Propafenone hydrochloride tablet production and processing technology

Abstract

The invention discloses a propafenone hydrochloride tablet production and processing technology. The technology comprises the following steps: crushing, weighing, premixing, granulating, drying and granulating, totally mixing, tabletting, coating and packaging. According to the propafenone hydrochloride tablet production and processing technology, in the smashing operation step, raw material smashing parameters are set, namely the feeding pressure is 5.5 + / -1.0 bar, the smashing pressure is 5.0 + / -1.0 bar, the feeding speed is 10-15 rpm, particle size distribution of main medicine is better controlled, in the premixing procedure, half of auxiliary materials except for an adhesive are adopted to be mixed with moistening and washing equipment firstly, the effect of protecting the main medicine can be achieved, and the effect of improving the quality of the main medicine is achieved. According to the present invention, in the drying operation step, after the drying temperature reaches 60 DEG C, the particles are turned over every half an hour, the drying disc on the drying vehicle is vertically exchanged, the position is changed, and the drying efficiency is improved; heat distribution in the drying oven can be more uniform, and the drying speed and the drying uniformity are improved.

Description

Technical Field

[0001] The invention relates to the technical field related to production and processing of propafenone hydrochloride, and in particular to a production and processing technology of propafenone hydrochloride tablets. Background Art

[0002] Propafenone hydrochloride, also known as propafenone, is an organic compound. Main treatment: prolong the time to symptomatic atrial fibrillation (AF) recurrence in patients with paroxysmal (most likely paroxysmal or persistent) AF without structural heart disease; prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with symptomatic ineffectiveness in patients without organic heart disease; treat documented life-threatening ventricular arrhythmias.

[0003] The existing production and processing technology of propafenone hydrochloride tablets cannot control the particle size distribution of the main drug when the raw materials are crushed, which easily affects the bioequivalence of the homemade preparation and the original reference preparation. Secondly, in the premixing process, it is impossible to ensure the content of the main drug in the preparation, the particle forming effect of the granulation method, and the uniformity of the wet granules. In view of the above problems, the existing equipment needs to be improved. Summary of the invention

[0004] The object of the present invention is to provide a production and processing technology of propafenone hydrochloride tablets to solve the problems of the existing production and processing technology of propafenone hydrochloride tablets proposed in the above background technology, that is, when the raw materials are crushed, the particle size distribution of the main drug cannot be controlled, which easily affects the bioequivalence of the homemade preparation and the original reference preparation, and secondly, in the premixing process, the content of the main drug in the preparation and the particle forming effect of the granulation method and the uniformity of the wet granules cannot be ensured.

[0005] To achieve the above object, the present invention provides the following technical solution: a production process of propafenone hydrochloride tablets, comprising the following steps:

[0006] 1. Preprocessing:

[0007] (1) Preparation: Use standard weights to calibrate electronic scales and balances; verify the name, specification, batch number, manufacturer, integrity and quantity of the propafenone hydrochloride API, and check whether the material properties are correct;

[0008] (2) Crushing: The weighed propafenone hydrochloride API is placed in a jet mill, and the crushing parameters are set as feed pressure 5.5±1.0 bar, crushing pressure 5.0±1.0 bar, and feeding speed 10-15 rpm. The API is subjected to jet milling, and the particle size needs to be controlled at D50≤10 μm and D90≤15 μm. When the particle size meets the requirements, it is formally crushed according to these parameters. After the crushing is completed, it is placed in a clean double-layer polyethylene bag and placed in a stainless steel barrel. After weighing, a label is attached between the two layers of polyethylene bags and outside the container, indicating the product name, batch number, specification, weight, date and operator. The polyethylene bag is sealed and sent to the temporary storage room for raw and auxiliary materials;

[0009] 2. Ingredients:

[0010] (1) Preparation: Check whether the weighing cover, container and production equipment are clean and within the effective period. If the effective period has expired, they must be cleaned again as required. Check the name, batch number and weight of the pre-processed raw and auxiliary materials according to the batch production instructions. Check whether the raw and auxiliary material packaging is intact and not damaged.

[0011] (2) Weighing: Weigh the prescribed amount of pre-treated propafenone hydrochloride API, microcrystalline cellulose, corn starch, hypromellose 2910, croscarmellose sodium, magnesium stearate, and film coating premix and place them separately into clean double-layer polyethylene bags. Attach a label between the two layers of polyethylene bags, indicating the product name, batch number, weight, date, and operator. Tie the polyethylene bags and place them into a numbered clean container. Weigh the prescribed amount of purified water and place it into a clean container.

[0012] 3. Premix:

[0013] (1) Preparation: Check that the LSH-400 wet mixer granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0014] (2) Operation: First, spread 1 / 2 of the prescribed amount of microcrystalline cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose on the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and rinse the pot wall for 2 minutes. Then, add the remaining microcrystalline cellulose, corn starch, cross-linked sodium carboxymethyl cellulose and propafenone hydrochloride raw materials into the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and the premixing time is 15 minutes.

[0015] 4. Granulation:

[0016] (1) Preparation of adhesive: Weigh 23 kg of purified water according to the prescription amount, start stirring and slowly add 2 kg of hypromellose powder, stir and disperse to dissolve (no lumps are observed visually), prepare a solution with a concentration of 8%, and set aside;

[0017] (2) Slurry granulation: set the stirring paddle speed of the wet mixing granulator to 150 rpm, the cutting blade speed to 2400 rpm, the peristaltic pump speed to 550 rpm and the atomizing air pressure to 0.5 MPa, turn on the liquid adding pump, turn on the atomizer, spray the prepared binder solution, control the slurry adding time to 4 min to 4 min 30 s, and record the slurry adding time;

[0018] 5. Wet granulation:

[0019] (1) Preparation: Check whether the YK-160 swing granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0020] (2) Operation: Add the wet granules into the swing granulator and pass through a 14-mesh screen for wet granulation. The screen should be intact after granulation. Put the wet granules into a clean stainless steel barrel and send them to the drying room for drying;

[0021] 6. Drying:

[0022] (1) Preparation: Check whether the CT-C-Ⅱ hot air circulation oven has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0023] (2) Operation: Spread the prepared wet granules evenly on the drying tray (about 2 / 3 of the volume of the drying tray, about 1 kg / tray), and place them on the drying cart in a top-down order. Push the drying cart into the oven to dry the wet granules. After reaching 60°C, turn the granules every half an hour, and switch the drying tray on the drying cart up and down to change the position. After drying is completed, close the steam valve and send clean air to cool the granules to room temperature;

[0024] 7. Dry whole grain:

[0025] (1) Preparation: Check that the YK-160 swing pellet machine (SB-17012) has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark, make it in operation, check whether the screen is in good condition and verify that the screen mesh is 30 meshes;

[0026] (2) Operation: Add the dry granules into the granulator and pass through a 30-mesh screen for granulation. The screen should be intact after granulation. The granules should be collected in a clean container.

[0027] 8. Total Mixing:

[0028] (1) Preparation: Check whether the HF-400 fixed hopper mixer has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0029] (2) Operation: Calculate the amount of magnesium stearate according to the amount of dry particles (magnesium stearate dosage = actual dry particle weight / theoretical dry particle weight × theoretical magnesium stearate amount), set the speed and time according to the performance of the mixer, the mixing speed is 10 rpm, the mixing time is 5 to 10 min, and the target is 7 min;

[0030] 9. Tableting:

[0031] (1) Preparation: Check whether the PG65 high-speed rotary tablet press has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark and put it in operation, check and confirm the die specifications (Φ9mm shallow concave) and finish, there should be no grooves, curling, missing corners, bursts and wear, install the die, and check the granule name, specification, batch number, weight and production date;

[0032] (2) Operation: Adjust the pre-pressure, main pressure, tableting speed, test tableting to check tablet weight, hardness, friability and appearance. After all indicators are qualified, formal operation can begin;

[0033] 10. Coating:

[0034] (1) Preparation: Check that the BGB150 high-efficiency coating machine in the coating room has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to ensure that it is in operation;

[0035] (2) Preparation of coating solution: Weigh the film coating premix according to 7.5% of the weight of the plain tablets, weigh purified water according to 10% of the solid content of the coating solution, start stirring to make the solvent form a vortex, add the film coating premix evenly into the vortex, reduce the stirring speed until the vortex just disappears, continue stirring for 60 minutes for use (keep a slight stirring state during the entire coating process);

[0036] (3) Operation: Put the plain tablets into the coating pot, set the air inlet temperature to 50-60°C, exhaust speed to 1000-2300rpm, main machine speed to 2.0-8.0rpm, peristaltic pump speed to 10-50rpm, atomization pressure to 0.1-0.6Mpa, and preheat the coating pot in steps until the tablet bed temperature is ≥40°C. Randomly take 100 tablets from the coating pot three times to measure the average tablet weight of 100 plain tablets, and start coating until the coating weight gain is 5.0%-7.5%. Reduce the coating pot speed to 2.0-5.0rpm, stop heating, and cool the tablet bed to room temperature.

[0037] 11. Packaging: bottling, full inspection, and warehousing.

[0038] Preferably, the actual batch amount of the bulk drug of the propafenone hydrochloride tablets = the theoretical batch amount of the bulk drug ÷ the content of the bulk drug (in terms of dry product) ÷ (1-loss on drying); when the content of the bulk drug exceeds 100.0%, it is calculated as 100.0%.

[0039] Preferably, the oven is a CT-C-Ⅱ type hot air circulation oven, and its loading method is: 4 cars / cabinet×15 layers / car×2 trays / layer.

[0040] Preferably, the drying temperature of the oven is controlled at 60°C ± 10°C, and the drying endpoint is determined as follows: drying to a moisture content of ≤ 3% (moisture content determination: 105°C, Auto).

[0041] Preferably, the instrument parameters of the high-speed rotary tablet press are set as pre-pressure 0.5-1.2 kN, main pressure 5.9-9.7 kN, and tableting speed 20-30 rpm during operation.

[0042] Preferably, the tableting controls the average tablet weight to be between 203.2 and 224.6 mg, and the hardness to be between 70 and 110 N. The operator takes samples from the tablet outlet of the tablet press once every 30 minutes for central control, randomly takes 10 tablets, and weighs the total tablet weight to ensure that the total tablet weight meets the requirements.

[0043] Preferably, the film coating premix ingredients include: polyethylene glycol 400, polyethylene glycol 6000, hypromellose, and titanium dioxide.

[0044] Compared with the prior art, the invention has the following beneficial effects: the production and processing technology of propafenone hydrochloride tablets is

[0045] (1) In order to solve the problem that the particle size distribution of the main drug cannot be controlled when the raw materials are crushed in the existing production and processing technology of propafenone hydrochloride tablets, which easily affects the bioequivalence of the homemade preparation and the original reference preparation, the present application sets the raw material crushing parameters of feed pressure 5.5±1.0 bar, crushing pressure 5.0±1.0 bar, and feeding speed 10-15 rpm during the crushing operation step, so as to better control the particle size distribution of the main drug. Controlling the particle size distribution of the main drug is related to the dissolution and release behavior of the preparation, thereby affecting the bioequivalence of the homemade preparation and the original reference preparation;

[0046] (2) In order to solve the problem that the existing production and processing technology of propafenone hydrochloride tablets cannot ensure the content of the main drug in the preparation, the particle forming effect of granulation and the uniformity of wet granules in the premixing process, the present application adopts half of the auxiliary materials except the binder to mix and rinse the equipment in the premixing process, which can protect the main drug and ensure the content of the main drug in the preparation. The main drug and the other half of the auxiliary materials are then added and premixed for 15 minutes, which can ensure the particle forming effect of wet granulation and the uniformity of wet granules;

[0047] (3) In order to solve the problems of poor uniformity and low drying speed in the drying process of the existing production and processing technology of propafenone hydrochloride tablets, in the drying operation step, the present application turns the particles every half an hour after the drying temperature reaches 60°C, and switches the baking tray on the drying cart up and down to change the position. This operation can make the heat distribution in the oven more uniform, and the drying speed and uniformity can be improved;

[0048] (4) In order to solve the problem that the existing production and processing technology of propafenone hydrochloride tablets cannot ensure the uniformity of the total weight of the preparation after coating in the coating process, the present application adopts the above-mentioned coating solution preparation method to prepare the coating solution in the coating operation step, which can ensure that the film coating premix is ​​evenly dispersed in the purified water, thereby ensuring the uniformity of the total weight of the preparation after coating. During coating, the inlet air temperature is set to 50-60°C, the exhaust air speed is set to 1000-2300rpm, the main engine speed is set to 2.0-8.0rpm, the peristaltic pump speed is set to 10-50rpm, and the atomization pressure is set to 0.1-0.6Mpa, so that the coating solution can be evenly wrapped on the plain tablets, and the uniformity of the tablet weight of the preparation is better, thereby affecting the dissolution and release behavior of the preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 It is a process flow chart of the present invention;

[0050] Figure 2 The chemical structure diagram of propafenone hydrochloride of the present invention;

[0051] Figure 3 This is a top-down sampling diagram of the premixed upper layer of the present invention;

[0052] Figure 4 This is a top-down sampling diagram of the premixed middle layer of the present invention;

[0053] Figure 5 This is a sampling diagram of the total mixing mixer of the present invention;

[0054] Figure 6 This is a sampling diagram of the total mixing uniformity of the present invention;

[0055] Figure 7 This is the original process flow chart of the present invention. DETAILED DESCRIPTION

[0056] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments 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 creative work are within the scope of protection of the present invention.

[0057] See also Figure 1-7The present invention provides a technical solution: a production and processing technology of propafenone hydrochloride tablets, comprising the following steps:

[0058] 1. Preprocessing:

[0059] (1) Preparation: Use standard weights to calibrate electronic scales and balances; verify the name, specification, batch number, manufacturer, integrity and quantity of the propafenone hydrochloride API, and check whether the material properties are correct;

[0060] (2) Crushing: The weighed propafenone hydrochloride API is placed in a jet mill, and the crushing parameters are set as feed pressure 5.5±1.0 bar, crushing pressure 5.0±1.0 bar, and feeding speed 10-15 rpm. The API is subjected to jet milling, and the particle size needs to be controlled at D50≤10 μm and D90≤15 μm. When the particle size meets the requirements, it is formally crushed according to these parameters. After the crushing is completed, it is placed in a clean double-layer polyethylene bag and placed in a stainless steel barrel. After weighing, a label is attached between the two layers of polyethylene bags and outside the container, indicating the product name, batch number, specification, weight, date and operator. The polyethylene bag is sealed and sent to the temporary storage room for raw and auxiliary materials;

[0061] 2. Ingredients:

[0062] (1) Preparation: Check whether the weighing cover, container and production equipment are clean and within the effective period. If the effective period has expired, they must be cleaned again as required. Check the name, batch number and weight of the pre-processed raw and auxiliary materials according to the batch production instructions. Check whether the raw and auxiliary material packaging is intact and not damaged.

[0063] (2) Weighing: Weigh the prescribed amount of pre-treated propafenone hydrochloride API, microcrystalline cellulose, corn starch, hypromellose 2910, croscarmellose sodium, magnesium stearate, and film coating premix and place them separately into clean double-layer polyethylene bags. Attach a label between the two layers of polyethylene bags, indicating the product name, batch number, weight, date, and operator. Tie the polyethylene bags and place them into a numbered clean container. Weigh the prescribed amount of purified water and place it into a clean container.

[0064] 3. Premix:

[0065] (1) Preparation: Check that the LSH-400 wet mixer granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0066] (2) Operation: First, spread 1 / 2 of the prescribed amount of microcrystalline cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose on the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and rinse the pot wall for 2 minutes. Then, add the remaining microcrystalline cellulose, corn starch, cross-linked sodium carboxymethyl cellulose and propafenone hydrochloride raw materials into the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and the premixing time is 15 minutes.

[0067] (3) Premix uniformity inspection: Use a sampler to take a sample (1 mL) according to the instructions. Figure 3 And the instruction manual Figure 4 Sampling was carried out at 10 sampling points in total, and three samples were taken from each sampling point, one for inspection and two for backup, with a sampling volume of 0.213g to 0.639g / sample;

[0068] 4. Granulation:

[0069] (1) Preparation of adhesive: Weigh 23 kg of purified water according to the prescription amount, start stirring and slowly add 2 kg of hypromellose powder, stir and disperse to dissolve (no lumps are observed visually), prepare a solution with a concentration of 8%, and set aside;

[0070] (2) Slurry granulation: set the stirring paddle speed of the wet mixing granulator to 150 rpm, the cutting blade speed to 2400 rpm, the peristaltic pump speed to 550 rpm and the atomizing air pressure to 0.5 MPa, turn on the liquid adding pump, turn on the atomizer, spray the prepared binder solution, control the slurry adding time to 4 min to 4 min 30 s, and record the slurry adding time;

[0071] 5. Wet granulation:

[0072] (1) Preparation: Check whether the YK-160 swing granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0073] (2) Operation: Add the wet granules into the swing granulator and pass through a 14-mesh screen for wet granulation. The screen should be intact after granulation. Put the wet granules into a clean stainless steel barrel and send them to the drying room for drying;

[0074] 6. Drying:

[0075] (1) Preparation: Check whether the CT-C-Ⅱ hot air circulation oven has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0076] (2) Operation: Spread the prepared wet granules evenly on the drying tray (about 2 / 3 of the volume of the drying tray, about 1 kg / tray), place them on the drying cart in a top-down order, push the drying cart into the oven (the loading method of the CT-C-Ⅱ hot air circulation oven is: 4 carts / cabinet × 15 layers / cart × 2 trays / layer), control the oven drying temperature to 60℃±10℃, place the wet granules on the tray and spread them flat, start drying, record the drying start time, and determine the drying end point: dry until the moisture content is ≤3% (moisture content is ≤3%). Determination: 105℃, Auto); after reaching 60℃, turn the pellets every half an hour, turn the baking tray on the drying cart up and down, change the position, record the displayed temperature value before turning the material and sampling each time, randomly sample and determine the moisture content during the black drying, and inspect the drying uniformity after the drying is completed. After the drying is completed, close the steam valve, send clean air to cool the pellets to room temperature, and move the drying cart out of the oven, put the pellets in the baking tray into a clean stainless steel barrel lined with double-layer polyethylene bags, cover it and send it to whole pellets;

[0077] 7. Dry whole grain:

[0078] (1) Preparation: Check that the YK-160 swing pellet machine (SB-17012) has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark, make it in operation, check whether the screen is in good condition and verify that the screen mesh is 30 meshes;

[0079] (2) Operation: Add the dry granules to the granulator and pass through a 30-mesh screen for granulation. The screen should be intact after granulation. The granules are collected in a clean container. After the dry granulation is completed, samples are taken to test the molecular properties of the intermediate product, and the yield and material balance are calculated by weighing;

[0080] 8. Total Mixing:

[0081] (1) Preparation: Check whether the HF-400 fixed hopper mixer has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation;

[0082] (2) Operation: Calculate the amount of magnesium stearate based on the amount of dry particles (magnesium stearate dosage = actual dry particle weight / theoretical dry particle weight × theoretical magnesium stearate amount). Set the speed and time according to the performance of the mixer. The mixing speed is 10 rpm, the mixing time is 5 to 10 min, and the target is 7 min. Put the mixed particles into a clean stainless steel barrel lined with a double-layer polyethylene bag, attach a label with the product name, batch number, specification, weight, date and operator, and send it to the temporary storage room. After mixing, weigh it to calculate the yield and material balance.

[0083] (3) Sampling: After mixing, start sampling using a 1mL sampler according to the instructions. Figure 5As shown, sampling is performed at 11 positions, including the upper part (1, 2, 3, 4, 5), the corner edge (6, 7, 8, 9, 10) and the discharge port (11) of the mixer. Sampling is performed in a full-volume transfer manner. The one-time sampling amount is 1 to 3 times the dosage, that is, the sampling amount of each sample is: 213.9 mg to 641.7 mg. Three samples are taken from each point, and two samples are used as backup samples to detect mixing uniformity.

[0084] (4) Verification of the uniformity of unloading of intermediate products (granules): Sampling of unloading uniformity items: 6 points are taken in the material barrel. The sampling points are as shown in the attached manual. Figure 6 As shown: 3 samples are taken at each point, each sample is about 1 to 3 times the single dose (213.9 mg to 641.7 mg), and the whole sample should be used for mixing uniformity detection. After mixing, the yield and material balance are calculated by weighing. The total mixed particles are placed in a clean and sealed container (double-layer LDPE bag + desiccant + sealed barrel), labeled with the product name, product code, batch number, production date, packer and weight, and placed in the middle station. After mixing, 100g is taken from each of the upper, middle and lower layers, and mixed as mixed particle samples to test the powder properties (bulk density, tap density, particle size distribution) and content;

[0085] 9. Tableting:

[0086] (1) Preparation: Check whether the PG65 high-speed rotary tablet press has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark and put it in operation, check and confirm the die specifications (Φ9mm shallow concave) and finish, there should be no grooves, curling, missing corners, bursts and wear, install the die, and check the granule name, specification, batch number, weight and production date;

[0087] (2) Set the instrument parameters: pre-pressure 0.5-1.2 kN, main pressure 5.9-9.7 kN, tableting speed 20-30 rpm;

[0088] (3) Operation: Adjust the pre-pressure, main pressure, and tableting speed, and test tablets to check tablet weight, hardness, friability, and appearance. After all indicators are qualified, formal tableting begins. The average tablet weight is controlled to be between 203.2 and 224.6 mg, and the hardness is between 70 and 110 N. The operator takes samples from the tablet press outlet every 30 minutes for central control. Ten tablets are randomly selected and the total tablet weight is weighed to ensure that the total tablet weight meets the requirements.

[0089] 10. Coating:

[0090] (1) Preparation: Check that the BGB150 high-efficiency coating machine in the coating room has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to ensure that it is in operation;

[0091] (2) Preparation of coating solution: Weigh the film coating premix according to 7.5% of the weight of the plain tablets, weigh purified water according to 10% of the solid content of the coating solution, start stirring to make the solvent form a vortex, add the film coating premix evenly into the vortex, reduce the stirring speed until the vortex just disappears, continue stirring for 60 minutes for use (keep a slight stirring state during the entire coating process);

[0092] (3) Put the plain tablets into the coating pot, set the air inlet temperature to 50-60°C, the exhaust speed to 1000-2300 rpm, the main machine speed to 2.0-8.0 rpm, the peristaltic pump speed to 10-50 rpm, the atomization pressure to 0.1-0.6 MPa, and preheat the coating pot in steps until the tablet bed temperature is ≥40°C. Randomly take 100 tablets from the coating pot three times to measure the average tablet weight of 100 plain tablets, and start coating until the coating weight gain is 5.0%-7.5%. Reduce the coating pot speed to 2.0-5.0 rpm, stop heating, and cool the tablet bed to room temperature.

[0093] 11. Packaging: bottling, full inspection, and warehousing.

[0094] The directions or positional relationships indicated by terms such as "center", "longitudinal", "lateral", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside" and "outside" are based on the directions or positional relationships shown in the accompanying drawings. They are merely simplified descriptions for the convenience of describing the present invention, and do not indicate or imply that the devices or elements referred to must have a specific direction, be constructed and operated in a specific direction. Therefore, they should not be understood as limitations on the protection content of the present invention.

[0095] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A production process of propafenone hydrochloride tablets, comprising the following steps:

1. Preprocessing: (1) Preparation: Use standard weights to calibrate electronic scales and balances; verify the name, specification, batch number, manufacturer, integrity and quantity of the propafenone hydrochloride API, and check whether the material properties are correct; (2) Crushing: The weighed propafenone hydrochloride API is placed in a jet mill, and the crushing parameters are set as feed pressure 5.5±1.0 bar, crushing pressure 5.0±1.0 bar, and feeding speed 10-15 rpm. The API is subjected to jet milling, and the particle size needs to be controlled at D50≤10 μm and D90≤15 μm. When the particle size meets the requirements, it is formally crushed according to these parameters. After the crushing is completed, it is placed in a clean double-layer polyethylene bag and placed in a stainless steel barrel. After weighing, a label is attached between the two layers of polyethylene bags and outside the container, indicating the product name, batch number, specification, weight, date and operator. The polyethylene bag is sealed and sent to the temporary storage room for raw and auxiliary materials; 2. Ingredients: (1) Preparation: Check whether the weighing cover, container and production equipment are clean and within the effective period. If the effective period has expired, they must be cleaned again as required. Check the name, batch number and weight of the pre-processed raw and auxiliary materials according to the batch production instructions. Check whether the raw and auxiliary material packaging is intact and not damaged. (2) Weighing: Weigh the prescribed amount of pre-treated propafenone hydrochloride API, microcrystalline cellulose, corn starch, hypromellose 2910, croscarmellose sodium, magnesium stearate, and film coating premix and place them separately into clean double-layer polyethylene bags. Attach a label between the two layers of polyethylene bags, indicating the product name, batch number, weight, date, and operator. Tie the polyethylene bags and place them into a numbered clean container. Weigh the prescribed amount of purified water and place it into a clean container.

3. Premix: (1) Preparation: Check that the LSH-400 wet mixer granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation; (2) Operation: First, spread 1 / 2 of the prescribed amount of microcrystalline cellulose, corn starch, and cross-linked sodium carboxymethyl cellulose on the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and rinse the pot wall for 2 minutes. Then, add the remaining microcrystalline cellulose, corn starch, cross-linked sodium carboxymethyl cellulose and propafenone hydrochloride raw materials into the pot of the LSH-400 wet mixer granulator, set the stirring blade speed to 150 rpm and the cutting blade speed to 1500 rpm, and the premixing time is 15 minutes.

4. Granulation: (1) Preparation of adhesive: Weigh 23 kg of purified water according to the prescription amount, start stirring and slowly add 2 kg of hypromellose powder, stir and disperse to dissolve (no lumps are observed visually), prepare a solution with a concentration of 8%, and set aside; (2) Slurry granulation: set the stirring paddle speed of the wet mixing granulator to 150 rpm, the cutting blade speed to 2400 rpm, the peristaltic pump speed to 550 rpm and the atomizing air pressure to 0.5 MPa, turn on the liquid adding pump, turn on the atomizer, spray the prepared binder solution, control the slurry adding time to 4 min to 4 min 30 s, and record the slurry adding time; 5. Wet granulation: (1) Preparation: Check whether the YK-160 swing granulator has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation; (2) Operation: Add the wet granules into the swing granulator and pass through a 14-mesh screen for wet granulation. The screen should be intact after granulation. Put the wet granules into a clean stainless steel barrel and send them to the drying room for drying; 6. Drying: (1) Preparation: Check whether the CT-C-Ⅱ hot air circulation oven has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation; (2) Operation: Spread the prepared wet granules evenly on the drying tray (about 2 / 3 of the volume of the drying tray, about 1 kg / tray), and place them on the drying cart in a top-down order. Push the drying cart into the oven to dry the wet granules. After reaching 60°C, turn the granules every half an hour, and switch the drying tray on the drying cart up and down to change the position. After drying is completed, close the steam valve and send clean air to cool the granules to room temperature; 7. Dry whole grain: (1) Preparation: Check that the YK-160 swing pellet machine (SB-17012) has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark, make it in operation, check whether the screen is in good condition and verify that the screen mesh is 30 meshes; (2) Operation: Add the dry granules into the granulator and pass through a 30-mesh screen for granulation. The screen should be intact after granulation. The granules should be collected in a clean container.

8. Total Mixing: (1) Preparation: Check whether the HF-400 fixed hopper mixer has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to make it in operation; (2) Operation: Calculate the amount of magnesium stearate according to the amount of dry particles (magnesium stearate dosage = actual dry particle weight / theoretical dry particle weight × theoretical magnesium stearate amount), set the speed and time according to the performance of the mixer, the mixing speed is 10 rpm, the mixing time is 5 to 10 min, and the target is 7 min; 9. Tableting: (1) Preparation: Check whether the PG65 high-speed rotary tablet press has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, replace the status mark and put it in operation, check and confirm the die specifications (Φ9mm shallow concave) and finish, there should be no grooves, curling, missing corners, bursts and wear, install the die, and check the granule name, specification, batch number, weight and production date; (2) Operation: Adjust the pre-pressure, main pressure, tableting speed, test tableting to check tablet weight, hardness, friability and appearance. After all indicators are qualified, formal operation can begin; 10. Coating: (1) Preparation: Check that the BGB150 high-efficiency coating machine in the coating room has been cleaned and is within the effective period of cleaning, whether the equipment is in good condition, and replace the status mark to ensure that it is in operation; (2) Preparation of coating solution: Weigh the film coating premix according to 7.5% of the weight of the plain tablets, weigh purified water according to 10% of the solid content of the coating solution, start stirring to make the solvent form a vortex, add the film coating premix evenly into the vortex, reduce the stirring speed until the vortex just disappears, continue stirring for 60 minutes for use (keep a slight stirring state during the entire coating process); (3) Operation: Put the plain tablets into the coating pot, set the air inlet temperature to 50-60°C, exhaust speed to 1000-2300rpm, main machine speed to 2.0-8.0rpm, peristaltic pump speed to 10-50rpm, atomization pressure to 0.1-0.6Mpa, and preheat the coating pot in steps until the tablet bed temperature is ≥40°C. Randomly take 100 tablets from the coating pot three times to measure the average tablet weight of 100 plain tablets, and start coating until the coating weight gain is 5.0%-7.5%. Reduce the coating pot speed to 2.0-5.0rpm, stop heating, and cool the tablet bed to room temperature.

11. Packaging: bottling, full inspection, and warehousing.

2. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The actual batch dosage of the raw material of propafenone hydrochloride tablets = the theoretical batch dosage of the raw material / the content of the raw material (calculated as dry product) / (1-loss on drying); when the content of the raw material exceeds 100.0%, it is calculated as 100.0%.

3. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The oven is a CT-C-Ⅱ type hot air circulation oven, and its loading method is: 4 cars / cabinet×15 layers / car×2 trays / layer.

4. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The drying temperature of the oven is controlled to be 60°C ± 10°C, and the drying end point is determined as follows: drying to a moisture content of ≤ 3% (moisture content determination: 105°C, Auto).

5. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The instrument parameters of the high-speed rotary tablet press are set as follows during operation: pre-pressure 0.5-1.2 kN, main pressure 5.9-9.7 kN, and tableting speed 20-30 rpm.

6. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The tablet pressing machine controls the average tablet weight to be between 203.2 and 224.6 mg, and the hardness to be between 70 and 110 N. The operator takes samples from the tablet outlet of the tablet press machine once every 30 minutes for central control, randomly takes 10 tablets, and weighs the total tablet weight to ensure that the total tablet weight meets the requirements.

7. The production and processing technology of propafenone hydrochloride tablets according to claim 1, characterized in that: The film coating premix comprises the following ingredients: polyethylene glycol 400, polyethylene glycol 6000, hypromellose and titanium dioxide.

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