Flash drying method for oxytetracycline alkali wet crystals

Abstract

The invention discloses a flash evaporation drying method for oxytetracycline alkali wet crystals. According to the method, a flash dryer is adopted for treatment; the inner wall of the main machine is of a spiral sleeve layer structure, and a crushing and stirring device is arranged at a central shaft; the crushing and stirring device is composed of a horizontal crushing and stirring cutter, a vertical crushing and stirring cutter and an inclined crushing and stirring cutter. Through the synergistic effect of the spiral jacket layer structure and the crushing and stirring cutter, materials from top to bottom are crushed and thrown to the wall of the crusher, the effects of strengthening crushing and accelerating drying are achieved, the problems that in a traditional drying process, metal is left, the crystal form of a product is prone to being damaged, and the color becomes deep are solved, and the crushing efficiency and the drying efficiency can be remarkably improved; meanwhile, the contact time of heat-sensitive substances in the materials and hot air flow is shortened, generation of related substances is reduced, the product quality is improved, the requirement and consumption of heat energy are reduced, and energy conservation and environment protection are achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of drying wet crystal solids of antibiotic bulk drugs, and particularly relates to a flash drying method for oxytetracycline base wet crystals. Background Art

[0002] Oxytetracycline base is a broad-spectrum antibiotic with inhibitory effects against Gram-positive and Gram-negative bacteria, Eperythrodia, Chlamydia, Mycoplasma, Rickettsia, Spirochetes, Actinomycetes, Vibrio, and certain protozoa (such as coccidia). At high concentrations, it has bactericidal effects against Gram-positive bacteria such as pneumococci, hemolytic Streptococci, some Staphylococci, anthrax, swine plague, swine dysentery, pullorum in calves, piglets, and chicks, and avian chlamydiosis. It can also be applied topically to treat metritis and necrotizing bacillosis in horses and cattle. It also has some efficacy against amorphous body (anaplasmosis), Theileriasis, actinomycosis, leptospirosis, and emphysematous gangrene. It can also be used to relieve stress and increase weight. It has been used in aquatic fish to treat vibriosis, scale disease, vertical gill rot, Edwardsiella disease in eels, trout sore, and red fin disease in eels.

[0003] CN111154827A discloses a method for producing oxytetracycline base, comprising the following steps: seed culture, fermentation culture, acidification, decolorization, crystallization, and drying. The drying process is performed using a swing granulator and an airflow dryer. Specifically, the swing granulator mechanically drives the drum to swing back and forth. After the wet crystal material enters the rotating drum, it is dried by the rotation of the drum and the swing of the mold, and the hot air flow simultaneously acts on the wet crystal material. The powder product is then passed through a 60-mesh sieve to obtain a powder product. However, this drying method has the following disadvantages:

[0004] (1) During the swing granulation process, friction between the rotating drum and the screen will inevitably occur, causing the screen to break, resulting in a certain amount of metal fine powder generated by friction entering the material, reducing product quality;

[0005] (2) The material is crushed in the swing granulator by repeatedly rubbing and squeezing it on the screen. However, during the repeated friction of forward and reverse rotation, the material will be "ground" into fine powder. The particle size is too small, and the original crystal shape is easily destroyed. The crystal shape is not beautiful and the color will become slightly darker.

[0006] (3) Low drying efficiency leads to low drying output and low production efficiency. At the same time, the heat-sensitive substances in the material are in contact with the drying hot air flow for a long time, which can easily increase the content of related substances and reduce product quality.

[0007] CN107739746A discloses a method for preparing a veterinary oxytetracycline calcium premix. The method uses a flash dryer to dry the oxytetracycline wet cake. Hot air enters the stirring and crushing drying chamber from the bottom of the dryer, exerting strong shearing, blowing, and rotating effects on the material. The material is subjected to centrifugation, shearing, collision, and friction, and is micronized. This flash drying method combines crushing and drying functions, solving the problem of oxytetracycline base screen damage caused by the swing granulator during airflow drying, which causes metal fines to enter the material. It also improves crushing and drying efficiency and reduces energy consumption.

[0008] However, compared with oxytetracycline calcium, oxytetracycline base is crystalline and has poor stability. Conventional flash dryers have technical problems such as low crushing efficiency, high drying temperature, and high content of related substances when processing wet crystal filter cakes.

[0009] In view of this, the present invention is proposed. Summary of the Invention

[0010] The object of the present invention is to provide a flash drying method for wet crystals of oxytetracycline base. By improving the structure of the flash dryer device and optimizing operating parameters such as the feed rate, stirring speed, air inlet temperature, and exhaust temperature, the purpose of obtaining high-quality crystals with higher drying efficiency and lower drying temperature is achieved, thereby solving the above-mentioned technical problems existing in the traditional air flow drying method for treating oxytetracycline base.

[0011] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0012] In a first aspect, the present invention provides a flash drying method for wet crystals of oxytetracycline base, which uses a flash dryer for drying; the inner wall of the flash dryer is a spiral sleeve structure; a crushing and stirring device is provided at the central axis of the flash dryer; the crushing and stirring device is composed of an upper multi-layer horizontal crushing and stirring blade, a middle vertical scraper-type crushing and stirring blade, and a lower inclined crushing and stirring blade.

[0013] Furthermore, in the upper multi-layer horizontal crushing and stirring blades, the length of the stirring blades increases layer by layer.

[0014] Furthermore, the middle vertical scraper-type crushing and stirring blade is close to the inner wall, the upper end of which is connected through a fixing frame perpendicular to the central axis, and the lower end is connected to the lowest end of the lower inclined crushing and stirring blade.

[0015] Furthermore, the scraper of the lower inclined crushing and mixing blade is at an angle of 60° to the horizontal plane.

[0016] Furthermore, the flash dryer includes a tank body with a cylindrical upper portion and an inverted conical lower portion; a feed port is provided on the upper portion of the side wall of the tank body, and an air duct is provided on the lower portion; the feed port is connected to a feed spiral wheel.

[0017] Furthermore, the operating parameters of the drying process are as follows: feed rate of 35±5 kg / min, stirring speed of 30±5 r / min, inlet air temperature of 150±30°C, tank temperature of 70±5°C, exhaust air temperature of 45±5°C, and drying time of 5±1 second. During the drying process, the feed rate, stirring speed, inlet air temperature, tank temperature, and exhaust air temperature are linked and controlled by a digital display central control program, achieving fully automated control.

[0018] Furthermore, the water content of the oxytetracycline base wet crystal filter cake is 40±5%.

[0019] In a second aspect, the present invention also provides a method for preparing oxytetracycline base, comprising the following steps: seed culture, fermentation culture, acidification treatment, decolorization treatment, crystallization treatment, separation and washing treatment, drying treatment, and mixed packaging;

[0020] The drying process includes flash drying and secondary drying; the flash drying adopts the above method.

[0021] In a specific embodiment of the present invention, the drying process further includes: performing secondary drying on the material treated by the flash dryer, and performing gas-solid separation in a cyclone separator after the moisture content meets the requirements, with the gas portion entering the tail gas collection and discharge system and the solid portion being screened by a vibrating screen.

[0022] In a third aspect, the present invention also provides an oxytetracycline base product obtained by the above preparation method.

[0023] The content of related substances in the oxytetracycline base does not exceed 2.26%, preferably does not exceed 2.15%, and more preferably does not exceed 2.09%.

[0024] The related substance is 2-acetyl-2-deamidooxytetracycline.

[0025] The oxytetracycline base does not contain metal fine powder.

[0026] The particle size of the oxytetracycline base is greater than 60 mesh.

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

[0028] 1. The present invention adopts flash drying technology to process wet crystal filter cake, which avoids the problem of metal residue in the product caused by screen friction during the operation of the swing granulator of traditional air flow drying, as well as the problem of repeated friction of wet crystals in the swing granulator (destroying the large crystal structure), resulting in too small material particle size, destroyed crystal morphology, and dark color.

[0029] 2. The flash drying method provided by the present invention optimizes the operating parameters through multiple crushing actions, significantly improves the crushing efficiency and drying efficiency of wet crystal materials, thereby shortening the contact time between sensitive materials and high-temperature airflow, effectively reducing the content of related substances (2-acetyl-2-deamidooxytetracycline), and improving product quality.

[0030] 3. The present invention introduces an automatic control system into the flash drying system, which can achieve precise temperature and humidity control; and the speed of the drum in the main machine is frequency conversion controlled and can be adjusted according to the feed speed to ensure that no matter how the feed speed changes, the material crushing effect can be uniform. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a schematic diagram of the structure of a flash dryer; in the figure: 1. Feed spiral wheel; 2. Main unit shell insulation layer; 3. Air duct; 4. Crushing and stirring device; 5. Crushing and stirring drive shaft; 6. Main unit support; 7. Crushing and stirring drive motor; 8. Spiral sleeve structure.

[0032] Figure 2 This is a structural diagram of the flash drying system; in the figure: A, blower; B, heat exchanger; C, flash dryer; D, secondary drying; E, cyclone separator; F, dust collector; G, induced draft fan.

[0033] Figure 3 This is the working flow diagram of the flash drying system. DETAILED DESCRIPTION

[0034] The present invention will be further described below with reference to specific examples, but the present invention is not limited to the following examples.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0036] Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained from commercial sources.

[0037] Example 1

[0038] This embodiment provides a flash drying method for wet crystals of oxytetracycline base, wherein the method uses a flash dryer with an improved structure for processing;

[0039] like Figure 1 As shown, the flash dryer includes a tank body with a cylindrical upper portion and an inverted conical lower portion; a feed port is provided on the upper side wall of the tank body, and the feed port is connected to a feed spiral wheel 1; an air duct 3 is provided on the lower side wall of the tank body, and the air duct is connected to a blower; and a main unit support 6 is provided below the flash dryer.

[0040] The inner wall of the tank body is a spiral jacket structure 8. The hot air flow in the air duct enters the tank from the bottom of the tank body along the tangent line from bottom to top, forming a spiral rising air flow under the action of the spiral jacket structure.

[0041] A crushing and stirring device 4 is provided at the central axis of the tank body; the crushing and stirring device consists of an upper multi-layer horizontal crushing and stirring blade, a middle vertical scraper-type crushing and stirring blade, and a lower inclined crushing and stirring blade; in the upper multi-layer horizontal crushing and stirring blade, the length of the stirring blade increases layer by layer; the middle vertical scraper-type crushing and stirring blade is close to the inner wall, and its upper end is connected through a fixed frame perpendicular to the central axis, and its lower end is connected to the lowest end of the lower inclined crushing and stirring blade.

[0042] The crushing and stirring device is connected to the crushing and stirring drive shaft 5; the crushing and stirring drive shaft is connected to the drive motor 7. The exterior of the flash dryer is provided with a main housing insulation layer 2.

[0043] The operating parameters of the drying process are as follows: feed rate of 35±5 kg / min, stirring speed of 30±5 rpm, inlet air temperature of 150±30°C, tank temperature of 70±5°C, exhaust air temperature of 45±5°C, and drying time of 5±1 s. During the drying process, the feed rate, stirring speed, inlet air temperature, tank temperature, and exhaust air temperature are controlled in a coordinated manner by a digital display central control program.

[0044] The water content of the oxytetracycline base wet crystal filter cake is 40±5%.

[0045] The working principle of the flash dryer is as follows:

[0046] (1) The oxytetracycline base wet crystal filter cake obtained in the separation and washing process is first sent to a storage bin for storage. After the exhaust temperature of the flash dryer reaches a preset value, the oxytetracycline base wet crystal filter cake is continuously transported to the feed port of the tank body of the flash dryer through the feed screw wheel 1; the storage bin body is made of stainless steel with a smooth surface and high corrosion resistance, which can avoid material adhesion and ensure the safety of the product.

[0047] (2) The hot air flow in the air duct 3 enters the tank from the bottom of the tank along the tangent line under the action of the spiral jacket 8 structure on the side wall of the tank body. The spiral rising air flow with strong centrifugal force can produce a synergistic effect with the various crushing and stirring devices 4 rotating in the tank, crushing the materials from top to bottom and throwing them to the wall of the device and dropping them to the bottom. The materials are crushed and micronized by collision, friction and shearing, thereby achieving the effect of strengthening crushing and accelerating drying.

[0048] The interior of the tank body has a spatial structure that is larger at the top and smaller at the bottom. The corresponding hot air flow velocity forms a velocity distribution that is smaller at the top and larger at the bottom. This velocity distribution matches the distribution of material particles that are larger at the top and smaller at the bottom. Therefore, for large particles that have fallen to the bottom of the tank body and have not been completely dried and crushed, they will be picked up again by the spiral rising airflow and crushed and dried again; at the same time, the picked up materials will collide with the fallen materials during the up and down movement, which also plays a crushing role; through the above-mentioned multiple crushing effects, while maintaining the good crystal morphology of the materials, the crushing efficiency is significantly improved, the drying time is shortened, and the drying efficiency is improved.

[0049] (3) The tiny granular materials with the required particle size and good crystal morphology are taken out of the tank by the spiral rising airflow for secondary drying, while the materials with larger particle size remain in the tank and continue to be crushed and dried until the particle size meets the requirements and is taken away by the hot airflow, thereby achieving the purpose of uniform drying of the materials.

[0050] Example 2, Preparation of Oxytetracycline Base

[0051] The specific steps are as follows:

[0052] 1) Seed culture: Spores of Streptomyces crassa are inoculated onto a mother slant containing a spore culture medium (composed by mass percentage of the following ingredients: 5.5% bran, 0.004% MgSO4, 0.01% KH2PO4, 0.015% (NH4)2HPO4, 2.0% agar powder, and the balance being water) and cultured until the spores mature; seed tank culture is then performed, and fermentation culture is performed when the secondary seed solution meets the process requirements (mycelium concentration ≥10%, pH ≤7.10, and titer ≥1000u / ml), is free of foreign bacteria, and has a thick, yellow, reticular appearance under microscopic examination.

[0053] 2) Fermentation culture: After the seed tank culture is completed, the fermentation culture is started. During the fermentation process, the total sugar content of the fermentation liquid is controlled within the specified range by adding feed medium (the feed medium is composed of the following components by mass percentage: corn starch 40%, peanut cake powder 0.4%, soybean cake powder 0.4%, yeast powder 0.3%, corn steep liquor 2.5%, calcium carbonate 0.5%, ammonium sulfate 0.6%, sodium chloride 0.4%, amylase 0.1%, defoamer 0.1%, and the balance is water) to ensure that the total sugar content of the fermentation liquid is not higher than 3% at the end of fermentation. The final fermentation liquid has the following indicators: fermentation period 136 h, titer = 33578 u / mL, and filtration rate 8 mL / 5 min.

[0054] 3) Acidification treatment: Use tap water (volume 60m 3 ) diluted fermentation broth (volume 70m 3) was added with 1600 kg of oxalic acid and 550 L of hydrochloric acid to adjust the pH to 1.89; oxytetracycline acidified solution was obtained; 0.3% of sodium ferrocyanide and 0.2% of zinc sulfate were added, and the mixture was allowed to stand for 50 minutes before filtering. The filter cake was top washed with an acidic aqueous solution at pH 2.0 to a concentration of ≤ 2000 u / ml, and the filtrate was collected and transported to the next process.

[0055] 4) Decolorization: The filtrate from the previous step is injected into a weakly acidic cation exchange resin column for decolorization. During the decolorization process, the transmittance of the decolorized liquid is controlled to be ≥90%.

[0056] 5) Crystallization treatment: Start the automatic control system, use the delivery pump to pump the decolorization liquid from the previous process into the preheater, raise the temperature to 28-32°C, and enter the mixing tank. At the same time, the alkali addition system is automatically started, and the amount of alkalizer is adjusted using the pH electrode measurement value. The pH in the mixing tank is always maintained between 4.4-4.8. The crystallization liquid with adjusted pH overflows from the mixing tank into the primary crystallization tank, the secondary crystallization tank, and the tertiary crystallization tank in turn. After the crystallization is completed, the crystallization liquid finally flows into the buffer tank and is transported to the next process by a pump.

[0057] 6) Separation and washing treatment: The crystallization liquid is pumped into a filter for filtration, and after filtration, it is washed with purified water (6000 L of water is used). After washing, it is squeezed at a pressure of 0.93 MPa; the squeezing time is 2.6 hours to obtain a wet crystal filter cake of oxytetracycline base with a water content of 37%.

[0058] 7) Drying treatment: The oxytetracycline base wet crystal filter cake is uniformly transported to the wet material storage bin via a conveyor belt, and the flash drying system (structure as shown in the figure) is turned on. Figure 2 ); the air is heated by the blower A and the heat exchanger B. When the exhaust temperature reaches 40°C, the feed screw impeller 1 is slowly started, and the flash dryer C begins to crush and stir. The feed amount and feed speed are appropriately adjusted according to the exhaust temperature (the feed amount is increased when the temperature rises, and the feed amount is reduced when the temperature drops). The exhaust temperature of the entire drying process is controlled at 45±5°C, and the inlet temperature is controlled at 150±30°C. The material after flash drying is then subjected to secondary drying treatment D. After the moisture content is tested to meet the requirements, it is subjected to gas-solid separation by the cyclone separator E. The gas part enters the exhaust gas collection and discharge system, and the solid part is sieved by a vibrating screen with a 60-mesh screen to obtain a crystalline powder product, which is collected by the dust collector F. The dust collector is connected to the induced draft fan G. The working flow diagram of the flash drying system is as follows Figure 3 shown.

[0059] 8) Mixing and packaging: The crystalline powder product obtained above is mixed in a mixer for 30 minutes to obtain the oxytetracycline base bulk drug.

[0060] Example 3, Preparation of Oxytetracycline Base

[0061] The specific steps are as follows:

[0062] 1) Seed culture: Spores of Streptomyces crassa are inoculated onto a mother slant containing a spore culture medium (composed by mass percentage of the following ingredients: 5.5% bran, 0.004% MgSO4, 0.01% KH2PO4, 0.015% (NH4)2HPO4, 2.0% agar powder, and the balance being water) and cultured until the spores mature; seed tank culture is then performed, and fermentation culture is performed when the secondary seed solution meets the process requirements (mycelium concentration ≥10%, pH ≤7.10, and titer ≥1000u / ml), is free of foreign bacteria, and has a thick, yellow, reticular appearance under microscopic examination.

[0063] 2) Fermentation culture: After the seed tank culture is completed, the fermentation culture is started. During the fermentation process, the total sugar content of the fermentation liquid is controlled within the specified range by adding feed medium (the feed medium is composed of the following components by mass percentage: corn starch 40%, peanut cake powder 0.4%, soybean cake powder 0.4%, yeast powder 0.3%, corn steep liquor 2.5%, calcium carbonate 0.5%, ammonium sulfate 0.6%, sodium chloride 0.4%, amylase 0.1%, defoamer 0.1%, and the balance is water) to ensure that the total sugar content of the fermentation liquid is not higher than 3% at the end of fermentation. The final fermentation liquid has the following indicators: fermentation period 134 h, titer = 33222 u / mL, and filtration rate 9 mL / 5 min.

[0064] 3) Acidification treatment: Use tap water (volume 60m 3 ) diluted fermentation broth (volume 700m 3 ) was added with 1600 kg of oxalic acid and 500 L of hydrochloric acid to adjust the pH to 1.91; oxytetracycline acidified solution was obtained; 0.3% of sodium ferrocyanide and 0.2% of zinc sulfate were added, and the mixture was allowed to stand for 50 minutes before filtering. The filter cake was top washed with an acidic aqueous solution at pH 2.0 to ≤ 2000 u / ml, and the filtrate was collected and transported to the next process.

[0065] 4) Decolorization: The filtrate from the previous step is injected into a weakly acidic cation exchange resin column for decolorization. During the decolorization process, the transmittance of the decolorized liquid is controlled to be ≥90%.

[0066] 5) Crystallization treatment: Start the automatic control system, use the delivery pump to pump the decolorization liquid from the previous process into the preheater to raise the temperature to 28-32°C and enter the mixing tank. At the same time, the alkali addition system is automatically started, and the amount of alkalizer is adjusted using the pH electrode measurement value. The pH in the mixing tank is always maintained between 4.4-4.8. The crystallization liquid with adjusted pH overflows from the mixing tank into the primary crystallization tank, the secondary crystallization tank, and the tertiary crystallization tank in turn. After the crystallization is completed, the crystallization liquid finally flows into the buffer tank and is pumped to the next process.

[0067] 6) Separation and washing treatment: The crystallized liquid is pumped into a filter for filtration, and then washed with purified water (5500 L of water is used). After washing, it is squeezed at a pressure of 0.95 MPa; the squeezing time is 2.5 hours to obtain a wet filter cake of oxytetracycline base with a water content of 36%.

[0068] 7) Drying: The oxytetracycline base wet crystal filter cake is uniformly conveyed to the wet material storage bin via a conveyor belt, and the flash drying system is turned on. When the exhaust air temperature reaches 40°C, the feed screw wheel is slowly started and the main machine begins to crush and stir. The feed amount and feed speed are appropriately adjusted according to the exhaust air temperature (the feed amount is increased as the temperature rises, and the feed amount is reduced as the temperature falls). The exhaust air temperature is controlled at 45±5°C and the inlet air temperature is controlled at 150±30°C during the entire drying process. After secondary drying and cyclone separator, the material is passed through a vibrating screen with a 60-mesh screen to obtain a crystalline powder product;

[0069] 8) Mixing and packaging: The crystalline powder product obtained above is mixed in a mixer for 30 minutes to obtain the oxytetracycline base bulk drug.

[0070] Example 4. Preparation of oxytetracycline base

[0071] The specific steps are as follows:

[0072] 1) Seed culture: Spores of Streptomyces crassa are inoculated onto a mother slant containing a spore culture medium (composed by mass percentage of the following ingredients: 5.5% bran, 0.004% MgSO4, 0.01% KH2PO4, 0.015% (NH4)2HPO4, 2.0% agar powder, and the balance being water) and cultured until the spores mature; seed tank culture is then performed, and fermentation culture is performed when the secondary seed solution meets the process requirements (mycelium concentration ≥10%, pH ≤7.10, and titer ≥1000u / ml), is free of foreign bacteria, and has a thick, yellow, reticular appearance under microscopic examination.

[0073] 2) Fermentation culture: After the seed tank culture is completed, the fermentation culture is started. During the fermentation process, the total sugar content of the fermentation liquid is controlled within the specified range by adding feed medium (the feed medium is composed of the following components by mass percentage: corn starch 40%, peanut cake powder 0.4%, soybean cake powder 0.4%, yeast powder 0.3%, corn steep liquor 2.5%, calcium carbonate 0.5%, ammonium sulfate 0.6%, sodium chloride 0.4%, amylase 0.1%, defoamer 0.1%, and the balance is water) to ensure that the total sugar content of the fermentation liquid is not higher than 3% at the end of fermentation. The final fermentation liquid has the following indicators: fermentation period 141h, titer = 32916u / mL, and filtration rate 10mL / 5min.

[0074] 3) Acidification treatment: Use tap water (volume 50m 3 ) diluted fermentation broth (volume 60m3 ) was added with 1250 kg of oxalic acid and 470 L of hydrochloric acid to adjust the pH to 1.92; oxytetracycline acidified solution was obtained; 0.3% of sodium ferrocyanide and 0.2% of zinc sulfate were added, and the mixture was allowed to stand for 50 minutes before filtering. The filter cake was top washed with an acidic aqueous solution at pH 2.0 to a concentration of ≤ 2000 u / ml, and the filtrate was collected and transported to the next process.

[0075] 4) Decolorization: The filtrate from the previous step is injected into a weakly acidic cation exchange resin column for decolorization. During the decolorization process, the transmittance of the decolorized liquid is controlled to be ≥90%.

[0076] 5) Crystallization treatment: Start the automatic control system, and use the delivery pump to pump the decolorized liquid from the previous process into the preheater to raise the temperature to 28-32°C and enter the mixing tank. At the same time, the alkali addition system is automatically started, and the amount of alkalizer is adjusted using the pH electrode measurement value. The pH in the mixing tank is always maintained between 4.4-4.8. The crystallization liquid with adjusted pH overflows from the mixing tank into the primary crystallization tank, the secondary crystallization tank, and the tertiary crystallization tank in turn. After the crystallization is completed, the crystallization liquid finally flows into the buffer tank and is pumped to the next process.

[0077] 6) Separation and washing treatment: The crystallized liquid is pumped into a filter for filtration, and then washed with purified water (5200 L of water is used). After washing, it is squeezed at a pressure of 0.95 MPa; the squeezing time is 2.3 hours to obtain a wet filter cake of oxytetracycline base with a water content of 37%.

[0078] 7) Drying: The oxytetracycline base wet crystal filter cake is uniformly conveyed to the wet material storage bin via a conveyor belt, and the flash drying system is turned on. When the exhaust air temperature reaches 40°C, the feed screw wheel is slowly started and the main machine begins to crush and stir. The feed amount and feed speed are appropriately adjusted according to the exhaust air temperature (the feed amount is increased as the temperature rises, and the feed amount is reduced as the temperature falls). The exhaust air temperature is controlled at 45±5°C and the inlet air temperature is controlled at 150±30°C during the entire drying process. After secondary drying and cyclone separator, the material is passed through a vibrating screen with a 60-mesh screen to obtain a crystalline powder product;

[0079] 8) Mixing and packaging: The crystalline powder product obtained above is mixed in a mixer for 30 minutes to obtain the oxytetracycline base bulk drug.

[0080] Oxytetracycline base product testing

[0081] The products obtained in Example 2-4 were tested according to the current edition of the Chinese Veterinary Pharmacopoeia. As shown in the following table, the products obtained in Example 2-4 met the requirements of the standard.

[0082] Table 1 Test results of oxytetracycline base products obtained in Examples 2-4

[0083]

[0084]

[0085] Comparative Example 1

[0086] The difference from Example 4 is that the drying method adopts the traditional airflow drying method, specifically: after the oxytetracycline base wet crystal material enters the rotating drum of the swing granulator, the swing granulator causes the drum to swing back and forth through mechanical transmission. As the drum rotates and the mold swings, the material is crushed and blown dry under the action of the hot air flow, and then sieved through a 60-mesh powder sifter to obtain a powder product.

[0087] 1. Comparison of products from two drying methods

[0088] The products obtained in Examples 2-4 were compared with the product in Comparative Example 1, and the results were as follows:

[0089] (1) Metal doping problem

[0090] The product obtained in Comparative Example 1 was mixed with metal fine powder produced by mechanical wear of the screen, while in Examples 2-4, no metal fine powder was contained in the products obtained because no screen was used during the drying process.

[0091] (2) Crystal morphology

[0092] It can be observed visually and under a microscope that the products obtained in Examples 2-4 have larger crystal particle size, better crystal morphology and better color; while the product obtained in Comparative Example 1 has more fine powder, very small particle size, and part of the crystal morphology is destroyed, with a darker color.

[0093] (3) Comparing the flash drying method of Example 4 with the air flow drying method of Comparative Example 1, the results are as follows.

[0094] Table 2 Comparison results of two drying methods

[0095]

[0096] It can be seen from the above table:

[0097] (1) The average output of the airflow drying method is 1476.3 kg, and the average drying speed is 597.3 kg / h, while the average output of the flash drying method is 3186 kg, and the average drying speed is 1318 kg / h. It can be seen that the flash drying method has a larger drying output, a faster drying speed, and a higher drying efficiency.

[0098] (2) The exhaust temperature of the air flow drying method is 75-80℃, while the exhaust temperature of the flash drying method is only 40-45℃. This shows that within the same drying time, the contact time between the heat-sensitive substances in the material and the higher temperature hot air flow in the flash drying method is shorter, which is more conducive to reducing the generation of related substances and improving product quality. At the same time, compared with air flow drying, the flash drying method has less demand and consumption of heat energy and is more energy-saving.

[0099] (3) The air inlet temperature of the air flow drying method is 120-135℃, and the air inlet temperature of the flash drying method is 130-150℃. This shows that when the same saturated steam is used to heat the air through the heat exchanger, the heat exchange ratio and heat utilization rate of the flash drying method are higher. The relatively high air inlet temperature provides a more stable heat medium environment for drying.

[0100] Comparative Example 2

[0101] The difference from Example 4 is that the flash drying method adopts a conventional flash dryer, the inner wall of the tank is a smooth side wall, there is no spiral jacket structure, and the tank is provided with a conventional length of the same multi-layer horizontal scraper type crushing and stirring blade.

[0102] The results showed that the drying time was 155 minutes, the exhaust temperature was 75-80℃, the drying output was 1576kg, and the drying speed was 610kg / h. This shows that the hot air flow in the air duct enters the tank from the bottom of the tank along the tangent from bottom to top. Although a spiral upward airflow is formed, the centrifugal force is weak, and the synergistic crushing effect with the agitator is not good, resulting in low material crushing efficiency.

[0103] Although the present invention has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A flash drying method for wet crystals of oxytetracycline base, characterized in that: The method adopts a flash dryer for drying; The inner wall of the flash dryer is a spiral jacket structure; A crushing and stirring device is provided at the central axis of the flash dryer; The crushing and stirring device consists of multiple layers of horizontal crushing and stirring blades at the top, vertical scraper-type crushing and stirring blades at the middle, and inclined crushing and stirring blades at the bottom.

2. The flash drying method according to claim 1, wherein The length of the upper multi-layer horizontal crushing and stirring blades increases layer by layer; The middle vertical scraper-type crushing and stirring blade is close to the inner wall, and its upper end is connected to a fixing frame perpendicular to the central axis, and its lower end is connected to the lowest end of the lower inclined crushing and stirring blade; The scraper of the lower inclined crushing and stirring blade is at an angle of 60° to the horizontal plane.

3. The flash drying method according to claim 1 or 2, wherein: The flash dryer comprises a tank body with a cylindrical upper portion and an inverted conical lower portion; The upper part of the side wall of the tank body is provided with a feed port, and the lower part is provided with an air duct; The feed port is connected to the feed spiral wheel.

4. The flash drying method according to any one of claims 1 to 3, characterized in that The operating parameters of the drying process are as follows: feed rate 35±5 kg / min, stirring speed 30±5 r / min, inlet air temperature 150±30°C, tank temperature 70±5°C, exhaust air temperature 45±5°C, and drying time 5±1 s; During the drying process, the feeding speed, stirring speed, air inlet temperature, tank temperature and exhaust air temperature are controlled in linkage by a digital display central control program.

5. The flash drying method according to claim 4, wherein: The water content of the oxytetracycline base wet crystal filter cake is 40±5%.

6. A method for preparing oxytetracycline base, comprising the following steps: seed culture, fermentation culture, acidification, decolorization, crystallization, separation and washing, drying, and mixed packaging; The drying process includes flash drying and secondary drying; The flash drying treatment adopts the method according to any one of claims 1 to 5.

7. Oxytetracycline base obtained by the preparation method according to claim 6.

8. Oxytetracycline base according to claim 7, characterized in that The content of the related substance 2-acetyl-2-deamidooxytetracycline in the oxytetracycline base does not exceed 2.26%.

9. Oxytetracycline base according to claim 7 or 8, characterized in that The oxytetracycline base does not contain metal fine powder.

10. Oxytetracycline base according to any one of claims 7 to 9, characterized in that The particle size of the oxytetracycline base is greater than 60 mesh.

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