CN117003689A - Crystal form of iodophosphate and preparation method thereof - Google Patents
Crystal form of iodophosphate and preparation method thereof Download PDFInfo
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- CN117003689A CN117003689A CN202311274916.1A CN202311274916A CN117003689A CN 117003689 A CN117003689 A CN 117003689A CN 202311274916 A CN202311274916 A CN 202311274916A CN 117003689 A CN117003689 A CN 117003689A
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- 239000013078 crystal Substances 0.000 title claims abstract description 47
- UWCWSEMVQFWUHB-UHFFFAOYSA-N iodophosphonic acid Chemical compound OP(O)(I)=O UWCWSEMVQFWUHB-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 24
- 239000012043 crude product Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 229960003456 pralidoxime chloride Drugs 0.000 claims description 9
- HIGSLXSBYYMVKI-UHFFFAOYSA-N pralidoxime chloride Chemical compound [Cl-].C[N+]1=CC=CC=C1\C=N\O HIGSLXSBYYMVKI-UHFFFAOYSA-N 0.000 claims description 9
- 229910001505 inorganic iodide Inorganic materials 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- QNBVYCDYFJUNLO-UHDJGPCESA-N [(e)-(1-methylpyridin-2-ylidene)methyl]-oxoazanium;iodide Chemical compound [I-].CN1C=CC=C\C1=C/[NH+]=O QNBVYCDYFJUNLO-UHDJGPCESA-N 0.000 claims description 6
- 229910001867 inorganic solvent Inorganic materials 0.000 claims description 6
- 239000003049 inorganic solvent Substances 0.000 claims description 6
- 229960002095 pralidoxime iodide Drugs 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 230000005855 radiation Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229910017488 Cu K Inorganic materials 0.000 claims description 3
- 229910017541 Cu-K Inorganic materials 0.000 claims description 3
- 230000004580 weight loss Effects 0.000 claims description 3
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 2
- 229940107816 ammonium iodide Drugs 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 2
- 238000002050 diffraction method Methods 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 150000004694 iodide salts Chemical class 0.000 abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 10
- 239000010452 phosphate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 7
- 238000002386 leaching Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- YALFRJYYBXBBOM-UHFFFAOYSA-N 1-methyl-2H-pyridine-2-carbaldehyde hydroiodide Chemical compound I.CN1C=CC=CC1C=O YALFRJYYBXBBOM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000002779 cholinesterase reactivator Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- -1 formaldehyde oxime iodide Chemical compound 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000003986 organophosphate insecticide Substances 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- QNBVYCDYFJUNLO-UHFFFAOYSA-N pralidoxime iodide Chemical compound [I-].C[N+]1=CC=CC=C1\C=N\O QNBVYCDYFJUNLO-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- MBURIAHQXJQKRE-UHFFFAOYSA-M sodium;octane-1-sulfonate;hydrate Chemical compound O.[Na+].CCCCCCCCS([O-])(=O)=O MBURIAHQXJQKRE-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a crystal form of iodophosphate and a preparation method thereof, and relates to the technical field of medicines, wherein the crystal form XRPD pattern has characteristic peaks at diffraction angles of 2 theta of 9.5+/-0.2 degrees, 11.9+/-0.2 degrees, 16.6+/-0.2 degrees, 19.1+/-0.2 degrees, 20.0+/-0.2 degrees, 21.0+/-0.2 degrees, 23.4+/-0.2 degrees, 25.7+/-0.2 degrees, 27.4+/-0.2 degrees, 28.8+/-0.2 degrees, 29.9+/-0.2 degrees, 30.3+/-0.2 degrees, 36.3+/-0.2 degrees, 41.2+/-0.2 degrees, 42.7+/-0.2 degrees, 44.7+/-0.2 degrees, 49.0+/-0.2 degrees, 51.7+/-0.2 degrees and 56.6+/-0.2 degrees. The purity of the crystal form is more than 99.9%, the preparation method does not involve organic solvents or organic iodides, and the iodophosphate with controllable quality and obvious crystal structure characteristics can be stably produced.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a crystal form of iodophosphate and a preparation method thereof.
Background
Iodophosphate (Pralidoxime Iodide), CAS number: 94-63-3, chemical name 1-methyl-2-pyridine formaldehyde oxime iodide, its structural formula is:in 1958, sumitomo in Japan was first marketed as cholinesterase reactivating agent, and is mainly used clinically for rescuing poisoning of various organophosphate insecticides.
The crystal forms can have influence on the solubility, bioavailability, stability and the like of the medicine, and the retrieval of the crystal forms of the iodophosphate is not reported in the literature, and the spectral characteristics of the crystal forms of the iodophosphate are not reported.
The synthetic process route of the iodophosphate is not reported much, and the indian.j.chem.b (2014,431) reports that pyridine-2-formaldehyde is taken as a raw material, methyl iodide is prepared into 2-formyl-1-methylpyridine iodide through methyl iodide, and then the 2-formyl-1-methylpyridine iodide and hydroxylamine hydrochloride undergo oximation reaction to prepare the iodophosphate. US2816113 reports the preparation of iodophosphate by methylation of 2-pyridine formaldoxime in acetone with methyl iodide and recrystallisation with organic solvent methanol to remove highly toxic methyl iodide, the melting point of the precipitated iodophosphate being 224-225 ℃. The processes of the above documents all use high-toxicity and expensive organic iodides, which are unfavorable for the clean production of raw materials and are not suitable for industrial production.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides the crystal form of the iodophosphate and the preparation method thereof, the purity of the prepared iodophosphate crystal form is more than 99.9 percent, the preparation method does not involve organic solvents or organic iodides, and the iodophosphate with controllable quality and obvious crystal structure characteristics can be stably produced.
In order to achieve the object of the invention, the following scheme is adopted:
the iodophosphate prepared by the invention has obvious crystal structure characteristics, and the crystal forms are characterized by X-ray powder diffraction (XRPD) and Differential Scanning Calorimeter (DSC).
When the iodized phosphate crystal form prepared by the invention is subjected to differential scanning calorimetric measurement, an obvious endothermic peak appears when the product is heated to 229.8-232.9 ℃, and the product has a melting point different from that reported in the prior literature.
The crystal form of the iodized phosphate prepared by the invention has the microscopic result of being shown as a crystal, and the crystal form of the crystal form is in a prismatic shape or a long block shape.
The crystal form of the iodized phosphate prepared by the invention uses Cu-K alpha radiation, and has characteristic peaks at diffraction angles of 2 theta of 9.5+/-0.2 degrees, 11.9+/-0.2 degrees, 16.6+/-0.2 degrees, 19.1+/-0.2 degrees, 20.0+/-0.2 degrees, 21.0+/-0.2 degrees, 23.4+/-0.2 degrees, 25.7+/-0.2 degrees, 27.4+/-0.2 degrees, 28.8+/-0.2 degrees, 29.9+/-0.2 degrees, 30.3+/-0.2 degrees, 36.3+/-0.2 degrees, 41.2+/-0.2 degrees, 42.7+/-0.2 degrees, 44.7+/-0.2 degrees, 49.0+/-0.2 degrees, 51.7+/-0.2 degrees and 56.6+/-0.2 degrees.
Further, as shown in table 1, the X-ray powder diffraction pattern of the crystal form expressed by 2 theta angle has characteristic diffraction peaks and relative intensities at the following positions:
table 1 shows the positions and relative intensities of the diffraction peaks
The preparation method of the crystal form of the iodophosphate comprises the following steps:
s1, dissolving the pralidoxime chloride in an inorganic solvent, and replacing the pralidoxime chloride with inorganic iodide to obtain a crude product of the pralidoxime iodide;
s2, dissolving the crude product of the iodophosphate by an inorganic solvent, and recrystallizing to obtain the crystal form of the iodophosphate.
Further, in the step S1, the inorganic iodide is selected from any one of potassium iodide, sodium iodide, and ammonium iodide.
Further, in the step S1, the molar ratio of the inorganic iodide to the pralidoxime chloride is 1.0 to 1.5:1.0.
further, in the step S1 and the step S2, the inorganic solvent is water.
Further, in the step S2, during recrystallization, stirring and crystallization are carried out for 1-2 hours at 0-10 ℃.
The invention has the beneficial effects that:
1. the invention provides the iodic phosphate crystal form which has good granularity, high crystallinity and good stability under various harsh conditions, and is favorable for long-term storage and preparation application of bulk drugs.
2. The high-purity iodophosphate is prepared by using the chlorophosphate as a raw material, replacing the chlorophosphate with inorganic iodide to form salt, and performing simple recrystallization. The replacement salt forming reaction and the refining do not use an organic solvent, and only water is used as a reaction solvent. The iodized salt is an inexpensive and clean inorganic iodized salt. The preparation method of the crystal form is simple, environment-friendly, convenient to operate, low in cost, more suitable for industrial production, stable and controllable in quality, and obvious in crystal structure characteristics.
Drawings
FIG. 1 is an HPLC chart of the form of iodophosphate prepared in example 1.
FIG. 2 is an X-ray powder diffraction pattern of the form of iodophosphate prepared in example 1.
FIG. 3 is a DSC chart of the form of iodophosphate prepared in example 1.
FIG. 4 is a TGA spectrum of the form of the iodophosphate prepared in example 1.
FIG. 5 is a microscopic image I of the form of the iodophosphate prepared in example 1.
FIG. 6 is a second microscopic image of the form of the iodophosphate prepared in example 1.
Fig. 7 is a microscopic image three of the form of the iodophosphate prepared in example 1.
Detailed Description
Test instrument and detection method for experiment:
1. high Performance Liquid Chromatography (HPLC)
Instrument model: shimadzu LC-20AD high performance liquid chromatograph;
chromatographic column: a C18 column; sample injection volume: 20. Mu.L;
mobile phase: phosphate buffer (sodium dihydrogen phosphate dihydrate 3.12g, sodium octane sulfonate monohydrate 2g, triethylamine 1ml, dissolved in water and diluted to 1000ml, pH 3.0 with phosphoric acid) -acetonitrile (90:10); flow rate: 1.0ml/min; detection wavelength: 265nm; column temperature: 25 ℃.
2. X-ray powder diffraction (XRPD)
Instrument model: a sharp (Empyrean) X-ray diffractometer;
scanning range: 3-60 deg..
3. Thermogravimetric analysis (TGA) and Differential Scanning Calorimeter (DSC)
Instrument model: TGA/DSC 2 LF/1100/155 thermogravimetric and simultaneous thermal analyzers;
sweep gas: nitrogen, 50ml/min;
detection range: 40-350 ℃;
rate of temperature rise: 10 ℃/min.
Example 1
S1, preparing a crude product of the iodophosphate:
adding 4.61kg of pralidoxime chloride (purity is 99.6%) into 9.38kg of water, stirring and dissolving, dropwise adding 50% potassium iodide aqueous solution (5.75 kg of potassium iodide plus 5.75kg of water prepared in advance) at the temperature of 20-30 ℃, precipitating a large amount of yellow solid after the dropwise adding, stirring for 2 hours at the temperature of 20-30 ℃, centrifuging and leaching to obtain crude product of the pralidoxime iodide.
S2, preparing an iodic phosphate dissolving crystal form:
32.23kg of water is heated to 70-75 ℃, crude product of the iodophosphate is added, the temperature is maintained to 65-75 ℃ and stirred for 10-30 minutes to dissolve, the filtration is carried out, the filtrate is slowly cooled to 0-10 ℃, the temperature is kept, the stirring and crystallization are carried out for 2 hours, the centrifugation, the leaching and the drying are carried out, 5.83kg of the iodophosphate crystal form (yellow crystalline powder) is obtained, the total yield is 82.7%, the purity is 99.94%, and the HPLC chart is shown in figure 1.
X-ray powder diffraction pattern is shown in figure 2, and Cu-K alpha radiation is used for preparing the iodized crystal form, and characteristic peaks are formed in diffraction angles 2 theta of 9.5+/-0.2 degrees, 11.9+/-0.2 degrees, 16.6+/-0.2 degrees, 19.1+/-0.2 degrees, 20.0+/-0.2 degrees, 21.0+/-0.2 degrees, 23.4+/-0.2 degrees, 25.7+/-0.2 degrees, 27.4+/-0.2 degrees, 28.8+/-0.2 degrees, 29.9+/-0.2 degrees, 30.3+/-0.2 degrees, 36.3+/-0.2 degrees, 41.2+/-0.2 degrees, 42.7+/-0.2 degrees, 44.7+/-0.2 degrees, 49.0+/-0.2 degrees, 51.7+/-0.2 degrees and 56.6+/-0.2 degrees.
The DSC graph is shown in figure 3, and when the obtained crystal form of the iodized phosphate is subjected to differential scanning calorimetric measurement, an obvious endothermic peak appears when the obtained crystal form is heated to 229.8-232.9 ℃, and the obtained crystal form is different from the melting point reported in the prior literature.
The endothermic peak is specifically:
integration: 210.36mJ; normalization: 18.62 Jg-1; starting point: 229.80 ℃; peak: 232.93 ℃.
The crystal form of the iodized phosphate prepared by the invention has a TGA spectrum with weight loss at 232.3-239.7 ℃ as shown in figure 4. The specific conditions of weight loss are:
step (2): 74.3408%; 8.4005mg;
starting point: 232.30 ℃;
end point: 239.74 ℃.
As shown in figures 5-7, the crystal form of the iodized phosphorus prepared by the invention is shown as a microscope result, and the crystal form is in a prismatic shape or a long block shape.
Example 2
S1, preparing a crude product of the iodophosphate:
160g of water is added with 80.4g of pralidoxime chloride (purity is 99.6%) and stirred for dissolution, 50% of potassium iodide aqueous solution (100 g of potassium iodide is prepared in advance and 100g of water) is added dropwise under the temperature of 30 ℃, a large amount of yellow solid is precipitated after the dripping, the mixture is stirred for 2.5 hours at room temperature, and the crude product of the pralidoxime iodide is obtained after filtering and leaching.
S2, preparing an iodic phosphate dissolving crystal form:
468g of water is heated to 70 ℃, 156.3g of crude product of the iodophosphate is added, the temperature is maintained between 65 ℃ and 75 ℃ and stirred for dissolution, filtration is carried out, the filtrate is cooled to 0 ℃ to 10 ℃ and stirred for crystallization for 1 hour, filtration, leaching and wet product drying are carried out, 101.2g of crystal form (yellow crystalline powder) of the iodophosphate is obtained, the total yield is 82.3 percent, and the purity is 99.92 percent.
Example 3
S1, preparing a crude product of the iodophosphate:
adding 90.1g of pralidoxime chloride (purity is 99.8%) into 180g of water, stirring and dissolving, dropwise adding 50% potassium iodide aqueous solution (112.5 g of potassium iodide+112.5 g of water is prepared in advance) below the temperature of 30 ℃, stirring at room temperature for 2 hours, filtering, leaching to obtain crude product of pralidoxime iodide.
S2, preparing an iodic phosphate dissolving crystal form:
620g of water is heated to 70 ℃, 157.9g of crude product of the iodophosphate is added, the temperature is maintained to be 60-70 ℃ and stirred for dissolution, filtration is carried out, the filtrate is cooled to 0-10 ℃ and stirred for crystallization for 2 hours, filtration, leaching and wet product drying are carried out, 106.9g of crystal form (yellow crystalline powder) of the iodophosphate is obtained, the total yield is 77.6%, and the purity is 99.97%.
Table 2 shows comparison of the results of the form of the iodophosphate crystals prepared in the examples of the present invention
The stability of the iodophosphate crystal form influence factors (high temperature, high humidity and illumination) prepared in example 1 is examined as follows:
according to four guidelines of the pharmacopoeia of the people's republic of China, 2020 edition and 9001 raw material medicaments and preparation stability test guidelines, carrying out an influence factor test of the iodic phosphate dissolving and fixing crystal form:
(1) High temperature test: the sample is placed in an incubator at 60 ℃ at the opening, and is sampled and detected on days 5, 10 and 30.
(2) High humidity test: the test sample (bare sample + tape package) was placed in a constant humidity closed container at 25℃under conditions of 92.5% relative humidity (KNO 3 Saturated solution), sampling and detection are carried out on the 5 th day, the 10 th day and the 30 th day.
(3) Strong light irradiation test: opening of sample (bare sample + tape package)Is placed in an illumination box, and the illumination is 5000Lux and 90 mu W/cm 2 Is placed under the condition of (1), and sampling and detection are carried out on the 5 th day, the 10 th day and the 30 th day.
TABLE 3 Table 3
As can be seen from table 3 above, the crystal form of the iodophosphate prepared in example 1 has good stability under high temperature, high humidity and light conditions after being packaged, and has good stability under normal storage conditions and even more severe conditions (high temperature, high humidity and light), and is suitable for long-term storage and formulation application.
The above embodiments are merely for illustrating the technical ideas and features of the present invention, and are not meant to be exclusive or limiting. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention.
Claims (8)
1. A crystal form of iodophosphate is characterized in that Cu-K alpha radiation is used and has characteristic peaks at diffraction angles 2 theta of 9.5+/-0.2 DEG, 11.9+/-0.2 DEG, 16.6+/-0.2 DEG, 19.1+/-0.2 DEG, 20.0+/-0.2 DEG, 21.0+/-0.2 DEG, 23.4+/-0.2 DEG, 25.7+/-0.2 DEG, 27.4+/-0.2 DEG, 28.9+/-0.2 DEG, 29.9+/-0.2 DEG, 30.3+/-0.2 DEG, 36.3+/-0.2 DEG, 41.2+/-0.2 DEG, 42.7+/-0.2 DEG, 44.7+/-0.2 DEG, 49.0+/-0.2 DEG, 51.7+/-0.2 DEG and 56.6+/-0.2 DEG according to a four-part 0451X radiation diffraction method of the pharmacopoeia of the 2020 edition of the pharmacopoeia of the people of the general republic of the China.
2. The crystalline form of iodophosphate according to claim 1, characterized by a differential scanning calorimetric profile exhibiting an endothermic peak at 229.8 ℃ to 232.9 ℃ and a thermogravimetric profile exhibiting weight loss at 232.3 ℃ to 239.7 ℃.
3. The crystalline form of iodophosphate according to claim 1, characterized in that it exhibits a microscopic appearance as crystals, the morphology of which appears as prisms or long blocks.
4. A process for the preparation of a crystalline form of iodophosphate according to any one of claims 1 to 3, comprising the steps of:
s1, dissolving the pralidoxime chloride in an inorganic solvent, and replacing the pralidoxime chloride with inorganic iodide to obtain a crude product of the pralidoxime iodide;
s2, dissolving the crude product of the iodophosphate by an inorganic solvent, and recrystallizing to obtain the crystal form of the iodophosphate.
5. The method according to claim 4, wherein in the step S1, the inorganic iodide is selected from any one of potassium iodide, sodium iodide, and ammonium iodide.
6. The method according to claim 4, wherein in the step S1, the molar ratio of the inorganic iodide to the pralidoxime chloride is 1.0 to 1.5:1.0.
7. the method according to claim 4, wherein the inorganic solvent used in step S1 and step S2 is water.
8. The method according to claim 4, wherein in the step S2, the recrystallization is performed at 0 to 10℃for 1 to 2 hours with stirring.
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| CA746513A (en) * | 1966-11-15 | A. Mcginn Francis | Halide salts of 2-(hydroxyiminomethyl)-1-methyl-pyridinium | |
| EP0665009A1 (en) * | 1992-10-14 | 1995-08-02 | Nippon Shinyaku Company, Limited | Crystalline condition dislocating method |
| US20160355792A1 (en) * | 2015-06-05 | 2016-12-08 | University Of Georgia Research Foundation, Inc. | Engineered organophosphorus acid anhydrolases and methods of use thereof |
| CN109640947A (en) * | 2016-08-05 | 2019-04-16 | 株式会社新日本科学 | Intranasal pharmaceutical powder composition |
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2023
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| CA746513A (en) * | 1966-11-15 | A. Mcginn Francis | Halide salts of 2-(hydroxyiminomethyl)-1-methyl-pyridinium | |
| EP0665009A1 (en) * | 1992-10-14 | 1995-08-02 | Nippon Shinyaku Company, Limited | Crystalline condition dislocating method |
| US20160355792A1 (en) * | 2015-06-05 | 2016-12-08 | University Of Georgia Research Foundation, Inc. | Engineered organophosphorus acid anhydrolases and methods of use thereof |
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