CN111518119B - Continuous amoxicillin crystallization process - Google Patents
Continuous amoxicillin crystallization process Download PDFInfo
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- CN111518119B CN111518119B CN202010456217.9A CN202010456217A CN111518119B CN 111518119 B CN111518119 B CN 111518119B CN 202010456217 A CN202010456217 A CN 202010456217A CN 111518119 B CN111518119 B CN 111518119B
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 137
- 230000008025 crystallization Effects 0.000 title claims abstract description 137
- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 89
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 89
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 238000000034 method Methods 0.000 title claims abstract description 72
- 230000008569 process Effects 0.000 title claims abstract description 66
- 239000013078 crystal Substances 0.000 claims abstract description 46
- 238000009833 condensation Methods 0.000 claims abstract description 19
- 230000005494 condensation Effects 0.000 claims abstract description 19
- 238000007599 discharging Methods 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims description 85
- 239000000243 solution Substances 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 24
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 24
- 239000000843 powder Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 6
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Natural products N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 230000002255 enzymatic effect Effects 0.000 claims description 3
- UYCKVJUNDXPDJH-UHFFFAOYSA-N methyl 2-amino-2-(4-hydroxyphenyl)acetate;hydrochloride Chemical compound Cl.COC(=O)C(N)C1=CC=C(O)C=C1 UYCKVJUNDXPDJH-UHFFFAOYSA-N 0.000 claims description 3
- 229940056360 penicillin g Drugs 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 239000012527 feed solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 18
- 230000008859 change Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 10
- 239000012452 mother liquor Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
- C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention belongs to the technical field of drug crystallization, and particularly relates to a continuous crystallization process for effectively improving the production efficiency of amoxicillin. According to the continuous amoxicillin crystallization process, firstly, an amoxicillin condensation solution is acidified to pH less than 1.5, and then different pHs are respectively controlled in three crystallization tanks to control crystal forms of crystals and change medicine quality, so that the amoxicillin crystallization rate is effectively improved, and the yield and quality of amoxicillin are effectively improved; in the whole crystallization process, the whole feeding, crystallization and discharging processes are completely uninterrupted, the use efficiency of the whole process equipment is high, and the continuous crystallization of the amoxicillin is really realized.
Description
Technical Field
The invention belongs to the technical field of drug crystallization, and particularly relates to a continuous crystallization process for effectively improving the production efficiency of amoxicillin.
Background
The amoxicillin is a broad-spectrum penicillin antibiotic, is widely applied at present, has increasingly strong market competitiveness because the domestic production capacity is increased year by year, and has important production efficiency and quality for improving the product competitiveness and occupying the market. At present, the process for producing amoxicillin by an enzymatic method is basically popularized in China, but a certain gap still exists between the product quality stability and the production cost, and the production efficiency and the product quality of the amoxicillin pharmaceutical process are to be further improved.
Crystallization is one of the most efficient methods for producing pure solids, and during crystallization, solutes in solution are separated due to their solubility from that of impurities, and the crystallization process also directly affects the crystal form and purity of the product. The traditional amoxicillin crystallization process is similar to the common crystallization process and can be basically divided into three processes of crystal nucleus formation, crystal form growth and crystal growing. It has been shown that the metastable zone of amoxicillin crystals is generally between pH1.5 and 8.5, outside of which amoxicillin is in dissolved state and the acidic condition exists in solution as positive ions. In the traditional crystallization process, after an amoxicillin condensation feed liquid enters a crystallization tank, the pH of the crystallization liquid is adjusted to the isoelectric point of amoxicillin by adding acid/alkali liquor. Under the condition of isoelectric point, the charge of amoxicillin is zero, crystals begin to form at the moment, the crystal form is controlled by continuously controlling and adjusting the pH speed and the cooling speed (controlling and cooling to 2.0-7.0 ℃) in the crystallization process, and the whole crystal nucleus formation, growth and crystal growing process are usually carried out in a crystallization tank. The process has the advantages of simple control and short process route, and has the problems of long crystallization process (about 7 hours), large-scale production needing to be put into a large number of crystallization tanks, low equipment use efficiency, large production input and high production cost. More importantly, because the whole crystallization process all takes place in a crystallizer, the local pH change in the crystallizer not only can seriously influence the formation of crystals, but also can cause the degradation of amoxicillin, and then produce impurities, influence crystal quality.
At present, a plurality of researches on amoxicillin crystallization optimization are reported in China. For example, the research of Wangbuyan et al in the study of Amoxicillin crystallization (Hebei chemical industry, vol. 30, No. 1 of 2007) and the optimization of Amoxicillin crystallization process in Liuhui Qin's Master thesis of Amoxicillin crystallization technology describe the crystallization process, influencing factors and optimization method of Amoxicillin in detail by means of crystallization kinetic calculation and experiment. However, the research on the amoxicillin crystallization process in the prior art including the above documents still remains in the optimization of the one-time crystallization process, i.e. only in the control of the process conditions such as the optimal stirring speed, concentration, pH and the like of the process, and the prior art still has no report on the continuous amoxicillin crystallization technology.
Disclosure of Invention
Therefore, the invention aims to provide an amoxicillin continuous crystallization technology to solve the problem of low production efficiency of the amoxicillin crystallization technology in the prior art.
In order to solve the technical problem, the continuous amoxicillin crystallization technology provided by the invention comprises the following steps:
(1) acidizing the amoxicillin condensation solution to obtain acidized solution;
(2) filtering the obtained acidified liquid, introducing into a first crystallization tank, adding alkali liquor to control the pH value of the liquid to be 1.6-2.0, and crystallizing;
(3) overflowing the feed liquid to a second crystallizing tank along with continuous crystal growth, continuously adding alkali liquor to control the pH value of the feed liquid to be 2.0-4.0, and starting crystal growth at the moment;
(4) with the continuous crystal growth, the feed liquid overflows to a third crystallization tank, and alkali liquor is continuously added to control the pH value of the feed liquid to be 4.5-6.0, and then crystallization is started;
(5) and (3) controlling the temperature of the system to be reduced to the discharge temperature of 2.0-7.0 ℃, collecting the crystallization liquid and separating the mother liquor to obtain the amoxicillin wet powder.
Specifically, in the step (1), the pH value of the acidizing fluid is controlled to be 0.8-1.5.
Specifically, in the step (1), the acidification step is to mix the amoxicillin condensation solution with hydrochloric acid at a ratio of 1.0-5.0m3Mixing and acidifying at the flow rate of/h.
Specifically, the hydrochloric acid is concentrated hydrochloric acid and water, wherein the weight ratio of the hydrochloric acid to the water is 1: 1 volume, no special requirement, and the optimal flow rate of 3.5-4.0m3The faster the flow rate, the higher the pH of the obtained solution and the slower the flow rate, which is not beneficial to improving the production efficiency, but the reduction of the flow rate is beneficial to fully dissolving the condensation solution, and finally dissolving the condensation solution until the condensation solution is clear.
Specifically, in the steps (2), (3) and (4), the alkali liquor independently comprises ammonia water.
Specifically, the ammonia water concentration is 4-8M, preferably 6M, and the preparation method comprises the following steps: according to ammonia (L): 1 part of technical drinking water (L): 1, adding ammonia water and drinking water for the process into an ammonia water preparation tank, and stirring for 25-35 minutes to obtain the product.
Specifically, in the steps (2), (3) and (4), when the volume of the feed liquid reaches 80% of the volume of the corresponding crystallization tank, overflow is started.
Specifically, the amoxicillin continuous crystallization technology comprises the following steps:
in the step (3), the overflow time in the first crystallization tank is controlled to be 1.0h-2.0 h;
in the step (4), the overflow time in the second crystallizing tank is controlled to be 1.0h-2.0 h.
Specifically, in the step (5), the crystallization time in the third crystallization tank is controlled to be 2.5h-3.5h
Specifically, the stirring rotation speeds of the first crystallization tank, the second crystallization tank and the third crystallization tank are controlled to be 20-30rad/min independently.
Specifically, in the step (2), after insoluble substances need to be filtered out from the acidizing solution, the clear solution is added into the first crystallization tank to reduce the influence of impurities on crystallization, the pH value in the step is controlled to be 1.6-2.0, amoxicillin is in a slightly-dissolved state at the pH value, the solution is turbid and is in a crystal precipitation stage, crystal growth begins, the crystal precipitation process is slowed down at the moment, the bonding effect between growth units is weakened, the growth of crystal nuclei is facilitated, and the reaction can be stably carried out under the control of the pH value of 1.6-2.0. Preferably, the pH in this step is also selected from 1.7-1.8, 1.8-1.9, 1.9-2.0, and most preferably 1.8-1.9. In the first crystallizing tank, the material liquid is discharged to the next crystallizing tank when the volume of the material liquid reaches 80% of the volume of the crystallizing tank. The crystallization process of the first crystallization tank is generally 1.0h-2.0h, the crystallization reaction can be visualized from the turbidity degree of the solution, the optimal crystallization reaction time is generally 1.4-1.6h, and the temperature in the period is normal temperature.
Specifically, in the step (3), after the feed liquid overflows into the second crystallizing tank, the pH value of the feed liquid in the second crystallizing tank is controlled to be 2.0-4.0 for crystal growth. In the step, medium-strength chemical bonds have important influence on the final image of the crystal under the change condition in production transition, and because the size and the shape of crystal nuclei are formed in the first crystallization tank, the step mainly controls the crystal growth so as to ensure that the crystal growth is uniform in particle size distribution, and further certain crystal seeds are formed. In the step, the reaction can be carried out under the condition that the pH is 2.0-4.0, and the amoxicillin still exists in an ionic form when the pH is less than 4, so that incomplete precipitation of the amoxicillin can be ensured, and the slow growth of the precipitated crystals can be ensured. In this step, the pH value can be selected to be 2.0-2.5, 2.5-3.0, 3.0-3.5, 3.5-4.0, and most preferably 3.0-3.3. In the step, when the volume of the feed liquid reaches 80% of the volume of the crystallization tank, the material can be discharged, the general operation time is 1.0h-2.0h, the feed liquid in the crystallization tank is more turbid than that in the first crystallization tank, the time is generally 1.4-1.6h optimal, and the temperature is normal temperature in the period.
Specifically, in the step (4), since crystals with uniform particle size distribution are formed in the first and second crystallization tanks according to the growth rule and are rapidly precipitated in the third crystallization tank, the pH and temperature control conditions are lowered, and in view of the isoelectric point of amoxicillin being pH4.5 to 6.0, the pH of about 5 is optimal, and the amoxicillin crystals are dissolved at a higher or lower pH, which causes impurities to be formed and then remain in the crystals. Therefore, it is important to stabilize the pH during this process. In addition, as amoxicillin crystallization is the same as a common crystallization process, the lower the temperature is, the lower the solubility is, and the acidity requirement is combined, the temperature is controlled to be 2.0-7.0 ℃ most suitably in the step, although the lower the temperature is, the higher the crystal precipitation rate is, the irregular crystal precipitation can be easily caused, the production requirement can be met at 2.0-7.0 ℃, and the optimal temperature is 3.8-4.5 ℃. The crystallization process of the step is about 2.5h-3.5h, generally about 3h, and a large amount of crystals in the solution are visible.
Specifically, the amoxicillin condensation solution is a feed solution in which 6-aminopenicillanic acid (6-APA) and p-hydroxyphenylglycine methyl ester hydrochloride undergo a condensation reaction under the catalysis of penicillin G acyl transfer in an enzymatic amoxicillin process.
The continuous amoxicillin crystallization process comprises the steps of firstly, acidifying amoxicillin condensation liquid until the pH value is less than 1.5, and then controlling different pH values in three crystallization tanks respectively to control the crystal form of crystals and change the quality of medicines; wherein, in a first crystallization tank, the pH value is controlled to be 1.6-2.0, so that the amoxicillin is always in a crystal precipitation stage; in a second crystallization tank, controlling the pH value to be 2.0-4.0 to ensure that the amoxicillin is always in the slow crystal growth stage; in the third crystallization tank, the pH is further reduced to the isoelectric point of amoxicillin, and the crystals in the tank are always in the rapid crystal generation stage through temperature reduction regulation, so that the crystallization rate of amoxicillin is effectively improved, and the crystallization process is short. In the crystallization process, each crystallization tank only controls one stage of the crystallization process, the pH value control change is small, the phenomenon of large pH local change is avoided, the degradation of amoxicillin crystals can be reduced to the maximum extent, the residual impurities in the amoxicillin crystals obtained by crystallization are low, the shape is regular, and the yield and the quality of amoxicillin are effectively improved; in the whole crystallization process, the feeding state can be kept in each crystallization tank all the time, so that the whole feeding, crystallization and discharging processes are completely uninterrupted, the use efficiency of the whole process equipment is high, and the continuous crystallization of amoxicillin is really realized. Compared with the traditional process of transferring materials and then adjusting pH for crystallization, the continuous amoxicillin crystallization process has the advantages of higher amoxicillin crystallization rate, shorter production period, lower production and equipment investment cost and effectively reduced production cost.
Detailed Description
The following examples of the invention:
the amoxicillin condensation liquid is a liquid obtained by carrying out condensation reaction on 6-aminopenicillanic acid (6-APA) and p-hydroxyphenylglycine methyl ester hydrochloride under the action of penicillin G acyl transfer catalysis in an enzymatic amoxicillin process;
the ammonia water concentration is 6M, and the preparation method comprises the following steps: according to ammonia (L): 1 part of technical drinking water (L): 1, adding ammonia water and drinking water for the process into an ammonia water preparation tank, and stirring for 25-35 minutes to obtain the product;
the hydrochloric acid is concentrated hydrochloric acid and water, wherein the weight ratio of the hydrochloric acid to the water is 1: 1 volume of 1: 1 hydrochloric acid solution.
Example 1
The continuous amoxicillin crystallization process comprises the following steps:
(1) mixing 1L of amoxicillin condensation solution with a mixture of 1: 1 hydrochloric acid at 2.0m3Mixing and acidifying at a flow rate of/h by a pipeline mixer to obtain an acidizing solution with a pH value of 1.0, and detecting that the content of the acidized amoxicillin is 60 mg/mL;
(2) filtering and clarifying the obtained acidified liquid, then feeding the acidified liquid into a first crystallizing tank, slowly adding 6M ammonia water, controlling the pH of the liquid to be 1.6, controlling the stirring speed in the first crystallizing tank to be 25r/min, discharging the liquid until the volume of the liquid reaches 80% of that of the crystallizing tank after about 1.2h, and feeding the liquid into a second-stage crystallizing tank;
(3) continuously adding 6M ammonia water into the second crystallizing tank to control the pH value of the feed liquid to be 2.5, controlling the stirring speed to be 25r/min, discharging the feed liquid to flow into a third crystallizing tank after the volume of the feed liquid reaches 80% of that of the crystallizing tank after about 1.2 hours;
(4) continuously adding 6M ammonia water into the third crystallization tank to control the pH value of the feed liquid to be 4.5, controlling the stirring speed to be 25r/min, and starting crystallization at the moment;
(5) and (3) controlling the temperature in the third crystallization tank to be reduced to 2.5 ℃, reacting for 2.5h, collecting crystallization liquid, separating mother liquor, and obtaining 50.1g of wet powder after drying.
Example 2
The continuous amoxicillin crystallization process comprises the following steps:
(1) mixing 1L of amoxicillin condensation solution with a mixture of 1: 1 hydrochloric acid at 4.5m3Mixing and acidifying at a flow rate of/h by a pipeline mixer to obtain an acidizing solution with a pH value of 1.5, and detecting that the content of the acidized amoxicillin is 60 mg/mL;
(2) filtering and clarifying the obtained acidified liquid, then feeding the acidified liquid into a first crystallizing tank, slowly adding 6M ammonia water, controlling the pH of the liquid to be 2.0, controlling the stirring speed in the first crystallizing tank to be 25r/min, discharging the liquid until the volume of the liquid reaches 80% of that of the crystallizing tank after about 2.0h, and feeding the liquid into a second-stage crystallizing tank;
(3) continuously adding 6M ammonia water into the second crystallizing tank to control the pH value of the feed liquid to be 4.0, controlling the stirring speed to be 25r/min, discharging the material liquid after about 2.0h to flow into a third crystallizing tank, wherein the volume of the feed liquid reaches 80% of that of the crystallizing tank;
(4) continuously adding 6M ammonia water into the third crystallization tank to control the pH value of the feed liquid to be 6.0, controlling the stirring speed to be 25r/min, and starting crystallization at the moment;
(5) and (3) controlling the temperature in the third crystallization tank to be reduced to 6.0 ℃, reacting for 3.5 hours, collecting crystallization liquid, separating mother liquor, and obtaining 50.21g of wet powder after drying.
Example 3
The continuous amoxicillin crystallization process comprises the following steps:
(1) mixing 1L of amoxicillin condensation solution with a mixture of 1: 1 hydrochloric acid at 3.8m3Mixing and acidifying at a flow rate of/h by a pipeline mixer to obtain an acidizing solution with a pH value of 1.3, and detecting that the content of the acidized amoxicillin is 60 mg/mL;
(2) filtering and clarifying the obtained acidified liquid, then feeding the acidified liquid into a first crystallizing tank, slowly adding 6M ammonia water, controlling the pH of the liquid to be 1.8, controlling the stirring speed in the first crystallizing tank to be 25r/min, discharging the liquid until the volume of the liquid reaches 80% of that of the crystallizing tank after about 1.5h, and feeding the liquid into a second-stage crystallizing tank;
(3) continuously adding 6M ammonia water into the second crystallizing tank to control the pH value of the feed liquid to be 3.3, controlling the stirring speed to be 25r/min, discharging the material liquid after about 1.5h to flow into a third crystallizing tank, wherein the volume of the feed liquid reaches 80% of that of the crystallizing tank;
(4) continuously adding 6M ammonia water into the third crystallization tank to control the pH value of the feed liquid to be 5.0, controlling the stirring speed to be 25r/min, and starting crystallization at the moment;
(5) controlling the temperature in the third crystallization tank to be reduced to 3.8 ℃, reacting for 3.0h, collecting crystallization liquid, separating mother liquor, and obtaining 51.25g of wet powder after pumping to dryness
Comparative example 1
The amoxicillin crystallization process of the comparative example adopts a traditional crystallization process, namely 1L of amoxicillin condensation liquid is condensed at 18 ℃, and 1: acidifying 1 hydrochloric acid to obtain an amoxicillin acidizing solution with the pH value of 1.0, filtering, adding the solution into a crystallizing tank, adding 6M ammonia water in a flowing mode, controlling the pH value to be about 5.5, slowly cooling to 4.0 ℃, performing crystal growing after the cooling is finished until crystals are not generated in the solution any more, continuing the whole crystallization process for 7.5 hours, collecting a crystallization solution, separating mother liquor, and obtaining 47.53g of wet powder after drying.
Comparative example 2
The amoxicillin crystallization process in the comparative example is the same as the method in example 3, and the difference is that the overflow feed liquid after the pH control in the first crystallization tank directly enters the third crystallization tank, and the crystallization is controlled according to the parameter conditions in the third crystallization tank; the method specifically comprises the following steps:
(1) mixing 1L of amoxicillin condensation solution with a mixture of 1: 1 hydrochloric acid at 3.8m3Mixing and acidifying at a flow rate of/h by a pipeline mixer to obtain an acidizing solution with a pH value of 1.2, and detecting that the content of the acidized amoxicillin is 60 mg/mL;
(2) filtering and clarifying the obtained acidified liquid, then feeding the acidified liquid into a first crystallizing tank, slowly adding 6M ammonia water, controlling the pH of the liquid to be 1.7, controlling the stirring speed in the first crystallizing tank to be 25r/min, discharging the liquid until the volume of the liquid reaches 80% of that of the crystallizing tank after about 1.5h, and feeding the liquid into a third-order crystallizing tank;
(3) continuously adding 6M ammonia water into the third crystallization tank to control the pH value of the feed liquid to be 5.0, controlling the stirring speed to be 25r/min, and starting crystallization at the moment;
(4) and (3) controlling the temperature in the third crystallization tank to be reduced to 3.6 ℃, reacting for 3.0h, collecting crystallization liquid, separating mother liquor, and pumping to dryness to obtain 46.97g of wet powder.
Comparative example 3
The amoxicillin crystallization process in the comparative example is the same as the method in example 3, and the difference is that the acidified liquid after acidification directly enters the second crystallization tank to adjust and control the corresponding pH value, and the adjusted and controlled overflow liquid continuously enters the third crystallization tank to control crystallization according to the parameter conditions in the third crystallization tank; the method specifically comprises the following steps:
(1) mixing 1L of amoxicillin condensation solution with a mixture of 1: 1 hydrochloric acid at 3.8m3Mixing and acidifying at a flow rate of/h by a pipeline mixer to obtain an acidizing solution with a pH value of 1.4, and detecting that the content of the acidized amoxicillin is 60 mg/mL;
(2) filtering and clarifying the obtained acidified liquid, then feeding the acidified liquid into a second crystallizing tank, adding 6M ammonia water in a flowing manner to control the pH value of the liquid to be 3.5, controlling the stirring speed to be 25r/min, discharging the liquid until the volume of the liquid reaches 80% of that of the crystallizing tank after about 1.5h, and then feeding the liquid into a third crystallizing tank;
(3) continuously adding 6M ammonia water into the third crystallization tank to control the pH value of the feed liquid to be 5.0, controlling the stirring speed to be 25r/min, and starting crystallization at the moment;
(4) and (3) controlling the temperature in the third crystallization tank to be reduced to 3.8 ℃, reacting for 3.0h, collecting crystallization liquid, separating mother liquor, and pumping to dryness to obtain 48.41g of wet powder.
Examples of the experiments
1. Yield of crystals
The yield (%) of amoxicillin obtained by the processes of examples 1-3 and comparative examples 1-3 is calculated respectively according to the following formula:
yield ═ wet powder output/aldehydic content of acidified liquor × (100% wet powder moisture + 12.8%);
the results of the calculations are shown in Table 1 below.
TABLE 1 Amoxicillin crystallization yield
| Numbering | Appearance of the product | Acidified amoxicillin content | Acidity of the solution | Moisture content | Yield of |
| Example 1 | White crystalline powder | 60mg/ml | 4.5 | 21％ | 91％ |
| Example 2 | White crystalline powder | 60mg/ml | 4.4 | 21％ | 91％ |
| Example 3 | White crystalline powder | 60mg/ml | 4.1 | 21％ | 93％ |
| Comparative example 1 | White crystalline powder | 60mg/ml | 4.9 | 21％ | 86％ |
| Comparative example 2 | White crystalline powder | 60mg/ml | 4.9 | 21％ | 85％ |
| Comparative example 3 | White crystalline powder | 60mg/ml | 4.9 | 21％ | 88％ |
Therefore, in the amoxicillin continuous crystallization process, the crystallization yield of amoxicillin is better.
2. Stability of crystallization
Taking 3L of the amoxicillin condensation solution, carrying out continuous crystallization treatment according to the process in the previous example 3, continuously producing 3 batches, detecting the stability of the continuous crystallization process, and the test data are shown in the following table 2.
TABLE 2 Amoxicillin crystallization stability test results
| Detecting items | Appearance of the product | Acidified amoxicillin content | Acidity of the solution | Moisture content | Amount of wet powder | Yield of |
| First batch | White crystalline powder | 60mg/ml | 4.1 | 21％ | 51.18g | 92.9％ |
| Second batch | White crystalline powder | 60mg/ml | 4.1 | 21％ | 51.29g | 93.1％ |
| Third batch | White crystalline powder | 60mg/ml | 4.1 | 21％ | 51.35g | 93.2％ |
As can be seen from the data in the table above, the amoxicillin continuous crystallization process has no obvious difference in performance among the products in each batch, and proves that the process has good stability and is suitable for industrial production.
3. Production efficiency
Tests show that the production cycle of the continuous crystallization process is basically equal to that of the traditional crystallization process, the yield of the target product in the scheme of the invention is obviously superior to that of the traditional crystallization process, and the yield of the product can be effectively improved by about 5 percent at least; the process can realize continuous production, has high equipment utilization rate, and can effectively reduce the production and equipment investment cost.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (2)
1. A continuous amoxicillin crystallization process is characterized by comprising the following steps:
(1) acidizing the amoxicillin condensation solution to obtain acidized solution;
the amoxicillin condensation solution is a feed solution in which 6-aminopenicillanic acid (6-APA) and p-hydroxyphenylglycine methyl ester hydrochloride undergo a condensation reaction under the action of penicillin G acyl transfer catalysis in an enzymatic amoxicillin process, and the pH value of the acidification solution is controlled to be 0.8-1.5;
(2) filtering the obtained acidified liquid, introducing into a first crystallization tank, adding ammonia water with the concentration of 4-8M as an alkali liquor, controlling the pH value of the feed liquid to be 1.6-2.0, and controlling the stirring speed of the first crystallization tank to be 20-30r/min, and then starting to crystallize;
(3) continuously crystallizing for 1.0-2.0 h, discharging the feed liquid to a second crystallizing tank when the volume of the feed liquid reaches 80% of the volume of the corresponding crystallizing tank, continuously adding ammonia water with the concentration of 4-8M as an alkali liquid, controlling the pH value of the feed liquid to be 2.0-4.0, controlling the stirring speed of the second crystallizing tank to be 20-30r/min, and then starting to grow crystals;
(4) continuously growing crystals for 1.0-2.0 h, discharging the feed liquid to a third crystallizing tank when the volume of the feed liquid reaches 80% of the volume of the corresponding crystallizing tank, continuously adding ammonia water with the concentration of 4-8M as an alkali liquid, controlling the pH value of the feed liquid to be 4.5-6.0, controlling the stirring rotating speed of the third crystallizing tank to be 20-30r/min, and then starting crystallizing;
(5) and controlling the crystallization time in the third crystallization tank to be 2.5h-3.5h, when the volume of the feed liquid reaches 80% of the volume of the corresponding crystallization tank, controlling the system to be cooled to the discharge temperature of 2.0-7.0 ℃, collecting the crystallization liquid and separating the mother liquid to obtain the required amoxicillin wet powder.
2. A continuous amoxicillin crystallization process according to claim 1, characterized in that in step (1), the acidification step is carried out by mixing amoxicillin condensate with hydrochloric acid at a ratio of 1.0-5.0m3Mixing and acidifying at the flow rate of/h.
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