CN117986268A - Crystal form of exetil Kang Jia sulfonate and preparation method thereof - Google Patents
Crystal form of exetil Kang Jia sulfonate and preparation method thereof Download PDFInfo
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- CN117986268A CN117986268A CN202211338570.2A CN202211338570A CN117986268A CN 117986268 A CN117986268 A CN 117986268A CN 202211338570 A CN202211338570 A CN 202211338570A CN 117986268 A CN117986268 A CN 117986268A
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- 239000013078 crystal Substances 0.000 title claims abstract description 90
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 32
- 230000005855 radiation Effects 0.000 claims abstract description 7
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 5
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 17
- 150000002576 ketones Chemical class 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 230000004580 weight loss Effects 0.000 claims description 10
- 238000002329 infrared spectrum Methods 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 238000000354 decomposition reaction Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims description 2
- 229960004341 escitalopram Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 6
- 150000001298 alcohols Chemical class 0.000 claims 4
- 239000002904 solvent Substances 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 239000012065 filter cake Substances 0.000 description 13
- 238000012512 characterization method Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000004683 dihydrates Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000000611 antibody drug conjugate Substances 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- -1 sulfonate dihydrate Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NDCQPJCNZBQYAO-UHFFFAOYSA-N 4-[[3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1COC1=CC=CC(C=2C3=CC=CC(=C3N=CC=2C(=O)C=2C=CC=CC=2)C(F)(F)F)=C1 NDCQPJCNZBQYAO-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- FXQZOHBMBQTBMJ-MWPGLPCQSA-N Exatecan mesilate hydrate Chemical compound O.O.CS(O)(=O)=O.C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 FXQZOHBMBQTBMJ-MWPGLPCQSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 240000005546 Piper methysticum Species 0.000 description 1
- 235000016787 Piper methysticum Nutrition 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 229950009429 exatecan Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a crystal form A of Eptification Kang Jia sulfonate, which is characterized in that the crystal form has characteristic peaks at diffraction angles 2 theta of 8.5, 14.2, 15.6, 16.0, 16.8, 17.3, 17.9, 18.7, 21.6 and 22.7+/-0.2 degrees in an X-ray powder diffraction pattern using a radiation source of Cu-K alpha; the crystal form A has the advantages of high purity, good stability, good solubility and the like; and the problems of low yield and poor crystallinity in the prior art are solved. The preparation method of the crystal form A is simple and convenient, the solvent is cheap and easy to obtain, the crystallization condition is mild, and the preparation method is suitable for industrial mass production.
Description
Technical Field
The invention relates to a novel crystal form of a drug and a preparation method thereof, in particular to a novel crystal form of exetil Kang Jia sulfonate and a preparation method thereof.
Background
The irinotecan is a camptothecin derivative, has topoisomerase I (TOP I) inhibitory activity, is widely applied to the research of antibody-drug conjugate (ADC) as an active molecule, and is shown in a chemical formula (I) as shown in a chemical formula of the irinotecan Kang Jia sulfonate (Exatecan mesylate):
In the prior art, the crystal form of the exetil Kang Jia sulfonate is freshly reported, and the exetil Kang Jia sulfonate dihydrate and the preparation method thereof are only disclosed in a patent document CN1050131C authorized in 2000, but the patent does not provide relevant crystal form characterization data generally accepted by research and development personnel in the technical field. According to the research, the defect that the crystal form stability is poor, the solubility in water is poor and the crystallinity is not high exists in the Epichetidine Kang Jia sulfonate dihydrate obtained by the preparation method of the patent CN 1050131C.
In view of the defects in the prior art, the development of a novel crystal form of the exetil Kang Jia sulfonate with better stability, higher solubility or higher crystallinity and other advantageous properties has very important significance.
Disclosure of Invention
The invention aims to provide a novel crystal form of the exetil Kang Jia sulfonate and a preparation method thereof, and compared with a reference crystal form, the novel crystal form of the exetil Kang Jia sulfonate has lower moisture content, better dissolution performance and better structural stability. The crystal form has the advantages of simple preparation process, higher yield, better product property, easier filtration and suitability for industrial production, thereby having better patent medicine prospect.
The invention provides a novel crystal form (called as 'crystal form A' in the invention) of the Eptification Kang Jia sulfonate, which is characterized in that the crystal form A has characteristic peaks at diffraction angles 2 theta of 8.5, 14.2, 15.6, 16.0, 16.8, 17.3, 17.9, 18.7, 21.6 and 22.7+/-0.2 degrees in an X-ray powder diffraction pattern using a radiation source of Cu-K alpha.
Preferably, form a has characteristic peaks at diffraction angles 2θ of 8.5, 14.2, 15.6, 16.0, 16.8, 17.3, 17.9, 18.7, 21.6, 22.7, 25.8, 27.3, and 30.4±0.2° in an X-ray powder diffraction pattern using cu—kα as the radiation source.
Further, the crystal form A has characteristic peaks at diffraction angles 2 theta of 5.7±0.2°、7.2±0.2°、7.5±0.2°、8.5±0.2°、12.2±0.2°、12.9±0.2°、14.2±0.2°、15.1±0.2°、15.6±0.2°、16.0±0.2°、16.8±0.2°、17.3±0.2°、17.9±0.2°、18.7±0.2°、19.5±0.2°、19.8±0.2°、21.6±0.2°、22.7±0.2°、25.8±0.2°、26.8±0.2°、27.3±0.2°、30.4±0.2° and 38.5 plus or minus 0.2 degrees in an X-ray powder diffraction pattern using a radiation source of Cu-K alpha.
In one embodiment of the present invention, without limitation, the X-ray powder diffraction pattern of form a is shown in figure 1.
In one embodiment of the present invention, without limitation, the present invention provides form a having two endothermic peaks between 40 and 150 ℃ when subjected to Differential Scanning Calorimetry (DSC) to heat up from room temperature to 250 ℃ at a heating rate of 10 ℃/min.
Further, the DSC profile of form a of the present invention includes absorption peaks at substantially the same temperatures as shown in fig. 2.
In one embodiment of the present invention, without limitation, form a of the present invention has a significant gradient weight loss when heated from room temperature to 300 ℃ using a thermogravimetric analyzer (TGA) at a heating rate of 10 ℃/min, and further, before room temperature to 150 ℃, exhibits two weight loss steps, the first weight loss step corresponding to one molecule of water and the second step corresponding to half molecule of water, starting to decompose the weight loss within a temperature range of 200 to 300 ℃ at a decomposition temperature of 261±5 ℃; in one embodiment the decomposition temperature is about 261 c.
Further, the TGA profile of form a of the present invention is substantially the same weight loss as shown in fig. 3.
Without limitation, the Fourier IR spectrum (IR) at form A of the present invention has characteristic peaks at wave numbers 3401、3082、2934、1743、1651、1585、1505、1452、1420、1385、1252、1164、1112、1077、1044、1004、990、952、884、869、773、689、634、604 and 553cm -1.
The invention also provides a preparation method of the novel crystal form A of the Eptification Kang Jia sulfonate, which comprises the following steps:
1) At 0-50 ℃, preferably at room temperature, placing the Yixitidine Kang Jia sulfonate in an ester, ether, ketone, alkane, ketone and ester mixed solution, an alcohol and ether mixed solution or a ketone and alkane mixed solution to obtain suspension;
2) Stirring is continued for 1-10 days, preferably 3-5 days, and the solid is collected by filtration and dried to obtain the crystal form A.
In certain embodiments, the ketone is preferably acetone; the alkane is preferably dichloromethane, pentane, n-hexane or n-heptane, and further preferably n-heptane or dichloromethane; the esters are preferably isopropyl acetate, methyl acetate; the ethers are preferably isopropyl ether, diethyl ether, methyl tert-butyl ether, and more preferably isopropyl ether and diethyl ether; the alcohol is preferably isopropanol.
In certain embodiments, the volume ratio of ketone to ester is preferably 2:1 to 1:15; preferably the ketone is acetone and the ester is ethyl acetate or isopropyl acetate; the volume ratio of the acetone to the ethyl acetate or the isopropyl acetate is 2:1-1:15, preferably 1:1-1:10;
In certain embodiments, the mass to volume ratio (g: mL) of the suspension is 1:5 to 100, preferably 1:15 to 30.
In certain embodiments, the drying is preferably vacuum or atmospheric drying at 20-40 ℃; preferably the drying time is 2 to 24 hours.
Preferably, filtration and drying are performed as conventional in the art. The filtration is conventional in the art, preferably vacuum filtration. After the filter cake is filtered, the filter cake is preferably washed with an experimental solvent.
The beneficial technical effects of the invention are as follows: the crystal form A has the advantages of high purity, good stability, good solubility and the like; and the problems of low yield and poor crystallinity in the prior art are solved. The preparation method of the crystal form A is simple and convenient, the solvent is cheap and easy to obtain, the crystallization condition is mild, and the preparation method is suitable for industrial mass production.
The crystal form A has good solubility, can ensure the curative effect of the medicine, reduces the difficulty of developing a preparation process and is beneficial to industrial production. The crystal form A has good stability, and can be stably placed under different humidity conditions; the crystal form A has better stability, so that the crystal form A is more controllable in the crystallization process, mixed crystals are not easy to occur, and the consistent and controllable quality of medicines is ensured. The crystal form A is easy to filter, the product form is good, and the product looseness is good.
Drawings
FIG. 1 is an X-ray powder diffraction (XPRD) spectrum of form A prepared in example 1;
FIG. 2 is a DSC spectrum of form A prepared in example 1;
FIG. 3 is a TGA spectrum of form A prepared in example 1;
FIG. 4 is an IR spectrum of form A prepared in example 1;
FIG. 5 is a graph of X-ray powder diffraction (XPRD) of a reference crystalline form prepared in comparative example 1;
FIG. 6 is a DSC chart of a reference crystal form prepared in comparative example 1;
FIG. 7 is a TGA spectrum of a reference crystal form prepared in comparative example 1;
FIG. 8 is an IR spectrum of a reference crystal form prepared in comparative example 1;
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the following embodiments are used to describe the technical solution of the present invention in detail, and will help to further understand advantages and effects of the technical solution of the present invention, and the embodiments do not limit the protection scope of the present invention, which is determined by the claims.
The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
The raw materials or reagents used in the examples were commercially available unless otherwise specified.
Unless otherwise indicated, the reagents described were used without purification. All solvents were purchased from commercial suppliers such as Aldrich (Aldrich) and used without treatment.
XPRD is collected on a Bruker D8 advanced diffractometer, and the method parameters of the X-ray powder diffraction are as follows:
X-ray reflection parameters: cu, K alpha
Tube voltage: 40 kilovolts (kV)
Tube current: 40 milliamperes (mA)
Slit: the primary optical path cable-stayed slit is 2.5 degrees, and the secondary optical path cable-stayed slit is 2.5 degrees
Scanning mode: continuous scanning
Step angle: 0.02 °, sampling time: 0.1 s/step;
Scanning range: from 3.0 to 40.0 DEG
The TGA spectrum is acquired on TA Instruments Discovery TGA instruments, and the method parameters of the thermogravimetric analysis are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
DSC spectrum is obtained by acquisition on TA Instruments Discovery DSC250,250 instruments
Test conditions: heating from 25 ℃ to 250 ℃ at a speed of 10 ℃/min;
Detecting environmental conditions: room temperature.
The infrared analysis method is acquired on an IR data instrument, and the parameters are as follows:
the sample preparation method comprises the following steps: by adopting a KBr tabletting method,
Infrared absorption spectrum scan range: 400-4000 cm -1
Scan time of sample and blank background: 32 seconds
Instrument resolution: 4cm -1.
Preparation of crude product of Eptification Kang Jia sulfonate
To 5g of (1S, 9S) -1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [ de ] pyrano [3',4':6,7] indolizino [1,2-b ] quinoline-10, 13 (9H, 15H) dione was added 150ml of water. To the resulting mixture, 75ml of methanesulfonic acid and 150ml of toluene were added, and heated under reflux for 6.5 hours. The reaction mixture was cooled and the aqueous phase was collected using a separatory funnel. The resulting aqueous phase was filtered through a glass funnel. The solvent in the filtrate was removed. To the resulting substrate was added 300ml of methanol and 200ml of ethanol. The resulting mixture was cooled. The precipitated crystals were collected by filtration and washed with ethanol, together with the mother liquor, to give a crude crystal of 2.6g of the edetate Kang Jia sulfonate.
1H-NMR(D2O)δ：0.73(3H,t),1.75(2H,q),2.13(3H,s),2.5-2.62(2H,m),2.65(3H,s),2.83-3.00(1H,m),3.18-3.30(1H,m),5.16-5.45(5H,m),7.06(1H,s),7.10(1H,d).
Comparative example 1
To 300mg of crude crystals of the escitalopram Kang Jia sulfonate obtained according to the above method was added an aqueous solvent (22.5 mL) of ethanol mixed at 4:1, and the substrate was dissolved by heating in the solvent, and the resulting solution was left overnight at room temperature, with reference to patent CN1050131C example 1. The precipitated crystals were collected by filtration and washed with ethanol to give 213mg of reference crystalline form in 71% yield, 99.68% HPLC purity, 6.5% of kava KF (theoretical dihydrate water content 6.3%), and no significant solvent residue was shown by magnetocaloric and residual solvent testing.
IR cm-1 3403、2936、1745、1657、1588、1504、1420、1252、1165、1111、1049、884、773、556.
The X-ray powder diffraction pattern is shown in figure 5.
The DSC chart is shown in figure 6.
The TGA profile is shown in figure 7.
The IR spectrum is shown in figure 8.
Example 1
300Mg of Eptification Kang Jia sulfonate is taken, 8.0mL of mixed solution of isopropyl ether and isopropanol (volume ratio is 1:1) is added, the mixture is stirred for 5 days at 0-10 ℃ and then is subjected to vacuum filtration, a filter cake is dried for 16h at room temperature at 25 ℃ to obtain off-white crystals, 284mg is weighed, the yield is 94.7%, and the HPLC purity is 99.88%.
The X-ray powder diffraction pattern XRPD pattern of the obtained solid product is shown in figure 1, and the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at the angles of 5.7±0.2°、7.2±0.2°、7.5±0.2°、8.5±0.2°、12.2±0.2°、12.9±0.2°、14.2±0.2°、15.1±0.2°、15.6±0.2°、16.0±0.2°、16.8±0.2°、17.3±0.2°、17.9±0.2°、18.7±0.2°、19.5±0.2°、19.8±0.2°、21.6±0.2°、22.7±0.2°、25.8±0.2°、26.8±0.2°、27.3±0.2°、30.4±0.2° and 38.5+/-0.2 degrees 2 theta.
The fourier infrared spectrum (IR) image of form a is shown in fig. 4, with characteristic peaks at wavenumbers 3401、3082、2934、1743、1651、1585、1505、1420、1385、1252、1164、1112、1077、1044、1004、990、884、869、773、689、634、604 and 553cm -1.
The DSC image of the crystal form A is shown in figure 2, and the TGA spectrum is shown in figure 3.
The results of nuclear magnetism and solvent residue of the crystal form A show no obvious residue, TGA data show that the crystal form has two gradients of weight loss when heated between 0 ℃ and 150 ℃, the total weight loss ratio is about 5.59%, the first weight loss step is about 3.3%, about 1 crystal water is reduced, the subsequent second gradient weight loss is about 2.2%, about 0.5 crystal water is reduced, correspondingly, a DSC curve has two broad endothermic peaks at 50 ℃ to 150 ℃, and the moisture detection result of a karma method is 4.5% (the water content of theoretical 1.5 hydrate is 4.8%), so that the crystal form is the Epichthyol Kang Jia sulfonate 1.5 hydrate is summarized.
Example 2
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.0mL of acetone, stirring at 0-5 ℃ for 5 days, vacuum-filtering, and vacuum-drying a filter cake at 25 ℃ for 16 hours to obtain crystals, wherein the weight of the crystals is 26.7mg, and the yield is 89%. The crystals were identified as form a by XRPD characterization.
Example 3
30Mg of Eptification Kang Jia sulfonate is taken, 1.0mL of methylene dichloride is added, the mixture is stirred for 5 days at 20-30 ℃ and then is subjected to vacuum suction filtration, a filter cake is dried for 16 hours at 25 ℃ in vacuum, and crystals are obtained, the weight of the crystals is 26.1mg, and the yield is 87%. The crystals were identified as form a by XRPD characterization.
Example 4
Taking 30mg of Eptification Kang Jia sulfonate, adding 0.6mL of n-heptane, stirring at 20-30 ℃ for 3 days, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16h to obtain crystals, wherein the weight of the crystals is 27.5mg, and the yield is 91.7%. The crystals were identified as form a by XRPD characterization.
Example 5
Taking 30mg of Eptification Kang Jia sulfonate, adding 0.5mL of methanol/isopropyl acetate (volume ratio is 1:1), stirring for 1 day at 20-30 ℃, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16h to obtain crystals, wherein the weight of the crystals is 25.9mg, and the yield is 86.3%. The crystals were identified as form a by XRPD characterization.
Example 6
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.0mL of acetone/isopropyl acetate (volume ratio is 2:1), stirring for 10 days at 20-30 ℃, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16h to obtain crystals, wherein the weight is 24.7mg, and the yield is 82.3%. The crystals were identified as form a by XRPD characterization.
Example 7
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.6mL of acetone/ethyl acetate (volume ratio is 1:1), stirring for 5 days at 20-30 ℃, vacuum filtering, and vacuum drying a filter cake at 20 ℃ for 24 hours to obtain crystals, wherein the weight of the crystals is 23.9mg, and the yield is 79.7%. The crystals were identified as form a by XRPD characterization.
Example 8
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.6mL of acetone/ethyl acetate (volume ratio is 1:15), stirring for 5 days at 20-30 ℃, vacuum filtering, and vacuum drying a filter cake at 40 ℃ for 2h to obtain crystals, weighing 24.4mg, wherein the yield is 81.3%. The crystals were identified as form a by XRPD characterization.
Example 9
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.0mL of isopropyl acetate, stirring at 40-50 ℃ for 5 days, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16 hours to obtain crystals, wherein the weight of the crystals is 26.5mg, and the yield is 80.6%. The crystals were identified as form a by XRPD characterization.
Example 10
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.0mL of isopropyl ether, stirring at 0-10 ℃ for 5 days, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16h to obtain crystals, wherein the weight of the crystals is 27.7mg, and the yield is 92.3%. The crystals were identified as form a by XRPD characterization.
Example 11
Taking 30mg of Eptification Kang Jia sulfonate, adding 1.0mL of acetone/isopropyl ether (volume ratio is 1:1), stirring for 5 days at 0-10 ℃, vacuum filtering, and vacuum drying a filter cake at 25 ℃ for 16h to obtain crystals, weighing 25.1mg, wherein the yield is 83.6%. The crystals were identified as form a by XRPD characterization.
Example 12
Stability test
The samples of the dihydrate obtained in example 1 and prepared in comparative example 1 were left open for 7 days at different temperatures and different humidity conditions, and XRPD and HPLC were measured on the samples, and the results are shown in table 1 below.
TABLE 1 stability study
From the data in table 1 above, form a of the present invention exhibited particularly outstanding form stability at both 40 ℃/75% rh and 25 ℃/60% rh, and the reference form was unstable at both 40 ℃/75% rh and 25 ℃/60% rh.
Example 13
Comparative examples of thermal stability
The form a sample obtained in example 1 above was heated to 150 ℃ at a rate of 10 ℃/min for 3 minutes under nitrogen atmosphere, cooled to room temperature after completion, and subjected to XRPD detection, which showed that form a was still present.
The experiment shows that under the conventional environmental conditions, the crystal form A has certain physical stability.
Example 15
Form stability study under Low humidity conditions
The form a sample was placed in a brown desiccator at 0-5% rh for 11 days and sampled for XRPD, showing that the crystalline form remained stable.
The above experiments show that the apparent form of form a as a hydrate sample shows that the water of crystallization is not easily lost under low humidity conditions. More precisely, the crystal skeleton of the crystal form is not easy to change even under the low humidity condition, and the crystal form can be kept stable for a certain period of time under the environment condition.
Example 16
Solubility experiment
The crystal form a prepared in example 1 and the dihydrate sample prepared in comparative example 1 were separately subjected to solubility in water under room temperature conditions (about 25 to 30 ℃). The experimental results are shown in table 2:
table 2 solubility comparative study
| Crystalline forms of the starting materials | Solubility (mg/mL) |
| Crystal form A | 16 |
| Reference crystal forms | 7 |
The results show that the crystal form A of the Eptification Kang Jia sulfonate prepared by the method has more remarkable dissolution advantage in water compared with the crystal form obtained in the comparative example 1, and the solubility is about 2.5 times higher than that of dihydrate in the patent.
In conclusion, the novel crystalline form a of the exetil Kang Jia sulfonate of the present invention has superior solubility and crystalline form stability compared to the dihydrate described in the CN1050131C patent. The crystal form A of the invention has lower water content, and has more excellent benefits for controlling the long-term stability of the medicine and developing the preparation process.
Those skilled in the art will appreciate that certain modifications and variations of the invention are possible in light of the teachings of this specification. Such modifications and variations are intended to be included within the scope of the present invention as defined in the appended claims.
Claims (10)
1. Form a of the salt of escitalopram Kang Jia characterised in that it has characteristic peaks in the X-ray powder diffraction pattern using Cu-ka as the radiation source at diffraction angles 2θ of 8.5, 14.2, 15.6, 16.0, 16.8, 17.3, 17.9, 18.7, 21.6 and 22.7±0.2°.
2. Form a of the salt of exetil Kang Jia according to claim 1, characterized in that: in the X-ray powder diffraction pattern using the radiation source Cu-K alpha, the crystal form A has characteristic peaks at diffraction angles 2 theta of 8.5, 14.2, 15.6, 16.0, 16.8, 17.3, 17.9, 18.7, 21.6, 22.7, 25.8, 27.3 and 30.4 plus or minus 0.2 degrees.
3. Form a of the salt of exetil Kang Jia according to claim 1, characterized in that: in an X-ray powder diffraction pattern using a radiation source of Cu-K alpha, the crystal form A has characteristic peaks at diffraction angles 2 theta of 5.7±0.2°、7.2±0.2°、7.5±0.2°、8.5±0.2°、12.2±0.2°、12.9±0.2°、14.2±0.2°、15.1±0.2°、15.6±0.2°、16.0±0.2°、16.8±0.2°、17.3±0.2°、17.9±0.2°、18.7±0.2°、19.5±0.2°、19.8±0.2°、21.6±0.2°、22.7±0.2°、25.8±0.2°、26.8±0.2°、27.3±0.2°、30.4±0.2° and 38.5 plus or minus 0.2 degrees;
or preferably the X-ray powder diffraction pattern of form a is consistent with figure 1.
4. Form a of the salt of exetil Kang Jia according to claim 1, characterized in that: the crystal form A has two endothermic peaks at 40-150 ℃; preferably and/or the DSC profile comprises absorption peaks at substantially the same temperatures as shown in figure 2.
5. Form a of the salt of exetil Kang Jia according to claim 1, characterized in that: when the temperature of the crystal form A is raised to 300 ℃ from room temperature by adopting a thermogravimetric analyzer TGA, the crystal form A has obvious gradient weightlessness, and further, before the room temperature is 150 ℃, the crystal form A is characterized by having two weightlessness steps, wherein the first weightlessness step corresponds to one molecule of water, the second step corresponds to half molecule of water, the decomposition weightlessness is started within the temperature range of 200-300 ℃, and the decomposition temperature is 261+/-5 ℃; preferably and/or form a has a TGA profile substantially the same weight loss as shown in figure 3.
6. Form a of the salt of exetil Kang Jia according to one of claims 1 to 5, characterized in that: the fourier infrared spectrum IR of form a has characteristic peaks at wavenumbers 3401、3082、2934、1743、1651、1585、1505、1452、1420、1385、1252、1164、1112、1077、1044、1004、990、952、884、869、773、689、634、604 and 553cm -1.
7. A process for preparing form a of claims 1-6 comprising the steps of:
1) At 0-50 ℃, placing the Yixitidine Kang Jia sulfonate in esters, ethers, ketones, alkanes, mixed solutions of ketones and esters, mixed solutions of alcohols and ethers or mixed solutions of ketones and alkanes to obtain suspension;
2) Stirring is continued for 1-10 days, and solid is collected by filtration and dried to obtain the crystal form A.
8. The process of form a according to claim 7, characterized in that:
1) At room temperature, placing the Eptification Kang Jia sulfonate in esters, ethers, ketones, alkanes, mixed solutions of ketones and esters, mixed solutions of alcohols and ethers or mixed solutions of ketones and alkanes to obtain suspension;
2) Stirring is continued for 3-5 days, and solid is collected by filtration and dried to obtain the crystal form A.
9. The process of form a according to claim 7 or 8, characterized in that: the ketone is selected from acetone; the alkanes are selected from dichloromethane, pentane, n-hexane or n-heptane, and the esters are selected from isopropyl acetate or methyl acetate; the ethers are selected from isopropyl ether, diethyl ether or methyl tertiary butyl ether; the alcohol is selected from isopropanol;
And/or preferably a mixed solution of alcohols and esters, wherein the volume ratio of the ketones to the esters is preferably 2:1-1:15;
and/or preferably in a mixed solution of alcohols and esters, wherein the ketone is acetone and the esters are ethyl acetate or isopropyl acetate; the volume ratio of the acetone to the ethyl acetate or the isopropyl acetate is 2:1-1:15, preferably 1:1-1:10.
10. The process of form a according to claim 9, characterized in that: the mass volume ratio (g: mL) of the suspension is 1:5-100, preferably 1:15-30;
And/or preferably said drying, vacuum or atmospheric drying at 20-40 ℃; drying time is 2-24 hours.
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