AU2021105992A4 - A Multi-gradient Continuous Crystallization Method Applicable for the Reactive Crystallization Process - Google Patents
A Multi-gradient Continuous Crystallization Method Applicable for the Reactive Crystallization Process Download PDFInfo
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 105
- 230000008025 crystallization Effects 0.000 title claims abstract description 87
- 238000000034 method Methods 0.000 title claims abstract description 53
- 230000008569 process Effects 0.000 title claims abstract description 45
- 239000013078 crystal Substances 0.000 claims abstract description 50
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 238000001556 precipitation Methods 0.000 claims abstract description 12
- 238000004090 dissolution Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims description 33
- 239000000463 material Substances 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 21
- 239000003929 acidic solution Substances 0.000 claims description 17
- 238000012546 transfer Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 claims description 4
- 238000006073 displacement reaction Methods 0.000 claims description 4
- 230000002572 peristaltic effect Effects 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- PTTPUWGBPLLBKW-UHFFFAOYSA-M sodium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound [Na+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 PTTPUWGBPLLBKW-UHFFFAOYSA-M 0.000 claims description 4
- 208000005156 Dehydration Diseases 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229960002676 cefmetazole sodium Drugs 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 22
- 238000010899 nucleation Methods 0.000 abstract description 14
- 230000006911 nucleation Effects 0.000 abstract description 14
- 238000009826 distribution Methods 0.000 abstract description 8
- 230000012010 growth Effects 0.000 abstract description 6
- 238000004062 sedimentation Methods 0.000 abstract description 5
- 238000004140 cleaning Methods 0.000 abstract description 4
- 238000007599 discharging Methods 0.000 abstract description 4
- 239000012634 fragment Substances 0.000 abstract description 4
- 230000029219 regulation of pH Effects 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 33
- 239000012535 impurity Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000499 gel Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 238000010923 batch production Methods 0.000 description 2
- 229960003585 cefmetazole Drugs 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B15/00—Pumps adapted to handle specific fluids, e.g. by selection of specific materials for pumps or pump parts
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ADstracy
The present invention discloses a multi-gradient continuous crystallization method
applicable for the reactive crystallization process, which relates to the field of continuation and
control of the industrial crystallization process. The present invention realized the classification
of oil precipitation stage and crystallization process, and thus, it can effectively control the whole
process of crystallization, and realize the hierarchical control of nucleation and crystal growth,
and further improve the product quality, the purity and the uniformity. Furthermore, the present
invention realized the coordinated regulation of pH value and temperature, so that it can control
the product quality precisely, and obtain products with different size distributions, and thus, the
size classification can be accomplished. In addition, the present invention allows to add acid at
intermediate stage via the mixer, and can improve the miscibility of solution, as well as reduce
the sedimentation of crystals in the crystallizer by discharging fragment of crystalline at each
stage, and control the temperature hierarchically, and thus, the heating, dissolution and cleaning
of the crystallizer can be accomplished.
drawings o uescripuons
Add Seed Crystal
Organic Slat Add Acid
' 1 Add Acid 2 Add Acid Add Acid
Figure21
OrganicSlat AddAcidT 2 TN,
Cooling Re-dissolution Cooling
Lout out Tout
P P.. Tl*...*ot dP
T~u
1Add Acid 2 Add AcidN Add Acid
Figure 3
Organic Slat Add Acid T dn T2en TNysti
Coolg ColingCooling
Lout T T,out
16 Add Acid 2 dd Acid' P Add 7Aci
Figure 3
Organic~~~ ~ ~ ~ /1tAdAcdTn 2i
Description
ADstracy
The present invention discloses a multi-gradient continuous crystallization method
applicable for the reactive crystallization process, which relates to the field of continuation and
control of the industrial crystallization process. The present invention realized the classification of oil precipitation stage and crystallization process, and thus, it can effectively control the whole process of crystallization, and realize the hierarchical control of nucleation and crystal growth,
and further improve the product quality, the purity and the uniformity. Furthermore, the present invention realized the coordinated regulation of pH value and temperature, so that it can control the product quality precisely, and obtain products with different size distributions, and thus, the size classification can be accomplished. In addition, the present invention allows to add acid at
intermediate stage via the mixer, and can improve the miscibility of solution, as well as reduce the sedimentation of crystals in the crystallizer by discharging fragment of crystalline at each stage, and control the temperature hierarchically, and thus, the heating, dissolution and cleaning
of the crystallizer can be accomplished.
drawings o uescripuons
Add Seed Crystal Organic Slat Add Acid
Lout out Tout ' 1 Add Acid 1Add Acid 22 Add Acid AcidN Add Add AcidAcid OrganicSlat AddAcidT 2 TN,
Cooling Re-dissolution Cooling
Figure21 P P.. Tl*...*ot dP T~u
Coolg ColingCooling
Figure 3 Lout T T,out
16 Add Acid 2 dd Acid' P Add 7Aci Organic Slat Add Acid T dn T2en TNysti
Figure 3
Organic~~~ ~~~ /1tAdAcdTn 2i ueseriptions
A Multi-gradient Continuous Crystallization Method Applicable for the
Reactive Crystallization Process
Technical Field
[0001] The present invention relates to the field of continuation and control of industrial crystallization processes, particularly to a multi-gradient continuous crystallization method applicable for the reactive crystallization process.
Background Technology
[0002] Reactive crystallization is one of the most common industrial crystallization methods, which has been widely applied in the fields of pharmaceuticals, food fermentation, and fine chemicals, etc. The crystallization process is of great significance to many pharmaceutical technologies. In addition, during the process of reactive crystallization, the pH value, the temperature, and the mixing method, etc., of the reactive crystallization would have a huge impact on the crystallization efficiency and product quality significantly, and further affect the crystal form and the purity of the product directly.
[0003] The reactive crystallization is always accompanied by an acidification process during the process of pharmaceutical production. At the early stage of reactive crystallization, organic molecules often exist in the form of oily with high viscosity, and the liquid-liquid separation would be occurred between the molecules and the solvent, which is called as oil precipitation phenomenon. In terms of the traditional batch production process, the formation of oily substance and the reactive crystallization are conducted in the same equipment, so that the supersaturation of organic molecules in the oil phase would continue to accumulate with the inflow of acidic solution, and thus it would eventually cause explosive nucleation, and further make the particle size of product be fine and the crystal is fragile as well as easy to agglomerate. All of which may result in the product being hard to filter, with excessive solvent residue, difficulty in washing, and requiring long drying time, as well as low purity, and further affect the product quality. Thus, it is necessary to further complete refined purification by recrystallization. This method for processing has low production efficiency, and requires a large amount of organic solvent to complete purification and refining, and thus, it would cause contaminate the product and pollute the environmental easily. In addition, in order to reduce the influence of oil precipitation on product quality during batch production, ueseriptions the frequently-used method is to add a large amount of seed crystals prior to the explosive nucleation of solution. This method not only puts forward higher requirements on the preparation of seed crystal, but also results in low yield of product batches on.
Summary of the Invention
[0004] The purpose of the present invention is to provide a multi-gradient continuous crystallization method applicable for the reactive crystallization process to address the existing problems of the prior art described herein, and further optimize particle size distribution, remove mingled impurities, and thus the product quality would be improved effectively.
[0005] For the purpose of achieving the above objectives, the present invention proposed the following scheme: the present invention provides a multi-gradient continuous crystallization method applicable for the reactive crystallization process, which comprises the following steps:
[0006] (1) Form oily substance by means of reaction: continuously add ibuprofen sodium salt solution or cefmetazole sodium solution to the independent oily substance forming tank, and add acidic solution to the independent oily substance forming tank simultaneously, and then, complete oil precipitation;
[0007] (2) Complete the first order of reactive crystallization: convey materials to the mixer through a transfer pump by the independent oily substance forming tank; and the acidic solution would be mixed with the materials after being transferred to the mixer through another transfer pump simultaneously, and then, the product enters the first order of reactive crystallizer.
After that, complete cooling crystallization based upon controlling the pH value of the materials in the first order of reactive crystallizer;
[0008] (3) Complete the second order of reactive crystallization: the materials in the first order
of reactive crystallizer would be further mixed with the acidic solution through the mixer, and then entered the second order of reactive crystallizer. After that, complete temperature-controlled crystallization based upon controlling the pH value of the materials in the second order of reactive crystallizer;
[0009] (4) Complete the n-order of reactive crystallization: after repeating the process of step (2) and step (3) several times, the finished crystal can be obtained by dehydration treatment.
[0010] Further, equip an independent oily substance forming tank to separate the processes of
oil precipitation and crystallization. Different from the existing technology which conveys both materials to the reactive crystallizer simultaneously, this method can make the independent oily ueseriptions substance forming tank complete the formation of oily substance by means of reaction without crystal nucleation; and the acidic solution would be mixed with the material in the mixer, and
) thus it can make the mixing more uniform, and improve the crystallization quality and efficiency.
[0011] Preferably, taking the existing technical shortcomings into consideration, this method
can control the nucleation and growth of crystals effectively, which can not only dissolve fine crystals, reduce the mingled impurities, and improve the uniformity and purity of the product through regulating the pH value and temperature segmentally, but also accomplish the size classification of products, and further improve the production efficiency and product quality.
[0012] The said acidic solution shall be one of hydrochloric acid, phosphoric acid, acetic acid, nitric acid, or sulfuric acid aqueous solution.
[0013] The said independent oily substance forming tank can be a reactive crystallization kettle;
and the said reactive crystallizer can be a tube type mold or an oscillating tubular reactor.
[0014] Further, the crystallization kettle has the function of stirring and heat preservation, and the oil precipitation can be completed in the crystallization kettle prior to accomplishing the crystallization of the solution, while there is no crystallization occurs.
[0015] Further, each reactive crystallizer can implement independent heat exchange and the inner surface of the reaction layer of the reactive crystallizer is smooth, which would facilitate the discharge of crystals.
[0016] There is a crystal outlet is arranged between the said reactive crystallizer of each
previous order and the mixer of next order.
[0017] Preferably, each order of the reactive crystallizer can obtain products of different degrees of crystallinity; which is applicable for product classification, and thus, the crystal
products with different size distributions can be obtained.
[0018] The said delivery pump can be a vane pump, a peristaltic pump or a positive displacement pump.
[0019] The finished crystals can be added to the first order of reactive crystallizer described in
step (2).
[0020] Preferably, the formation of oily, gel, jelly or amorphous solids at the early stage conforms to the Ostwald distribution law, which refers to that in any process, the state formed
initially is the most unstable state with the free energy that is closest to the original state instead of the most stable state. This has become a postulation: i.e., the initial state of the crystallization ueseriptions process is an amorphous aggregate, and the difference in the time constant for transformation into a more stable crystalline state (crystal nucleus) is a critical and decisive factor related to the crystallization. At the early stage, it is difficult to distinguish the formation, nucleation, agglomeration and growth of aggregate.
[0021] The following possibilities, which are concluded depend on the time constant and the
physicochemical properties of the specific compound and system, can be deduced qualitatively: the initial oily or gel substance would agglomerate into large agglomerates instead of proceeding to transform into crystals. The initial oily or gel substance is transformed into an amorphous solid and stays at this stage instead of going on crystallization, while the
agglomerates would be formed. The initial oily or gel substance transforms into crystals as slowly as possible, and there is amorphous substance, and thus the agglomerates can be formed prior to obtaining discrete crystals.
[0022] Once the crystal is formed, whether it is slow or fast, there is almost no amorphous substance and the stable crystals can be obtained.
[0023] As we all know, some compounds never be crystallized out, and products obtained through phase separation are stable oily substance or amorphous solids. It is necessary to carry
out trial and error related to searching for solvents and conditions, or introducing exotic particle seeds to induce the crystal formation of new compounds. Fortunately, the development of combination techniques, which may facilitate such assessment, has not ceased. A key factor to success may be the removal of impurities to achieve extremely high purity, as at this stage,
even very few impurities are likely to have a strong impact on homogeneous nucleation.
[0024] The problems caused by agglomeration include the occlusion of solvents and impurities in crystalline aggregates. When these agglomerates are decomposed into small crystals
subsequently, such crystals would be captured during nucleation without growing up. Thus, the fine crystals would cause trouble for the downstream process.
[0025] Further, based upon the above reasons, the agglomeration shall be avoided generally. Thus, the first-stage of heuristic crystallization would be completed by nucleation for the first
time.
[0026] The temperature-controlled crystallization described in step (3) can be accomplished by means of continuous cooling crystallization or heating and re-dissolution.
[0027] Preferably, the process of heating and re-dissolution can realize the dissolution of some fine crystals, and eliminate some fine crystals, as well as optimize the particle size distribution, ueseriptions and thus, the mingled impurities caused by nucleation can be reduced. Compared with the prior art, the uniformity and purity of products have been improved, while the size classification can be achieved, and thus, this process can improve production efficiency and product quality.
[0028] The pH value of the reactive crystallizer of each adjacent previous order shall be greater than or equal to that of the reactive crystallizer of next order.
[0029] The present invention revealed the following technical effects: the present invention realized the classification of oil precipitation stage and crystallization process, and thus, it can effectively control the whole process of crystallization, and realize the hierarchical control of nucleation and crystal growth, and further improve the product quality, the purity and the uniformity. Furthermore, the present invention realized the coordinated regulation of pH value and temperature, so that it can control the product quality precisely. In addition, the present invention can obtain products with different size distributions, and thus, the size classification can be accomplished. Meanwhile, the present invention allows to add acid at intermediate stage via the mixer, and can improve the miscibility of solution, as well as reduce the sedimentation of crystals in the crystallizer by discharging fragment of crystalline at each stage, and control the temperature hierarchically, and thus, the heating, dissolution and cleaning of the crystallizer can be accomplished.
Brief Description of the Drawings
[0030] For the purpose of illustrating the embodiments of the present invention or the technical schemes in the prior art more clearly, the text below will describe the drawings needed in the embodiments briefly. It is obvious that accompanying drawings described herein only represent certain embodiments of the present invention, for those of ordinary skill in the art, other drawings can be obtained based on these drawings without paying creative labor.
[0031] Figure 1 is a schematic diagram of the process flow of the present invention.
[0032] Figure 2 is a schematic diagram of the crystallization by interlace operation of rising and lowering temperature of the present invention.
[0033] Figure 3 is a schematic diagram of the crystallization by continuous cooling of the present invention.
Detailed Description of the Presently Preferred Embodiments
[0034] The text below will describe the technical schemes of the embodiments of the present ueseriptions invention clearly and completely in conjunction with the accompanying drawings of the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. For those of ordinary skill in the art, all other embodiments obtained based on the embodiments of the present invention and without paying creative labor shall fall within the protection scope of the present invention.
[0035] For the purpose of make the above objectives, features and advantages of the present invention more obvious and understandable, the text below will describe the present invention in detail below in conjunction with the accompanying drawings and specific embodiments.
[0036] In an embodiment of the present invention, the present invention provides a multi-gradient continuous crystallization method applicable for the reactive crystallization process, taking the application of the process of ibuprofen reactive crystallization as an
example, as shown in figure 2, it comprises the following steps:
[0037] (1) Form oily substance by means of reaction: continuously added ibuprofen sodium salt solution or cefmetazole sodium salt, and then added the hydrochloric acidic solution with the concentration of 50% slowly, when the solution reached 2/3-3/4 of the volume of the oily
substance forming tank. Meanwhile, kept stirring the solution in the oily substance forming tank to mix it quickly and evenly, and thus, the pH value of the solution could be controlled at 6.0-7.0, and the temperature of the solution could be controlled at 35-45°C, and then, completed oil precipitation;
[0038] (2) Complete the first order of reactive crystallization: conveyed materials to the mixer through a transfer pump by the independent oily substance forming tank; and supplement acidic solution to the mixer through another transfer pump simultaneously, then the solution would be
mixed with the materials, and the product entered the first order of reactive crystallizer after mixing. Wherein, the pH value of the materials in the first order of reactive crystallizer shall be controlled at 6.0-6.5, and the temperature of the crystallizer should be controlled at 35-45°C, and, then, completed cooling crystallization;
[0039] (3) Complete the second order of reactive crystallization: the materials in the first order of reactive crystallizer would be further mixed with the acidic solution through the mixer, and then entered the second order of reactive crystallizer, wherein, the pH value of the materials in
the second order of reactive crystallizer should be controlled at 5.1-6.0, the temperature should be controlled at 40-55°C. Then, re-dissolved the fine crystals by rising temperature; ueseriptions
[0040] (4) Complete the third order of reactive crystallization: the materials in the second order of reactive crystallizer would be further mixed with the acidic solution through the mixer, and
then entered the third order of reactive crystallizer, wherein, the pH value of the materials in the third order of reactive crystallizer should be controlled at 3.1-4.0, the temperature should be controlled at 35-40°C. Then, completed cooling crystallization; and the independent oily
substance forming tank could be a reactive crystallization kettle; as well as the reactive crystallizer could be a tube type mold or an oscillating tubular reactor.
[0041] There was a crystal outlet should be arranged between the said reactive crystallizer of each previous order and the mixer of next order.
[0042] The delivery pump could be a vane pump, a peristaltic pump or a positive displacement
pump.
[0043] For step (2), 1%-10% of seed crystals could be added to the first order of reactive
crystallizer.
[0044] For step (3), the temperature-controlled crystallization could be accomplished by means of continuous cooling crystallization or heating and re-dissolution.
[0045] The pH value of the reactive crystallizer of each adjacent previous order should be
greater than or equal to that of the reactive crystallizer of next order.
[0046] For another embodiment of the present invention, as shown in figure 3, the present invention provides a multi-gradient continuous crystallization method applicable for the reactive crystallization process, taking the application of the process of ibuprofen reactive
crystallization as an example, as shown in figure 2, it comprises the following steps:
[0047] (1) Form oily substance by means of reaction: continuously added ibuprofen sodium salt solution or cefmetazole sodium salt, and then added the hydrochloric acidic solution with the
concentration of 60% slowly, when the solution reached 2/3-3/4 of the volume of the oily substance forming tank. Meanwhile, kept stirring the solution in the oily substance forming tank to mix it quickly and evenly, and thus, the pH value of the solution could be controlled at 6.0-7.0, and the temperature of the solution could be controlled at 45-50°C, and then,
completed oil precipitation;
[0048] (2) Complete the first order of reactive crystallization: conveyed materials to the mixer through a transfer pump by the independent oily substance forming tank; and supplement acidic
solution to the mixer through another transfer pump simultaneously, then the solution would be mixed with the materials, and the product entered the first order of reactive crystallizer after ueseriptions mixing. Wherein, the pH value of the materials in the first order of reactive crystallizer shall be controlled at 6.0-6.5, and the temperature of the crystallizer should be controlled at 35-45°C, and, then, completed cooling crystallization. After that, a part of crystals should be classified through the discharge pipe, and the average size of the crystal should be 45[m;
[0049] (3) Complete the second order of reactive crystallization: the materials in the first order
of reactive crystallizer would be further mixed with the acidic solution through the mixer, and then entered the second order of reactive crystallizer, wherein, the pH value of the materials in the second order of reactive crystallizer should be controlled at 5.1-6.0, the temperature should be controlled at 35-40°C. Then, re-dissolved the fine crystals by rising temperature. After that,
a part of crystals should be classified through the discharge pipe, and the average size of the crystal should be 60[m;
[0050] (4) Complete the third order of reactive crystallization: the materials in the second order
of reactive crystallizer would be further mixed with the acidic solution through the mixer, and then entered the third order of reactive crystallizer, wherein, the pH value of the materials in the third order of reactive crystallizer should be controlled at 3.1-3.5, the temperature should be controlled at 35-40°C. Then, completed cooling crystallization; and the independent oily
substance forming tank could be a reactive crystallization kettle; as well as the reactive crystallizer could be a tube type mold or an oscillating tubular reactor. After that, a part of crystals should be classified through the discharge pipe, and the average size of the crystal should be 80[m;
[0051] There was a crystal outlet should be arranged between the said reactive crystallizer of each previous order and the mixer of next order.
[0052] The delivery pump could be a vane pump, a peristaltic pump or a positive displacement
pump.
[0053] For step (2), 1%-10% of seed crystals could be added to the first order of reactive crystallizer.
[0054] For step (3), the temperature-controlled crystallization could be accomplished by means
of continuous cooling crystallization
[0055] The pH value of the reactive crystallizer of each adjacent previous order should be greater than or equal to that of the reactive crystallizer of next order.
[0056] For the embodiment of the present invention, as shown in Figure 1, an independent oily substance forming tank has been utilized to form the oily substance by means of reaction, while ueseriptions there was no crystal nucleation occurred. Then, transferred the solution with oily substance to the mixer through a transfer pump, and the addition of acid and the mixture would be accomplished in the mixer. After that, regulated the pH value to an appropriate level, and transferred the product to the first order of reactive crystallizer. Then, the first-stage of heuristic crystallization would be accomplished during the first order of process.
[0057] After the heuristic crystallization was accomplished during the first order of process, the product entered in the mixer. Then, added appropriate amount of acid as required, and accomplished the full mixture of solution to avoid the crystals from sedimentation with the proceeding of crystallization. Meanwhile, kept cooling on the second order of crystallization, and discharged the materials at the outlet of each segment of the crystallizer as needed, and thus, the classification of the product can be accomplished. In addition, the settled crystals could be discharged in time, so that it could avoid clogging the crystallization pipeline.
[0058] The present invention revealed the following technical effects: The present invention realized the classification of oil precipitation stage and crystallization process, and thus, it can effectively control the whole process of crystallization, and realize the hierarchical control of nucleation and crystal growth, and further improve the product quality, the purity and the uniformity. Furthermore, the present invention realized the coordinated regulation of pH value and temperature, so that it can control the product quality precisely. In addition, the present invention can obtain products with different size distributions, and thus, the size classification can be accomplished. Meanwhile, the present invention allows to add acid at intermediate stage via the mixer, and can improve the miscibility of solution, as well as reduce the sedimentation of crystals in the crystallizer by discharging fragment of crystalline at each stage, and control the temperature hierarchically, and thus, the heating, dissolution and cleaning of the crystallizer can be accomplished.
[0059] For the description of the present invention, it should be understood that the terms indicating the orientation or positional relationship, including "longitudinal","transverse", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "internal" and "external", etc. are all based on the orientation or positional relationship shown in the drawings, which are only used for the convenience of describing the present invention, rather than indicating or implying that the designated device or element must have a specific orientation, or be constructed and operated in a specific orientation, and thus such terms cannot be deemed as imposing restrictions on the present invention.
ueseriptions
[0060] The aforesaid embodiments only describe the preferred methods of the present invention, rather than imposing restrictions on the scope of the present invention. For those of ordinary skill in the art, any variations and improvements made to the technical scheme of the present invention without departing from the design spirit of the present invention shall fall within the protection scope of the claims of the present invention.
Claims (8)
1. A multi-gradient continuous crystallization method applicable for the reactive crystallization process, characterized in that comprising the following steps:
(1) Form oily substance by means of reaction: continuously add ibuprofen sodium salt solution or cefmetazole sodium solution to the independent oily substance forming tank, and add acidic solution to the independent oily substance forming tank simultaneously, wherein, the temperature of the solution shall be controlled at 0-20°C or 35- 50°C, and then, complete
oil precipitation; (2) Complete the first order of reactive crystallization: convey materials to the mixer through a transfer pump by the independent oily substance forming tank; and the acidic
solution would be mixed with the materials after being transferred to the mixer through another transfer pump simultaneously, and then, the product enters the first order of reactive crystallizer. Wherein, the temperature of the crystallizer shall be controlled at 0-15°C or
35-45°C, and the pH value of the materials in the first order of reactive crystallizer shall be controlled at 6.0-6.8, then, complete cooling crystallization; (3) Complete the second order of reactive crystallization: the materials in the first order of reactive crystallizer would be further mixed with the acidic solution through the mixer, and
then entered the second order of reactive crystallizer, wherein, the pH value of the materials in the second order of reactive crystallizer shall be controlled at 5.1-6.0, then, complete temperature-controlled crystallization; (4) Complete the n-order of reactive crystallization: after repeating the process of step (2)
and step (3) several times, the finished crystal can be obtained by dehydration treatment.
2. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that the said acidic solution shall
be one of hydrochloric acid, phosphoric acid, acetic acid, nitric acid, or sulfuric acid aqueous solution.
3. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that: the said independent oily
substance forming tank can be a reactive crystallization kettle; and the said reactive crystallizer can be a tube type mold or an oscillating tubular reactor.
4. The said multi-gradient continuous crystallization method applicable for the reactive
crystallization process according to claim 1, characterized in that: there is a crystal outlet is arranged between the said reactive crystallizer of each previous order and the mixer of next t01alms order.
5. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that: the said delivery pump can be a vane pump, a peristaltic pump or a positive displacement pump.
6. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that: for step (2), the finished crystals can be added to the said first order of reactive crystallizer.
7. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that: for step (3), the temperature-controlled crystallization can be accomplished by means of continuous cooling crystallization or heating and re-dissolution.
8. The said multi-gradient continuous crystallization method applicable for the reactive crystallization process according to claim 1, characterized in that: the pH value of the reactive crystallizer of each adjacent previous order shall be greater than or equal to that of the reactive crystallizer of next order.
2021105992 Drawings of Descriptions
Figure 1
Figure 2
Figure 3
1/1
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