A production process of ranitidine hydrochloride injection

Abstract

The invention discloses a production process of ranitidine hydrochloride injection, comprising the following steps: S1. Calculated by weight, weighing 275-285 parts of ranitidine hydrochloride, 45-55 parts of disodium hydrogen phosphate dodecahydrate, 2.5-3.5 parts of anhydrous citric acid, 1-3 parts of activated carbon, and 10L of water for injection; S2. Concentrated preparation; S3. Dilute preparation; S4. Potting; S5. Sterilization leak detection, lamp inspection, and packaging. The injection prepared by the present invention has good dispersibility, can ensure good dispersibility in different environments, can resist terminal sterilization by controlling the product pH value in an appropriate range, does not contain components such as preservatives, does not produce toxic and side effects, and has good product safety.

Description

Technical Field

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

[0002] The production process of ranitidine hydrochloride injection mainly includes concentrated preparation and diluted preparation. Add an appropriate amount of water for injection to the concentrated preparation tank, cool it to below 30°C, and pass nitrogen for half an hour. Dissolve the weighed disodium hydrogen phosphate and citric acid with an appropriate amount of water for injection completely, add them to the concentrated preparation tank, stir evenly, and then add the weighed ranitidine hydrochloride to the concentrated preparation tank and stir to completely dissolve it. Add weighed activated carbon and stir evenly. After stirring and refluxing for 15 minutes, filter the drug solution through a 5μm decarbonization filter and pump it into the diluted preparation tank. Add an appropriate amount of water for injection to the concentrated preparation tank, circulate for 5 minutes, cool the water for injection to below 30°C, and pump the flushing liquid into the diluted preparation tank. Repeat the operation once. The drug solution enters the diluted preparation tank from the concentrated preparation, passes nitrogen for protection, and adds water for injection to the preparation amount. While stirring and refluxing the drug liquid in the tank for 20 minutes, turn on the cooling water to cool the drug liquid temperature to below 30°C, take samples at the sampling port of the dilution tank and send them to the intermediate for testing of content, pH value and color. If qualified, filter the drug liquid through 0.45μm and 0.22μm microporous filter elements and send them to the liquid storage tank.

[0003] Whether in the process of concentrated or diluted preparation, the medicine in the tank needs to be stirred. When the existing stirring device is used in conjunction with the concentrated preparation tank and the diluted preparation tank, there is a problem of cumbersome addition of medicine and activated carbon. It is easy to condense into agglomerates in the tank, resulting in increased stirring time and poor mixing effect with water for injection. Summary of the invention

[0004] The object of the present invention is to provide a production process of ranitidine hydrochloride injection to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a production process of ranitidine hydrochloride injection, comprising the following steps:

[0007] S1. Calculated by weight, weigh 275-285 parts of ranitidine hydrochloride, 45-55 parts of disodium hydrogen phosphate dodecahydrate, 2.5-3.5 parts of anhydrous citric acid, 1-3 parts of activated carbon, and 10L of water for injection;

[0008] S2. Under nitrogen protection, add water for injection to the concentrated preparation tank, cool to below 30°C, dissolve disodium hydrogen phosphate and citric acid in water for injection completely, add to the concentrated preparation tank, stir evenly, add ranitidine hydrochloride to the concentrated preparation tank, stir to completely dissolve, add activated carbon, stir and reflux for 10-20 minutes, filter the liquid through a decarbonization filter and pump it into the dilute preparation tank;

[0009] S3. Under nitrogen protection, add injection water to the dilution tank to the configured amount, stir and reflux the drug solution in the dilution tank for 15-25 minutes, cool to below 30°C, take samples from the sampling port of the dilution tank and send them to the intermediate for content, pH value and color testing. If qualified, filter the drug solution through a microporous filter element and send it to the liquid storage tank;

[0010] S4. After the liquid in the liquid storage tank is filtered through a sterilizing filter, it is sent to a filling machine for filling at a filling speed of 430-550 bottles / min;

[0011] S5. Sterilization leak detection, light inspection, and packaging;

[0012] The equipment used in the above-mentioned production process includes a concentrated mixing tank, a dilute mixing tank, a filling machine, a sterilization leak detection machine, a light inspection machine, and a packaging machine. The concentrated mixing tank and the dilute mixing tank are both provided with a stirring device, and the stirring device includes a stirring tank. A top cover is installed on the top of the stirring tank so as to rotate around the central axis of the stirring tank, and a rotary drive assembly is provided between the top cover and the top edge of the stirring tank. A cooling water circulation mechanism is provided in the stirring tank, and a nitrogen protection mechanism is provided on the outer ring of the cooling water circulation mechanism. A stirring mechanism is provided on the top cover, and the stirring mechanism is synchronously connected to a dilution mechanism.

[0013] The transmission gear of the present invention is connected with the gear of the driven gear of the driven gear, and the gear of the driven gear is meshed with each other, and the gear of the driven gear is meshed with each other, and the gear of the driven gear is meshed with each other.

[0014] Furthermore, in step S1, 279 parts of ranitidine hydrochloride, 50 parts of disodium hydrogen phosphate dodecahydrate, 3 parts of anhydrous citric acid, 2 parts of activated carbon, and 10 L of water for injection are weighed in parts by weight.

[0015] Furthermore, in step S2, the filter element diameter of the decarbonization filter is 5 μm.

[0016] Furthermore, in step S3, two microporous filter elements are provided, and the filter element diameters are 0.45 μm and 0.22 μm respectively.

[0017] Furthermore, in step S4, the filter element diameter of the sterilizing filter is 0.22 μm.

[0018] Furthermore, the time interval from the start of the concentrated formulation to the end of the diluted formulation does not exceed 4 hours.

[0019] Furthermore, the time interval from the end of dilution to the end of filling shall not exceed 8 hours.

[0020] Furthermore, the dilution mechanism includes a transfer assembly, which is connected to a driving screw, a pumping assembly is provided on the top cover, the pumping assembly includes a mounting plate arranged on the top cover, a rotating shaft is rotatably mounted on the mounting plate, the transfer assembly is connected to the rotating shaft, a rotating disk is provided at the end of the rotating shaft, a pumping box is provided on the top cover, the pumping box passes through the top cover and a pumping pipe is provided at the bottom of the pumping box, a one-way valve is provided at the connecting portion between the pumping pipe and the pumping box, a pumping piston is provided at the bottom of the pumping box, a push-pull rod is provided between the rotating disk and the pumping piston, a stuffing cylinder is provided on the top cover, a sealing cover is provided on the stuffing cylinder, a connecting pipe is provided between the stuffing cylinder and the pumping box, a return pipe is provided at the bottom of the stuffing cylinder, the return pipe is connected to a sliding matching block, and a pipe inner cavity communicating with the stirring shaft and the return pipe is provided in the sliding matching block.

[0021] Furthermore, the transfer assembly includes a transfer pulley 1 coaxially installed with the driving screw, a transfer pulley 2 and a transfer pulley 3 are rotatably installed on the bottom of the top cover, the transfer pulley 2 and the transfer pulley 3 are rigidly connected, a mounting plate is provided on the upper side of the top cover, the rotating shaft is rotatably installed between the mounting plate, a transfer pulley 4 is provided at the end of the rotating shaft away from the turntable, and a transfer belt 1 and a transfer belt 2 are respectively provided between the transfer pulley 1 and the transfer pulley 2, and between the transfer pulley 3 and the transfer pulley 4.

[0022] Furthermore, the stirring shaft is hollow, and the sides of the stirring shaft are evenly provided with discharge holes.

[0023] Furthermore, the cooling water circulation mechanism includes a vertical pipe 1 and a vertical pipe 2 arranged on the inner side of the stirring tank, the top of the vertical pipe 1 passes through the stirring tank and is connected to a water inlet joint, the bottom end of the vertical pipe 2 passes through the stirring tank and is connected to a water outlet joint, a plurality of groups of annular pipes are continuously arranged between the vertical pipe 1 and the vertical pipe 2, the two ends of the annular pipes are respectively connected to the vertical pipe 1 and the vertical pipe 2, and a cooling water generator is connected between the water inlet joint and the water outlet joint.

[0024] Furthermore, the nitrogen protection mechanism includes two groups of parallelly arranged spiral tubes 1 and 2, the inner side of the spiral tube 1 is evenly provided with inclined nozzle 1, and the inner side of the spiral tube 2 is evenly provided with inclined nozzle 2, the inclined nozzle 1 is arranged clockwise, and the inclined nozzle 2 is arranged counterclockwise, the spiral tube 1 and the spiral tube 2 are located at the bottom end of the stirring tank and are closed, the upper end points of the spiral tube 1 and the spiral tube 2 pass through the stirring tank and are connected to a switching component, the spiral tube 1 and the spiral tube 2 are connected to an air supply joint through the switching component, and the spiral tube 1 and the spiral tube 2 are sleeved on the outside of the cooling water circulation mechanism.

[0025] Furthermore, the switching assembly includes a conversion tube, both ends of which are respectively connected to the ends of spiral tube one and spiral tube two, the air supply joint is connected to the middle part of the conversion tube, a sealing piston is arranged in the conversion tube, a telescopic motor is fixedly arranged on spiral tube one, a connecting shaft of the telescopic motor penetrates into spiral tube one and is connected to the sealing piston, and a diameter of the connecting shaft is smaller than an inner diameter of spiral tube one.

[0026] Furthermore, the rotary drive assembly includes a mounting ring arranged on the top of the mixing tank, the top cover is clamped with the mounting ring through a clamping ring, an outer gear ring is arranged on the edge of the clamping ring, a bending frame is fixedly arranged on the mounting ring, a rotary motor is fixedly arranged on the bending frame, the rotary motor is connected to a driving gear, and the driving gear and the outer gear ring are meshed with each other.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The injection prepared by the present invention has good dispersibility and can ensure good dispersibility in different environments. By controlling the pH value of the product within an appropriate range, it can withstand terminal sterilization, does not contain components such as preservatives, does not produce toxic side effects, and has good product safety.

[0029] 2. The present invention uses a stirring tank including a stirring device to produce the injection solution during both the concentrated and diluted preparation processes, and adds the diluted disodium hydrogen phosphate and citric acid into the stirring tank in combination with a dilution mechanism, and stirs and adds the diluted ingredients together with the stirring mechanism to maximize the stirring efficiency. The stirring and adding method can reduce the power of the stirring motor, avoid the generation of more foam in the stirring tank due to high-power stirring, and shorten the time required for stirring until uniformity, avoiding the problem of bursting and other problems that may be caused by the direct addition of disodium hydrogen phosphate and citric acid.

[0030] 3. The driving screw is driven to rotate by the active bevel gear and the driven bevel gear, thereby driving the sliding matching block to move back and forth in the sliding clamping frame, adjusting the position of the stirring shaft in the stirring tank back and forth, and cooperating with the rotating top cover to realize the movable installation of the stirring shaft in the stirring tank, thereby further improving the stirring effect. In conjunction with the nitrogen protection mechanism arranged on the outer ring of the cooling circulation mechanism, while the nitrogen is fed into the stirring tank, the injection water in the stirring tank is driven to flow through the nitrogen blowing airflow, thereby further improving the stirring effect and avoiding the occurrence of stirring dead corners. When adding activated carbon to decolorize the injection solution, the activated carbon powder mixed with the injection water can also be added to the stirring tank in combination with the dilution mechanism to maximize the dispersion of the activated carbon powder, while avoiding the activated carbon powder adhering to the nitrogen protection mechanism and the cooling water circulation mechanism to cause stirring dead corners.

[0031] 4. The power of the stirring motor is diverted to the pumping assembly through the transfer assembly. The push-pull rod and the pumping piston are driven to move up and down in the pumping tank in combination with the turntable. The injection water in the stirring tank is continuously pumped up and sent into the filling cylinder in combination with the pumping pipe. When disodium hydrogen phosphate, citric acid, and activated carbon powder need to be added, they are directly put into the filling cylinder, diluted with injection water, and then sent into the stirring tank in combination with the return pipe and the stirring shaft to achieve the effect of adding while stirring.

[0032] 5. Nitrogen is intermittently introduced into the stirring tank through spiral tube 1 and spiral tube 2, and nitrogen is respectively sent into the water for injection through inclined nozzle 1 and inclined nozzle 2. The airflow blown by nitrogen drives the water for injection to flow in the stirring tank and form a vortex, thereby cooperating with the stirring mechanism to improve the stirring effect. The purpose of using spiral tube 1 and spiral tube 2 for ventilation in sequence is to avoid the gradual strengthening of the vortex in the stirring tank caused by continuous ventilation using spiral tube 1 or spiral tube 2 alone, thereby preventing the water for injection from overflowing the stirring tank. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a flow chart of the present invention.

[0034] Figure 2 It is a schematic diagram of the overall structure of the stirring device in the present invention.

[0035] Figure 3Schematic diagram of the internal structure of the stirring device in the present invention.

[0036] Figure 4 It is a structural schematic diagram of the cooling water circulation mechanism in the present invention.

[0037] Figure 5 It is a structural schematic diagram of the nitrogen protection mechanism in the present invention.

[0038] Figure 6 It is a structural schematic diagram of the switching component in the nitrogen protection mechanism of the present invention.

[0039] Figure 7 It is a schematic diagram of the installation of the stirring mechanism in the present invention.

[0040] Figure 8 It is a schematic diagram of the structure of the rotary drive assembly in the present invention.

[0041] Fig. 9 It is a structural schematic diagram of the stirring mechanism in the present invention.

[0042] Fig.10 It is a structural schematic diagram of the dilution mechanism in the present invention.

[0043] Fig.11 It is a schematic diagram of the connection between the filling cylinder and the stirring shaft in the present invention.

[0044] Fig.12 It is a schematic diagram of the structure of the stirring shaft in the present invention.

[0045] In the figure: 1, stirring tank; 10, mounting ring; 2, top cover; 20, clamping ring; 21, outer gear ring; 3, cooling water circulation mechanism; 30, vertical pipe 1; 31, annular pipe; 32, water inlet joint; 33, vertical pipe 2; 34, water outlet joint; 4, nitrogen protection mechanism; 40, spiral pipe 1; 41, inclined nozzle 1; 42, spiral pipe 2; 43, inclined nozzle 2; 44, air supply joint; 45, conversion pipe; 46, blocking piston; 47, telescopic motor; 5, stirring mechanism; 50, stirring motor; 51, output shaft; 52, driving bevel gear; 53, sliding clamping frame; 54, driving screw; 55, driven bevel gear; 56, sliding matching block; 57, stirring shaft; 58, driving screw Driving pulley; 59, driving belt; 510, tensioning wheel; 511, driven pulley one; 512, driven pulley two; 6, dilution mechanism; 60, transfer pulley one; 61, transfer belt one; 62, transfer pulley two; 63, transfer pulley three; 64, transfer belt two; 65, mounting plate; 66, rotating shaft; 67, transfer pulley four; 68, water pumping box; 680, one-way valve; 69, rotating plate; 610, push-pull rod; 611, water pumping piston; 612, water pumping pipe; 613, stuffing cylinder; 614, return pipe; 615, connecting pipe; 6120, discharge hole; 6121, stirring rod; 7, rotary drive assembly; 70, bending frame; 71, rotary motor; 72, driving gear. DETAILED DESCRIPTION

[0046] In the description of the present invention, it is necessary to understand that the orientations or positional relationships indicated by terms such as “longitudinal”, “lateral”, “upper”, “lower”, “top”, “bottom”, “inside” and “outside” are based on the orientations or positional relationships shown in the accompanying drawings and are only for the convenience of describing the present invention and simplifying the description. They do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0047] In addition, the terms "one" and "two" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, a feature defined as "one" or "two" may explicitly or implicitly include one or more of the feature. In the description of the present invention, the meaning of "multiple" is two or more, unless otherwise clearly and specifically defined.

[0048] In the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0049] The technical solution of the present invention is further described in detail below in conjunction with specific implementation methods.

[0050] like Figure 1-12 As shown, the present invention provides a production process of ranitidine hydrochloride injection, comprising the following steps:

[0051] S1. Calculated by weight, weigh 279 parts of ranitidine hydrochloride, 50 parts of disodium hydrogen phosphate dodecahydrate, 3 parts of anhydrous citric acid, 2 parts of activated carbon, and 10L of water for injection;

[0052] S2. Under nitrogen protection, add water for injection to the concentrated preparation tank, cool to below 30°C, dissolve disodium hydrogen phosphate and citric acid in water for injection completely, add to the concentrated preparation tank, stir evenly, add ranitidine hydrochloride to the concentrated preparation tank, stir to completely dissolve, add activated carbon, stir and reflux for 10-20 minutes, filter the liquid through a 5μm decarbonization filter and pump it into the dilute preparation tank;

[0053] S3. Under nitrogen protection, add injection water to the dilution tank to the prepared amount, stir and reflux the drug solution in the dilution tank for 15-25 minutes, cool to below 30°C, take samples from the sampling port of the dilution tank and send them to the intermediate for content, pH value and color testing. After passing the test, filter the drug solution through 0.45μm and 0.22μm microporous filter elements and send it to the liquid storage tank. The time interval from the start of concentrated preparation to the end of diluted preparation shall not exceed 4 hours;

[0054] S4. After the liquid in the storage tank is filtered through a 0.22μm sterilizing filter, it is sent to the filling machine and filled at a filling speed of 430-550 bottles / min. The time interval from the end of dilution to the end of filling shall not exceed 8 hours;

[0055] S5. The semi-finished products after filling are placed into a stainless steel tray from the bottle outlet, and the bottle receiving operator puts them into the tray card. According to the product transfer card, after checking the product name, specification, batch number and quantity are correct, they are moved into the cabinet from the front door of the sterilization cabinet, the front door is closed, and the start button is pressed. Sterilize in a water bath at 100℃ for 15 minutes. After the sterilization and leak detection procedures are all completed (the process is controlled by a computer), the rear door is opened, the products are taken out, and the unqualified products are removed after leak detection. After the status label is hung, they are sent to the transfer room to wait for light inspection. The drugs sterilized in separate cabinets should be placed separately and marked. QA takes samples according to the cabinet after the product is sterilized, and QC performs sterility testing. The time from the end of filling to sterilization shall not exceed 4 hours;

[0056] According to the batch number, the sterilized semi-finished products are pushed from the transfer room to the light inspection room. After checking the product name, specification, batch number and quantity, the light inspector removes the bubble heads, burnt heads, hook heads, broken heads, etc., and then conducts visible foreign matter inspection according to the "Standard Operating Procedures for Visible Foreign Matter Inspection". Needles and medicines containing glass chips, white spots, fibers, turbidity, crystals, precipitation, color spots and other foreign matters visible to the naked eye, as well as waste products such as small capacity, empty bottles, cold explosions, leaking bottles, and colored water bottles are removed. After each light inspection of a tray, the light inspector puts the tray card, and the tray card is marked with the product name, specification, batch number, and work number. The QA will randomly select 200 from every 9 trays. There must be no obvious visible foreign matter and glass chips. If there is one obvious foreign matter, it will be handed over to the operator for re-light inspection, or the JAZ800 / 20 ampoule injection foreign matter automatic light inspection machine will be used for inspection;

[0057] The operator checks the product name, specification, batch number, quantity, etc. according to the product transfer card, and installs the resin plate according to the product name, specification, batch number (the product name, batch number, and specification are checked by the section manager and QA);

[0058] After verification, the printing and packaging machine is started, and each ampoule is printed with "product name, specification, batch number, expiration date" and other words;

[0059] At the same time, check whether the printed words are clear. After printing, the products are packed into cartons through an automatic cartoning machine. Every 10 ampoules are packed into one box. The box is printed with "batch number, production date, and expiration date" (checked by the operator, section manager and QA);

[0060] "Batch number, production date, expiration date" are printed on both sides of the outer box (checked by the operator, section manager and QA);

[0061] The upper and lower bottoms of the outer box are sealed with plastic tape and the electronic supervision code is affixed;

[0062] Further, such as Figure 2As shown, the equipment used in the above production process includes a concentrated mixing tank, a diluted mixing tank, a filling machine, a sterilization leak detection machine, a light inspection machine, and a packaging machine. The concentrated mixing tank and the diluted mixing tank are both provided with a stirring device, the stirring device includes a stirring tank 1, a top cover 2 is installed on the top of the stirring tank 1 to rotate around the central axis of the stirring tank 1, a rotary drive assembly 7 is provided between the top cover 2 and the top edge of the stirring tank 1, a cooling water circulation mechanism 3 is provided in the stirring tank 1, a nitrogen protection mechanism 4 is provided on the outer ring of the cooling water circulation mechanism 3, a stirring mechanism 5 is provided on the top cover 2, and the stirring mechanism 5 is synchronously connected to the dilution mechanism 6.

[0063] Further, such as Fig. 9 As shown, the stirring mechanism 5 includes a stirring motor 50 arranged at the center of the top cover 2, the stirring motor 50 is connected to an output shaft 51, the output shaft 51 is connected to a driving bevel gear 52, a sliding clamping frame 53 is arranged at the bottom of the top cover 2, a sliding matching block 56 is installed in the sliding clamping frame 53, a driving screw 54 is rotatably installed in the sliding clamping frame 53, the sliding matching block 56 is threadedly connected to the driving screw 54, and a driven bevel gear 55 is arranged at one end of the driving screw 54 facing the driving bevel gear 52, and the driven bevel gear 55 and the driving bevel gear 52 mesh with each other. The driving bevel gear 52 is coaxially mounted with a driving pulley 58, a stirring shaft 57 is rotatably mounted on the bottom of the sliding matching block 56, a driven pulley 1 511 is arranged at the end of the sliding clamping frame 53, a driven pulley 2 512 is arranged on the stirring shaft 57, a driving belt 59 is arranged between the driving pulley 58 and the driven pulleys 1 511 and 512, the sliding clamping frame 53 is provided with tensioning wheels 510 on both sides of the driving belt 59, the tensioning wheels 510 abut against the outer side of the driving belt 59, and stirring rods 6121 are evenly arranged on the stirring shaft 57.

[0064] Specifically, during the stirring process, first inject an appropriate amount of water for injection into the stirring tank 1, and adjust the water for injection in the stirring tank 1 to below 30°C in combination with the cooling water circulation mechanism 3. And continuously introduce nitrogen into the stirring tank 1 in combination with the nitrogen protection mechanism 4. After half an hour of introducing nitrogen, add the diluted disodium hydrogen phosphate and citric acid into the stirring tank 1 in combination with the dilution mechanism 6, and add while stirring in combination with the stirring mechanism 5 to maximize the stirring efficiency. The method of adding while stirring can reduce the power of the stirring motor 50 and avoid the generation of more foam in the stirring tank 1 due to high-power stirring. At the same time, the time required for stirring to be uniform can be shortened, avoiding problems such as bursting caused by the direct addition of disodium hydrogen phosphate and citric acid.

[0065] More specifically, the driving screw 54 is driven to rotate by the active bevel gear 52 and the driven bevel gear 55, thereby driving the sliding matching block 56 to move back and forth in the sliding clamping frame 53, adjusting the position of the stirring shaft 57 in the stirring tank 1 back and forth, and cooperating with the rotatably installed top cover 2 to realize the movable installation of the stirring shaft 57 in the stirring tank 1, further improving the stirring effect. In conjunction with the nitrogen protection mechanism 4 set on the outer ring of the cooling circulation mechanism, while the nitrogen is fed into the stirring tank 1, the injection water in the stirring tank 1 is driven to flow through the nitrogen blowing airflow, further improving the stirring effect and avoiding the occurrence of stirring dead corners. When adding activated carbon to decolorize the injection solution later, the activated carbon powder mixed with the injection water can also be added to the stirring tank 1 in combination with the dilution mechanism 6, so that the activated carbon powder is dispersed to the maximum extent, while avoiding the activated carbon powder adhering to the nitrogen protection mechanism 4 and the cooling water circulation mechanism 3 to cause stirring dead corners.

[0066] More specifically, since the nitrogen protection mechanism 4 continuously supplies nitrogen into the stirring tank 1, causing a positive pressure inside the stirring tank 1, when adding disodium hydrogen phosphate, citric acid, and activated carbon powder, it is necessary to close the recovery pipe on the top cover 2 for recovering nitrogen, so that the nitrogen is sprayed outward from the open parts of the dilution mechanism 6 and the stirring mechanism 5, thereby ensuring the nitrogen protection effect of the water for injection when adding disodium hydrogen phosphate, citric acid, and activated carbon powder.

[0067] Further, such as Fig.10 , Fig.11 As shown, the dilution mechanism 6 includes a transfer assembly, which is connected to the driving screw 54. The top cover 2 is provided with a pumping assembly, which includes a mounting plate 65 provided on the top cover 2, on which a rotary shaft 66 is rotatably mounted, the transfer assembly is connected to the rotary shaft 66, and a rotary disk 69 is provided at the end of the rotary shaft 66. The top cover 2 is provided with a pumping box 68, which passes through the top cover 2 and a pumping pipe 612 is provided at the bottom of the pumping box 68, and a one-way valve is provided at the connection between the pumping pipe 612 and the pumping box 68. 680, a water pumping piston 611 is provided at the bottom of the water pumping box 68, a push-pull rod 610 is provided between the rotating disk 69 and the water pumping piston 611, a stuffing cylinder 613 is provided on the top cover 2, the stuffing cylinder 613 is provided with a sealing cover, a connecting pipe 615 is provided between the stuffing cylinder 613 and the water pumping box 68, a return pipe 614 is provided at the bottom of the stuffing cylinder 613, the return pipe 614 is connected to the sliding matching block 56, and a pipe inner cavity connected to the stirring shaft 57 and the return pipe 614 is provided in the sliding matching block 56.

[0068] Specifically, the power of the stirring motor 50 is diverted to the pumping assembly through the transfer assembly, and the push-pull rod 610 and the pumping piston 611 are driven to reciprocate and rise and fall in the pumping box 68 in combination with the turntable 69. The injection water in the stirring tank 1 is continuously pumped up and sent into the filling tube 613 in combination with the pumping pipe 612. When disodium hydrogen phosphate, citric acid, and activated carbon powder need to be added, they are directly put into the filling tube 613, diluted with injection water, and then sent into the stirring tank 1 in combination with the return pipe 614 and the stirring shaft 57, so as to achieve the effect of adding while stirring.

[0069] Further, such as Fig. 9 , Fig.10 As shown, the transfer assembly includes a transfer pulley 1 60 coaxially mounted with the drive screw 54, a transfer pulley 2 62 and a transfer pulley 3 63 are rotatably mounted on the bottom of the top cover 2, the transfer pulley 2 62 and the transfer pulley 3 63 are rigidly connected, a mounting plate 65 is provided on the upper side of the top cover 2, a rotary shaft 66 is rotatably mounted between the mounting plate 65, a transfer pulley 4 67 is provided at the end of the rotary shaft 66 away from the turntable 69, a transfer belt 1 61 and a transfer belt 2 64 are respectively provided between the transfer pulley 1 60 and the transfer pulley 2 62, and between the transfer pulley 3 63 and the transfer pulley 4 67.

[0070] Further, such as Fig.12 As shown, the stirring shaft 57 is hollow, and the side of the stirring shaft 57 is evenly provided with discharge holes 6120.

[0071] Further, such as Figure 4 As shown, the cooling water circulation mechanism 3 includes a vertical pipe 1 30 and a vertical pipe 2 33 arranged on the inner side of the stirring tank 1. The top of the vertical pipe 1 30 passes through the stirring tank 1 and is connected to a water inlet joint 32. The bottom end of the vertical pipe 2 33 passes through the stirring tank 1 and is connected to a water outlet joint 34. A plurality of groups of annular pipes 31 are continuously arranged between the vertical pipe 1 30 and the vertical pipe 2 33. Both ends of the annular pipes 31 are respectively connected to the vertical pipe 1 30 and the vertical pipe 2 33. A cooling water generator is connected between the water inlet joint 32 and the water outlet joint 34.

[0072] Specifically, cooling water is injected into the vertical pipe 1 30 through the water inlet joint 32 , and the vertical pipe 1 30 disperses the cooling water into the annular pipe 31 and sends it out in combination with the vertical pipe 2 33 and the water outlet joint 34 , forming a cooling water circulation.

[0073] Further, such as Figure 5As shown, the nitrogen protection mechanism 4 includes two groups of parallelly arranged spiral tubes 1 40 and spiral tubes 2 42, the inner side of the spiral tube 1 40 is evenly provided with inclined nozzles 1 41, and the inner side of the spiral tube 2 42 is evenly provided with inclined nozzles 2 43, the inclined nozzles 1 41 are arranged clockwise, and the inclined nozzles 2 43 are arranged counterclockwise, the spiral tubes 1 40 and the spiral tubes 2 42 are located at the bottom end of the stirring tank 1 and are closed, the upper ends of the spiral tubes 1 40 and the spiral tubes 2 42 pass through the stirring tank 1 and are connected to a switching component, the spiral tubes 1 40 and the spiral tubes 2 42 are connected to an air supply joint 44 through the switching component, and the spiral tubes 1 40 and the spiral tubes 2 42 are sleeved on the outside of the cooling water circulation mechanism 3.

[0074] Specifically, after the water for injection is injected into the stirring tank 1, nitrogen is intermittently introduced into the stirring tank 1 through the spiral tube 1 40 and the spiral tube 2 42, and the nitrogen is respectively sent into the water for injection by the inclined nozzle 1 41 and the inclined nozzle 2 43, and the airflow blown by the nitrogen drives the water for injection to flow in the stirring tank 1 and form a vortex, thereby cooperating with the stirring mechanism 5 to improve the stirring effect. The purpose of using the spiral tube 1 40 and the spiral tube 2 42 for ventilation in sequence is to avoid the vortex in the stirring tank 1 being gradually strengthened due to the continuous ventilation of the spiral tube 1 40 or the spiral tube 2 42 alone, thereby preventing the water for injection from overflowing the stirring tank 1.

[0075] Further, such as Figure 6 As shown, the switching assembly includes a conversion tube 45, both ends of which are respectively connected to the ends of spiral tube 1 40 and spiral tube 2 42, an air supply connector 44 is connected to the middle of the conversion tube 45, a blocking piston 46 is arranged in the conversion tube 45, a telescopic motor 47 is fixedly arranged on the spiral tube 1 40, a connecting shaft of the telescopic motor 47 penetrates into the spiral tube 1 40 and is connected to the blocking piston 46, and a diameter of the connecting shaft is smaller than an inner diameter of the spiral tube 1 40.

[0076] Specifically, the telescopic motor 47 is used to drive the blocking piston 46 to move in the conversion tube 45, so that the nitrogen from the gas supply connector 44 is switched to the spiral tube 1 40 or the spiral tube 2 42.

[0077] Further, such as Figure 7 , Figure 8 As shown, the rotary drive assembly 7 includes a mounting ring 10 arranged on the top of the mixing tank 1, the top cover 2 is clamped with the mounting ring 10 through a clamping ring 20, an outer gear ring 21 is arranged on the edge of the clamping ring 20, a bending frame 70 is fixedly arranged on the mounting ring 10, a rotary motor 71 is fixedly arranged on the bending frame 70, the rotary motor 71 is connected to a driving gear 72, and the driving gear 72 is meshed with the outer gear ring 21.

[0078] Specifically, the driving gear 72, in conjunction with the outer gear ring 21, drives the top cover 2 and the stirring mechanism 5 and the dilution mechanism 6 installed on the top cover 2 to rotate around the central axis of the stirring tank 1, thereby achieving all-round stirring in the stirring tank 1 and continuous and uniform addition of disodium hydrogen phosphate, citric acid, and activated carbon powder, further improving the stirring effect.

[0079] The working principle of the embodiment of the present invention is:

[0080] like Figure 1-Figure 12 As shown, first inject an appropriate amount of water for injection into the stirring tank 1, and adjust the water for injection in the stirring tank 1 to below 30°C in combination with the cooling water circulation mechanism 3. And continuously introduce nitrogen into the stirring tank 1 in combination with the nitrogen protection mechanism 4. After half an hour of introducing nitrogen, add the diluted disodium hydrogen phosphate and citric acid into the stirring tank 1 in combination with the dilution mechanism 6, and add while stirring in combination with the stirring mechanism 5 to maximize the stirring efficiency. The method of adding while stirring can reduce the power of the stirring motor 50 and avoid the generation of more foam in the stirring tank 1 due to high-power stirring. At the same time, it can shorten the time required for stirring to be uniform, and avoid problems such as bursting caused by the direct addition of disodium hydrogen phosphate and citric acid. The power of the stirring motor 50 is diverted to the pumping assembly through the transfer assembly, and the push-pull rod 610 and the pumping piston 611 are driven to rise and fall back and forth in the pumping box 68 in combination with the rotating disk 69. The water for injection in the stirring tank 1 is continuously pumped up and sent to the filling tube 613 in combination with the pumping pipe 612. When disodium hydrogen phosphate, citric acid, and activated carbon powder need to be added, they are directly put into the filling tube 613, diluted with injection water, and sent into the stirring tank 1 in combination with the return pipe 614 and the stirring shaft 57, so as to achieve the effect of adding while stirring. After completing the concentrated and diluted preparations, the filling machine is used for filling, and the filling speed is set to 430-550 pieces / minute. The filled medicine bottles are inspected by the sterilization leak detector and the light inspection machine, and then packaged by the packaging machine.

[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention. Any reference numeral in a claim shall not be regarded as limiting the claim involved.

[0082] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A production equipment for ranitidine hydrochloride injection, characterized in that, The invention comprises a concentrated mixing tank, a diluted mixing tank, a filling machine, a sterilizing leak detection machine, a light inspection machine, and a packaging machine. The concentrated mixing tank and the diluted mixing tank are both provided with a stirring device. The stirring device comprises a stirring tank (1). A top cover (2) is installed on the top of the stirring tank (1) so as to rotate around the central axis of the stirring tank (1). A rotary drive assembly (7) is provided between the top cover (2) and the top edge of the stirring tank (1). A cooling water circulation mechanism (3) is provided in the stirring tank (1). A nitrogen protection mechanism (4) is provided on the outer ring of the cooling water circulation mechanism (3). A stirring mechanism (5) is provided on the top cover (2). The stirring mechanism (5) is synchronously connected with a dilution mechanism (6). The stirring mechanism (5) comprises a stirring motor (50) arranged at the center of the top cover (2), the stirring motor (50) being connected to an output shaft (51), the output shaft (51) being connected to a driving bevel gear (52), a sliding clamping frame (53) being arranged at the bottom of the top cover (2), a sliding matching block (56) being installed in the sliding clamping frame (53), a driving screw (54) being rotatably installed in the sliding clamping frame (53), the sliding matching block (56) being threadedly connected to the driving screw (54), a driven bevel gear (55) being arranged at one end of the driving screw (54) facing the driving bevel gear (52), the driven bevel gear (55) being mutually connected to the driving bevel gear (52). The driving bevel gear (52) is meshed, a driving pulley (58) is coaxially mounted on the driving bevel gear (52), a stirring shaft (57) is rotatably mounted on the bottom of the sliding matching block (56), a driven pulley 1 (511) is arranged at the end of the sliding clamping frame (53), a driven pulley 2 (512) is arranged on the stirring shaft (57), a driving belt (59) is arranged between the driving pulley (58) and the driven pulley 1 (511) and the driven pulley 2 (512), the sliding clamping frame (53) is provided with tensioning wheels (510) on both sides of the driving belt (59), the tensioning wheels (510) are pressed against the outer side of the driving belt (59), and stirring rods (6121) are evenly arranged on the stirring shaft (57); The dilution mechanism (6) comprises a transfer assembly, the transfer assembly is connected to the driving screw (54), the top cover (2) is provided with a pumping assembly, the pumping assembly comprises a mounting plate (65) arranged on the top cover (2), a rotary shaft (66) is rotatably mounted on the mounting plate (65), the transfer assembly is connected to the rotary shaft (66), a rotary disk (69) is arranged at the end of the rotary shaft (66), a pumping box (68) is arranged on the top cover (2), the pumping box (68) passes through the top cover (2), a pumping pipe (612) is arranged at the bottom of the pumping box (68), and a one-way valve is arranged at the connection between the pumping pipe (612) and the pumping box (68). (680), a water pumping piston (611) is provided at the bottom of the water pumping box (68), a push-pull rod (610) is provided between the rotating disk (69) and the water pumping piston (611), a stuffing cylinder (613) is provided on the top cover (2), the stuffing cylinder (613) is provided with a sealing cover, a connecting pipe (615) is provided between the stuffing cylinder (613) and the water pumping box (68), a return pipe (614) is provided at the bottom of the stuffing cylinder (613), the return pipe (614) is connected to the sliding matching block (56), and a pipe inner cavity is provided in the sliding matching block (56) and is connected to the stirring shaft (57) and the return pipe (614); The transfer assembly comprises a transfer pulley 1 (60) coaxially mounted with the driving screw (54); a transfer pulley 2 (62) and a transfer pulley 3 (63) are rotatably mounted on the bottom of the top cover (2); the transfer pulley 2 (62) and the transfer pulley 3 (63) are rigidly connected; a mounting plate (65) is disposed on the upper side of the top cover (2); the rotating shaft (66) is rotatably mounted between the mounting plate (65); a transfer pulley 4 (67) is disposed at one end of the rotating shaft (66) away from the rotating disk (69); a transfer belt 1 (61) and a transfer belt 2 (64) are respectively disposed between the transfer pulley 1 (60) and the transfer pulley 2 (62), and between the transfer pulley 3 (63) and the transfer pulley 4 (67).

2. A production process of ranitidine hydrochloride injection, characterized in that: The production device according to claim 1 comprises the following steps: S1. Calculated by weight, weigh 275-285 parts of ranitidine hydrochloride, 45-55 parts of disodium hydrogen phosphate dodecahydrate, 2.5-3.5 parts of anhydrous citric acid, 1-3 parts of activated carbon, and 10L of water for injection; S2. Under nitrogen protection, add water for injection to the concentrated preparation tank, cool to below 30°C, dissolve disodium hydrogen phosphate and citric acid in water for injection completely, add to the concentrated preparation tank, stir evenly, add ranitidine hydrochloride to the concentrated preparation tank, stir to completely dissolve, add activated carbon, stir and reflux for 10-20 minutes, filter the liquid through a decarbonization filter and pump it into the dilute preparation tank; S3. Under nitrogen protection, add injection water to the dilution tank to the configured amount, stir and reflux the drug solution in the dilution tank for 15-25 minutes, cool to below 30°C, take samples from the sampling port of the dilution tank and send them to the intermediate for content, pH value and color testing. If qualified, filter the drug solution through a microporous filter element and send it to the liquid storage tank; S4. After the liquid in the liquid storage tank is filtered through a sterilizing filter, it is sent to a filling machine for filling at a filling speed of 430-550 bottles / min; S5. Sterilization leak detection, light inspection, and packaging; When adding disodium hydrogen phosphate, citric acid and activated carbon powder, the recovery pipe on the top cover (2) for recovering nitrogen is closed, so that nitrogen is ejected outward from the open parts in the dilution mechanism (6) and the stirring mechanism (5), thereby ensuring the nitrogen protection effect of the water for injection when adding disodium hydrogen phosphate, citric acid and activated carbon powder.

3. A production process for ranitidine hydrochloride injection according to claim 2, characterized in that: In the step S1, 279 parts of ranitidine hydrochloride, 50 parts of disodium hydrogen phosphate dodecahydrate, 3 parts of anhydrous citric acid, 2 parts of activated carbon, and 10 L of water for injection are weighed in parts by weight.

4. A production process for ranitidine hydrochloride injection according to claim 2, characterized in that: In the step S2, the filter element diameter of the decarbonization filter is 5 μm.

5. A production process for ranitidine hydrochloride injection according to claim 2, characterized in that: In step S3, two microporous filter elements are provided, and the filter element diameters are 0.45 μm and 0.22 μm respectively.

6. The production process of ranitidine hydrochloride injection according to claim 2, characterized in that: In step S4, the filter element diameter of the sterilizing filter is 0.22 μm.

7. The production process of ranitidine hydrochloride injection according to claim 2, characterized in that: The time interval from the beginning of concentrated mixing to the end of diluted mixing shall not exceed 4 hours.

8. The production process of ranitidine hydrochloride injection according to claim 2, characterized in that: The time interval from the end of dilution to the end of filling shall not exceed 8 hours.

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