Method for increasing yield of aureomycin premix

Abstract

The invention belongs to the technical field of antibiotic production, and particularly relates to a method for increasing the yield of an aureomycin premix. The method comprises the following steps: sampling aureomycin fermentation liquor, detecting the titer of the fermentation liquor and the dry matter of the fermentation liquor, calculating the use amount of calcium carbonate according to the preparation specification of the aureomycin premix to be produced, the volume of the fermentation liquor and the actual yield value, and adding calcium hydrophosphate and ethoxyquin according to the corresponding proportion to obtain the aureomycin calcium salt complex. And carrying out plate frame filtration and flash evaporation drying to obtain the aureomycin premix. According to the invention, the stability of the aureomycin calcium salt is effectively improved, and the yield of the aureomycin premix is improved. The method is simple in technological process, controllable in operation, stable in product quality and low in production cost.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of antibiotic production, and particularly relates to a method for improving the yield of chlortetracycline premix. BACKGROUND

[0002] Chlortetracycline (CTC) is a broad-spectrum and high-efficiency tetracycline antibiotic, which has the characteristics of high efficiency, low toxicity and low drug resistance, and is a widely used feed additive. As a biological veterinary drug additive, it has excellent bacteriostatic effect, improves feed utilization rate, and has low production cost, so it has broad prospects in the domestic and foreign markets.

[0003] At present, the mainstream production process of domestic chlortetracycline premix is biological fermentation method. This method uses Streptomyces aureus to synthesize chlortetracycline through secondary metabolism. After fermentation, a certain proportion of carrier (such as calcium carbonate) or other alkaline substances (for adjusting pH value) is usually added to the fermentation broth, and then the processes of plate and frame filtration, drying, screening and mixing are carried out to finally obtain chlortetracycline premix product.

[0004] However, the above existing production process has significant problems. First, in the plate and frame filtration step, a considerable part of chlortetracycline cannot be effectively adsorbed or intercepted by the carrier, but remains in the filtrate, directly causing the loss of effective ingredients. Secondly, in the subsequent filter cake drying process (especially the drying method exposed to air for a long time), chlortetracycline may be oxidized to cause the decrease of stability; in addition, if high-temperature drying methods such as flash drying are used, additional chlortetracycline degradation loss may also occur due to heat sensitivity. These factors (filtrate residue, oxidative degradation and thermal degradation) together cause a significant reduction in the yield of the final product. The multiple losses of effective ingredients not only reduce the production efficiency, but also increase the production cost. Therefore, how to effectively reduce the loss of chlortetracycline in the filtration and drying process, improve the yield and stability of the product, is a key technical problem to be solved in the current production of chlortetracycline premix. SUMMARY

[0005] In order to solve the above technical problems, the application provides a method for improving the yield of chlortetracycline premix, characterized in that it comprises the following steps:

[0006] S1: sampling and detecting the fermentation broth of chlortetracycline to obtain the titer U2 (u / g) and the dry matter content Z (kg / m 3 ) of the fermentation broth, and calculating the calcium carbonate dosage Y (kg) according to the preparation specification U2 (u / g) of the chlortetracycline premix to be produced, the fermentation broth volume V (m 3 ), and the actual yield value;

[0007] The calculation formula of the calcium carbonate dosage is: Y (kg) = 0.9 x V (m3 ) x 1000 x (U1 (u / mL) / U2 (u / g)) - Z (kg / m 3 ) V (m 3 )

[0008] The aureomycin fermentation liquor is added into calcium carbonate, calcium hydrogen phosphate and ethoxyquin respectively and stirred uniformly to obtain aureomycin calcium salt complex;

[0009] The ratio of the added amount of the calcium hydrogen phosphate to the volume of the fermentation liquor is (1.0-10.0) kg:1 m 3 ;

[0010] The ratio of the added amount of the ethoxyquin to the volume of the fermentation liquor is (0.05-0.2) kg:1 m 3 ;

[0011] S2: The aureomycin calcium salt complex obtained in step S1 is subjected to plate-frame filtration to obtain aureomycin filter cake;

[0012] S3: The aureomycin filter cake obtained in step S2 is subjected to flash drying to obtain aureomycin premix.

[0013] Preferably, the ratio of the added amount of the calcium hydrogen phosphate to the volume of the fermentation liquor is (1.0-5.0) kg:1 m 3 .

[0014] Preferably, the ratio of the added amount of the calcium hydrogen phosphate to the volume of the fermentation liquor is (2.0-5.0) kg:1 m 3 .

[0015] Preferably, the ratio of the added amount of the calcium hydrogen phosphate to the volume of the fermentation liquor is 5.0 kg:1 m 3 .

[0016] Preferably, the ratio of the added amount of the ethoxyquin to the volume of the fermentation liquor is (0.05-0.15) kg:1 m 3 .

[0017] Preferably, the ratio of the added amount of the ethoxyquin to the volume of the fermentation liquor is (0.05-0.1) kg:1 m 3 .

[0018] Further, the plate-frame filtration condition in step S2 is that the feeding pressure is ≤0.6 Mpa, the drum membrane pressure is 0.4±0.1 Mpa and the pressure filtration is 1.0±0.5 h.

[0019] Further, the flash drying condition in step S3 is that the air inlet temperature is 180±20℃, the mixing chamber temperature is 60±20℃ and the air outlet temperature is 50±20℃.

[0020] The application further provides a aureomycin premix prepared by the method for improving the yield of aureomycin premix.

[0021] The application has the following beneficial effects over the prior art:

[0022] The application effectively improves the stability of aureomycin calcium salt by adding calcium carbonate, calcium hydrogen phosphate and ethoxyquin, thereby reducing the loss of aureomycin in the plate and frame filter pressing process. In the flash drying process, the stability and antioxidant property of aureomycin are improved, further improving the yield of aureomycin premix. The process flow of the application is simple, the operation is controllable, the product quality is stable, and the production cost is low. DETAILED DESCRIPTION

[0023] The application will be further described below in combination with examples, and those skilled in the art should understand that the examples are only for illustration and do not constitute any limitation on the application.

[0024] Example 1: stabilizer screening test

[0025] The aureomycin fermentation liquor was evenly divided into 6 groups of containers, 400 mL in each group.

[0026] Control group (group 1): calcium carbonate (20 g / L) was added to the fermentation liquor.

[0027] Experimental group (groups 2-6): calcium carbonate (20 g / L) and the tested stabilizer (3 g / L) were added to the fermentation liquor. The tested stabilizers were as follows:

[0028] Group 2: calcium phosphate

[0029] Group 3: calcium dihydrogen phosphate

[0030] Group 4: calcium hydrogen phosphate

[0031] Group 5: calcium oxide

[0032] Group 6: diatomite

[0033] All groups were placed on a constant temperature magnetic stirrer and stirred at a constant speed of 300 rpm at room temperature (25±2℃) for 30 minutes to ensure thorough mixing.

[0034] After stirring, each group of mixed liquor was immediately vacuum filtered.

[0035] The filtrate was collected, and the titer (U / mL) of aureomycin in the filtrate was detected by the method specified in the Pharmacopoeia of the People's Republic of China.

[0036] This experiment was a single factor (stabilizer type) test, each group of experiments was independently repeated for 3 times (batches), the average value was taken and the raw data was recorded.

[0037] The experimental results are shown in Table 1, which include the titer and average value of the chlortetracycline filtrate obtained by three repeated experiments in each group under different stabilizer treatments.

[0038] Table 1: Effects of different stabilizer types on the potency of chlortetracycline filtrate

[0039]

[0040] As can be seen from the data in Table 1, compared with the control group (average titer 436.0 U / mL), the addition of calcium hydrogen phosphate significantly reduced the titer of chlortetracycline filtrate (average titer 317.0 U / mL). Therefore, this experiment screened and determined that calcium hydrogen phosphate was the optimal stabilizer.

[0041] Based on the above screening results, the laboratory further optimized the dosage range of calcium hydrogen phosphate and divided them into the following groups:

[0042] Group 1: calcium carbonate (20g / L) + calcium hydrogen phosphate 1.0g / L

[0043] Group 2: calcium carbonate (20g / L) + calcium hydrogen phosphate 2.0g / L

[0044] Group 3: calcium carbonate (20g / L) + calcium hydrogen phosphate 3.0g / L

[0045] Group 4: calcium carbonate (20g / L) + calcium hydrogen phosphate 5.0g / L

[0046] Group 5: calcium carbonate (20g / L) + calcium hydrogen phosphate 7.5g / L

[0047] Group 6: calcium carbonate (20 g / L) + calcium hydrogen phosphate 10.0 g / L

[0048] The optimization test results are shown in the following table (Table 2)

[0049] Table 2: Effect of calcium hydrogen phosphate dosage on the potency of chlortetracycline filtrate

[0050]

[0051] The data in Table 2 show that the average potency of the chlortetracycline filtrate was lowest (316.0 U / mL) when the calcium hydrogen phosphate dosage was 5.0 g / L, confirming that the optimal calcium hydrogen phosphate dosage was 5.0 g / L. Considering the overall efficacy, process stability, and production cost, the effective dosage range was determined to be 1.0-5.0 g / L.

[0052] Example 2 Antioxidant Screening Test

[0053] Based on the selected stabilizer (calcium hydrogen phosphate), an antioxidant suitable for improving the yield of chlortetracycline was screened.

[0054] The aureomycin fermentation broth was evenly divided into 3 groups, 400 mL for each group.

[0055] Control group (Group 1): The basic components, calcium carbonate (20 g / L) and the selected stabilizer, calcium hydrogen phosphate (3 g / L), were added to the fermentation broth.

[0056] Experimental group (Groups 2-3): The basic components (calcium carbonate 20 g / L + calcium hydrogen phosphate 3 g / L) and the antioxidant to be tested (0.5 g / L) were added to the fermentation broth. The antioxidants to be tested were: Group 2: ethoxyquin; Group 3: ascorbic acid.

[0057] All groups were placed on a constant temperature magnetic stirrer and stirred at a constant speed of 300 rpm for 30 minutes at room temperature (25 ± 2°C) to ensure thorough mixing.

[0058] After stirring, each group of mixed solution was immediately vacuum filtered.

[0059] The filter cake was collected and dried at 80°C for 2 hours.

[0060] The content of aureomycin in the dried filter cake was detected using the method specified in the "Pharmacopoeia of the People's Republic of China".

[0061] The aureomycin yield (%) calculation formula: Aureomycin yield (%) = (aureomycin titer (u / g) in dried filter cake × weight of dried filter cake (g)) / (aureomycin titer (u / mL) in fermentation broth × volume of fermentation broth (mL)) × 100%.

[0062] This experiment was a single factor (antioxidant type) experiment, each group was independently repeated 3 times (batches), the results were averaged and the raw data was recorded.

[0063] The experimental results are shown in Table 3. After adding different antioxidants, the aureomycin yield results and average values measured by three repeated experiments of each group were obtained.

[0064] Table 3: Effect of different antioxidant types on aureomycin yield

[0065]

[0066] From the data in Table 3, it can be seen that compared with the control group (average yield 88.69%), the addition of ethoxyquin significantly improved the aureomycin yield (average yield 90.94%). This indicates that ethoxyquin effectively reduces the loss of aureomycin caused by oxidation and heat sensitivity during the drying process of the filter cake, and improves the yield of the final product. This experiment determines that ethoxyquin is the optimal antioxidant.

[0067] Based on the above experimental results, the dosage range of ethoxyquin was further optimized and grouped as follows:

[0068] Group 1 : Calcium carbonate (20 g / L) + calcium hydrogen phosphate (1.0 g / L) + ethoxyquin (0.025 g / L)

[0069] Group 2: Calcium carbonate (20 g / L) + calcium hydrogen phosphate 2.0 g / L + ethoxyquin (0.05 g / L)

[0070] Group 3: Calcium carbonate (20 g / L) + calcium hydrogen phosphate 3.0 g / L + ethoxyquin (0.10 g / L)

[0071] Group 4: Calcium carbonate (20 g / L) + calcium hydrogen phosphate 5.0 g / L + ethoxyquin (0.15 g / L)

[0072] Group 5: Calcium carbonate (20 g / L) + calcium hydrogen phosphate 7.5 g / L + ethoxyquin (0.20 g / L)

[0073] The results of the optimization test are as follows in the table (Table 4)

[0074] Table 4: Effect of ethoxyquin dosage on aureomycin yield

[0075]

[0076] From the data in Table 4, it can be seen that when the dosage of ethoxyquin is 0.05-0.10 g / L, the yield of aureomycin is basically stable (average 90.50%-90.53%), and further increasing the dosage does not further improve the yield. In view of the production operation and cost, the dosage range is determined to be 0.05-0.10 g / L.

[0077] Example 3: Production method of aureomycin premix

[0078] (1) Aureomycin fermentation broth is sampled for detection of fermentation broth titer U2 (u / g) and fermentation broth dry matter Z (kg / m 3 ), and the dosage of calcium carbonate Y (kg) is calculated according to the preparation specification U2 (u / g) of the aureomycin premix to be produced, the volume V (m 3 ) of the fermentation broth, and the actual yield value;

[0079] The calculation formula of the dosage of calcium carbonate is: Y 碳酸钙 = 0.9 x V (m 3 ) x 1000 x (U1 (u / mL) / U2 (u / g)) - Z (kg / m 3 ) V (m 3 );

[0080] The aureomycin fermentation broth is placed in a pretreatment tank, calcium carbonate is added and stirred uniformly, then calcium hydrogen phosphate and ethoxyquin are added, and stirred for 30 min to obtain an aureomycin calcium salt complex.

[0081] Calcium hydrogen phosphate W (kg) dosage: W 磷酸氢钙 : V 发酵液体积 = (1.0 ~ 10.0) kg: 1m 3 , that is, the ratio of the amount of calcium hydrogen phosphate added to the volume of fermentation broth is (1.0 ~ 10.0) kg: 1m 3 ;

[0082] Ethoxyquin C (kg) dosage: C 乙氧基喹啉 : V 发酵液体积 = (0.05 ~ 0.2) kg: 1m 3 , that is, the ratio of the amount of ethoxyquin added to the volume of fermentation broth is (0.05 ~ 0.2) kg: 1m 3 .

[0083] Wherein:

[0084] V (m 3 ): the volume of fermentation broth, refers to the total volume of fermentation broth, unit m 3 ;

[0085] U1 (u / mL): the titer of fermentation broth, refers to the content of pure active ingredient (CTC) of chlortetracycline in fermentation broth, unit u / mL;

[0086] U2 (u / g): the preparation specification of chlortetracycline premix, refers to the content of pure active ingredient (CTC) of chlortetracycline in finished product, unit u / g;

[0087] Z (kg / m 3 ): dry matter of fermentation broth, refers to the total mass of dry matter in fermentation broth, which represents the mass of dry matter per cubic meter of fermentation broth.

[0088] The determination method of the titer of fermentation broth is:

[0089] ① Preparation of reference solution

[0090] Take an appropriate amount of natamycin reference substance (about equivalent to 12.5 mg of natamycin), place it in a 25 mL volumetric flask, add a certain amount of DMF to dissolve, dilute to the mark to prepare a stock solution. Precisely take 5 mL of the stock solution into a 50 mL volumetric flask, and make up to the volume with methanol to prepare a reference solution containing about 0.05 mg / mL.

[0091] ② Preparation of test solution

[0092] The fermentation broth was mixed uniformly, 2 ml of the fermentation broth was precisely taken and placed in a 100 ml brown volumetric flask, 5 ml of 0.05 mol / L phosphate buffer was added, and the mixture was ultrasonically treated with DMF for 20 min, then cooled to room temperature, and then diluted with DMF, shaken uniformly, filtered with qualitative filter paper, and the filtrate was filtered with a micro membrane and placed in a brown volumetric flask for liquid chromatography determination.

[0093] ③ Chromatographic conditions

[0094] Octadecylsilane-bonded silica gel was used as the filler, acetonitrile-0.025% phosphoric acid aqueous solution (50:50) was used as the mobile phase, the detection wavelength was 241 nm, the flow rate was 1 mL / min, the column temperature was 30°C, and the injection amount was 20 μL

[0095] The determination method of the dry matter of the fermentation broth was as follows:

[0096] ① Sampling: 1 L of the uniformly mixed fermentation broth was accurately taken.

[0097] ② Filtration: the taken fermentation broth was filtered with filter paper to collect the filter cake.

[0098] ③ Drying: the collected filter cake was placed in an oven at 80°C for drying.

[0099] ④ Weighing: after drying to a constant weight, the weight of the dry filter cake was measured.

[0100] ⑤ Calculation: according to the weight of the dry filter cake, the amount of dry matter in per cubic meter of the fermentation broth was calculated.

[0101] 0.9 is the actual yield value, which is the actual yield value of the aureomycin premix produced in the workshop. This value is the average value obtained from production data statistics, reflecting the average yield under normal production conditions in the workshop. The average yield in the workshop is basically maintained at 90%, i.e. 0.9. The specific calculation process is as follows: yield = ((product quantity x product titer) / (fermentation broth volume x fermentation broth titer)) x 100;

[0102] Product quantity: refers to the total weight of the final produced aureomycin premix, in kg;

[0103] Product titer: refers to the content of pure active ingredient (CTC) of aureomycin in the product, in u / g.

[0104] (2) The plate and frame filtration process is: plate and frame filtration (1) treated fermentation broth, feed pressure ≤0.6 Mpa. After the feed is finished, under the eardrum pressure of 0.4±0.1 Mpa, pressure filtration for 1.0±0.5 h, to obtain aureomycin filter cake.

[0105] (3) The flash drying process is as follows: flash drying the chlortetracycline filter cake in (2), with a flash air inlet temperature of 180±20°C, a mixing chamber temperature of 60±20°C, and an air outlet temperature of 50±20°C, and drying and sieving to obtain a chlortetracycline premix of a certain specification.

[0106] Test Example 1 Preparation of 15% Chlortetracycline Premix

[0107] (1) Take 37ml of chlortetracycline fermentation liquid 3 To produce 15% premix, add 2370kg of calcium carbonate according to the calcium carbonate formula and 1.0kg / m2 of calcium hydrogen phosphate. 3 Add 37kg (W 磷酸氢钙 :V 发酵液体积 =1:1), ethoxyquinoline at 0.05kg / m 3 Add 1.85kg (C 乙氧基喹啉 :V 发酵液体积 =0.05:1), stirring for 30 min;

[0108] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was detected after 10 minutes of feeding. The feeding pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filtration was performed for 1.0 h after the feeding was completed;

[0109] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 15% chlortetracycline premix.

[0110] During the test, the fermentation broth titer (u / mL), filtrate titer (u / mL), and premix titer (ug / g) were tested, and the yield (%) was calculated after the test.

[0111] Comparative Example 1

[0112] Take 37ml of chlortetracycline fermentation liquid 3 Calculated according to the calcium carbonate formula, 2370 kg of calcium carbonate was added. The filtration and drying processes were the same as those in Experimental Example 1. Calcium hydrogen phosphate and ethoxyquinoline were not added to compare their effects on the stability and yield of chlortetracycline.

[0113] Test Example 2 Preparation of 15% Chlortetracycline Premix

[0114] (1) Take 35ml of chlortetracycline fermentation liquid 3 To produce 15% premix, add 2450kg of calcium carbonate according to the calcium carbonate formula, and 2.0kg / m2 of calcium hydrogen phosphate. 3 Add 70kg (W 磷酸氢钙 :V 发酵液体积 =2:1), ethoxyquinoline at 0.05kg / m 3 Add 1.75kg (C乙氧基喹啉 :V 发酵液体积 =0.05:1), stirring for 30 min;

[0115] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was detected after 10 minutes of feeding. The feeding pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filtration was performed for 1.0 h after the feeding was completed;

[0116] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 15% chlortetracycline premix.

[0117] During the test, the fermentation broth titer (u / mL), filtrate titer (u / mL), and premix titer (ug / g) were tested, and the yield (%) was calculated after the test.

[0118] Comparative Example 2

[0119] Take 35ml of chlortetracycline fermentation liquid 3 , 2450kg of calcium carbonate was added according to the calcium carbonate formula, and the filtration and drying processes were the same as in Experimental Example 2. Calcium hydrogen phosphate and ethoxyquinoline were not added to compare their effects on the stability and yield of chlortetracycline.

[0120] Test Example 3 Preparation of 15% Chlortetracycline Premix

[0121] (1) Take 36ml of chlortetracycline fermentation liquid 3 To produce 15% premix, add 2390kg of calcium carbonate according to the calcium carbonate formula, and 3.0kg / m2 of calcium hydrogen phosphate. 3 Add 108kg (W 磷酸氢钙 :V 发酵液体积 =3:1), ethoxyquinoline at 0.05kg / m 3 Add 1.75kg (C 乙氧基喹啉 :V 发酵液体积 =0.05:1), stirring for 30 min;

[0122] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was tested 10 minutes after feeding. The feed pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filter was pressed for 1.5 hours after the feeding was completed;

[0123] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 15% chlortetracycline premix.

[0124] During the test, the fermentation broth titer (u / mL), filtrate titer (u / mL), and premix titer (ug / g) were tested, and the yield (%) was calculated after the test.

[0125] Comparative Example 3

[0126] Take 36ml of chlortetracycline fermentation liquid 3 , 2390 kg of calcium carbonate was added according to the calcium carbonate formula, and the filtration and drying processes were the same as those in Experimental Example 3. Calcium hydrogen phosphate and ethoxyquinoline were not added to compare their effects on the stability and yield of chlortetracycline.

[0127] Test Example 4 Preparation of 20% Chlortetracycline Premix

[0128] (1) Take 38ml of chlortetracycline fermentation liquid 3 To produce 20% premix, add 1290kg of calcium carbonate according to the calcium carbonate formula and 2.0kg / m2 of calcium hydrogen phosphate. 3 Add 76kg (W 磷酸氢钙 :V 发酵液体积 =2:1), ethoxyquinoline at 0.1kg / m 3 Add 3.8kg (C 乙氧基喹啉 :V 发酵液体积 =0.1:1), stirring for 30 min;

[0129] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was detected after 10 minutes of feeding. The feeding pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filtration was performed for 1.0 h after the feeding was completed;

[0130] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 20% chlortetracycline premix.

[0131] During the test, the fermentation broth titer (u / mL), filtrate titer (u / mL), and premix titer (ug / g) were tested, and the yield (%) was calculated after the test.

[0132] Comparative Example 4

[0133] Take 38ml of chlortetracycline fermentation liquid 3 Calculated according to the calcium carbonate formula, 1290 kg of calcium carbonate was added. The filtration and drying processes were the same as those in Experimental Example 4. Calcium hydrogen phosphate and ethoxyquinoline were not added to compare their effects on the stability and yield of chlortetracycline.

[0134] Test Example 5 Preparation of 20% Chlortetracycline Premix

[0135] (1) Take 36ml of chlortetracycline fermentation liquid 3 Calculate the calcium carbonate formula according to the 20% premix specification and add 1040kg of calcium carbonate and 3.0kg / m2 of calcium hydrogen phosphate. 3 Add 108kg (W 磷酸氢钙 :V发酵液体积 =3:1), ethoxyquinoline at 0.1kg / m 3 Add 3.6kg (C 乙氧基喹啉 :V 发酵液体 Product = 0.1:1), stirring for 30min;

[0136] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was tested 10 minutes after feeding. The feed pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filter was pressed for 1.5 hours after the feeding was completed;

[0137] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 20% chlortetracycline premix.

[0138] During the test, the fermentation broth titer (u / mL), filtrate titer (u / mL), and premix titer (ug / g) were tested, and the yield (%) was calculated after the test.

[0139] Comparative Example 5:

[0140] Take 36ml of chlortetracycline fermentation liquid 3 Calculated according to the calcium carbonate formula, 1040 kg of calcium carbonate was added. The filtration and drying processes were the same as those in Experimental Example 5. Calcium hydrogen phosphate and ethoxyquinoline were not added to compare their effects on the stability and yield of chlortetracycline.

[0141] Test Example 6 Preparation of 20% Chlortetracycline Premix

[0142] (1) Take 38ml of chlortetracycline fermentation liquid 3 Calculate the calcium carbonate formula according to the 20% premix specification and add 1340kg of calcium carbonate and 5.0kg / m2 of calcium hydrogen phosphate. 3 Add 190kg (W 磷酸氢钙 :V 发酵液体积 =5:1), ethoxyquinoline at 0.1kg / m 3 Add 3.8kg (C 乙氧基喹啉 :V 发酵液体 Product = 0.1:1), stirring for 30min;

[0143] (2) The feed liquid was plate-and-frame filtered, and the titer of the filtrate was tested 10 minutes after feeding. The feed pressure was ≤0.6 MPa, the tympanic membrane pressure was 0.4±0.1 MPa, and the filter was pressed for 1.5 hours after the feeding was completed;

[0144] (3) Collect the filter cake and send it into flash drying, with the air inlet temperature of 180±20℃, the mixing chamber temperature of 60±20℃, and the air outlet temperature of 50±20℃. Sieve and mix to obtain 20% chlortetracycline premix.

[0145] During the experiment, the titer of the fermentation broth (u / mL), the titer of the filtrate (u / mL) and the titer of the premix (ug / g) were detected, and the yield (%) was calculated after the experiment.

[0146] Comparative Example 6:

[0147] 38m of aureomycin fermentation broth was taken 3 Calcium carbonate 1340 kg was added according to the calcium carbonate formula, the filtration and drying process was the same as that of Test Example 6, and calcium hydrogen phosphate and ethoxyquin were not added to compare their effects on the stability and yield of aureomycin.

[0148] Table 5 Effect comparison of different test examples and comparative examples

[0149]

[0150]

[0151] The test results are shown in Table 5. By adding calcium hydrogen phosphate and ethoxyquin in the pretreatment stage of the fermentation filtrate, the residual amount of aureomycin in the filtrate can be effectively reduced, and the reduction is more than 20%. At the same time, the process significantly improves the yield of aureomycin premix, and the yield is increased by more than 2.0%.

[0152] The above embodiments are only one specific embodiment of the present application, and the protection scope of the present application is not limited to the above embodiments. Based on the technical solutions disclosed in the present application, those skilled in the art can make reasonable improvements or extensions based on the existing technology, as long as the technical solutions do not exceed the protection scope required by the present application, and they should be recognized as equivalent to the protection scope of the present application. Therefore, the protection scope of the present application should cover all reasonable improvements and applications based on the disclosure of the present application.

Claims

1. A method for increasing the yield of chlortetracycline premix, characterized in that: The following steps are involved: S1: Take samples of chlortetracycline fermentation broth to test the titer U2 (u / g) and dry matter content Z (kg / m 3 ), according to the preparation specifications U2 (u / g) of the chlortetracycline premix to be produced, the volume of the fermentation liquid V (m 3 ), calculate the actual yield value of calcium carbonate dosage Y (kg); The calculation formula of the amount of calcium carbonate is: Y (kg) = 0.9 × V (m 3 )×1000×(U1(u / mL) / U2(u / g))-Z(kg / m 3 )V(m 3 ) adding calcium carbonate, calcium hydrogen phosphate and ethoxyquinoline to the chlortetracycline fermentation broth respectively and stirring evenly to obtain a chlortetracycline calcium salt complex; The ratio of the amount of calcium hydrogen phosphate added to the volume of the fermentation liquid is (1.0-10.0) kg:1m 3 ; The ratio of the amount of ethoxyquinoline added to the volume of the fermentation liquid is (0.05-0.2) kg:1m 3 ; S2: performing plate-and-frame filtration on the chlortetracycline calcium salt complex obtained in step S1 to obtain a chlortetracycline filter cake; S3: flash-drying the chlortetracycline filter cake obtained in step S2 to obtain a chlortetracycline premix.

2. The method for increasing the yield of chlortetracycline premix according to claim 1, wherein: The ratio of the amount of calcium hydrogen phosphate added to the volume of the fermentation liquid is (1.0-5.0) kg:1m 3 .

3. The method for increasing the yield of chlortetracycline premix according to claim 2, wherein: The ratio of the amount of calcium hydrogen phosphate added to the volume of the fermentation liquid is (2.0-5.0) kg:1m 3 .

4. The method for increasing the yield of chlortetracycline premix according to claim 3, wherein: The ratio of the amount of calcium hydrogen phosphate added to the volume of the fermentation liquid is 5.0 kg: 1 m 3 .

5. The method for increasing the yield of chlortetracycline premix according to claim 1, wherein: The ratio of the amount of ethoxyquinoline added to the volume of the fermentation liquid is (0.05-0.15) kg:1m 3 .

6. The method for increasing the yield of chlortetracycline premix according to claim 5, characterized in that: The ratio of the amount of ethoxyquinoline added to the volume of the fermentation liquid is (0.05-0.1) kg:1 m 3 .

7. The method for increasing the yield of chlortetracycline premix according to claim 1, wherein: The plate and frame filtration conditions in step S2 are: feed pressure ≤ 0.6 MPa, tympanic membrane pressure 0.4 ± 0.1 MPa, and filter press 1.0 ± 0.5 h.

8. The method for increasing the yield of chlortetracycline premix according to claim 1, wherein: The flash drying conditions in step S3 are: air inlet temperature 180±20°C, mixing chamber temperature 60±20°C, and air outlet temperature 50±20°C.

9. A premix for improving chlortetracycline, characterized in that: The chlortetracycline premix is ​​prepared by the method for increasing the yield of chlortetracycline premix according to any one of claims 1 to 8.

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