 Test results of accelerated test of Terbinafine Hydrochloride Tablets

[0100]

[0101]

[0102]

[0103] The test results show that the terbinafine hydrochloride tablets prepared by the present invention, under the combined action of polymethacrylic acid resin and glycolic acid, have better dissolution, hardness and related substances than the comparative example under accelerated conditions.

[0104] The preparation processes of the following Examples 1 to 4 and Comparative Examples 1 to 3 are the same as the preparation process in the prescription screening test of Test Example 1.

[0105] Example 1

[0106] Prescription composition:

[0107] Components Dosage (g) Terbinafine hydrochloride 169.7 Croscarmellose sodium 13.6 Hydroxypropyl methylcellulose 3.6 Polymethacrylate resin 27.3 glycolic acid 2.3 colloidal silica 1.2 magnesium stearate 0.9

[0108] Hydroxyacetic acid aqueous solution concentration 5%.

[0109] Preparation process:

[0110] (1) The terbinafine hydrochloride raw material, hypromellose and colloidal silicon dioxide were all passed through an 80-mesh sieve; the polymethacrylic acid resin was passed through an 80-mesh sieve and set aside;

[0111] (2) Premixing and granulation: Terbinafine hydrochloride, cross-linked sodium carboxymethyl cellulose, hypromellose, and polymethacrylic acid resin were added to a wet granulation mixer and mixed for 10 min. A glycolic acid aqueous solution (added according to the prescription requirements) was added for granulation. The stirring speed of the granulation was 400 rpm and the shear rate was 1500 rpm. The slurry addition was completed within 1 min. The granulation was continued for 6 min. The material was discharged and the soft material was granulated using a swing granulator with a 24-mesh steel mesh.

[0112] (4) Drying: The granules obtained in step (3) are dried using a boiling dryer to control the moisture content to <3%;

[0113] (5) Granulation: The dried granules obtained in step (4) are granulated using an oscillating granulator, and the granulation screen is a 24-mesh steel mesh;

[0114] (6) Total mixing: Add the granules obtained in step (5) into a three-dimensional motion mixer, add the converted amount of colloidal silicon dioxide and mix for 5 minutes, then add magnesium stearate and mix for 5 minutes;

[0115] (7) Tablet pressing: Use a φ11mm punch for tablet pressing, and the hardness is controlled at 100N.

[0116] Example 2

[0117] Prescription composition:

[0118] Components Dosage (g) Terbinafine hydrochloride 155.6 Cross-linked polyvinylpyrrolidone 8.3 Hydroxypropylcellulose 1.7 Polymethacrylate resin 29.2 glycolic acid 1.3 colloidal silica 1.1 magnesium stearate 0.8

[0119] Hydroxyacetic acid aqueous solution concentration 5%.

[0120] Preparation process:

[0121] (1) mixing terbinafine hydrochloride, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, and polymethacrylic acid resin uniformly;

[0122] (2) The uniformly mixed materials are subjected to wet granulation, colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0123] Example 3

[0124] Prescription composition:

[0125]

[0126]

[0127] Hydroxyacetic acid aqueous solution concentration 5%.

[0128] Preparation process:

[0129] (1) Mix terbinafine hydrochloride, sodium starch glycolate, povidone K30, and polymethacrylic acid resin uniformly;

[0130] (2) The uniformly mixed materials are subjected to wet granulation, colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0131] Example 4

[0132] Prescription composition:

[0133] Components Dosage (g) Terbinafine hydrochloride 143.6 Low-substituted hydroxypropyl cellulose 15.4 Hydroxypropyl methylcellulose 3.1 Polymethacrylate resin 21.5 glycolic acid 1.4 colloidal silica 1.0 talcum powder 1.2

[0134] Hydroxyacetic acid aqueous solution concentration 5%.

[0135] Preparation process:

[0136] (1) Terbinafine hydrochloride, low-substituted hydroxypropyl cellulose, hypromellose, and polymethacrylic acid resin are uniformly mixed;

[0137] (2) The uniformly mixed materials are subjected to wet granulation, colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0138] Comparative Example 1

[0139] Prescription composition:

[0140]

[0141]

[0142] Preparation process:

[0143] (1) Mix terbinafine hydrochloride, hypromellose, ethyl cellulose, and cross-linked polyvinylpyrrolidone uniformly;

[0144] (2) The uniformly mixed materials are wet granulated with purified water, colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0145] Comparative Example 2

[0146] Prescription composition:

[0147] Components Dosage (g) Terbinafine hydrochloride 186.7 Hydroxypropyl methylcellulose 4.0 Cross-linked polyvinylpyrrolidone 10.0 glycolic acid 2.5 colloidal silica 1.3 magnesium stearate 1.0

[0148] Hydroxyacetic acid aqueous solution concentration 5%.

[0149] Preparation process:

[0150] (1) Mix terbinafine hydrochloride, hypromellose, and cross-linked polyvinylpyrrolidone uniformly;

[0151] (2) The uniformly mixed materials are subjected to wet granulation, colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0152] Comparative Example 3

[0153] Prescription composition:

[0154]

[0155]

[0156] Preparation process:

[0157] (1) Mix terbinafine hydrochloride, hypromellose, polymethacrylic acid resin, cross-linked polyvinylpyrrolidone, and citric acid uniformly;

[0158] (2) The uniformly mixed material is wet granulated with purified water, and then colloidal silicon dioxide is added and mixed, and magnesium stearate is added for total mixing and tableting to obtain terbinafine hydrochloride tablets.

[0159] In summary, the organic acid glycolic acid is added to the granulation solvent of the present invention to maintain an acidic environment for the tablets, thereby obtaining a product with better stability. After investigation of influencing factors and acceleration, related substances all meet the requirements. The use of polymethacrylic acid resin as a filler can significantly improve the compressibility of the material. The stability of the tablet hardness is maintained throughout the storage period. After investigation of acceleration and influencing factors, the product hardness range changes slightly, which has little impact on product quality. The polymethacrylic acid resin and glycolic acid are used together in this prescription, and the related substances of the product are optimal. The product of the present invention is simple and easy to produce and operate, and is suitable for industrial production.

Claims

1. A terbinafine hydrochloride tablet, characterized in that include: The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch; The binder is selected from one or more of hydroxypropyl cellulose, hypromellose and povidone; The glidant is selected from colloidal silicon dioxide; The lubricant is selected from magnesium stearate and / or micro powder silica gel.

2. Terbinafine hydrochloride tablets according to claim 1, characterized in that, The terbinafine hydrochloride tablets are tested for related substances by high-performance liquid chromatography; the stationary phase of the high-performance liquid chromatography is octadecylsilane bonded silica gel; the mobile phase of the high-performance liquid chromatography includes mobile phase A and mobile phase B; the mobile phase A is a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 40:20:40; the mobile phase B is a mixed solution of triethylamine buffer, methanol and acetonitrile in a volume ratio of 10:50:

40.

3. Terbinafine hydrochloride tablets according to claim 2, characterized in that, The high performance liquid chromatography adopts linear gradient elution, and the elution procedure is as follows in terms of volume fraction: 。 4. A method for preparing terbinafine hydrochloride tablets according to claim 1, characterized in that, include: Terbinafine hydrochloride, a disintegrant, a binder and a polymethacrylic acid resin are mixed, and a glycolic acid aqueous solution is added for wet granulation. After drying and granulation, a flow aid and a lubricant are added for total mixing, and tableting is performed to obtain terbinafine hydrochloride tablets.

5. The preparation method according to claim 4, characterized in that The terbinafine hydrochloride, disintegrant, binder and polymethacrylic acid resin are mixed for 5 to 10 minutes, and then glycolic acid aqueous solution is added.

6. The preparation method according to claim 4, characterized in that The mass concentration of the glycolic acid aqueous solution is 3% to 8%; the glycolic acid aqueous solution is added within 1 minute.

7. The preparation method according to claim 4, characterized in that Add the flow aid and mix for 3 to 5 minutes, then add the lubricant and mix for a total of 3 to 5 minutes.

8. The preparation method according to claim 4, characterized in that The hardness of the tablet is 80-100N.

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