CN115260323A - Processing device and preparation method of high-purity icodextrin - Google Patents
Processing device and preparation method of high-purity icodextrin Download PDFInfo
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- CN115260323A CN115260323A CN202210813415.5A CN202210813415A CN115260323A CN 115260323 A CN115260323 A CN 115260323A CN 202210813415 A CN202210813415 A CN 202210813415A CN 115260323 A CN115260323 A CN 115260323A
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- decoloring
- ultrafiltration
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- 229920002177 Icodextrin Polymers 0.000 title claims abstract description 46
- 229940016836 icodextrin Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000012545 processing Methods 0.000 title claims abstract description 12
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 230000007246 mechanism Effects 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 29
- 239000007788 liquid Substances 0.000 claims abstract description 20
- 238000012544 monitoring process Methods 0.000 claims abstract description 13
- 229920002472 Starch Polymers 0.000 claims abstract description 12
- 239000008107 starch Substances 0.000 claims abstract description 12
- 235000019698 starch Nutrition 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000012216 screening Methods 0.000 claims abstract description 8
- 239000012528 membrane Substances 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 230000005540 biological transmission Effects 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- 230000003472 neutralizing effect Effects 0.000 claims description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- 238000007599 discharging Methods 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical group C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 17
- 238000009826 distribution Methods 0.000 abstract description 16
- 238000002474 experimental method Methods 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 38
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 239000011630 iodine Substances 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 8
- 239000012085 test solution Substances 0.000 description 8
- 235000013339 cereals Nutrition 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 150000004676 glycans Chemical class 0.000 description 5
- 229920001282 polysaccharide Polymers 0.000 description 5
- 239000005017 polysaccharide Substances 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 241000237509 Patinopecten sp. Species 0.000 description 3
- 239000000385 dialysis solution Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 235000020637 scallop Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003712 decolorant Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002357 osmotic agent Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
- C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
- C08B30/16—Apparatus therefor
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B30/00—Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
- C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
- C08B30/18—Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
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- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The invention discloses a processing device and a preparation method of high-purity icodextrin, wherein the whole decoloring mechanism is hollow, the bottom of the decoloring mechanism is in a conical barrel-shaped structure, a discharge pipeline is arranged below the decoloring mechanism and is communicated with a decoloring cavity in the decoloring mechanism, a discharge switch valve is arranged on the discharge pipeline, the ultrafiltration mechanism is sleeved outside the decoloring mechanism, a liquid outlet pipeline is arranged below the decoloring mechanism and is communicated with an ultrafiltration cavity in the ultrafiltration mechanism, and a liquid outlet switch valve is arranged on the liquid outlet pipeline; the inventor of the invention determines the optimal process combination for preparing icodextrin through a large amount of experiments and experiences, and selects the process parameters and raw materials in the starch hydrolysis process and monitors the hydrolysis reaction process, and the ultrafiltration method is used for molecular weight screening, so that the obtained icodextrin has narrower molecular weight distribution range and more centralized molecular weight, the monitoring method of the reaction process is simple and easy to realize, and the finally obtained icodextrin has uniform granularity and low water content (less than or equal to 9.5 wt%). The whole preparation method is simple and easy to realize industrial production.
Description
Technical Field
The invention relates to icodextrin, in particular to a processing device and a preparation method of high-purity icodextrin.
Background
Icodextrin is the main active ingredient in icodextrin peritoneal dialysis solution. Renal dialysis is a simple, effective, inexpensive procedure suitable for almost all ESRD patients. Icodextrin (Icodextrin) is a water-soluble glucose polymer made from cereal starch connected by alpha-1, 4 and less than 10% alpha-1, 6 glycosidic linkages, and has a weight average molecular weight of 13000-19000 Da and a number average molecular weight of 5000-6500 Da. Icodextrin acts as a colloidal osmotic agent to accomplish ultrafiltration during long-term peritoneal dialysis indwelling periods. In the existing literature on icodextrin peritoneal dialysis solutions, only the application of icodextrin in peritoneal dialysis solutions and the advantages and difficulties faced by the present application of such macromolecular polysaccharide osmotic agents in pharmaceutical clinics are provided, but no specific method and specific implementation equipment are provided for the preparation of icodextrin.
Disclosure of Invention
In order to solve the technical problems, the invention provides a processing device of high-purity icodextrin and a preparation method thereof.
The technical scheme of the invention is realized as follows:
a processing device of high-purity icodextrin comprises a decoloring mechanism and an ultrafiltration mechanism;
the decoloring mechanism is integrally hollow, the bottom of the decoloring mechanism is of a conical barrel-shaped structure, a discharge pipeline is arranged below the decoloring mechanism and is communicated with a decoloring cavity in the decoloring mechanism, a discharge switch valve is arranged on the discharge pipeline, the ultrafiltration mechanism is sleeved outside the decoloring mechanism, a liquid outlet pipeline is arranged below the ultrafiltration mechanism and is communicated with an ultrafiltration cavity in the ultrafiltration mechanism, and a liquid outlet switch valve is arranged on the liquid outlet pipeline;
the decoloring mechanism further includes: the device comprises a decoloring rotating device and a feeding hole, wherein the decoloring rotating device is fixedly arranged above the inside of the decoloring cavity, a transmission motor in the decoloring rotating device is fixedly arranged on the outer side of the top wall of the decoloring cavity, and the feeding hole is formed in the top wall of the decoloring cavity;
the decoloring rotating device further includes: the decoloration rotating shaft and the decoloration rotating wing piece, the output end of the transmission motor penetrates through the top wall of the decoloration cavity and is in transmission connection with the decoloration rotating shaft, and the decoloration rotating shaft is provided with a plurality of the decoloration rotating wing pieces along the axis direction.
Furthermore, a sealing cover is arranged on the feeding hole.
Further, the ultrafiltration mechanism further comprises: lateral wall, pressurized port, ultrafiltration hole, ultrafiltration membrane pipe, inside wall and booster pump, the ultrafiltration cavity by the inside wall with the lateral wall constitutes, the inside wall has seted up a plurality of along the periphery annular direction ultrafiltration hole, the downthehole ultrafiltration is equipped with the ultrafiltration membrane pipe, seted up on the roof of decoloration cavity the pressurized port, the booster pump is arranged in the ultrafiltration cavity is outside to through the hose with the pressurized port is connected, pressure sensor install in on the roof of decoloration cavity, its test connector along stretch to inside the decoloration cavity.
Furthermore, an upper layer of ultrafiltration membrane and a lower layer of ultrafiltration membrane are arranged in the ultrafiltration membrane tube, and a filtration membrane tube cover is arranged at one end of the ultrafiltration membrane tube positioned on one side of the decoloring cavity.
Further, the filter membrane tube cap comprises: tube cap upper cover, tube cap axle and tube cap lower cover, the tube cap upper cover with the tube cap lower cover is discoid structure, and has a plurality of fan-shaped hole respectively along even interval on the circumferencial direction, and interval arc length is not less than fan-shaped hole arc width between per two adjacent fan-shaped holes, and tube cap center department is equipped with the tube cap axle, the tube cap upper cover with the tube cap lower cover passes through tube cap axle swivelling joint.
Furthermore, the signal output end of the pressure sensor is connected with the signal input end of the controller, and the signal output end of the controller is connected with the signal input ends of the discharging switch valve, the liquid outlet switch valve, the booster pump and the filter membrane pipe cover.
A preparation method of icodextrin comprises the following steps:
A. preparing grain starch and water into a solution with a substrate concentration of 40-50wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.1-1.5% (V/V), performing hydrolysis reaction at the temperature of 70-80 ℃, monitoring the reaction process, neutralizing the reaction solution to pH7 with an alkali solution when the outflow time of the reaction solution is 2-4min measured by a Ubbelohde viscometer with the capillary inner diameter of 0.9-1.0mm, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 0.5-4h;
B. screening the product 1 by molecular weight to obtain a product 2 with the weight-average molecular weight of 1.3-1.9 ten thousand Da;
C. drying and curing the product 2 to obtain the product;
the acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid and acetic acid;
the alkali solution is an alkali solution which can be neutralized with acid to generate nontoxic and harmless salt.
In some embodiments, step a is: preparing grain starch and water into a solution with a substrate concentration of 40-50wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.365-0.73% (V/V), performing hydrolysis reaction at a temperature of 75-80 ℃, monitoring the reaction process, measuring the outflow time of the reaction solution by using a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm for 2-4min, neutralizing the reaction solution to pH7 by using an alkali solution, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 1-4h.
In some embodiments, step a is: preparing grain starch and water into a solution with a substrate concentration of 35wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.51% (V/V), performing hydrolysis reaction at a temperature of 85 ℃, simultaneously monitoring the reaction process, when the outflow time of the reaction solution is measured by a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm to be 2min54s +/-2 s, neutralizing the reaction solution to pH7 by using an alkali solution, and terminating the hydrolysis reaction to obtain a product 1, wherein the reaction time is 2.5h.
In general, the faster the hydrolysis reaction rate, the shorter the duration of the appearance of the product of interest (icodextrin), and the less easily controllable the end point of the reaction. The acid concentration, the reaction temperature and the reaction time are selected mainly by considering the reaction rate and the duration of the target product (icodextrin) in the presence, so that the reaction rate is high, the duration of the target product (icodextrin) in the presence is long, and the reaction endpoint is easy to control. Another main reason is the distribution range of the molecular weight, and for the present reaction, the narrower the distribution range of the molecular weight of the final product (icodextrin) is, the better the molecular weight distribution index can reach 2.3-3.5, and the narrower the distribution range indicates the more concentrated the molecular weight distribution of the final product (icodextrin). The inventors have conducted extensive experiments to find that the relationship between the intrinsic viscosity and the weight average molecular weight is the most intimate and can be used to monitor the weight average molecular weight of the reaction solution to determine the time for terminating the hydrolysis reaction. The substrate concentration is selected primarily in consideration of the reaction rate, the molecular weight distribution range, and the production efficiency. Based on the consideration, the inventor finally determines appropriate process parameters and combines the determination of intrinsic viscosity to monitor the reaction progress, so that the molecular weight distribution of the final product (icodextrin) is narrower and more concentrated.
In some of the embodiments, in the step A, when the reaction solution has an outflow time of 2 to 4min measured by an Ubbelohde viscometer with a capillary inner diameter of 0.9 to 1.0mm and an optical rotation of 0.2 to 1.6 measured, the hydrolysis reaction is terminated.
Optical rotation is an important physical parameter of polysaccharide and the parameter is related to chain length, structure and the like of polysaccharide, and the progress of the hydrolysis reaction can be monitored by measuring the optical rotation. The optical rotation is measured according to appendix VI E of the second part of Chinese pharmacopoeia 2010.
The invention can also adopt an iodine test solution monitoring method, the iodine test solution is mainly characterized in that the color reaction phenomena with iodine at different stages in the whole process of starch hydrolysis are different, the hydrolysis reaction process can be monitored by using the iodine test solution, and the reaction is properly stopped when the iodine test solution is faint yellow.
The monitoring method has the advantages of simple and convenient operation, low cost and high efficiency.
In some of the examples, the molecular weight screening of step B is to dilute the product 1 to 3-15 times, and then screen the molecular weight of the product 1 with 100KD and 6KD ultrafiltration membranes in sequence.
Diluting the product 1 to 3-15 times, stirring for 10-20 minutes at a certain rotating speed, uniformly mixing, and then carrying out primary ultrafiltration on the product 1 by using an ultrafiltration membrane package with 100KD to remove the part with the molecular weight more than 8 ten thousand Da in the product 1; the lower ultrafiltration was then carried out using a 6KD ultrafiltration membrane pack to remove the fraction of product 1 having a molecular weight of less than 6000Da and product 2 having a weight average molecular weight of 1.3-1.9 ten thousand Da.
The original process adopts a water extraction and alcohol precipitation method, but the drying of a sample treated by the method is difficult, and the accuracy of the method for molecular weight screening is poor.
In some embodiments, the acid is one or more of hydrochloric acid, sulfuric acid, and nitric acid.
In some of the embodiments, the alkali solution is one or more of a sodium hydroxide solution, a potassium hydroxide solution, and a carbonate solution.
In some embodiments, in step C, the drying and solidifying manner adopted for the product 2 is atmospheric drying, reduced pressure drying, spray drying or freeze drying.
In some embodiments, in step C, the drying and solidifying manner used for the product 2 is spray drying or freeze drying.
The invention also provides the icodextrin prepared by the preparation method.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the inventor of the invention determines the optimal process combination for preparing the icodextrin through a large amount of experiments and experiences, and selects the process parameters and raw materials in the starch hydrolysis process and monitors the hydrolysis reaction process by an ultrafiltration method to screen the molecular weight, so that the obtained icodextrin has narrower molecular weight distribution range and more concentrated molecular weight, the monitoring method of the reaction process is simple and easy to realize, and the finally obtained icodextrin has uniform granularity and low water content (less than or equal to 9.5 wt%). The whole preparation method is simple and easy to realize industrial production.
Drawings
FIG. 1 is a schematic diagram of a combined apparatus for producing icodextrin drug substance;
FIG. 2 is an enlarged view of a portion of the invention at A;
FIG. 3 is a schematic view of the structure of the membrane cover of the present invention.
Description of reference numerals:
1. a decoloring mechanism, 2, an ultrafiltration mechanism, 3 and a controller,
11. a decoloring cavity 12, a decoloring rotating device 13, a discharge pipeline 14 and a feed inlet,
121. a transmission motor 122, a decoloration rotating shaft 123, a decoloration rotating wing panel,
131. a discharging switch valve is arranged on the bottom of the container,
141. a sealing cover is arranged on the upper portion of the shell,
21. an ultrafiltration cavity body 22, an outer side wall 23, a liquid outlet pipeline 24, a pressurizing port 25, an ultrafiltration hole 26, an ultrafiltration membrane pipe 27, an inner side wall 28 and a booster pump,
221. a pressure sensor is arranged on the base plate,
231. a liquid outlet switch valve is arranged on the lower end of the water tank,
261. an ultrafiltration membrane 262, a filter membrane tube cover,
2621. tube cover upper cover 2622, tube cover axle, 2623, tube cover lower cover.
Detailed Description
The following description of the embodiments of the present invention refers to the accompanying drawings and examples:
it should be noted that the structures, proportions, sizes, and other dimensions shown in the drawings and described in the specification are only for the purpose of understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined by the following claims, and any modifications of the structures, changes in the proportions and adjustments of the sizes, without affecting the efficacy and attainment of the same, are intended to fall within the scope of the present disclosure.
In addition, the terms "upper", "lower", "left", "right", "middle" and "one" used in the present specification are used for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the terms may be changed or adjusted without substantial change in the technical content.
The invention relates to a processing device of high-purity icodextrin, which is combined with figures 1-3 and comprises the following components: a decoloring mechanism 1 and an ultrafiltration mechanism 2.
The whole decoloring mechanism 1 is hollow, the bottom of the decoloring mechanism 1 is of a conical barrel-shaped structure, a discharge pipeline 13 is arranged below the decoloring mechanism 1 and communicated with a decoloring cavity 11 in the decoloring mechanism 1, a discharge switch valve 131 is arranged on the discharge pipeline 13, the ultrafiltration mechanism 2 is sleeved outside the decoloring mechanism 1, a liquid outlet pipeline 23 is arranged below the ultrafiltration mechanism 2 and communicated with an ultrafiltration cavity 21 in the ultrafiltration mechanism 2, and a liquid outlet switch valve 231 is arranged on the liquid outlet pipeline 23.
The decoloring mechanism 1 further includes: decoloration rotary device 12 and feed inlet 14, decoloration rotary device 12 fixed mounting is in the inside top of decoloration cavity 11, and driving motor 121 fixed mounting in decoloration rotary device 12 is in the outside of decoloration cavity 11 roof, has seted up feed inlet 14 on the decoloration cavity 11 roof.
The decoloring rotating device 12 further includes: the device comprises a decoloring rotating shaft 122 and decoloring rotating fins 123, wherein the output end of a transmission motor 121 penetrates through the top wall of the decoloring cavity 11 to be in transmission connection with the decoloring rotating shaft 122, and the decoloring rotating shaft 122 is provided with a plurality of decoloring rotating fins 123 along the axis direction.
The feed port 14 is provided with a sealing cover 141.
The ultrafiltration mechanism 2 further comprises: lateral wall 22, pressure port 24, ultrafiltration hole 25, ultrafiltration membrane tube 26, inside wall 27 and booster pump 28, ultrafiltration cavity 21 comprises inside wall 27 and lateral wall 22, inside wall 27 has seted up a plurality of ultrafiltration hole 25 on the periphery annular direction, be equipped with ultrafiltration membrane tube 26 in the ultrafiltration hole 25, pressure port 24 has been seted up on the roof of decoloration cavity 11, ultrafiltration cavity 21 outside is arranged in to booster pump 28, and be connected with pressure port 24 through the hose, pressure sensor 221 installs on the roof of decoloration cavity 11, its test connector is inside along stretching to decoloration cavity 11.
An upper layer of ultrafiltration membrane 261 and a lower layer of ultrafiltration membrane 261 are arranged in the ultrafiltration membrane tube 26, and a filter membrane tube cover 262 is arranged at one end of the ultrafiltration membrane tube 26 positioned at one side of the decolorizing cavity 11.
The filter membrane tube cap 262 includes: tube cap upper cover 2621, tube cap axle 2622 and tube cap lower cover 2623, tube cap upper cover 2621 and tube cap lower cover 2623 are discoid structure, and have a plurality of scallop hole respectively along even interval in the circumferencial direction, and interval arc length is not less than the scallop hole arc width between per two adjacent scallop holes, and tube cap center department is equipped with tube cap axle 2622, and tube cap upper cover 2621 and tube cap lower cover 2623 rotate through tube cap axle 2622 and are connected.
Further, the signal output end of the pressure sensor 221 is connected with the signal input end of the controller 3, and the signal output end of the controller 3 is connected with the signal input ends of the discharging switch valve 131, the liquid outlet switch valve 231, the booster pump 28 and the filter membrane tube cover 262.
The working principle of the invention is as follows: carry reactant to decoloration cavity 11 inside to add certain decolorant, at this moment, filter membrane tube cap 262 is in the closed condition, opens driving motor 121, and driving motor 121 drives rotatory fin 123 of decoloration and rotates, carries out intensive mixing to reactant and decolorant for stirring efficiency, and then promotes decoloration efficiency.
The pressurizing pump is started to pressurize the interior of the decoloring cavity 11, the controller 3 controls the filter membrane pipe cover 262 to be opened, the mixed material is filtered and screened by the ultrafiltration membrane 261 under the action of the internal and external pressure difference, the obtained material liquid enters an ultrafiltration inner cavity, after decoloring and ultrafiltration are completed, the controller 3 respectively controls the discharge switch valve 131 and the liquid outlet switch valve 231 to be opened, and the material liquid and the adsorbed decoloring agent are conveyed to the next process.
The invention relates to a preparation method of icodextrin, which comprises the following steps:
A. preparing grain starch and water into a solution with a substrate concentration of 40-50wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.1-1.5% (V/V), performing hydrolysis reaction at the temperature of 70-80 ℃, monitoring the reaction process, neutralizing the reaction solution to pH7 with an alkali solution when the outflow time of the reaction solution is 2-4min as measured by a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 0.5-4h;
B. screening the molecular weight of the product 1 to obtain a product 2 with the weight-average molecular weight of 1.3-1.9 ten thousand Da;
C. drying and curing the product 2 to obtain the product;
the acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid and acetic acid;
the alkali solution is an alkali solution which can be neutralized with acid to generate nontoxic and harmless salt.
In some embodiments, step a is: preparing grain starch and water into a solution with a substrate concentration of 20-45wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.365-0.73% (V/V), performing hydrolysis reaction at a temperature of 75-90 ℃, monitoring the reaction process, measuring the outflow time of the reaction solution by using a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm for 2-4min, neutralizing the reaction solution to pH7 by using an alkali solution, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 1-4h.
The step A is as follows: preparing grain starch and water into a solution with a substrate concentration of 40wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.51% (V/V), performing hydrolysis reaction at a temperature of 85 ℃, simultaneously monitoring the reaction process, when the outflow time of the reaction solution is measured by a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm to be 2min54s +/-2 s, neutralizing the reaction solution to pH7 by using an alkali solution, and terminating the hydrolysis reaction to obtain a product 1, wherein the reaction time is 2.5h.
In general, the faster the hydrolysis reaction rate, the shorter the duration of the appearance of the desired product (icodextrin), and the less easily controllable the end point of the reaction. The acid concentration, the reaction temperature and the reaction time are selected mainly by considering the reaction rate and the duration of the target product (icodextrin) in the presence, so that the reaction rate is high, the duration of the target product (icodextrin) in the presence is long, and the reaction endpoint is easy to control. Another main reason is the distribution range of the molecular weight, and for the present reaction, the narrower the distribution range of the molecular weight of the final product (icodextrin) is, the better the molecular weight distribution index can reach 2.3-3.5, and the narrower the distribution range indicates the more concentrated the molecular weight distribution of the final product (icodextrin). The inventors have conducted extensive experiments to find that the relationship between the intrinsic viscosity and the weight average molecular weight is the most intimate and can be used to monitor the weight average molecular weight of the reaction solution to determine the time for terminating the hydrolysis reaction. The substrate concentration is selected primarily in consideration of the reaction rate, molecular weight distribution range, and production efficiency. Based on the consideration, the inventor finally determines appropriate process parameters and combines with the determination of intrinsic viscosity to monitor the reaction progress, so that the molecular weight distribution of the final product (icodextrin) is narrower and more concentrated.
In the step A, when the outflow time of the reaction liquid is measured by an Ubbelohde viscometer with the inner diameter of a capillary tube of 0.9-1.0mm and the optical rotation of the reaction liquid is measured to be 0.2-1.6, the hydrolysis reaction is stopped.
Optical rotation is an important physical parameter of polysaccharides and is related to the chain length, structure and the like of the polysaccharides, and the progress of the hydrolysis reaction can be monitored by measuring the optical rotation. The optical rotation is measured according to appendix VI E of the second part of Chinese pharmacopoeia 2010.
The invention can also adopt an iodine test solution monitoring method, the iodine test solution is mainly characterized in that the color reaction phenomena with iodine are different in different stages in the whole process of starch hydrolysis, the hydrolysis reaction process can be monitored by using an iodine test solution test, and the reaction is properly stopped when the iodine test solution is in a light yellow color.
The monitoring method has the advantages of simple operation, low cost and high efficiency.
And the molecular weight screening of the step B is to dilute the product 1 to 3-15 times, and screen the molecular weight of the product 1 by using ultrafiltration membranes with 100KD and 5KD in sequence.
Diluting the product 1 to 3-15 times, stirring for 10-20 minutes at a certain rotating speed, uniformly mixing, and then carrying out primary ultrafiltration on the product 1 by using an ultrafiltration membrane package with 100KD to remove the part with the molecular weight more than 8 ten thousand Da in the product 1; the lower ultrafiltration was then carried out using a 6KD ultrafiltration membrane pack to remove the fraction of product 1 having a molecular weight of less than 6000Da and product 2 having a weight average molecular weight of 1.3-1.9 ten thousand Da.
The original process adopts a water extraction and alcohol precipitation method, but the drying of a sample treated by the method is difficult, and the accuracy of the method for molecular weight screening is poor.
The acid is one or more of hydrochloric acid, sulfuric acid and nitric acid.
The alkali solution is one or more of sodium hydroxide solution, potassium hydroxide solution and carbonate solution.
In the step C, the drying and solidifying mode adopted by the product 2 is normal pressure drying, reduced pressure drying, spray drying or freeze drying.
In the step C, the drying and solidifying mode adopted by the product 2 is spray drying or freeze drying.
The invention also provides the icodextrin prepared by the preparation method.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Claims (7)
1. The utility model provides a processingequipment of high-purity icodextrin which characterized in that: comprises a decoloring mechanism and an ultrafiltration mechanism;
the decoloring mechanism is integrally hollow, the bottom of the decoloring mechanism is of a conical barrel-shaped structure, a discharge pipeline is arranged below the decoloring mechanism and is communicated with a decoloring cavity in the decoloring mechanism, a discharge switch valve is arranged on the discharge pipeline, the ultrafiltration mechanism is sleeved outside the decoloring mechanism, a liquid outlet pipeline is arranged below the ultrafiltration mechanism and is communicated with an ultrafiltration cavity in the ultrafiltration mechanism, and a liquid outlet switch valve is arranged on the liquid outlet pipeline; the decoloring mechanism further includes: the device comprises a decoloring rotating device and a feeding hole, wherein the decoloring rotating device is fixedly arranged above the inside of the decoloring cavity, a transmission motor in the decoloring rotating device is fixedly arranged on the outer side of the top wall of the decoloring cavity, and the feeding hole is formed in the top wall of the decoloring cavity; the decoloring rotating device further includes: the decoloration rotating shaft and the decoloration rotating wing piece, the output end of the transmission motor penetrates through the top wall of the decoloration cavity and is in transmission connection with the decoloration rotating shaft, and the decoloration rotating shaft is provided with a plurality of the decoloration rotating wing pieces along the axis direction.
2. The apparatus for processing high-purity icodextrin according to claim 1, characterized in that: and a sealing cover is arranged on the feeding hole.
3. The apparatus for processing high-purity icodextrin according to claim 1, wherein: the ultrafiltration mechanism further comprises: lateral wall, pressurized port, ultrafiltration hole, ultrafiltration membrane pipe, inside wall and booster pump, the ultrafiltration cavity by the inside wall with the lateral wall constitutes, the inside wall has seted up a plurality of along the periphery annular direction ultrafiltration hole, the downthehole ultrafiltration is equipped with the ultrafiltration membrane pipe, seted up on the roof of decoloration cavity the pressurized port, the booster pump is arranged in the ultrafiltration cavity is outside to through the hose with the pressurized port is connected, pressure sensor install in on the roof of decoloration cavity, its test connector along stretch to inside the decoloration cavity.
4. The apparatus for processing high-purity icodextrin according to claim 1, characterized in that: an upper ultrafiltration membrane layer and a lower ultrafiltration membrane layer are arranged in the ultrafiltration membrane tube, and a filtration membrane tube cover is arranged at one end of the ultrafiltration membrane tube positioned on one side of the decoloring cavity.
5. The apparatus for processing high-purity icodextrin according to claim 1, characterized in that: the filter membrane tube cover comprises: tube cap upper cover, tube cap axle and tube cap lower cover, the tube cap upper cover with the tube cap lower cover is discoid structure, and has a plurality of fan-shaped hole respectively along even interval on the circumferencial direction, and interval arc length is not less than fan-shaped hole arc width between per two adjacent fan-shaped holes, and tube cap center department is equipped with the tube cap axle, the tube cap upper cover with the tube cap lower cover passes through tube cap axle swivelling joint.
6. The apparatus for processing high-purity icodextrin according to claim 1, wherein: the signal output end of the pressure sensor is connected with the signal input end of the controller, and the signal output end of the controller is connected with the signal input ends of the discharging switch valve, the liquid outlet switch valve, the booster pump and the filter membrane pipe cover.
7. A preparation method of icodextrin is characterized by comprising the following steps: the method comprises the following steps:
A. preparing grain starch and water into a solution with a substrate concentration of 40-50wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.1-1.5% (V/V), performing an acid hydrolysis reaction at a temperature of 70-80 ℃, monitoring the reaction process, neutralizing the reaction solution to pH7 with an alkali solution when the outflow time of the reaction solution is 2-4min as measured by a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 0.5-6h;
B. screening the molecular weight of the product 1 to obtain a product 2 with the weight-average molecular weight of 1.6-1.9 ten thousand Da;
C. drying and curing the product 2 to obtain the product;
the acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, citric acid and acetic acid;
the alkali solution is an alkali solution which can be neutralized with acid to generate nontoxic and harmless salt.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467608A (en) * | 2013-09-27 | 2013-12-25 | 华仁药业股份有限公司 | Icodextrin and preparing method thereof |
| CN208081918U (en) * | 2018-02-11 | 2018-11-13 | 孟州市华兴生物化工有限责任公司 | A kind of beta-cyclodextrin decoloration device |
| CN110862461A (en) * | 2019-11-12 | 2020-03-06 | 潍坊盛泰药业有限公司 | Preparation method of resistant dextrin |
| CN214436684U (en) * | 2020-11-30 | 2021-10-22 | 青岛力腾医药科技有限公司 | Combined equipment for producing icodextrin raw material medicine |
| CN217724655U (en) * | 2022-06-09 | 2022-11-04 | 石家庄市惠源淀粉有限公司 | Production device of medicinal maltodextrin |
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2022
- 2022-07-11 CN CN202210813415.5A patent/CN115260323A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467608A (en) * | 2013-09-27 | 2013-12-25 | 华仁药业股份有限公司 | Icodextrin and preparing method thereof |
| CN208081918U (en) * | 2018-02-11 | 2018-11-13 | 孟州市华兴生物化工有限责任公司 | A kind of beta-cyclodextrin decoloration device |
| CN110862461A (en) * | 2019-11-12 | 2020-03-06 | 潍坊盛泰药业有限公司 | Preparation method of resistant dextrin |
| CN214436684U (en) * | 2020-11-30 | 2021-10-22 | 青岛力腾医药科技有限公司 | Combined equipment for producing icodextrin raw material medicine |
| CN217724655U (en) * | 2022-06-09 | 2022-11-04 | 石家庄市惠源淀粉有限公司 | Production device of medicinal maltodextrin |
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Application publication date: 20221101 |