A 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet

Abstract

The present invention relates to a 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet, comprising 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, glyceryl monostearate and other oral solid excipients. The present invention not only solves the problems of sticking and corrosion to equipment during tableting by using glyceryl monostearate in the tablet, but also improves the stability of the product. The production process is simple and easy to control, and is suitable for mass production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine preparation, and particularly relates to 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablets and a preparation method thereof. Background Art

[0002] 2-(4-Methylthiazol-5-yl)ethyl nitrate hydrochloride (structural formula shown below) is a white powder or off-white powder with a melting point of 105-112°C. It is very soluble in water, easily soluble in methanol, soluble in ethanol, very slightly soluble in acetone, and insoluble in ether, ethyl acetate, and dichloromethane.

[0003]

[0004] 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is used for preventing and / or treating cardiovascular and cerebrovascular diseases and neurodegenerative diseases by alleviating individual neurodegeneration, achieving neuroprotection and / or achieving cognitive enhancement.

[0005] Chinese patent document CN110433161A discloses a tablet for treating neurodegenerative diseases, containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride or 2-(4-methylthiazol-5-yl)ethyl nitrate maleate, filler, disintegrant, and lubricant. The process of direct powder tableting is adopted, and all auxiliary materials are passed through a 100-mesh sieve; the main drug is ground into powder, and the general grinding time is 1-30 minutes; the main drug, filler, and disintegrant ground in the prescribed amount are mixed, lubricant is added, mixed, and tableted. The tablets obtained by the above prescription and preparation process have poor stability, are easy to sublimate during preparation and storage and transportation, impurities grow rapidly, and are severely hygroscopic, and the environmental humidity requirements are strict, which is not conducive to large-scale market applications. Summary of the invention

[0006] In view of the existing technical problems, the present invention provides a 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet, which solves the problems of poor product stability, sticking and corrosion of equipment during tableting, and disadvantages for large-scale production.

[0007] The specific technical solutions of the present invention are as follows:

[0008] A 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet comprises 2-(4-methylthiazol-5-yl)ethyl nitrate salt, a protective agent and other auxiliary materials, wherein the protective agent is glyceryl monostearate, and the other auxiliary materials are selected from one or more of a filler, a disintegrant and a lubricant. The tablet is prepared by first mixing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride with glyceryl monostearate, then premixing with other auxiliary materials, and then tableting after the premix is ​​mixed.

[0009] Preferably, the mass ratio of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride to glyceryl monostearate is 1:0.1 to 1:0.5.

[0010] Preferably, the filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, and pregelatinized starch; the disintegrant is selected from one or more of starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; and the lubricant is selected from one or more of stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, palmitostearin, magnesium lauryl sulfate, polyethylene glycol, and sodium stearyl fumarate.

[0011] In a preferred embodiment of the present invention, the filler is lactose, the disintegrant is low-substituted hydroxypropyl cellulose, and the lubricant is magnesium stearate.

[0012] The tablet of the present invention preferably has the following components in parts by weight:

[0013] 100-200 parts of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, 10-50 parts of a protective agent, 800-900 parts of a filler, 40-60 parts of a disintegrant, and 4-7 parts of a lubricant.

[0014] Preferably, the particle size D50 of the 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is 20 to 170 μm.

[0015] The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablets of the present invention are prepared by the following method:

[0016] Step 1: Use a mixer to premix 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate at a mixing speed of 5 to 15 rpm for a mixing time of more than 5 minutes.

[0017] Step 2: Add the premix of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate, filler, disintegrant and lubricant into a wet mixer granulator set at 200 rpm and 1500 rpm for premixing for 6 minutes.

[0018] Step 3: Mix the premix in a mixer at 15 rpm for 5 min.

[0019] Step 4: Tablet pressing.

[0020] Advantages of the present invention:

[0021] The present invention found in the test process that 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride corrodes the tablet press seriously and has the problem of sticking. By using glyceryl monostearate, sticking and equipment corrosion can be avoided. In addition, the use of glyceryl monostearate can also significantly improve the stability of the product. The tablet formulation process of the present invention improves the stability of the product, avoids the corrosion of the equipment, and can be produced under a higher environmental humidity. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a picture of the corrosion of the high-speed tablet press in Example 1.

[0023] Figure 2 This is the punch after tabletting in Example 1. DETAILED DESCRIPTION

[0024] The following is a further detailed description of the above contents of the present invention through specific implementation methods in the form of embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention, and unless otherwise specified, the following embodiments are all completed using conventional existing technologies.

[0025] Examples 1 to 7

[0026] To investigate the effect of excipients that may have the function of isolating or encapsulating APIs as protective agents on improving sticking and corrosion of equipment.

[0027] 20,000 tablets prescription (kg)

[0028]

[0029] 2. Process

[0030] 1. Premix

[0031] Add the prescribed amount of each ingredient into the wet mixing granulator and set the stirring speed to 200 rpm and the cutting speed to 1500 rpm for premixing for 6 minutes.

[0032] 2. Mix

[0033] The premix was placed in a mixer and mixed at 15 rpm for 5 min.

[0034] 3. Tablet pressing

[0035] Tablets were pressed in an environment with a relative humidity of 60%±5%, using a high-speed tablet press and a 12mm round flat-bevel punch. The tablet weight was controlled to be an average of 500mg±15mg, and the main pressure was 25±5KN.

[0036] 3. Tablet Compression Results

[0037] Non-stick punching: The surface is complete and smooth, and there is no attachment on the mold surface.

[0038] Slight sticking: The surface of the piece is slightly rough and uneven, and there is a small amount of attachment on the surface of the mold.

[0039] Sticking: A thin layer of the tablet surface is removed by the punch, and a large amount of attachments are stuck to the surface of the mold, affecting tableting.

[0040] Slight corrosion: Yellow corrosion occurs when tableting is performed for more than 30 minutes.

[0041] Severe corrosion: Yellow corrosion occurs within 5 minutes of tableting.

[0042]

[0043] Figure 1 This is a corrosion picture of the high-speed tablet press in Example 1. Obvious corrosion marks can be seen on the surface of the equipment.

[0044] Figure 2 This is the punch after the tabletting in Example 1 was sticky. It can be seen from the figure that the sticking is obvious.

[0045] Conclusion

[0046] The above results show that among all the protective agents, only glyceryl monostearate can significantly improve the sticking problem in the tableting process and also improve the corrosion of the material to the equipment.

[0047] Embodiment 8~11 process research

[0048] 1. Purpose

[0049] The formulation of Example 2 was used to study different mixing processes.

[0050]

[0051] 2. Process

[0052] 1. Premix 1

[0053] Use a mixer to put 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate into a total mixer, and set the speed and time according to the plan to mix.

[0054] 2. Premix 2

[0055] Add 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate mixture, lactose, low-substituted hydroxypropyl cellulose and magnesium stearate into a wet mixing granulator set to stir at 200 rpm and cutter at 1500 rpm, and pre-mix for 6 minutes.

[0056] 3. Total Mixing

[0057] The premix was placed in a mixer and mixed at 15 rpm for 5 min.

[0058] 4. Tablet pressing

[0059] The tablets were pressed using a high-speed tablet press and a 12 mm round flat-bevel die, with the tablet weight controlled at an average of 500 mg ± 15 mg and a main pressure of 25 ± 5 KN. The ambient humidity was 60% ± 5% during the entire tablet pressing process.

[0060] 2. Results and Conclusion

[0061] index Example 8 Example 9 Example 10 Embodiment 11 Sticking situation Non-stick punch Non-stick punch Non-stick punch Non-stick punch Corrosion to equipment slight No corrosion No corrosion No corrosion

[0062] The addition of premixing step 1 to the recipe of Example 2 has better process feasibility. Only in Example 8, there was slight corrosion to the equipment, which may be due to the short mixing time. When the mixing time was greater than 5 minutes, there was no sticking and corrosion to the equipment.

[0063] The rotation speed has little effect on the process feasibility, and the premixing 1 mixing time is preferably greater than 5 minutes.

[0064] Examples 12 to 18 Prescription Optimization

[0065] 1. Prescription

[0066] The effects of formulation factors such as raw material particle size, raw material and glyceryl monostearate ratio on process feasibility were investigated.

[0067] 20,000 tablets prescription (kg)

[0068]

[0069] 2. Process

[0070] 1. Premix 1

[0071] Use a mixer to mix 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate, set the total mixer to a speed of 10 rpm, and mix for 10 minutes.

[0072] 2. Premix 2

[0073] Add 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate mixture, lactose, low-substituted hydroxypropyl cellulose and magnesium stearate into a wet mixing granulator set to stir at 200 rpm and cutter at 1500 rpm, and pre-mix for 6 minutes.

[0074] 3. Total Mixing

[0075] The premix was placed in a mixer and mixed at 15 rpm for 5 min.

[0076] 4. Tablet pressing

[0077] The tablets were pressed using a high-speed tablet press and a 12 mm round flat-bevel die, with the tablet weight controlled at an average of 500 mg ± 15 mg and a main pressure of 25 ± 5 KN. The ambient humidity was 60% ± 5% during the entire tablet pressing process.

[0078] 2. Results and Conclusion

[0079]

[0080] According to the above results, when the content of glyceryl monostearate is less than that of the raw material and the raw material particle size is larger, the process feasibility is poor and the equipment is corroded significantly, so it is necessary to control the ratio of raw material to glyceryl monostearate and the raw material particle size. The preferred raw material to glyceryl monostearate mass is between 1:0.1 and 1:0.5, and the raw material particle size D50: 20 to 170 um.

[0081] Example 19 Stability Study

[0082] 1. Methods

[0083] Related substances

[0084] The chromatographic conditions were as follows: phenyl bonded silica gel was used as filler, 0.01% phosphoric acid was used as mobile phase A, acetonitrile was used as mobile phase B, and gradient elution was adopted; the detection wavelength was 250 nm; the injection volume was 10 μl; the column temperature was 30° C.; and the flow rate was 1.0 ml per minute.

[0085] Test solution: Take 5 tablets of this product, add appropriate amount of acetonitrile-water (10:90), sonicate and dilute to make a solution with a concentration of 1 mg / ml, filter, and take the filtrate.

[0086] Reference solution: Take appropriate amount of impurity A, B, C reference substances, add appropriate amount of acetonitrile-water (10:90) to dissolve and quantitatively dilute to make a solution with a concentration of 2μg / ml.

[0087] Sensitivity solution: Take an appropriate amount of the reference solution and quantitatively dilute it with acetonitrile-water (10:90) to make a solution with a concentration of 0.5μg / ml.

[0088] Impurity A Impurity B Impurity C

[0089]

[0090] content:

[0091] Chromatographic conditions: phenyl bonded silica gel was used as filler, acetonitrile-0.01% phosphoric acid solution (35:65) was used as mobile phase for isocratic elution; detection wavelength was 250 nm; injection volume was 10 μl; column temperature was 30° C.; flow rate was 1.5 ml per minute.

[0092] Test solution: Take 5 tablets of this product, add appropriate amount of acetonitrile-water (10:90), sonicate and dilute to make a solution with a concentration of 1 mg / ml, filter, and take the filtrate.

[0093] Reference substance solution: Take an appropriate amount of reference substance, add an appropriate amount of acetonitrile-water (10:90) to dissolve and quantitatively dilute to make a solution with a concentration of 1 mg / ml.

[0094] 2. Results

[0095]

[0096]

[0097] 2. Conclusion

[0098] The above results show that the present invention not only solves the problems of sticking and corrosion of equipment in the process, but also can better improve the stability of the product through the use of glyceryl monostearate and the optimization of the feed ratio, process and raw material particle size.

Claims

1. A 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet, characterized in that The invention comprises 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, a protective agent and other auxiliary materials, wherein the protective agent is glyceryl monostearate, and the other auxiliary materials are selected from one or more of a filler, a disintegrant and a lubricant. The tablet is prepared by first mixing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride with glyceryl monostearate, then premixing with other auxiliary materials, and then tabletting the premix. The mass ratio of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride to glyceryl monostearate is 1:0.1-1:0.5, and the particle size D50 of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is 20-170µm.

2. The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet according to claim 1, characterized in that The filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, and pregelatinized starch; the disintegrant is selected from one or more of starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; and the lubricant is selected from one or more of stearic acid, calcium stearate, magnesium stearate, zinc stearate, talc, palmitostearin, magnesium lauryl sulfate, polyethylene glycol, and sodium stearyl fumarate.

3. The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet according to claim 2, characterized in that The filler is lactose, the disintegrant is low-substituted hydroxypropyl cellulose, and the lubricant is magnesium stearate.

4. The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet according to claim 1, characterized in that The weight parts of each component are as follows: 100-200 parts of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, 800-900 parts of filler, 40-60 parts of disintegrant, and 4-7 parts of lubricant.

5. The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablet according to any one of claims 1 to 4, characterized in that The preparation method is as follows: Step 1: Use a mixer to premix 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate at a mixing speed of 5-15 rpm for a mixing time of more than 5 minutes; Step 2: Add the premix of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride and glyceryl monostearate, filler, disintegrant and lubricant into a wet mixer granulator set at 200 rpm and 1500 rpm for premixing for 6 minutes; Step 3: Place the premix in a mixer and mix at 15 rpm for 5 min; Step 4: Tablet pressing.

Images