CN113336804A - Continuous crystallization method of etimicin sulfate - Google Patents
Continuous crystallization method of etimicin sulfate Download PDFInfo
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- CN113336804A CN113336804A CN202110715195.8A CN202110715195A CN113336804A CN 113336804 A CN113336804 A CN 113336804A CN 202110715195 A CN202110715195 A CN 202110715195A CN 113336804 A CN113336804 A CN 113336804A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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Abstract
The invention relates to a method for crystallizing etimicin sulfate, which comprises the following steps: a) purifying the reaction hydrolysate containing etimicin sulfate obtained in the last step of preparing etimicin sulfate by a continuous crystallization process. b) After dissolving, the etimicin sulfate with high purity is obtained by a membrane concentration method.
Description
Technical Field
The invention relates to a production technology of aminoglycoside antibiotics, in particular to a continuous crystallization process of aminoglycoside antibiotics etimicin sulfate.
Background
Etimicin sulfate (Etimicin sulfate) is self-developed by Chinese researchers, has independent intellectual property rights, is a new generation of high-efficiency, low-toxicity and drug-resistant bacteria-resistant semi-prepared aminoglycoside antibiotic, and is the only anti-infective drug for obtaining a new drug certificate in China. The action mechanism is that the normal protein of the sensitive bacteria is resisted to be prepared, the antibacterial activity is higher for Escherichia coli, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus mirabilis, Salmonella, Haemophilus influenzae, staphylococcus and the like, the antibacterial activity is certain for part of Pseudomonas and Acinetobacter, and the MIC value is still in the blood concentration range of the therapeutic dose of the product for part of gentamycin, micronomicin and cefazolin drug-resistant Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. It also has antibacterial activity against part of staphylococci producing penicillinase and part of staphylococci with low-level Methicillin Resistance (MRSA).
A crystallization process is required in the preparation process of etimicin sulfate, and the prior art (patent number cn201210002719.x) discloses a preparation method: "1-N-ethyl gentamicin C1a, 1-N-ethyl gentamicin C1a (pH6.5-8.0) partially forming sulfate or 1-N-ethyl gentamicin C1a sulfate raw material are made into any solution from 100mg/mL aqueous solution to saturated aqueous solution thereof, the preferred concentration is 200-800mg/mL, and the optimal concentration is 400-600 mg/mL; adding a certain amount of mixed solution of any one or more of methanol, ethanol and dimethyl sulfoxide mixed with water in any proportion, and fully and uniformly mixing; dripping any sulfuric acid aqueous solution with the concentration of 1-14.8mol/L while stirring until the final pH of the mother solution is between 4.0-6.5; the mother liquor was filtered to obtain crystalline solid particles and dried in vacuo. "
The existing process has the disadvantages of discontinuous production process, low equipment utilization rate, low productivity, large batch-to-batch difference and yield of only 65 percent. Therefore, the method has the problems of low yield and complicated process.
The invention has the advantages that: the method has the advantages of simple process, mild production conditions, high yield and low cost, can be carried out at normal temperature and normal pressure, and is a green chemical industry without environmental pollution.
Disclosure of Invention
The invention aims to overcome the problems of low yield and complicated process, provides innovation and provides a continuous crystallizer which is easy to operate, uniform in crystal grain distribution and high in product yield and a continuous crystallization process thereof. The technical scheme for realizing the invention is as follows: a method of etimicin sulfate crystallization having the steps of: a method of etimicin sulfate crystallization having the steps of:
a) purifying the reaction hydrolysate containing etimicin sulfate obtained in the last step of preparing etimicin sulfate by a continuous crystallization process
b) After dissolving, the etimicin sulfate with high purity is obtained by a membrane concentration method.
The method comprises the step of controlling the mass concentration of the etimicin sulfate in the etimicin sulfate hydrolysate in the step a) to be 5-15%.
The method comprises the step of a), wherein the mass concentration of the etimicin sulfate in the etimicin sulfate hydrolysate in the step a) is 10%.
The method of the invention, wherein the continuous crystallization method in the step a) comprises the steps of using a cooling crystallization system and a constant temperature condensation system; the cooling crystallization system comprises a feeding tank and a crystallization tank, the etimicin sulfate reaction liquid is communicated with a first liquid inlet arranged at the top of the crystallization tank through a pipeline, and an interlayer is arranged on the side wall of the crystallization tank; a guide flow cylinder is arranged in the middle of the crystallizing tank along the vertical direction, a baffle is arranged between the inner wall of the crystallizing tank and the outer wall of the guide flow cylinder and in an upper clear liquid area of the crystallizing tank, and a liquid outlet arranged on the feeding tank is communicated with a second liquid inlet arranged on the top of the crystallizing tank through a pipeline; the bottom of the crystallization tank is also provided with a first liquid outlet and a second liquid outlet for discharging the finished product crystallization liquid; the discharged liquid discharged from the second liquid discharge port in the crystallization tank is a mixed material with a solid-liquid ratio of 30-40%, wherein the effective volume of the crystallization tank is 0.5m3, and one or more sets of crystallization tanks are selected according to actual production requirements;
the constant-temperature condensing system comprises a heat exchanger and a constant-temperature water tank, wherein a heat exchange liquid inlet and a heat exchange liquid outlet are formed in the heat exchanger; the heat exchange liquid inlet is communicated with the first liquid discharge port through a pipeline, the heat exchange liquid discharge port is communicated with a water inlet formed in the bottom of the constant-temperature water tank, and a water outlet formed in the top of the constant-temperature water tank is communicated with the upper portion of the side wall of the crystallizing tank through a pipeline.
And a plurality of circulating pumps are arranged on the communicated pipelines according to actual requirements in the cooling crystallization system and the circulating constant-temperature condensation system.
The method of the invention is characterized in that: step a), the etimicin hydrolysate enters a preparation tank through a pipeline, sulfuric acid is dropwise added under stirring until the final pH of the mother solution is 3.0-4.0, preferably 4.0, and the temperature is controlled between 20-60 ℃.
The method of the invention is characterized in that: the continuous crystallization process of step a), comprising the steps of:
(1) the etimicin hydrolysate enters a preparation tank through a pipeline, sulfuric acid is dropwise added under stirring until the final pH of the mother solution is 3.0-4.0, preferably 4.0, and the temperature is controlled between 20-60 ℃;
(2) introducing constant-temperature liquid into an interlayer on the side wall of the crystallizer to heat the crystallizer until the temperature in the crystallizer is the same as the temperature of the fed material, and pumping the crystallization stock solution into the crystallizer from a first liquid inlet through a feed pump; and opening a feeding tank, wherein the concentration of methanol or ethanol in the feeding tank is between 30 and 100 percent, and the liquid in the clear liquid zone of the crystallizer is introduced into the feeding tank through a pipeline and then introduced into the crystallizer through a second liquid inlet for circulation.
(3) The heat exchanger is opened, and cooling water flows into the heat exchanger from the cooling water inlet to exchange heat and then is discharged from the cooling water return port; the heat exchange liquid in the interlayer of the side wall of the crystallizer is discharged through a first liquid discharge port arranged at the bottom of the side wall of the crystallizer, flows into a heat exchanger through a liquid inlet of the heat exchanger for heat exchange, is discharged into a constant temperature water tank through a liquid discharge port of the heat exchanger, and finally is introduced into the crystallizer again; the constant temperature water tank and the heat exchanger control the temperature of constant temperature liquid in an interlayer of the side wall of the crystallizer and the temperature of liquid in the guide cylinder, and the temperature difference of a circulating water inlet and a circulating water outlet is constant;
(4) after the solution in the crystallizer reaches the set capacity, the temperature in the crystallizer is slowly reduced to the discharge temperature, the first liquid inlet of the crystallizer feeds continuously, and the second liquid outlet of the crystallizer discharges continuously;
(5) and (4) repeating the steps (1) to (4) to continuously obtain the crystals.
The method of the invention, wherein, the step b) of the membrane concentration method comprises the following steps: dissolving etimicin sulfate crystals in purified water under the conditions that the operating pressure is 0.12-0.35 Mpa and the operating temperature is 5-40 ℃, and concentrating to 5% -15%; and heating the vacuum film by using steam for concentration, wherein the vacuum degree is 0.02-0.15 Mpa, the operation temperature is 30-70 ℃, and the concentration is carried out until the mass concentration of the etimicin sulfate is 15-35%. The concentrated solution obtained after concentration is subjected to freeze drying or spray drying to obtain etimicin sulfate, the purity of the etimicin sulfate is more than or equal to 99%, the water content of the etimicin sulfate is less than or equal to 5%, the nanofiltration membrane is made of cellulose acetate, sulfonated polysulfone, sulfonated polyether sulfone or polyvinyl alcohol, and the molecular weight cutoff is 150-400.
The invention lies in, adopt a kind of continuous crystallization apparatus, through adjusting to the technological parameter, confirm, get a specialized operation craft used in the characteristic scope, the invention uses the following apparatus for this reason, the said apparatus includes preparing the pot (1), the charging pot (2), the crystallizer (3), the thermostatted water tank (4) and heat exchanger (5); wherein, a first liquid inlet (6), a second liquid inlet (7), a first liquid outlet (8) and a second liquid outlet (9) are arranged on the crystallizer; the side wall is provided with an interlayer (10) and a baffle (11); the stirrer at the bottom is provided with a guide shell (12), and the heat exchanger is provided with a liquid outlet (13) and a liquid inlet (14). (the apparatus is shown in FIG. 1)
The invention is an improvement of the prior art, which is as follows:
the pseudopolymorph of etimicin sulphate, its preparation and its use are described in the patent number cn201210002719. x: 2g of 1-N-ethyl gentamicin C1a sulfate was dissolved in 10ml of water and added to the reaction kettle. Then 30ml of methanol were added to the reaction kettle, maintaining the temperature at 40 ℃ with stirring. And dropwise adding a 4mol/L sulfuric acid aqueous solution into the reaction kettle, and adjusting the final pH of the mother liquor to 5.0. After stirring for 1 hour, filtration was carried out to obtain 1.3g of a dry crystalline solid.
The differences between the present invention and the prior art are as follows:
the improved patent technology is that the pH value of etimicin hydrolysate is controlled at 4.0 at 20 ℃, and then ethanol is dripped.
② the crystallization process is a continuous crystallization process.
Compared with the prior art, the invention has the beneficial effects that:
| item | Prior art patent technology | The invention relates to the patent technology |
| Yield of crystals | 65％ | 84％ |
| (Mode) | Batch type crystallization | Continuous crystallization |
| Solvent(s) | Use of methanol, high toxicity | Use of ethanol, low toxicity |
According to the continuous crystallizer and the continuous crystallization process thereof, the continuous crystallizer is easy to operate, the product is not easy to hang on the wall during crystallization, the crystal grains are uniformly distributed, the product yield is high, and high-quality raw materials are provided for reprocessing of downstream products.
Description of the drawings:
FIG. 1 is a schematic view of a connection structure of a continuous crystallizer
Detailed Description
The invention is described in further detail below with reference to the figures and examples.
Example 1
A continuous crystallizer shown in figure 1 comprises a cooling crystallization system and a circulating constant temperature condensation system,
wherein: the cooling crystallization system comprises a feeding tank, a crystallization tank and a preparation tank for ensuring the feeding to adjust the pH value, wherein a crystallization stock solution is communicated with a liquid inlet of the preparation tank through a pipeline, a liquid outlet of the preparation tank is communicated with a first liquid inlet arranged at the top of the crystallization tank 3 through a pipeline, and an interlayer is arranged on the side wall of the crystallization tank; a guide flow cylinder is arranged in the middle of the crystallizing tank along the vertical direction, a baffle is arranged between the inner wall of the crystallizing tank and the outer wall of the guide flow cylinder and in an upper clear liquid area of the crystallizing tank, the upper part of the side wall of the crystallizing tank is communicated with a liquid inlet arranged at the bottom of the feeding tank through a pipeline, and a liquid outlet arranged at the top of the feeding tank is communicated with a second liquid inlet arranged at the top of the crystallizing tank through a pipeline; the bottom of the crystallizing tank is also provided with a first liquid outlet and a second liquid outlet for discharging the finished product crystallized liquid. Wherein: the circulating constant-temperature condensing system comprises a constant-temperature water tank and a heat exchanger, and a heat exchange liquid inlet and a heat exchange liquid outlet are formed in the heat exchanger; the heat exchange liquid inlet is communicated with the first liquid discharge port through a pipeline, the heat exchange liquid discharge port is communicated with a water inlet formed in the bottom of the constant-temperature water tank, and a water outlet formed in the top of the constant-temperature water tank is communicated with the upper portion of the side wall of the crystallizing tank through a pipeline.
The raw crystallization liquid in the preparation tank is etimicin hydrolysate with the pH value of 4.0.
And the discharged liquid discharged from the second liquid discharge port in the crystallization tank is a mixed material with the solid-liquid ratio of 30-40%. The temperature of the liquid in the guide shell is the same as that of the heat exchange liquid in the interlayer of the crystallization tank.
And a plurality of circulating pumps are arranged on the communicated pipelines according to actual requirements in the cooling crystallization system and the circulating constant-temperature condensation system.
The effective volume of the crystallizer is 0.5m3And selecting one or more sets according to actual production requirements.
Example 2
A continuous crystallization process in a continuous crystallizer, comprising the steps of:
(1) the etimicin hydrolysate enters a preparation tank through a pipeline, sulfuric acid is dropwise added under stirring until the final pH of the mother solution is 4.0, and the temperature is controlled at 20 ℃;
(2) introducing constant-temperature liquid into an interlayer on the side wall of the crystallizer to heat the crystallizer until the temperature in the crystallizer is the same as the temperature of the fed material, and pumping the crystallization stock solution into the crystallizer from a first liquid inlet through a feed pump; opening a feeding tank, wherein the concentration of methanol or ethanol in the feeding tank is between 30 and 100 percent, and the liquid in the clear liquid zone of the crystallizer is introduced into the feeding tank through a pipeline and then introduced into the crystallizer through a second liquid inlet for circulation;
(3) the heat exchanger is opened, and cooling water flows into the heat exchanger from the cooling water inlet to exchange heat and then is discharged from the cooling water return port; the heat exchange liquid in the interlayer of the side wall of the crystallizer is discharged through a first liquid discharge port arranged at the bottom of the side wall of the crystallizer, flows into a heat exchanger through a liquid inlet of the heat exchanger for heat exchange, is discharged into a constant temperature water tank through a liquid discharge port of the heat exchanger, and finally is introduced into the crystallizer again; the constant temperature water tank and the heat exchanger control the temperature of constant temperature liquid in an interlayer of the side wall of the crystallizer and the temperature of liquid in the guide cylinder, and the temperature difference of a circulating water inlet and a circulating water outlet is constant;
(4) after the solution in the crystallizer reaches the set capacity, the temperature in the crystallizer is slowly reduced to the discharge temperature, the first liquid inlet of the crystallizer feeds continuously, and the second liquid outlet of the crystallizer discharges continuously;
(5) and (4) repeating the steps (1) to (4) to continuously obtain the crystals.
In the step (2), the ethanol concentration is kept at 80%.
In the step (5), the flow rate of the material pumped back into the crystallizer through the feeding tank must not exceed 1/4 of the flow rate of the material entering the crystallizer from the preparation tank.
Claims (7)
1. A method of etimicin sulfate crystallization having the steps of:
a) purifying the reaction hydrolysate containing etimicin sulfate obtained in the last step of preparing etimicin sulfate by a continuous crystallization process
b) After dissolving, the etimicin sulfate with high purity is obtained by a membrane concentration method.
2. The method as claimed in claim 1, wherein the concentration by mass of etimicin sulfate in the etimicin sulfate hydrolysate in step a) is 5% -15%.
3. The method as claimed in claim 1, wherein the concentration by mass of etimicin sulfate in the etimicin sulfate hydrolysate in step a) is 10%.
4. The process of claim 1, wherein step a) the continuous crystallization process comprises using a cooled crystallization system and a constant temperature condensation system; the cooling crystallization system comprises a feeding tank and a crystallization tank, the etimicin sulfate reaction liquid is communicated with a first liquid inlet arranged at the top of the crystallization tank through a pipeline, and an interlayer is arranged on the side wall of the crystallization tank; a guide flow cylinder is arranged in the middle of the crystallizing tank along the vertical direction, a baffle is arranged between the inner wall of the crystallizing tank and the outer wall of the guide flow cylinder and in an upper clear liquid area of the crystallizing tank, and a liquid outlet arranged on the feeding tank is communicated with a second liquid inlet arranged on the top of the crystallizing tank through a pipeline; the bottom of the crystallization tank is also provided with a first liquid outlet and a second liquid outlet for discharging the finished product crystallization liquid; the discharged liquid discharged from the second liquid discharge port in the crystallization tank is a mixed material with a solid-liquid ratio of 30-40%, wherein the effective volume of the crystallization tank is 0.5m3, and one or more sets of crystallization tanks are selected according to actual production requirements;
the constant-temperature condensing system comprises a heat exchanger and a constant-temperature water tank, wherein a heat exchange liquid inlet and a heat exchange liquid outlet are formed in the heat exchanger; the heat exchange liquid inlet is communicated with the first liquid discharge port through a pipeline, the heat exchange liquid discharge port is communicated with a water inlet formed in the bottom of the constant-temperature water tank, and a water outlet formed in the top of the constant-temperature water tank is communicated with the upper portion of the side wall of the crystallizing tank through a pipeline.
And a plurality of circulating pumps are arranged on the communicated pipelines according to actual requirements in the cooling crystallization system and the circulating constant-temperature condensation system.
5. The method of claim 1, wherein: step a), the etimicin hydrolysate enters a preparation tank through a pipeline, sulfuric acid is dropwise added under stirring until the final pH of the mother solution is 3.0-4.0, preferably 4.0, and the temperature is controlled between 20-60 ℃.
6. The method of claim 1, wherein: the continuous crystallization process of step a), comprising the steps of:
(1) the etimicin hydrolysate enters a preparation tank through a pipeline, sulfuric acid is dropwise added under stirring until the final pH of the mother solution is 3.0-4.0, preferably 4.0, and the temperature is controlled between 20-60 ℃;
(2) introducing constant-temperature liquid into an interlayer on the side wall of the crystallizer to heat the crystallizer until the temperature in the crystallizer is the same as the temperature of the fed material, and pumping the crystallization stock solution into the crystallizer from a first liquid inlet through a feed pump; and opening a feeding tank, wherein the concentration of methanol or ethanol in the feeding tank is between 30 and 100 percent, and the liquid in the clear liquid zone of the crystallizer is introduced into the feeding tank through a pipeline and then introduced into the crystallizer through a second liquid inlet for circulation.
(3) The heat exchanger is opened, and cooling water flows into the heat exchanger from the cooling water inlet to exchange heat and then is discharged from the cooling water return port; the heat exchange liquid in the interlayer of the side wall of the crystallizer is discharged through a first liquid discharge port arranged at the bottom of the side wall of the crystallizer, flows into a heat exchanger through a liquid inlet of the heat exchanger for heat exchange, is discharged into a constant temperature water tank through a liquid discharge port of the heat exchanger, and finally is introduced into the crystallizer again; the constant temperature water tank and the heat exchanger control the temperature of constant temperature liquid in an interlayer of the side wall of the crystallizer and the temperature of liquid in the guide cylinder, and the temperature difference of a circulating water inlet and a circulating water outlet is constant;
(4) after the solution in the crystallizer reaches the set capacity, the temperature in the crystallizer is slowly reduced to the discharge temperature, the first liquid inlet of the crystallizer feeds continuously, and the second liquid outlet of the crystallizer discharges continuously;
(5) and (4) repeating the steps (1) to (4) to continuously obtain the crystals.
7. The method of claim 1, wherein step b) is a membrane concentration method comprising the steps of: dissolving etimicin sulfate crystals in purified water under the conditions that the operating pressure is 0.12-0.35 Mpa and the operating temperature is 5-40 ℃, and concentrating to 5% -15%; and heating the vacuum film by using steam for concentration, wherein the vacuum degree is 0.02-0.15 Mpa, the operation temperature is 30-70 ℃, and the concentration is carried out until the mass concentration of the etimicin sulfate is 15-35%. The concentrated solution obtained after concentration is subjected to freeze drying or spray drying to obtain etimicin sulfate, the purity of the etimicin sulfate is more than or equal to 99%, the water content of the etimicin sulfate is less than or equal to 5%, the nanofiltration membrane is made of cellulose acetate, sulfonated polysulfone, sulfonated polyether sulfone or polyvinyl alcohol, and the molecular weight cutoff is 150-400.
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| CN202110715195.8A CN113336804A (en) | 2021-06-26 | 2021-06-26 | Continuous crystallization method of etimicin sulfate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796149A (en) * | 2012-07-25 | 2012-11-28 | 无锡济民可信山禾药业股份有限公司 | Continuous separation and purification technology for etimicin |
| CN110870984A (en) * | 2018-09-04 | 2020-03-10 | 山西卓联锐科科技有限公司 | Continuous crystallizer and continuous crystallization process thereof |
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- 2021-06-26 CN CN202110715195.8A patent/CN113336804A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796149A (en) * | 2012-07-25 | 2012-11-28 | 无锡济民可信山禾药业股份有限公司 | Continuous separation and purification technology for etimicin |
| CN110870984A (en) * | 2018-09-04 | 2020-03-10 | 山西卓联锐科科技有限公司 | Continuous crystallizer and continuous crystallization process thereof |
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