Production process of ivabradine hydrochloride tablet

Abstract

The invention provides a production process of ivabradine hydrochloride tablets, which comprises the following steps: A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and performing wet granulation; b) drying wet granules obtained by wet granulation in a fluidized bed, and then finishing the granules; and C) mixing the whole granules, magnesium stearate and colloidal silicon dioxide, tabletting and coating to obtain the magnesium stearate-colloidal silicon dioxide tablet. Compared with a production process in the prior art, the ivabradine hydrochloride tablet adopting a wet granulation process has the advantages of high stability, high efficiency and low impurity content. Meanwhile, the production process is simple.

Description

Technical Field

[0001] The invention relates to the field of injection preparation, in particular to a production process of ivabradine hydrochloride tablets. Background Art

[0002] Ivabradine hydrochloride is the hydrochloride of ivabradine. This drug is suitable for some patients with chronic stable angina pectoris who are contraindicated or have poor tolerance to alpha blockers and have normal sinus rhythm. Ivabradine is the first If current blocker drug. If current is the inward current in phase 4 of the cardiac action potential. The inflowing ions are mainly Na+, and K+ also participate. It is the main pacemaker current of the sinoatrial node. Ivabradine specifically and selectively inhibits the inflow of If in the sinoatrial node, delaying the diastolic depolarization of the action potential of the pacemaker cells, thereby slowing the heart rate. The high selectivity of this drug for If slows the heart rate moderately, avoiding excessive slowing of the heart rate when taken by healthy volunteers and patients with coronary heart disease.

[0003] The chemical name of ivabradine hydrochloride is 3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octane-1,3,5-triene]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepine-4-one hydrochloric acid, and the compound is a polymorphic drug. Amorphous drugs are in a high energy state, and have the characteristics of high solubility, poor stability, and easy transformation to a low energy state, i.e., a crystalline form; stable crystalline drugs have the characteristics of high melting point, good stability, poor solubility, etc., which leads to slow dissolution and poor efficacy. In order to improve the solubility of crystalline drugs in preparations, surfactant solubilization technology, micronization technology, solid dispersion technology, inclusion technology, etc. are commonly used. However, large amounts of surfactants are highly irritating to the gastrointestinal tract. Micronization technology is used to reduce the particle size of drugs, but the drugs are prone to aggregation. Solid dispersion technology prepares drugs into amorphous forms, but solid dispersions are prone to aging. Inclusion technology is used to prepare compounds, and the process is relatively complicated.

[0004] The drug in the stable state of ivabradine has the characteristic of poor solubility. In order to improve the solubility of the crystalline drug in the preparation, the prior art often uses micronization technology, solid dispersion technology, surfactant solubilization technology, inclusion technology, etc. However, micronization easily causes drug aggregation, resulting in limited improvement in solubility; solid dispersions are prone to aging, which also causes a decrease in drug solubility; surfactant solubilization easily causes gastrointestinal irritation; inclusion technology has a more complicated process. In the existing public technology, although there is a technology for preparing preparations using amorphous ivabradine hydrochloride raw materials, there is no report on improving the stability of amorphous ivabradine hydrochloride raw materials. If the drug undergoes a crystal transformation during storage, it will not only affect the dissolution of the drug, but also cause differences in drug efficacy, which will bring hidden dangers to clinical medication.

[0005] Therefore, it is very necessary to provide a production process for ivabradine hydrochloride tablets with good drug stability, rapid dissolution of the prepared preparation and simple process. Summary of the invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a production process of ivabradine hydrochloride tablets. The ivabradine hydrochloride tablets provided by the present invention have good stability, low impurity content and simple process.

[0007] The present invention provides a production process of ivabradine hydrochloride tablets, comprising:

[0008] A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and wet granulating;

[0009] B) drying the wet granules obtained by wet granulation in a fluidized bed and then granulating;

[0010] C) Mixing the granules after granulation, magnesium stearate and colloidal silicon dioxide, tableting and coating to obtain the product.

[0011] In some specific embodiments, the mass ratio of the lactose, maltodextrin, corn starch and ivabradine hydrochloride mixed in step A) is (60-70): (8-12): (15-25): (5-7).

[0012] In some specific embodiments, the parameters of the premixing in step A) include: stirring at 35-45 Hz, granulation at 10-20 Hz, and mixing for 4-6 minutes.

[0013] In some specific embodiments, the parameters of the premixing in step A) include: stirring at 40 Hz, granulation at 15 Hz, and mixing for 5 minutes.

[0014] In some specific embodiments, the wet granulation parameters in step A) include:

[0015] Stir at 35-45 Hz and granulate at 10-20 Hz, add purified water within 60 s, and continue granulating for 2-4 min after adding purified water.

[0016] In some specific embodiments, the wet granulation parameters in step A) include:

[0017] Stir at 40 Hz and granulate at 40 Hz, add purified water within 60 s, and continue granulating for 3 min after adding purified water.

[0018] In some specific embodiments, the fluidized bed drying parameters in step B) include: air inlet temperature of 50-70° C., fan speed of 1000-2000 rpm, and drying until the moisture content of the particles is less than 3%.

[0019] In some specific implementations, the granulation in step C) includes: selecting a sieve with an aperture of 0.8 mm and setting a granulation frequency of 10 to 30 Hz.

[0020] In some specific embodiments, in step C), the colloidal silicon dioxide and part of the sized particles are mixed and passed through a 40-mesh sieve to obtain a mixed material; and the remaining sized particles, magnesium stearate and the 40-mesh sieve mixed material are mixed;

[0021] The added amount of magnesium stearate is 0.4wt% to 0.6wt% of the mass percentage of the granules after granulation; the added amount of colloidal silicon dioxide is 0.1wt% to 0.3wt% of the mass percentage of the granules after granulation.

[0022] In some specific embodiments, the mixing speed in step C) is 13 rpm, and the mixing time is 4 to 6 min, preferably 5 minutes.

[0023] In some specific embodiments, the tableting parameters include: tableting using a 8.5×4.5 mm notched special-shaped mold, a main pressure of 6 to 16 KN, a tablet press speed of 15 to 25 Hz, a weight difference of ±7.5%, and a hardness range of 4 to 9 kg;

[0024] The coating parameters include: the distance between the spray gun and the tablet bed is 10-60 cm, the main engine speed is set to 2-8 RPM, the atomization pressure is adjusted to 0.1-0.3 MPa, and the inlet air temperature is 40-45°C.

[0025] The present invention provides an ivabradine hydrochloride tablet, which is prepared by the preparation method described in any one of the above technical solutions.

[0026] Compared with the prior art, the present invention provides a production process of ivabradine hydrochloride tablets, comprising: A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and wet granulating; B) drying the wet granules obtained by wet granulation in a fluidized bed, and then granulating; C) mixing the granules after granulation, magnesium stearate and colloidal silicon dioxide, tableting, coating, and obtaining. Compared with the production process of the prior art, the wet granulation process adopted in the present invention makes the ivabradine hydrochloride tablets have high stability, high efficiency and low impurity content. At the same time, the production process of the present invention is simple. DETAILED DESCRIPTION

[0027] The present invention provides a production process of ivabradine hydrochloride tablets. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar replacements and modifications are obvious to those skilled in the art, and they all belong to the scope of protection of the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application of this article without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

[0028] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0029] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0030] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural.

[0031] The invention provides a production process of ivabradine hydrochloride tablets. The produced product has good drug stability, the prepared preparation dissolves quickly, the process is simple, and the tablets are suitable for industrial production.

[0032] The present invention provides a production process of ivabradine hydrochloride tablets, comprising:

[0033] A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and wet granulating;

[0034] B) drying the wet granules obtained by wet granulation in a fluidized bed and then granulating;

[0035] C) Mixing the granules after granulation, magnesium stearate and colloidal silicon dioxide, tableting and coating to obtain the product.

[0036] The structure of ivabradine hydrochloride provided by the present invention is as follows:

[0037]

[0038] Premix lactose, maltodextrin, corn starch, and ivabradine hydrochloride;

[0039] In some specific embodiments, the prescribed amount of lactose, maltodextrin, corn starch and ivabradine hydrochloride are placed in a wet granulator in sequence, stirred at 35-45 Hz, granulated at 10-20 Hz, and mixed for 4-6 minutes; preferably, stirring at 40 Hz, granulating at 15 Hz, and mixing for 5 minutes.

[0040] In some specific embodiments, the mass ratio of the lactose, maltodextrin, corn starch and ivabradine hydrochloride mixed in step A) is (60-70): (8-12): (15-25): (5-7).

[0041] Then, purified water was added and wet granulation was performed.

[0042] The wet granulation parameters of the present invention include: stirring at 35-45 Hz and granulation at 10-20 Hz, adding purified water within 60 seconds, and continuing granulation for 2-4 minutes after adding purified water.

[0043] Preferably, the wet granulation parameters include: stirring at 40 Hz and granulation at 40 Hz, adding purified water within 60 s, and continuing granulation for 3 min after adding purified water.

[0044] The wet granules obtained by wet granulation are dried in a fluidized bed.

[0045] In some specific embodiments, the wet granules are placed in a fluidized bed for drying, the air inlet temperature is set at 50-70° C., the fan speed is set at 1000-2000 rpm, and the granules are dried until the moisture content is less than 3%.

[0046] In some specific embodiments, the inlet air temperature is 50°C, 52°C, 55°C, 58°C, 60°C, 63°C, 65°C, 67°C, 70°C; or a range between any two of the above.

[0047] In some specific implementations, the fan speed is 1000 rpm, 1200 rpm, 1400 rpm, 1500 rpm, 1600 rpm, 1800 rpm, 2000 rpm; or a range value between any two of the above.

[0048] Granulation: Granulate the dried granules, select a 0.8mm sieve, and set the granulation frequency to 10-30Hz, which can be 10Hz, 15Hz, 20Hz, 25Hz, 30Hz, or any range between the above two.

[0049] According to the weight of the granules after granulation, magnesium stearate and colloidal silicon dioxide are weighed according to the prescription ratio, and the colloidal silicon dioxide and an appropriate amount of the granules after granulation are mixed and passed through a 40-mesh sieve.

[0050] The colloidal silicon dioxide and part of the sized particles are mixed and passed through a 40-mesh sieve to obtain a mixed material; the remaining part of the sized particles, magnesium stearate and the mixed material after passing through a 40-mesh sieve are mixed; wherein the mass percentage of the part of the sized particles to the total sized particles is 0.1wt% to 0.5wt%.

[0051] According to the present invention, the amount of magnesium stearate added is 0.4wt% to 0.6wt% of the mass percentage of the granules after granulation; the amount of colloidal silicon dioxide added is 0.1wt% to 0.3wt% of the mass percentage of the granules after granulation. The granules after granulation, magnesium stearate and the mixed material after passing through a 40-mesh sieve are placed in a mixer, the mixer speed is set to 12 to 14 rpm, and the mixture is mixed for 4 to 6 minutes.

[0052] Tablet pressing: The tablet weight is calculated based on the intermediate content, and a 8.5×4.5mm notched special-shaped die is used for tablet pressing. The main pressure is 6-16KN, the tablet press speed is 15-25Hz, the weight difference is controlled to be ±7.5%, the hardness range is 4-9kg, the friability weight loss shall not exceed 1%, and broken, cracked and crushed tablets shall not be detected. Coating:

[0053] Preparation of coating solution: Weigh purified water (coating) and film coating premix according to the prescription amount, add purified water into the liquid preparation container, start stirring, add film coating premix, stir for more than 45 minutes to evenly disperse the film coating premix, prepare a film coating premix aqueous solution with a solid content of 10%, pass through an 80-mesh sieve, and set aside. The present invention does not limit the film coating premix, and commercially available ones known to those skilled in the art can be used.

[0054] Preparation of polishing liquid: Weigh purified water (polishing) and polyethylene glycol 6000 according to the prescribed amount, add purified water into the liquid preparation container, start stirring, add polyethylene glycol 6000, stir for more than 10 minutes to evenly disperse the polyethylene glycol 6000, and prepare a polyethylene glycol 6000 aqueous solution with a solid content of 10%, and set aside.

[0055] Coating parameters:

[0056] Coating: Place the tablet core in the coating pot, adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main machine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. Coating weight gain is 2 to 3%.

[0057] Polishing: Adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main engine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. The weight gain of polishing shall not exceed 0.1%. After polishing, turn off the spray system and continue drying for 3 to 5 minutes before taking it out.

[0058] The present invention provides an ivabradine hydrochloride tablet, which is prepared by the preparation method described in any one of the above technical solutions.

[0059] The present invention has clearly described the above preparation method, which will not be repeated here.

[0060] The present invention provides a production process of ivabradine hydrochloride tablets, comprising: A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and wet granulating; B) drying the wet granules obtained by wet granulation in a fluidized bed, and then granulating; C) mixing the granules after granulation, magnesium stearate and colloidal silicon dioxide, tableting, and coating to obtain. Compared with the production process of wet granulation in the prior art, the process of fluidized bed granulation adopted in the present invention makes ivabradine hydrochloride tablets have high stability, high efficiency and low impurity content. At the same time, the production process of the present invention is simple.

[0061] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0062] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0063] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0064] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0065] Some cases are recorded in the embodiments and comparative examples of the present invention, wherein the embodiments show certain implementation modes of the present invention. However, this does not mean that the effects of the present invention can only be achieved in these cases.

[0066] In order to further illustrate the present invention, the production process of an ivabradine hydrochloride tablet provided by the present invention is described in detail below in conjunction with examples.

[0067] Example 1

[0068] 1. Weigh ingredients: weigh lactose, maltodextrin, corn starch and ivabradine hydrochloride according to the prescription amount.

[0069] 2. Premixing: Place the prescribed amount of lactose, maltodextrin, corn starch and ivabradine hydrochloride in a wet granulator in sequence, start stirring at 35 Hz and granulation at 10 Hz, and mix for 4 minutes.

[0070] 3. Wet granulation: Turn on stirring at 40 Hz and granulation at 40 Hz, add purified water according to the prescription amount (add within 60 seconds, increase or decrease the amount of purified water according to the granulation situation), and continue granulation for 3 minutes after adding water.

[0071] 4. Drying: Place the wet granules in a fluidized bed for drying, set the air inlet temperature to 50-70°C, the fan speed to 1000-2000rpm, and dry until the granule moisture content is less than 3%.

[0072] 5. Granulation: Granulate the dried granules, select a sieve with an aperture of 0.8 mm, and set the granulation frequency to 10-30 Hz.

[0073] 6. Total mixing: According to the weight of the granules after whole granulation, weigh magnesium stearate and colloidal silicon dioxide according to the prescription ratio, mix the colloidal silicon dioxide and an appropriate amount of the granules after whole granulation and pass through a 40-mesh sieve.

[0074] The whole granules, magnesium stearate and the mixed material after passing through a 40-mesh sieve are placed in a mixer, the mixer speed is set to 13 rpm, and the mixing is performed for 4 minutes.

[0075] 7. Tablet pressing: The tablet weight is converted according to the intermediate content, and the tablet is pressed using a 8.5×4.5mm special-shaped mold with notches. The main pressure is 6-16KN, the tablet press speed is 15-25Hz, the weight difference is controlled to be ±7.5%, the hardness range is 4-9kg, the brittleness loss weight shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected.

[0076] 8. Coating:

[0077] 8.1 Preparation of coating solution: Weigh purified water (coating) and film coating premix according to the prescription amount, add purified water into the liquid preparation container, start stirring, add film coating premix, stir for more than 45 minutes to evenly disperse the film coating premix, prepare a film coating premix aqueous solution with a solid content of 10%, pass through an 80-mesh sieve, and set aside.

[0078] 8.2 Preparation of polishing liquid: Weigh purified water (polishing) and polyethylene glycol 6000 according to the prescribed amount, add purified water into the liquid preparation container, start stirring, add polyethylene glycol 6000, stir for more than 10 minutes to evenly disperse the polyethylene glycol 6000, and prepare a polyethylene glycol 6000 aqueous solution with a solid content of 10%, and set aside.

[0079] 8.3 Coating parameters:

[0080] Coating: Place the tablet core in the coating pot, adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main machine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. Coating weight gain is 2 to 3%.

[0081] Polishing: Adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main engine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. The weight gain of polishing shall not exceed 0.1%. After polishing, turn off the spray system and continue drying for 3 to 5 minutes before taking it out.

[0082] Example 2

[0083] 1. Weigh ingredients: weigh lactose, maltodextrin, corn starch and ivabradine hydrochloride according to the prescription amount.

[0084] 2. Premixing: Place the prescribed amount of lactose, maltodextrin, corn starch and ivabradine hydrochloride in a wet granulator in sequence, start stirring at 40 Hz and granulation at 15 Hz, and mix for 5 minutes.

[0085] 3. Wet granulation: Turn on stirring at 40 Hz and granulation at 40 Hz, add purified water according to the prescription amount (add within 60 seconds, increase or decrease the amount of purified water according to the granulation situation), and continue granulation for 3 minutes after adding water.

[0086] 4. Drying: Place the wet granules in a fluidized bed for drying, set the air inlet temperature to 50-70°C, the fan speed to 1000-2000rpm, and dry until the granule moisture content is less than 3%.

[0087] 5. Granulation: Granulate the dried granules, select a sieve with an aperture of 0.8 mm, and set the granulation frequency to 10-30 Hz.

[0088] 6. Total mixing: According to the weight of the granules after whole granulation, weigh magnesium stearate and colloidal silicon dioxide according to the prescription ratio, mix the colloidal silicon dioxide and an appropriate amount of the granules after whole granulation and pass through a 40-mesh sieve.

[0089] The whole granules, magnesium stearate and the mixed material after passing through a 40-mesh sieve are placed in a mixer, the mixer speed is set to 13 rpm, and the mixture is mixed for 5 minutes.

[0090] 7. Tabletting: The tablet weight is calculated according to the intermediate content. A 8.5×4.5mm notched special-shaped die is used for tabletting. The main pressure is 6-16KN, the tablet press speed is 15-25Hz, the weight difference is controlled to be ±7.5%, the hardness range is 4-9kg, the friability weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected.

[0091] 8. Coating:

[0092] 8.1 Preparation of coating solution: Weigh purified water (coating) and film coating premix according to the prescription amount, add purified water into the liquid preparation container, start stirring, add film coating premix, stir for more than 45 minutes to evenly disperse the film coating premix, prepare a film coating premix aqueous solution with a solid content of 10%, pass through an 80-mesh sieve, and set aside.

[0093] 8.2 Preparation of polishing liquid: Weigh purified water (polishing) and polyethylene glycol 6000 according to the prescribed amount, add purified water into the liquid preparation container, start stirring, add polyethylene glycol 6000, stir for more than 10 minutes to evenly disperse the polyethylene glycol 6000, and prepare a polyethylene glycol 6000 aqueous solution with a solid content of 10%, and set aside.

[0094] 8.3 Coating parameters:

[0095] Coating: Place the tablet core in the coating pot, adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main machine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. Coating weight gain is 2 to 3%.

[0096] Polishing: Adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main engine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. The weight gain of polishing shall not exceed 0.1%. After polishing, turn off the spray system and continue drying for 3 to 5 minutes before taking it out.

[0097] Example 3

[0098] 1. Weigh ingredients: weigh lactose, maltodextrin, corn starch and ivabradine hydrochloride according to the prescription amount.

[0099] 2. Premixing: Place the prescribed amount of lactose, maltodextrin, corn starch and ivabradine hydrochloride in a wet granulator in sequence, start stirring at 45 Hz and granulation at 15 Hz, and mix for 5 minutes.

[0100] 3. Wet granulation: Turn on stirring at 40 Hz and granulation at 40 Hz, add purified water according to the prescription amount (add within 60 seconds, increase or decrease the amount of purified water according to the granulation situation), and continue granulation for 3 minutes after adding water.

[0101] 4. Drying: Place the wet granules in a fluidized bed for drying, set the air inlet temperature to 50-70°C, the fan speed to 1000-2000 rpm, and dry until the granule moisture content is less than 3%.

[0102] 5. Granulation: Granulate the dried granules, select a sieve with an aperture of 0.8 mm, and set the granulation frequency to 10-30 Hz.

[0103] 6. Total mixing: According to the weight of the granules after whole granulation, weigh magnesium stearate and colloidal silicon dioxide according to the prescription ratio, mix the colloidal silicon dioxide and an appropriate amount of the granules after whole granulation and pass them through a 40-mesh sieve.

[0104] The whole granules, magnesium stearate and the mixed material after passing through a 40-mesh sieve are placed in a mixer, the mixer speed is set to 13 rpm, and the mixture is mixed for 6 minutes.

[0105] 7. Tabletting: The tablet weight is calculated according to the intermediate content. A 8.5×4.5mm notched special-shaped die is used for tabletting. The main pressure is 6-16KN, the tablet press speed is 15-25Hz, the weight difference is controlled to be ±7.5%, the hardness range is 4-9kg, the friability weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected.

[0106] 8. Coating:

[0107] 8.1 Preparation of coating solution: Weigh purified water (coating) and film coating premix according to the prescription amount, add purified water into the liquid preparation container, start stirring, add film coating premix, stir for more than 45 minutes to evenly disperse the film coating premix, prepare a film coating premix aqueous solution with a solid content of 10%, pass through an 80-mesh sieve, and set aside.

[0108] 8.2 Preparation of polishing liquid: Weigh purified water (polishing) and polyethylene glycol 6000 according to the prescribed amount, add purified water into the liquid preparation container, start stirring, add polyethylene glycol 6000, stir for more than 10 minutes to evenly disperse the polyethylene glycol 6000, and prepare a polyethylene glycol 6000 aqueous solution with a solid content of 10%, and set aside.

[0109] 9.3 Coating parameters:

[0110] Coating: Place the tablet core in the coating pot, adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main machine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. Coating weight gain is 2 to 3%.

[0111] Polishing: Adjust the distance between the spray gun and the tablet bed to between 10 and 60 cm, set the main engine speed to 2 to 8 RPM, adjust the atomization pressure to about 0.1 to 0.3 MPa, and the inlet air temperature to control the tablet bed temperature at 40 to 45°C. The weight gain of polishing shall not exceed 0.1%. After polishing, turn off the spray system and continue drying for 3 to 5 minutes before taking it out.

[0112] Table 1

[0113]

[0114]

[0115] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A production process of ivabradine hydrochloride tablets, characterized in that: include: A) premixing lactose, maltodextrin, corn starch and ivabradine hydrochloride, adding purified water, and wet granulating; B) drying the wet granules obtained by wet granulation in a fluidized bed and then granulating; C) Mixing the granules after granulation, magnesium stearate and colloidal silicon dioxide, tableting and coating to obtain the product.

2. The production process according to claim 1, characterized in that: In step A), the mass ratio of the lactose, maltodextrin, corn starch and ivabradine hydrochloride mixed is (60-70):(8-12):(15-25):(5-7).

3. The production process according to claim 1, characterized in that: Step A) The premixing parameters include: stirring at 35-45 Hz, granulation at 10-20 Hz, and mixing for 4-6 minutes.

4. The production process according to claim 1, characterized in that: Step A) The wet granulation parameters include: Stir at 35-45 Hz and granulate at 10-20 Hz, add purified water within 60 s, and continue granulating for 2-4 min after adding purified water.

5. The production process according to claim 1, characterized in that: Step B) The fluidized bed drying parameters include: air inlet temperature 50-70°C, fan speed 1000-2000 rpm, and drying until the particle moisture content is less than 3%.

6. The production process according to claim 1, characterized in that: Step C) the granulation comprises: selecting a sieve with an aperture of 0.8 mm and setting a granulation frequency of 10 to 30 Hz.

7. The production process according to claim 6, characterized in that: Step C) mixing colloidal silicon dioxide and part of the sized particles through a 40-mesh sieve to obtain a mixed material; mixing the remaining sized particles, magnesium stearate and the 40-mesh sieve-sieved mixed material; the amount of magnesium stearate added is 0.4wt% to 0.6wt% of the mass percentage of the sized particles; the amount of colloidal silicon dioxide added is 0.1wt% to 0.3wt% of the mass percentage of the sized particles.

8. The production process according to claim 6, characterized in that: Step C) The mixing speed is 13 rpm and the mixing time is 4-6 minutes.

9. The production process according to claim 1, characterized in that: Step C) The tableting parameters include: using a 8.5×4.5mm special-shaped die with notches for tableting, a main pressure of 6 to 16KN, a tablet press speed of 15 to 25Hz, a weight difference of ±7.5%, and a hardness range of 4 to 9kg; The coating parameters include: the distance between the spray gun and the tablet bed is 10-60 cm, the main engine speed is set to 2-8 RPM, the atomization pressure is adjusted to 0.1-0.3 MPa, and the inlet air temperature is 40-45°C.

10. An ivabradine hydrochloride tablet, characterized in that: The compound is prepared by the preparation method according to any one of claims 1 to 9.

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