CN114716415B - Apparatus for producing liquid composition, method for producing the same and use thereof - Google Patents
Apparatus for producing liquid composition, method for producing the same and use thereof Download PDFInfo
- Publication number
- CN114716415B CN114716415B CN202210647010.9A CN202210647010A CN114716415B CN 114716415 B CN114716415 B CN 114716415B CN 202210647010 A CN202210647010 A CN 202210647010A CN 114716415 B CN114716415 B CN 114716415B
- Authority
- CN
- China
- Prior art keywords
- valve
- interface
- port
- compound
- module
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The present application provides a process for the production of 2-tert-butyl-4-chloro-5- ((3- ((4- ((2- (2-fluoro-), [ 2 ]) 18 F]Ethoxy) methyl) -1H-1,2, 3-triazol-1-yl) methyl) benzyl) oxy) pyridazin-3 (2H) -a device for the liquid composition of ketones (hereinafter "compound i"), comprising: a pre-processing module for enriching 18 F ions; a reaction module for enriching 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I; the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I; and a prescription module for enriching and prescribing the purified compound I pure product into a compound I liquid composition. The above-described apparatus provided herein produces a liquid composition of compound i for immediate clinical use. The application also provides a method for preparing the compound I liquid composition by the device and the application of the device in preparing the compound I liquid composition.
Description
Technical Field
The present application relates to the field of radiopharmaceutical technology, and in particular to an apparatus for producing a liquid composition, a method of preparation and use thereof.
Background
Coronary heart disease is one of the most serious diseases threatening human health. In China, the morbidity and mortality of coronary heart disease are in an increasing trend. In 2007, the data published by the ministry of health showed: about 300 million people who die of cardiovascular diseases in China every year become the first death cause of urban and rural people in China, and account for nearly 40% of the death causes of residents in China.
Myocardial Perfusion (MPI) Single Photon Emission Computed Tomography (SPECT) imaging technology is the main method of non-invasive perfusion imaging currently used clinically for coronary heart disease detection and prognosis evaluation. However, compared with SPECT, Positron Emission Tomography (PET) imaging has higher spatial and temporal resolution, can effectively reduce tissue attenuation, and can achieve absolute quantification of coronary flow using standard tissue attenuation correction methods. In addition, the short half-life of the positive electron nuclide can effectively reduce the radiation dose around the target tissue, and the short half-life can also shorten the rest and motion imaging interval. General useThe myocardial perfusion PET imaging agent comprises: 15 O-H 2 O， 13 N-NH 3 ·H 2 o and 82 rb and the like. However, the imaging agents have short half-lives and are limited in clinical application. While 18 F has a longer half-life (t) relative to other positive electron species 1/2 109.8 min); has a lower positron energy (mean energy 249.8keV) and is less radiation damaging to normal tissue; the Van der Waals radius (1.35) of the compound is similar to that of hydrogen (1.2), and the bioactivity of the labeled compound cannot be influenced, so that the development of a novel fluorine-18 labeled myocardial perfusion imaging agent has important practical significance.
2-tert-butyl-4-chloro-5- ((3- ((4- ((2- (2-fluoro-)) 18 F]Ethoxy) methyl) -1H-1,2, 3-triazol-1-yl) methyl) benzyl) oxy) pyridazin-3 (2H) -Ketone (hereinafter "Compound I") is a radionuclide 18 The F-labeled analogue of the respiratory chain complex-I (MC-I) inhibitor in the mitochondria can be retained in the myocardium for a long time, and the uptake value in the heart is positively correlated with the myocardial blood flow. The structure of the compound I is shown as the following figure:
the compound I has high cardiac uptake and liver uptake 15 minutes after intravenous injection, has good cardiac/liver ratio 60 minutes after injection, and has good myocardial perfusion imaging potential and clinical benefit.
At present, a non-full-automatic production mode does not perform complete radiation protection, manual marking cannot prepare a large amount of compound I liquid compositions (such as injection), single preparation can only meet the use requirement of 1-2 people, and clinical use is limited.
Therefore, it is important to develop an apparatus for producing a liquid composition of compound I (e.g., an injection solution).
Disclosure of Invention
To solve the problems of the prior art, the present application provides an apparatus for producing a liquid composition of compound i (e.g., an injection solution) and a method for producing the same. The technical scheme of the application is as follows:
1. an apparatus for producing a liquid composition of compound i comprising:
a pre-processing module for enriching 18 F ions;
a reaction module for enriching 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I;
a prescription module, which enriches and prescribes the purified compound I into a compound I liquid composition;
a compound I.
2. The apparatus of item 1, the pre-processing module comprising:
the first valve to the sixth valve respectively comprise at least a first interface, a second interface and a third interface, and any two interfaces of the three interfaces can be conducted or none of the three interfaces can be conducted by the first valve to the sixth valve; the first interface of the first valve is connected with a first positive pressure pipeline, the second interface of the first valve is connected with the first interface of the second valve, the second interface of the second valve is connected with the first interface of the third valve, the second interface of the third valve is connected with the first interface of the fourth valve, the second interface of the fourth valve is connected with the first interface of the fifth valve, and the second interface of the fifth valve is connected with the first interface of the sixth valve;
the first recovery container is respectively connected with the first negative pressure pipeline and the third interface of the first valve;
a first reagent container connected to the third port of the second valve;
a first injector connected to the third port of the third valve;
18 an F ion enrichment bin connected between the third port of the fourth valve and the third port of the fifth valve;
and the second injector is connected with the third interface of the sixth valve.
Preferably, the first valve, the second valve, the third valve, the fourth valve, the fifth valve and the sixth valve are all electrically controlled valves.
3. The apparatus of item 2, the pre-processing module further comprising:
the first linear driving device can drive the piston of the first syringe to move in the hollow cylinder;
and the second linear driving device can drive the piston of the second syringe to move in the hollow cylinder.
Preferably, the first linear driving device and the second linear driving device are selected from one of a pneumatic rod, a hydraulic rod and a lead screw;
further preferably, the first linear driving device and the second linear driving device are both lead screws, and the lead screws are driven by stepping motors.
4. The apparatus of claim 2, the pre-processing module further comprising a positive pressure and negative pressure line and a charge line, each extending through the piston of the second syringe into the second syringe.
Preferably, a flow meter is arranged on the liquid feeding pipeline.
5. The apparatus of item 2, the reaction module comprising:
the system comprises a seventh valve, an eighth valve, a ninth valve, a tenth valve, an eleventh valve and a tenth valve, wherein the seventh valve to the twelfth valve respectively at least comprise a first interface, a second interface and a third interface, and the seventh valve to the twelfth valve can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first interface of the seventh valve is connected with the pretreatment module, the second interface of the seventh valve is connected with the first interface of the eighth valve, the second interface of the eighth valve is connected with the first interface of the ninth valve, the second interface of the ninth valve is connected with the first interface of the tenth valve, the second interface of the tenth valve is connected with the first interface of the eleventh valve, the second interface of the eleventh valve is connected with the first interface of the tenth valve, and the third interface of the tenth valve is connected with the purification module;
the reaction container is respectively connected with a second negative pressure pipeline and a third interface of the seventh valve;
the temperature control assembly is used for heating and/or cooling the reaction container;
a third syringe connected to the third port of the eighth valve;
a second reagent container connected to the third port of the ninth valve;
a fourth syringe connected to the third port of the tenth valve;
a third reagent container coupled to the third port of the eleventh valve.
Preferably, the seventh valve, the eighth valve, the ninth valve, the tenth valve, the eleventh valve and the twelfth valve are all electrically controlled valves.
6. The apparatus of clause 5, the reaction module further comprising:
the third linear driving device can drive the piston of the third syringe to move in the hollow cylinder;
and the fourth linear driving device can drive the piston of the fourth syringe to move in the hollow cylinder.
Preferably, the third linear driving device and the fourth linear driving device are selected from one of a pneumatic rod, a hydraulic rod and a lead screw;
further preferably, the third linear driving device and the fourth linear driving device are both screw rods, and the screw rods are driven by stepping motors.
7. The apparatus of clause 5, the purification module comprising:
the third valve and the fourteenth valve can be switched between a first mode and a second mode, the first mode is that the first interface is communicated with the second interface, the third interface is communicated with the fourth interface, and the fifth interface is communicated with the sixth interface; the second mode is that the second interface is communicated with the third interface, the fourth interface is communicated with the fifth interface, and the sixth interface is communicated with the first interface; wherein the fourth interface of the thirteenth valve is connected with the reaction module; the second port of the thirteenth valve is connected with the first port of the fourteenth valve; the second port of the fourteenth valve is connected with the third port of the fourteenth valve through an external pipeline;
a chromatography column assembly connected between the fifth interface of the fourteenth valve and the sixth interface of the fourteenth valve;
a dosing ring connected between the third port of the tenth and the sixth port of the thirteenth valve;
a liquid delivery pump connected to the first port of the thirteenth valve;
a second recovery tank connected to a fifth port of the thirteenth valve;
the fifteenth valve at least comprises a first interface, a second interface and a third interface, and the fifteenth valve can realize the conduction of the first interface and the second interface or the conduction of the first interface and the third interface; the first port of the fifteenth valve is connected with the fourth port of the fourteenth valve, the second port of the fifteenth valve is connected with the prescription module, and the third port of the fifteenth valve is connected with the second recovery container.
Preferably, the thirteenth valve, the fourteenth valve and the fifteenth valve are all electrically controlled valves.
8. The apparatus of item 7, the prescribing module comprising:
the valve assembly comprises a sixteenth valve, a seventeenth valve, an eighteenth valve, a nineteenth valve, a twentieth valve and a twenty-first valve, wherein the sixteenth valve to the twenty-first valve respectively at least comprise a first interface, a second interface and a third interface, and the sixteenth valve to the twenty-first valve can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first interface of the sixteenth valve is connected with the second interface of the tenth valve, the second interface of the sixteenth valve is connected with the first interface of the seventeenth valve, the second interface of the seventeenth valve is connected with the first interface of the eighteenth valve, the second interface of the eighteenth valve is connected with the first interface of the nineteenth valve, the second interface of the nineteenth valve is connected with the first interface of the twentieth valve, the second interface of the twentieth valve is connected with the first interface of the twenty-first valve, the third interface of the sixteenth valve is connected with the purification module, and the second interface of the twenty-first valve is connected with a third negative pressure pipeline;
a fourth reagent container connected to the third port of the seventeenth valve;
a compound i enrichment bin connected between the third port of the eighteenth valve and the third port of the nineteenth valve;
the first transfer container is connected with the third interface of the twentieth valve;
a finished product collection container;
and the second transfer container is respectively connected with the third interface of the twenty-first valve, the finished product collecting container and a fourth negative pressure pipeline.
9. A method for producing a liquid composition of compound I using the apparatus as set forth in any one of items 1 to 8, comprising:
enrichment using a pre-processing module 18 F ions;
using reaction modules for enrichment 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
purifying the crude product of the compound I by using a purification module to obtain a pure product of the compound I;
the purified compound i purified product was enriched and formulated into compound i liquid composition using a formulation module.
10. Use of the apparatus of any one of items 1 to 8 for producing a compound i liquid composition.
The equipment for producing the liquid composition of the compound I can prepare crude compound I, and purify, enrich and formulate the crude compound I to prepare the liquid composition of the compound I for direct clinical application. Moreover, the automation of the equipment can be realized by controlling each valve and the like through a microprocessor control system (such as PLC and the like). Also, the present application provides methods of using the above-described apparatus.
The above description is only an overview of the technical solutions of the present application, and in order to make the technical means of the present application more clearly understood, the present application is described below in the following detailed description of the present application in order to make the implementation of the technical means of the present application possible to a person skilled in the art according to the content of the present specification, and in order to make the above and other objects, features, and advantages of the present application more obvious.
Drawings
FIG. 1: the pretreatment module, the reaction module and the prescription module of the equipment for producing the compound I are assembled schematically.
FIG. 2 (a) to FIG. 2 (b): schematic purification module of the plant for producing compound i (purification module by switching between the fig. 2 (a) mode and the fig. 2 (b) mode).
FIG. 3 (a) to FIG. 3 (h): the schematic structure of the three-way valve (fig. 3 (a) is a schematic diagram of three ports in the three-way valve being communicated, fig. 3 (b) to 3 (d) are schematic diagrams of two ports in the three-way valve being communicated, respectively, and fig. 3 (e) to 3 (h) are schematic diagrams of three ports in the three-way valve being not communicated with each other, respectively).
FIG. 4 (a) to FIG. 4 (d): is a schematic diagram of the three-way valve of fig. 3 (fig. 4 (a) is a schematic diagram of the three-way valve corresponding to fig. 3 (b); fig. 4 (b) is a schematic diagram of the three-way valve corresponding to fig. 3 (c); fig. 4 (c) is a schematic diagram of the three-way valve corresponding to fig. 3 (d); and fig. 4 (d) is a schematic diagram of the three-way valve corresponding to fig. 3 (e) to fig. 3 (h)).
FIG. 5 (a) to FIG. 5 (b): the six-way valve is schematically shown in the structure (fig. 5 (a) and 5 (b) are respectively schematic diagrams of the valve core of the six-way valve in different working positions).
Fig. 6 (a) to 6 (c):the working principle of the pre-processing module is schematically illustrated (the pre-processing module is implemented according to the sequence of FIG. 6 (a) to FIG. 6 (c)) 18 F ion enrichment and feeding to the reaction module).
FIG. 7 (a) to FIG. 7 (g): the reaction module is schematically shown in the working principle (the reaction module carries out the reactions according to the sequence of FIGS. 7 (a), 7 (b), 7 (c), 7 (d), 7 (e), 7 (f) and 7 (g)).
FIG. 8 (a) to FIG. 8 (g): schematic diagram of working principle of prescription module (prescription module carries out prescription and collects final product according to sequence of fig. 8 (a), 8 (b), 8 (c), 8 (d), 8 (b), 8 (d), 8 (e), 8 (f) and 8 (g)).
FIG. 9: the total negative pressure pipeline is connected with a schematic diagram.
Description of reference numerals:
1 to 21, first to twenty-first valves; v1, three-way valve body; v2, three-way valve spool; v3, six-way valve body; v4, six-way valve core;
22. a first recovery tank; 23. a first reagent container; 24. a first syringe; 25. 18 an F ion enrichment bin; 26. a second syringe; 27. a positive pressure and negative pressure pipeline; 28. a liquid feeding pipeline;
29. a reaction vessel; 30. a third syringe; 31. a second reagent container; 32. A fourth syringe; 33. a third reagent container;
34. a chromatography column assembly; 35. a dosing ring; 36. a liquid delivery pump; 37. a second recovery vessel;
38. a fourth reagent container; 39. a compound I enrichment bin; 40. a first transfer vessel; 41. a second transfer vessel; 42. a finished product collection container;
43. a third recovery vessel;
p0, a positive pressure pipeline of the positive pressure and negative pressure pipeline; p1, a first positive pressure pipeline;
n, a total negative pressure pipeline; n0, a negative pressure pipeline of the positive pressure negative pressure pipeline; n1, a first negative pressure pipeline; n2, a second negative pressure pipeline; n3, a third negative pressure pipeline; n4, a fourth negative pressure pipeline.
Detailed Description
The following embodiments of the present application are merely illustrative of specific embodiments for carrying out the present application and should not be construed as limiting the present application. Other changes, modifications, substitutions, combinations, and simplifications which may be made without departing from the spirit and principles of the present application are intended to be equivalent substitutions and are within the scope of the present application.
This example provides a method for producing 2-tert-butyl-4-chloro-5- ((3- ((4- ((2- (2-fluoro-) 18 F]Ethoxy) methyl) -1H-1,2, 3-triazol-1-yl) methyl) benzyl) oxy) pyridazin-3 (2H) -a ketone (hereinafter "compound i") liquid composition (e.g. an injection solution) comprising:
a pre-processing module for enriching 18 F ions;
reaction module for enriched 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I;
and a prescription module for enriching and prescribing the purified compound I pure product into a compound I liquid composition.
As shown in the following figure, Compound I is prepared by reacting a precursor of Compound I with radioactive fluorine [, [ solution ] or a salt thereof 18 F]The ions are used as starting materials and are prepared by one-step reaction. Fluorine [ 2 ] 18 F]And (3) performing ion nucleophilic substitution on tosyloxy (-OTs) in the precursor of the compound I to obtain a crude product of the compound I. The synthetic route of the crude compound I is shown in the following figure.
In the figure, K 222 Is 4,7,13,16,21, 24-hexaoxy-1, 10-diazabicyclo [8.8.8]The eicosanoid is called aminopolyether for short.
This example shows an apparatus for producing a liquid composition of compound I (e.g., an injection solution) which is first enriched by a pre-treatment module 18 F ions; after enrichment 18 F ions enter the reaction module, and thenReacting with a precursor of the compound I in a reaction module to obtain a crude product of the compound I; purifying the crude product of the compound I in a purification module to obtain a pure product of the compound I; further, the pure compound I enters a prescription module, and the pure compound I is enriched and prescribed into a liquid compound I composition.
Through the technical scheme of the embodiment, the crude compound I can be obtained, and the crude compound I is purified, enriched and formulated to be directly used in clinic.
In addition, the term "crude product" and "pure product" in the present application refer to the product before and after purification, respectively; the prescription in the embodiment specifically refers to that a pure compound I and auxiliary materials are prepared into a compound I liquid composition.
In one embodiment, as shown in fig. 1, 3, 4, 6, the preprocessing module comprises:
the valve comprises a first valve 1, a second valve 2, a third valve 3, a fourth valve 4, a fifth valve 5 and a sixth valve 6, wherein the first valve 1 to the sixth valve 6 respectively at least comprise a first interface, a second interface and a third interface, and the first valve 1 to the sixth valve 6 can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first port of the first valve 1 is connected to a first positive pressure line P1, the second port of the first valve 1 is connected to the first port of the second valve 2, the second port of the second valve 2 is connected to the first port of the third valve 3, the second port of the third valve 3 is connected to the first port of the fourth valve 4, the second port of the fourth valve 4 is connected to the first port of the fifth valve 5, and the second port of the fifth valve 5 is connected to the first port of the sixth valve 6;
a first recovery container 22 connected to a first negative pressure line N1 and a third port of the first valve 1, respectively;
a first reagent container 23 connected to the third port of the second valve, the first reagent container 23 being used for containing 18 F leacheate (e.g. acetonitrile + water + K) 222 +K 2 CO 3 Etc.);
a first injector 24 connected to the third port of the third valve 3;
18 an F ion enrichment bin 25 connected between the third port of the fourth valve 4 and the third port of the fifth valve 5, the 18 The F ion enrichment bin 25 is filled with anion exchange resin;
a second syringe 26 connected to the third port of the sixth valve 6;
preferably, the first valve 1, the second valve 2, the third valve 3, the fourth valve 4, the fifth valve 5 and the sixth valve 6 are all electrically controlled valves (such as electromagnetic valves).
First, as shown in fig. 3, a three-way valve is provided, which can realize the functions of the first to sixth valves 1 to 6, and certainly can also realize the functions of the seventh to tenth valves 7 to 12 and the sixteenth to twenty-first valves 16 to 21, which will not be described in detail below.
Specifically, as shown in fig. 3 (a) to 3 (h), the three-way valve includes a three-way valve element V2 with a circular cross section and a three-way valve body V1 outside the three-way valve element V2, the three-way valve body V1 is provided with a first port on the left side, a second port on the right side, a third port on the upper side, and a T-shaped flow passage is provided in the three-way valve element V2. By rotating the valve plug V2, the first port (shown in fig. 3 b) can be communicated with the third port (shown in fig. 3 c), the first port (shown in fig. 3 c) can be communicated with the second port (shown in fig. 3 d), the second port (shown in fig. 3 d) can be communicated with the third port (shown in fig. 3 e-3 h), and the three ports are not communicated (shown in fig. 3 e-3 h). In addition, given the above three-way valve structure, those skilled in the art know how to control the three-way valve spool V2 to rotate at a fixed angle relative to the three-way valve body V1 according to the prior art to achieve electrical (electromagnetic) control of the three-way valve (e.g., setting a stepper motor to control the rotation of the three-way valve spool V2). In addition, in order to be able to briefly describe the state of the three-way valve in the following, fig. 4 gives a schematic view of the three-way valve in fig. 3, wherein fig. 4 (a) is a schematic view of the three-way valve corresponding to fig. 3 (b); FIG. 4 (b) is a schematic view of a three-way valve corresponding to FIG. 3 (c); FIG. 4 (c) is a schematic view of a three-way valve corresponding to FIG. 3 (d); fig. 4 (d) is a schematic diagram of the three-way valve corresponding to fig. 3 (e) to 3 (h).
In addition, the first negative pressure pipeline N1 is specifically configured to provide negative pressure by vacuum pumping, and the negative pressure pipeline N0, the second negative pressure pipeline N2, the third negative pressure pipeline N3, and the fourth negative pressure pipeline N4 of the positive pressure and negative pressure pipeline hereinafter may also provide negative pressure by vacuum pumping, which is not described in detail below. And the negative pressure pipeline N0, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3 and the fourth negative pressure pipeline N4 of the positive pressure negative pressure pipeline may be connected to one vacuum-pumping device alone, or two or more of them may be connected to one vacuum-pumping device/pipeline. Specifically, as shown in fig. 9, the third recovery container 43 is connected to the total negative pressure pipeline N, and other negative pressure pipelines (more than one of the negative pressure pipeline N0, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3, and the fourth negative pressure pipeline N4 of the positive pressure negative pressure pipeline) are also connected to the third recovery container 43 (specifically, connected to the pipeline on the left side of the third recovery container 43 in fig. 9), so that one vacuuming device can drive more than one negative pressure pipeline to operate, and the third recovery container 43 can store liquid flowing from the negative pressure pipeline.
The first positive pressure line P1 provides positive pressure by blowing out inert gas (such as nitrogen, argon, etc.), and a filter membrane may be installed in the first positive pressure line P1 to ensure the cleanness of the inert gas entering the equipment. The positive pressure line P0 of the following positive pressure and negative pressure line may also provide positive pressure in this manner, and will not be described in detail below.
Moreover, as known to those skilled in the art, generally, control valves (such as electric control valves, specifically electromagnetic valves) may be disposed on the negative pressure pipeline N0, the first negative pressure pipeline N1, the second negative pressure pipeline N2, the third negative pressure pipeline N3, the third negative pressure pipeline N4, the positive pressure pipeline P0 of the positive pressure negative pressure pipeline, and the first positive pressure pipeline P1 of the positive pressure negative pressure pipeline to control the on/off of the pipelines, and/or flow valves/flow meters to control the magnitude of the positive pressure/negative pressure, etc., which are not described herein again.
As known to those skilled in the art, the hollow cylinder and the piston in the hollow cylinder are necessary components of the syringe. The piston can be in a long strip structure, and the piston and the hollow cylinder can move relatively by pushing the part of the piston outside the hollow cylinder; the piston can also be only a rubber head which has a sealing effect and is positioned in the hollow cylinder, and at the moment, the piston can be provided with a core rod, and the piston and the hollow cylinder can be driven to move relatively by pushing the core rod. As shown in FIG. 1, the structure of the syringe is shown to consist of an empty barrel, a plunger and a core rod.
Pre-processing module enrichment 18 The specific process of F ion can be as shown in fig. 6 (a) -6 (c),
initially, the first to sixth valves 1 to 6 are in a state shown in fig. 6 (a), and at this time, the first negative pressure line N1 is evacuated. The second syringe 26 will contain 18 Oxygen [ alpha ] of F ion 18 O]Eighteen Water is pushed out and contained 18 Oxygen [ alpha ] of F ion 18 O]Eighteen water flows through 18 When the F ion-enriching bin 25 is in use, 18 f ion is in 18 The F ion enrichment bin 25 is used for enrichment, and the rest liquid flows into the first recovery container 22;
thereafter, as shown in FIG. 6 (b), the second to third valves 2 to 3 are in the state that the first syringe 24 is drawn into the first reagent container 23 18 F, leacheate;
finally, the third to sixth valves 3 to 6 are in the state shown in FIG. 6 (c), and the first syringe 24 is set to the state shown in FIG. 6 18 F when the leacheate is pushed out, then 18 F leacheate will be enriched in 18 In the F ion enrichment bin 18 F ions are sent to the reaction module.
This embodiment provides a specific preprocessing module, which can be easily and conveniently implemented 18 F ions are enriched and the enriched F ions are 18 The F ions are leached and sent to a subsequent reaction module. Especially when the valves, the positive pressure pipeline, the negative pressure pipeline and the injector are automatically controlled, the automatic control can be realized 18 F, enriching and leaching the ions, and sending the ions into a reaction module for automatic treatment.
In one embodiment, the pre-processing module further comprises:
a first linear drive (not shown in the drawings) capable of moving the piston of the first syringe 24 inside the hollow cylinder;
a second linear drive (not shown in the drawings) capable of moving the piston of the second syringe 26 inside the hollow cylinder;
preferably, the first linear driving device and the second linear driving device are selected from one of a pneumatic rod, a hydraulic rod and a lead screw;
further preferably, the first linear driving device and the second linear driving device are both lead screws, and the lead screws are driven by stepping motors.
In the present embodiment, the first and second linear driving devices are provided to control the first and second syringes 24 and 26.
When the pneumatic rod and the hydraulic rod are used for matching with controllers such as a PLC and the like, the automatic control of the first injector 24 and the second injector 26 is conveniently realized.
The lead screw can be used for accurately controlling the strokes of the pistons in the first injector 24 and the second injector 26, and particularly when the lead screw is driven by a stepping motor, the lead screw is conveniently matched with a microprocessor control system (PLC and the like) to realize automatic and accurate control of the first injector 24 and the second injector 26. The lead screw driven by the stepping motor can be assembled by the user, and an electric push rod (a lead screw system) finished product can be directly purchased.
In one embodiment, as shown in fig. 1, the pretreatment module further comprises a positive pressure and negative pressure pipeline 27 and a liquid feeding pipeline 28, wherein the positive pressure and negative pressure pipeline 27 and the liquid feeding pipeline 28 respectively penetrate through the piston of the second syringe 26 and extend into the closed space formed by the piston of the second syringe 26 and the empty cylinder;
preferably, the liquid feeding line 28 is provided with a flow meter so as to control the amount of liquid to be fed, and/or the liquid feeding line 28 is provided with a control valve (e.g. an electrically controlled valve, specifically an electromagnetic valve) which can control the on/off of the line so as to control whether to feed liquid or not.
In the present application, the positive pressure and negative pressure pipeline 27 is a positive pressure pipeline P0 of the positive pressure and negative pressure pipeline, and the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline is connected to one pipeline, and the one pipeline penetrates through the piston (as shown in fig. 1); or the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline and the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline respectively penetrate through the piston.
The present application thus provides a means for filling second syringe 26 with fluid (including 18 Oxygen [ alpha ] of F ion 18 O]Eighteen water), and in particular, the liquid is added through the liquid adding pipeline 28, and meanwhile, in order to prevent the pressure in the second syringe 26 from being too high, the vacuum is pumped through the negative pressure pipeline N0 of the positive pressure and negative pressure pipeline, so that the liquid adding is realized. After filling, the liquid in the second syringe 26 may be discharged for subsequent processing by pushing the piston down/pushing out inert gas (pressurized) through the positive pressure line P0 of the positive pressure negative pressure line.
This example shows a solution for filling the second syringe 26. Thereby providing more contents 18 Oxygen [ alpha ] of F ion 18 O]Eighteen water to 18 F ion enrichment provides more and continuous subsequent reactions 18 And F ions. And positive pressure can be provided through the positive pressure pipeline P0 of the positive pressure and negative pressure pipeline to charge the subsequent process, or the piston is pushed to more accurately charge the subsequent process.
In one embodiment, as shown in fig. 1, the reaction module comprises:
the valve assembly comprises a seventh valve 7, an eighth valve 8, a ninth valve 9, a tenth valve 10, an eleventh valve 11 and a twelfth valve 12, wherein the seventh valve 7 to the twelfth valve 12 respectively comprise at least a first interface, a second interface and a third interface, and the seventh valve 7 to the tenth valve 12 can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first port of the seventh valve 7 is connected to the pre-treatment module (the second port of the sixth valve 6), the second port of the seventh valve 7 is connected to the first port of the eighth valve 8, the second port of the eighth valve 8 is connected to the first port of the ninth valve 9, the second port of the ninth valve 9 is connected to the first port of the tenth valve 10, the second port of the tenth valve 10 is connected to the first port of the eleventh valve 11, the second port of the eleventh valve 11 is connected to the first port of the twelfth valve 12, and the third port of the twelfth valve 12 is connected to the purification module (the fourth port of the tenth valve 13);
the reaction vessel 29 is connected to the second negative pressure pipeline N2 and the third port of the seventh valve 7, respectively, wherein preferably, control valves (such as electric control valves, specifically, electromagnetic valves) are disposed on the pipelines between the second negative pressure pipeline N2, the reaction vessel 29 and the third port of the seventh valve 7, and the control valves can control the on-off of the pipelines, so as to ensure that the reaction is performed in the reaction vessel 29;
a temperature control component (not shown in the drawings) for heating and/or cooling the reaction vessel 29, wherein the heating may be performed by an electric heating manner, and the cooling may be performed by an air cooling manner, which may specifically refer to the prior art and is not described herein again;
a third syringe 30 connected to the third port of the eighth valve 8, wherein the third syringe 30 contains a compound i precursor;
a second reagent container 31 connected to the third port of the ninth valve 9, wherein the second reagent container 31 contains an acetonitrile solution;
a fourth syringe 32 connected to the third port of the tenth valve 10;
and a third reagent container 33 connected to the third port of the eleventh valve 11, wherein the third reagent container 33 contains a sodium chloride solution.
Preferably, the seventh valve 7, the eighth valve 8, the ninth valve 9, the tenth valve 10, the eleventh valve 11 and the twelfth valve 12 are all electrically controlled valves (such as electromagnetic valves).
The structures of the seventh valve 7 to the twelfth valve 12, the third syringe 30, the fourth syringe 32, and the like in this embodiment have been described above, and will not be described herein again.
The specific process of the reaction module for carrying out the reaction is shown in FIGS. 7 (a) to 7 (g),
initially, the seventh valve 7 is in the condition shown in FIG. 7 (a), at which point it is being enriched by the pre-processing module 18 The F ions and the like enter the reaction vessel 29 (reaction flask) through the seventh valve 7.
Thereafter, the first valve 1 toThe seventh valve 7 is in a state shown in fig. 7 (b), in which the first positive pressure line P1 outputs a positive pressure (inert gas input) to the reaction vessel 29, the second negative pressure line N2 is evacuated, the temperature control unit heats the reaction vessel 29 to remove the solvent, the heating temperature is 80 to 130 ℃, and the activated reaction vessel can be obtained 18 And F ions.
Thereafter, the eighth valve 8 to the ninth valve 9 are in the state shown in fig. 7 (c), and the third syringe 30 draws the acetonitrile solution in the second reagent container 31 to form the acetonitrile solution as the precursor of compound i in the third syringe 30;
then, the seventh to eighth valves 7 to 8 are in the state shown in fig. 7 (d), and the third syringe 30 pushes the acetonitrile solution as the precursor of compound i (0.2 to 5ml of the acetonitrile solution containing 0.8 to 20mg of the precursor of compound i) into the reaction vessel 29; heating the temperature control component to 90-140 ℃ under a closed condition, reacting for 5-60 min, and reacting the precursor of the compound I with the precursor K 18 F/K 222 Nucleophilic substitution reaction is carried out to generate a compound I;
then, as shown in fig. 7 (e), the tenth valve 10 to the eleventh valve 11 are in the state, and the fourth syringe 32 extracts the sodium chloride solution contained in the third reagent container 33;
then, the seventh valve 7 to the tenth valve 10 are in the state shown in fig. 7 (f), and the fourth syringe 32 pushes the extracted sodium chloride solution into the reaction vessel 29 to form a crude compound i solution; thereafter, the fourth syringe 32 withdraws the crude compound i solution from the reaction vessel 29;
finally, the tenth valve 10-the tenth valve 12 are in the condition shown in FIG. 7 (g), and the fourth syringe 32 pushes the crude compound I solution into the purification module.
In this embodiment, a specific reaction module is provided, and the combination of the first positive pressure line P1, the second negative pressure line N2, the reaction vessel 29 and the temperature control module is achieved by simple equipment 18 F/K 222 Nucleophilic substitution reaction is carried out to generate a crude product of the compound I. Especially when valves, positive pressure pipelines, negative pressure pipelines, injectorsWhen the reaction is automatically controlled, the automation of the two-step reaction can be realized.
In one embodiment, the reaction module further comprises:
a third linear drive (not shown in the drawings) capable of moving the piston of the third syringe 30 inside the hollow cylinder;
a fourth linear driving device, which can drive the piston of the fourth syringe 32 to move in the hollow cylinder.
Preferably, the third linear driving device and the fourth linear driving device are selected from one of a pneumatic rod, a hydraulic rod and a lead screw;
further preferably, the third linear driving device and the fourth linear driving device are lead screws, and the lead screws are driven by stepping motors.
In the present embodiment, the third and fourth linear driving devices are provided to control the third and fourth injectors 30 and 32, respectively.
When the pneumatic rod and the hydraulic rod are used together with controllers such as a PLC and the like, the third injector 30 and the fourth injector 32 can be automatically controlled conveniently.
The lead screw is used, so that the strokes of the pistons in the third injector 30 and the fourth injector 32 can be accurately controlled, and particularly, when the lead screw is driven by a stepping motor, the lead screw is conveniently matched with a microprocessor control system (PLC and the like) to realize automatic and accurate control of the third injector 30 and the fourth injector 32. The lead screw driven by the stepping motor can be assembled by the user, and an electric push rod (a lead screw system) finished product can be directly purchased.
In one embodiment, as shown in fig. 2, the purification module comprises:
the thirteenth valve 13 and the fourteenth valve 14 at least include a first port, a second port, a third port, a fourth port, a fifth port, and a sixth port (corresponding to ((r) - (g) in fig. 5), respectively), and both the thirteenth valve 13 and the fourteenth valve 14 can be switched between a first mode and a second mode, where the first mode is that the first port and the second port are communicated, the third port and the fourth port are communicated, and the fifth port and the sixth port are communicated; the second mode is that the second interface is communicated with the third interface, the fourth interface is communicated with the fifth interface, and the sixth interface is communicated with the first interface; wherein the fourth port of the tenth valve 13 is connected to the reaction module (the third port of the twelfth valve 12) (the pipeline a is communicated with the pipeline a'); the second port of the thirteenth valve 13 is connected to the first port of the fourteenth valve 14; the second port of the fourteenth valve 14 is connected with the third port of the fourteenth valve 14 through an external pipeline;
a chromatography column assembly 34, said chromatography column assembly 34 being connected between the fifth interface of said fourteenth valve 14 and the sixth interface of said fourteenth valve 14;
a quantitative ring 35 (also called a sample feeding ring), wherein the quantitative ring 35 is connected between the third port of the thirteenth valve 13 and the sixth port of the thirteenth valve 13;
a liquid delivery pump 36 connected to the first port of the thirteenth valve 13, for delivering a fluid (a solution of acetonitrile and water, in a ratio of acetonitrile/water = 0.2/1-2/1);
a second recovery tank 37 connected to the fifth port of the tenth valve 13;
a fifteenth valve 15, where the fifteenth valve 15 at least includes a first port, a second port, and a third port, and the fifteenth valve 15 is capable of enabling the first port to be communicated with the second port or the first port to be communicated with the third port; the first port of the fifteenth valve 15 is connected with the fourth port of the fourteenth valve, the second port of the fifteenth valve 15 is connected with the prescription module (the third port of the sixteenth valve 16), and the third port of the fifteenth valve 15 is connected with the second recovery vessel 37;
preferably, the thirteenth valve 13, the fourteenth valve 14 and the fifteenth valve 15 are all electrically controlled valves.
First, as shown in fig. 5, a six-way valve is provided, which can perform the functions of the thirteenth valve 13 and the fourteenth valve 14.
Specifically, as shown in fig. 5 (a) to 5 (b), the six-way valve includes a six-way valve spool V4 having a circular cross section, and a six-way valve body V3 outside the six-way valve spool V4, and the six-way valve body V3 is provided with a first port (i), a second port (ii), a third port (iii), a fourth port (iv), a fifth port (V), and a sixth port (iv) in the counterclockwise direction. Through the rotary valve plug V4, the first port is communicated with the second port, the third port is communicated with the fourth port, the fifth port is communicated with the sixth port (as shown in fig. 5 (a)), or the second port is communicated with the third port, the fourth port is communicated with the fifth port, and the sixth port is communicated with the first port (as shown in fig. 5 (b)). In addition, given the above six-way valve structure, those skilled in the art know how to control the six-way valve spool V4 to rotate relative to the six-way valve body V3 by a fixed angle to achieve electric (electromagnetic) control of the six-way valve (e.g., set the stepper motor control spool V4 to rotate).
In addition, as shown in fig. 2 (a) and 2 (b), the fifteenth valve 15 is a three-way valve which can realize the communication between the first port (i) and the second port (ii) or between the first port (i) and the third port (iii), which is a prior art, and a corresponding electrically-operated valve (e.g., an electromagnetic valve) can be directly purchased in the market.
Chromatography columns are prior art and will not be described in detail herein. The column assembly 34 of the present application is an existing column or a combination of columns (e.g., multiple columns in series and/or parallel).
The specific process of purification by the purification module can be as shown in fig. 2 (a) and 2 (b).
At the beginning, the states of the thirteenth valve 13 and the fourteenth valve 14 are shown in fig. 2 (a), at this time, the solution dissolving the crude compound i flowing from the reaction module enters the quantitative loop 35 through the fourth port of the thirteenth valve 13 and the third port, and a small amount of redundant solution flows into the second recovery container 37 through the sixth port of the twelfth valve 13 and the fifth port, and at this time, the solution dissolving the crude compound i remains in the quantitative loop 35.
Thereafter, the thirteenth valve 13 and the fourteenth valve 14 are in the state shown in fig. 2 (b), and the fifteenth valve 15 opens the first port and the third port, and at this time, the liquid feed pump 36 starts to operate. The liquid transfer pump 36 pushes out the fluid (acetonitrile and water), and the fluid flows through the first port and the sixth port of the thirteenth valve 13, and then carries out purification by taking out the solution of the crude dissolved compound I in the quantitative ring 35 through the third port, the second port, the fourteenth valve 14, the first port, the sixth port, the chromatographic column assembly 34, the fourteenth valve 14, the fifth port and the fourth port of the thirteenth valve 13. Finally, the fifteenth valve 15 connects the first port (first) and the second port (second), and the purified solution of compound i product is introduced into the prescribing module by the fluid from the liquid transfer pump 36.
In addition, when the inlet ends of the liquid delivery pumps 36 are respectively connected to two or more pipelines, particularly when the fluids (acetonitrile and water) for purification and the fluid for rinsing (e.g., water) are respectively connected through the pipelines, the purification module is configured as shown in fig. 2 (b) when the apparatus is used (the liquid composition is produced), and the fluid for rinsing is pushed out by the liquid delivery pumps 36, so that the purification module and other modules connected to the purification module can be rinsed.
In this embodiment, a specific purification module is provided, and the thirteenth valve 13, the fourteenth valve 14, and the fifteenth valve 15 are changed in different working states and cooperate with the liquid transfer pump 36 to purify the crude compound i to obtain a pure compound i. The above-described automation of purification can be achieved especially when the valves, the liquid transfer pump 36, are automatically controlled.
In one embodiment, the prescribing module includes:
the valve assembly comprises a sixteenth valve 16, a seventeenth valve 17, an eighteenth valve 18, a nineteenth valve 19, a twentieth valve 20 and a twenty-first valve 21, wherein the sixteenth valve 16 to the twenty-first valve 21 respectively at least comprise a first interface, a second interface and a third interface, and the sixteenth valve 16 to the twenty-first valve 21 can realize that any two interfaces in the three interfaces are conducted or the three interfaces are not conducted; wherein the first port of the sixteenth valve 16 is connected to the second port of the tenth valve 12, the second port of the sixteenth valve 16 is connected to the first port of the seventeenth valve 17, the second port of the seventeenth valve 17 is connected to the first port of the eighteenth valve 18, the second port of the eighteenth valve 18 is connected to the first port of the nineteenth valve 19, the second port of the nineteenth valve 19 is connected to the first port of the twentieth valve 20, the second port of the twentieth valve 20 is connected to the first port of the twenty-first valve 21, the third port of the sixteenth valve 16 is connected to the purification module (the second port of the fifteenth valve 15) (the line B is communicated to the line B'), and the second port of the twenty-first valve 21 is connected to the third negative pressure line N3;
a fourth reagent container 38 connected to the third port of the seventeenth valve 17, wherein the fourth reagent container 38 is configured to contain absolute ethanol;
a compound i enrichment bin 39 connected between the third port of the eighteenth valve 18 and the third port of the nineteenth valve 19, wherein the compound i enrichment bin 39 is filled with octadecyl bonded silica gel;
a first transfer vessel 40 connected to the third port of the twentieth valve 20;
a finished product collection container 42 connected to the second relay container 41;
and a second transfer container 41 connected to the third port of the twenty-first valve 21, the finished product collecting container 42, and a fourth negative pressure line N4, wherein the second transfer container 41 contains polyethylene glycol 400 and a sodium chloride solution (such as sodium chloride injection) for prescription.
The structures of the sixteenth valve 16 to the twenty-first valve 21 and the like in this embodiment have been described above and will not be described herein.
The specific process of enriching and prescribing by the prescribing module is shown in FIGS. 8 (a) -8 (g),
initially, the sixteenth valve 16 to the twentieth valve 20 are in the state shown in fig. 8 (a), and at this time, the purified product of compound i flowing out of the purification module enters the first transit container 40 (transit bottle);
thereafter, the tenth valve 10 and the eleventh valve 11 are in the state shown in fig. 8 (b), and the fourth syringe 32 draws the sodium chloride solution in the third reagent container 33;
thereafter, the tenth to twelfth valves 10 to 12 and the sixteenth to twentieth valves 16 to 20 are in the states shown in fig. 8 (c), and the fourth syringe 32 pushes the extracted sodium chloride solution into the first intermediate container 40; after the pure compound I in the first transfer container 40 is diluted, the diluted compound I solution is pumped into the fourth syringe 32;
then, the tenth valve 10 to the twelfth valve 12 and the sixteenth valve 16 to the twenty-first valve 21 are in the states shown in fig. 8 (d), the fourth syringe 32 pushes out the extracted compound i solution through the compound i enrichment bin 39 and the third negative pressure line N3, and the compound i is enriched in the compound i enrichment bin 39;
then, the tenth valve 10 and the eleventh valve 11 are in the state shown in fig. 8 (b), and the fourth syringe 32 draws the sodium chloride solution in the third reagent container 33;
thereafter, the tenth valve 10 to the twenty-first valve 21 are in the states shown in fig. 8 (d), and the fourth syringe pushes out the drawn sodium chloride solution through the compound i enrichment bin 39 and the third negative pressure line N3, thereby further enriching the compound i;
thereafter, the tenth valve 10 to the twelfth valve 12 and the sixteenth valve 16 to the seventeenth valve 17 are in the states shown in fig. 8 (e), and the fourth syringe 32 draws the absolute ethanol in the fourth reagent container 38;
then, the tenth valve 10 to the twelfth valve 12 and the sixteenth valve 16 to the twenty-first valve 21 are in the states shown in fig. 8 (f), and the fourth injector 32 pushes the extracted absolute ethanol into the second transfer container 41 through the compound i enrichment bin 39, so that the pure compound i in the compound i enrichment bin 39 is rinsed into the second transfer container 41, thereby achieving the prescription. Meanwhile, the fourth negative pressure pipeline N4 is vacuumized to counteract the increased pressure in the second transfer container 41 caused by the absolute ethyl alcohol and the pure compound i;
finally, as shown in fig. 8 (g), the first to tenth valves 1 to 12 and the sixteenth to twenty-first valves 16 to 21 are in the state, and positive pressure is applied to the first positive pressure line P1, and the formulated compound i solution is pushed into the finished product collection container 42, so that the compound i liquid composition (injection) is collected.
Preferably, a filter (e.g. a needle filter) is disposed between the second transfer container 41 and the finished product collection container 42, so that the compound i solution flowing out of the second transfer container 41 is filter sterilized to obtain a final liquid composition (e.g. an injection) of compound i.
This embodiment shows a specific prescribing module, which realizes the enrichment and prescribing of the purified compound i by controlling the sixteenth valve 16 to the twenty-first valve 21, and cooperating with the purification module and the reaction module, and further collecting the liquid composition of the compound i. Particularly, when the sixteenth valve 16 to the twenty-first valve 21 and the like are automatically controlled, the above-described automation of prescription and collection can be achieved.
In addition, in the above technical solution, a detection/monitoring device is provided to detect the operation of the device. In particular, can be in pairs 18 Radioactivity detectors are disposed at one or more positions in the piping between the F ion enrichment bin 25, the fourth injector 32, the fourteenth valve 14, and the fifteenth valve 15 to detect radioactivity. An ultraviolet detector and a radioactivity detector may be provided on the chromatography column assembly 34 to determine whether control begins collection of the purified mobile phase.
This example provides a method of producing a liquid composition of compound i using the apparatus described above, comprising:
enrichment using a pre-processing module 18 F ions;
using reaction modules for enrichment 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
purifying the crude product of the compound I by using a purification module to obtain a pure product of the compound I;
the purified compound i purified product was enriched and formulated into compound i liquid composition using a formulation module.
More specific operation steps have been described above and will not be described further.
While embodiments of the present application have been described above, the present application is not limited to the specific embodiments and applications described above, which are intended to be illustrative, instructive, and not limiting. Those skilled in the art, having the benefit of this disclosure, may effect numerous modifications thereto and changes may be made without departing from the scope of the invention as defined by the appended claims.
Claims (7)
1. An apparatus for producing a liquid composition of compound i, comprising:
a pre-processing module for enriching 18 F ions;
a reaction module for enriching the concentrated solution 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
the purification module is used for purifying the crude product of the compound I to obtain a pure product of the compound I;
a prescription module, which enriches and prescriptively prepares a purified product of the compound I into a compound I liquid composition;
a compound I;
the preprocessing module comprises:
the first valve to the sixth valve respectively comprise at least a first interface, a second interface and a third interface, and the first valve to the sixth valve can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first interface of the first valve is connected with the first positive pressure pipeline, the second interface of the first valve is connected with the first interface of the second valve, the second interface of the second valve is connected with the first interface of the third valve, the second interface of the third valve is connected with the first interface of the fourth valve, the second interface of the fourth valve is connected with the first interface of the fifth valve, and the second interface of the fifth valve is connected with the first interface of the sixth valve;
the first recovery container is respectively connected with the first negative pressure pipeline and the third interface of the first valve;
a first reagent container connected to the third port of the second valve;
a first injector connected to a third port of the third valve;
18 an F ion enrichment bin connected between the third port of the fourth valve and the third port of the fifth valve;
the second injector is connected with the third interface of the sixth valve;
the pretreatment module further comprises a positive pressure negative pressure pipeline and a liquid adding pipeline, and the positive pressure negative pressure pipeline and the liquid adding pipeline respectively penetrate through the piston of the second injector and extend into the second injector; a core rod for driving the piston and the hollow cylinder to move relatively is arranged in the piston of the second injector;
the reaction module includes:
the system comprises a seventh valve, an eighth valve, a ninth valve, a tenth valve, an eleventh valve and a tenth valve, wherein the seventh valve to the twelfth valve respectively at least comprise a first interface, a second interface and a third interface, and the seventh valve to the twelfth valve can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first interface of the seventh valve is connected with the pretreatment module, the second interface of the seventh valve is connected with the first interface of the eighth valve, the second interface of the eighth valve is connected with the first interface of the ninth valve, the second interface of the ninth valve is connected with the first interface of the tenth valve, the second interface of the tenth valve is connected with the first interface of the eleventh valve, the second interface of the eleventh valve is connected with the first interface of the tenth valve, and the third interface of the tenth valve is connected with the purification module;
the reaction container is respectively connected with a second negative pressure pipeline and a third interface of the seventh valve; a pipeline which is connected with the reaction vessel and a third interface of the seventh valve extends into the bottom of the reaction vessel; control valves for controlling the on-off of the pipelines are arranged on the second negative pressure pipeline, the pipelines between the reaction container and the third interface of the seventh valve;
the temperature control assembly is used for heating and/or cooling the reaction container;
a third syringe connected to the third port of the eighth valve;
a second reagent container connected to the third port of the ninth valve;
a fourth syringe connected to the third port of the tenth valve;
a third reagent container coupled to the third port of the eleventh valve.
2. The apparatus of claim 1,
the preprocessing module further comprises:
the first linear driving device can drive the piston of the first syringe to move in the hollow cylinder;
and the second linear driving device can drive the piston of the second syringe to move in the hollow cylinder.
3. The apparatus of claim 1,
the reaction module further comprises:
the third linear driving device can drive the piston of the third injector to move in the hollow cylinder;
and the fourth linear driving device can drive the piston of the fourth syringe to move in the hollow cylinder.
4. The apparatus of claim 1,
the purification module comprises:
the third valve and the fourteenth valve can be switched between a first mode and a second mode, the first mode is that the first interface is communicated with the second interface, the third interface is communicated with the fourth interface, and the fifth interface is communicated with the sixth interface; the second mode is that the second interface is communicated with the third interface, the fourth interface is communicated with the fifth interface, and the sixth interface is communicated with the first interface; wherein the fourth port of the thirteenth valve is connected to the reaction module; the second port of the thirteenth valve is connected with the first port of the fourteenth valve; the second port of the fourteenth valve is connected with the third port of the fourteenth valve through an external pipeline;
a chromatography column assembly connected between the fifth port of the fourteenth valve and the sixth port of the fourteenth valve;
a metering ring connected between the third port of the thirteenth valve and the sixth port of the thirteenth valve;
a liquid delivery pump connected to the first port of the thirteenth valve;
a second recovery tank connected to a fifth port of the thirteenth valve;
the fifteenth valve at least comprises a first interface, a second interface and a third interface, and the fifteenth valve can realize the conduction of the first interface and the second interface or the conduction of the first interface and the third interface; the first port of the fifteenth valve is connected with the fourth port of the fourteenth valve, the second port of the fifteenth valve is connected with the prescription module, and the third port of the fifteenth valve is connected with the second recovery container.
5. The apparatus of claim 4,
the prescribing module includes:
the valve assembly comprises a sixteenth valve, a seventeenth valve, an eighteenth valve, a nineteenth valve, a twentieth valve and a twenty-first valve, wherein the sixteenth valve to the twenty-first valve respectively at least comprise a first interface, a second interface and a third interface, and the sixteenth valve to the twenty-first valve can realize the conduction of any two interfaces in the three interfaces or make the three interfaces non-conductive; the first port of the sixteenth valve is connected with the second port of the tenth valve, the second port of the sixteenth valve is connected with the first port of the seventeenth valve, the second port of the seventeenth valve is connected with the first port of the eighteenth valve, the second port of the eighteenth valve is connected with the first port of the nineteenth valve, the second port of the nineteenth valve is connected with the first port of the twentieth valve, the second port of the twentieth valve is connected with the first port of the twenty-first valve, the third port of the sixteenth valve is connected with the purification module, and the second port of the twenty-first valve is connected with a third negative pressure pipeline;
a fourth reagent container connected to the third port of the seventeenth valve;
a compound i enrichment bin connected between the third port of the eighteenth valve and the third port of the nineteenth valve;
the first transfer container is connected with the third interface of the twentieth valve;
a finished product collection container;
and the second transfer container is respectively connected with the third interface of the twenty-first valve, the finished product collecting container and a fourth negative pressure pipeline.
6. A process for producing a liquid composition of compound I, using the apparatus of any one of claims 1 to 5, comprising:
enrichment using a pre-processing module 18 F ions;
using reaction modules for enrichment 18 Reacting the F ions with a precursor of the compound I to obtain a crude product of the compound I;
purifying the crude product of the compound I by using a purification module to obtain a pure product of the compound I;
the purified compound i pure product was enriched and formulated into compound i liquid compositions using a formulation module.
7. Use of the apparatus of any one of claims 1 to 5 in the production of a liquid composition of compound i.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210647010.9A CN114716415B (en) | 2022-06-09 | 2022-06-09 | Apparatus for producing liquid composition, method for producing the same and use thereof |
| PCT/CN2023/099327 WO2023237091A1 (en) | 2022-06-09 | 2023-06-09 | Device for producing liquid composition, preparation method thereof and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210647010.9A CN114716415B (en) | 2022-06-09 | 2022-06-09 | Apparatus for producing liquid composition, method for producing the same and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114716415A CN114716415A (en) | 2022-07-08 |
| CN114716415B true CN114716415B (en) | 2022-09-02 |
Family
ID=82233071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210647010.9A Active CN114716415B (en) | 2022-06-09 | 2022-06-09 | Apparatus for producing liquid composition, method for producing the same and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114716415B (en) |
| WO (1) | WO2023237091A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116351339A (en) * | 2022-06-07 | 2023-06-30 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition, preparation method and application thereof |
| CN114716415B (en) * | 2022-06-09 | 2022-09-02 | 北京先通国际医药科技股份有限公司 | Apparatus for producing liquid composition, method for producing the same and use thereof |
| CN114732918B (en) * | 2022-06-10 | 2022-09-13 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition and preparation method and application thereof |
| CN115785075A (en) * | 2023-02-06 | 2023-03-14 | 北京先通国际医药科技股份有限公司 | Drug crystallization method, drug crystal and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102438660A (en) * | 2009-03-23 | 2012-05-02 | 美国西门子医疗解决公司 | Imaging agents for detecting neurological disorders |
| CN102608342A (en) * | 2012-02-29 | 2012-07-25 | 北京工业大学 | Sampling device for enzyme injection type glucose biosensor online analyzer |
| CN102858752A (en) * | 2010-02-08 | 2013-01-02 | 兰休斯医疗成像公司 | Methods and apparatus for synthesizing imaging agents, and intermediates thereof |
| CN104220401A (en) * | 2011-12-20 | 2014-12-17 | 通用电气健康护理有限公司 | Radiofluorination method |
| CN104718193A (en) * | 2012-08-10 | 2015-06-17 | 蓝瑟斯医学影像公司 | Compositions, methods, and systems for the synthesis and use of imaging agents |
| CN112807276A (en) * | 2021-01-26 | 2021-05-18 | 北京先通国际医药科技股份有限公司 | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110003981A1 (en) * | 2006-09-06 | 2011-01-06 | Nihon Medi-Physics Co., Ltd. | Process for producing radioactive fluorine labeled organic compound, and relevant synthetic apparatus and program |
| WO2013049608A2 (en) * | 2011-09-30 | 2013-04-04 | Ge Healthcare Limited | Synthesizer diagnostic cassette simulator |
| CN104230613B (en) * | 2014-09-30 | 2016-07-06 | 北京善为正子医药技术有限公司 | Small modules formula multifunction automatic11C flag PET pharmaceutical synthesis instrument |
| CN107970458A (en) * | 2018-01-03 | 2018-05-01 | 山东省肿瘤防治研究院（山东省肿瘤医院） | A kind of positron emitting tracer Fully automated synthesis module based on 18F-BF3 marks |
| CN108218651B (en) * | 2018-02-27 | 2023-11-03 | 首都医科大学宣武医院 | Disposable auxiliary device and method for preparing radiopharmaceuticals |
| CN110862343A (en) * | 2019-10-29 | 2020-03-06 | 北京宾派生物技术有限公司 | A [ 2 ]18F]Automatic preparation method and device of D3FSP |
| CN116351339A (en) * | 2022-06-07 | 2023-06-30 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition, preparation method and application thereof |
| CN114713157A (en) * | 2022-06-09 | 2022-07-08 | 北京先通国际医药科技股份有限公司 | Apparatus for producing liquid composition, method for producing the same and use thereof |
| CN114716415B (en) * | 2022-06-09 | 2022-09-02 | 北京先通国际医药科技股份有限公司 | Apparatus for producing liquid composition, method for producing the same and use thereof |
| CN114732918B (en) * | 2022-06-10 | 2022-09-13 | 北京先通国际医药科技股份有限公司 | Production equipment of liquid composition and preparation method and application thereof |
| CN115651009A (en) * | 2022-11-14 | 2023-01-31 | 中山大学附属第一医院 | A [ 2 ] 18 F]Automatic synthesis method of F-LuFL |
| CN115784250A (en) * | 2022-11-14 | 2023-03-14 | 中山大学附属第一医院 | A kind of 18 Preparation method of F-TFB |
-
2022
- 2022-06-09 CN CN202210647010.9A patent/CN114716415B/en active Active
-
2023
- 2023-06-09 WO PCT/CN2023/099327 patent/WO2023237091A1/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102438660A (en) * | 2009-03-23 | 2012-05-02 | 美国西门子医疗解决公司 | Imaging agents for detecting neurological disorders |
| CN102858752A (en) * | 2010-02-08 | 2013-01-02 | 兰休斯医疗成像公司 | Methods and apparatus for synthesizing imaging agents, and intermediates thereof |
| CN104220401A (en) * | 2011-12-20 | 2014-12-17 | 通用电气健康护理有限公司 | Radiofluorination method |
| CN102608342A (en) * | 2012-02-29 | 2012-07-25 | 北京工业大学 | Sampling device for enzyme injection type glucose biosensor online analyzer |
| CN104718193A (en) * | 2012-08-10 | 2015-06-17 | 蓝瑟斯医学影像公司 | Compositions, methods, and systems for the synthesis and use of imaging agents |
| CN112807276A (en) * | 2021-01-26 | 2021-05-18 | 北京先通国际医药科技股份有限公司 | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114716415A (en) | 2022-07-08 |
| WO2023237091A1 (en) | 2023-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114716415B (en) | Apparatus for producing liquid composition, method for producing the same and use thereof | |
| CN114713157A (en) | Apparatus for producing liquid composition, method for producing the same and use thereof | |
| CN114700006B (en) | Production equipment of liquid composition and preparation method and application thereof | |
| CN114732918B (en) | Production equipment of liquid composition and preparation method and application thereof | |
| US11037690B2 (en) | Method and apparatus for the production of lead 212 for medical use | |
| US6567492B2 (en) | Process and apparatus for production of F-18 fluoride | |
| Schultz et al. | A new automated NaCl based robust method for routine production of gallium-68 labeled peptides | |
| Haynes et al. | Performance of a 62Zn/62Cu generator in clinical trials of PET perfusion agent 62Cu-PTSM | |
| CN113353306B (en) | Technetium [ alpha ], [ alpha ]99mTc]Automatic leaching, synthesizing and subpackaging method for marked medicines | |
| TWI397421B (en) | Gallium-68 radioisotope generator and generating method thereof | |
| Petrik et al. | Radiolabelling of peptides for PET, SPECT and therapeutic applications using a fully automated disposable cassette system | |
| CN103263849B (en) | The fast separating process of activation products gallium in a kind of fission product | |
| CN108409595A (en) | 18The automated production equipment and production method of the fluoro- L-Glutamines of F- (2S, 4R) -4- | |
| CN208604046U (en) | 18The automated production equipment of the fluoro- L-Glutamine of F- (2S, 4R) -4- | |
| Berridge et al. | Preparation of oxygen-15 butanol for positron tomography | |
| CN103301652B (en) | Separation device for gallium-containing radioactive solution | |
| CN105152960B (en) | Automatic preparation method and device for ＜18＞F-(2S,4R)-4-fluoro-L-glutamine | |
| CN102793967A (en) | Intravenous injection method of radiopharmaceutical | |
| CN117062296B (en) | Semi-automatic 18F sodium fluoride preparation device | |
| CN217450185U (en) | Multifunctional full-automatic synthesis device for radiopharmaceuticals | |
| CN207445295U (en) | A kind of radiopharmaceutical automatic subpackaging injection instrument | |
| CN2905751Y (en) | Automatic split-packing instrument for radioactive nuclide liquor | |
| CN217594625U (en) | Ferrule type device for automatically synthesizing aluminum fluoride labeled radioactive drug | |
| CN2484953Y (en) | Medical radiative nucleary generator with concentrator | |
| CN117594277A (en) | Enrichment from reactor irradiation 46 Extracting Ca target material 47 Sc device and method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |