CN105503802A - Preparation method of dapagliflozin-citric acid eutectic - Google Patents
Preparation method of dapagliflozin-citric acid eutectic Download PDFInfo
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- CN105503802A CN105503802A CN201610029562.8A CN201610029562A CN105503802A CN 105503802 A CN105503802 A CN 105503802A CN 201610029562 A CN201610029562 A CN 201610029562A CN 105503802 A CN105503802 A CN 105503802A
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- citric acid
- gelie
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- eutectic
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 title claims abstract description 236
- 230000005496 eutectics Effects 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000003756 stirring Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000010521 absorption reaction Methods 0.000 abstract description 8
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 abstract description 5
- 229960003834 dapagliflozin Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000008186 active pharmaceutical agent Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 28
- 238000012360 testing method Methods 0.000 description 15
- 238000001291 vacuum drying Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 102000034534 Cotransporters Human genes 0.000 description 1
- 108020003264 Cotransporters Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108091006269 SLC5A2 Proteins 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010309 melting process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- QMYDVDBERNLWKB-UHFFFAOYSA-N propane-1,2-diol;hydrate Chemical compound O.CC(O)CO QMYDVDBERNLWKB-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method of dapagliflozin-citric acid eutectic. The molar ratio of dapagliflozin to citric acid in the eutectic is 1:1. The moisture absorption of the dapagliflozin-citric acid eutectic is worse than that of active pharmaceutical ingredients, the stability is relatively good, and the preparation is easy. The dapagliflozin-citric acid eutectic prepared in the invention is superior to dapagliflozin and dapagliflozin-propylene glycol-water eutectic in hygroscopicity, thus the drug stability is beneficially improved, the error generated in study and production caused by moisture absorption is reduced, and the smooth implementation of a dapagliflozin production process is facilitated. The dapagliflozin-citric acid eutectic provided by the invention is easy to prepare, and the involved preparation method has the advantages of mild reaction conditions, easiness in operation, good reproducibility and low production cost.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of Da Gelie clean-preparation method of citric acid eutectic.
Background technology
Da Gelie clean (Dapagliflozin) is 2 type sodium ion dependent form glucose cotransporter (sodium-dependentglucosecotransporter2, SGLT2) inhibitor is the medicine being used for the treatment of type ii diabetes of Bristol Myers Squibb (Bristol-MyersSquibb) company research and development.The clean chemistry of Da Gelie is called: (1S)-1,5-dehydration-1-C-[the chloro-3-of 4-[(4-ethoxyl phenenyl) methyl] phenyl]-D-Glucose alcohol, molecular formula is C
21h
25clO
6, chemical structural formula is as follows:
Da Gelie is amorphous only, draw more by force moist because it has, cause research, produce in weigh inaccurate and produce deviation.Meanwhile, variable thickness or become oil after the clean moisture absorption of Da Gelie, it can affect carrying out smoothly of production process and formulation manufacturing processes.In addition, the clean excessively strong water absorbability of Da Gelie result in its poor storage stability.For head it off, medicament forms of its listing be Da Gelie clean-propylene glycol-water eutectic, its commodity are called Forxiga.
Summary of the invention
The object of the present invention is to provide the eutectic that the clean and citric acid of a kind of Da Gelie is formed;
Another object of the present invention is to provide a kind of Da Gelie clean-preparation method of citric acid eutectic.
The technical solution used in the present invention is:
The clean eutectic formed with citric acid of Da Gelie, wherein Da Gelie only and the mol ratio of citric acid be 1:1.
Preferably, Da Gelie is clean-and the X-ray powder diffraction of citric acid eutectic at angle of diffraction 2 θ is: 8.9 ± 0.2, 12.2 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 15.3 ± 0.2, 16.2 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.4 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.9 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.6 ± 0.2, 29.2 ± 0.2, 30.0 ± 0.2, 32.0 ± 0.2, 32.8 ± 0.2, 33.2 ± 0.2, 33.9 ± 0.2, 35.5 ± 0.2, 36.1 ± 0.2, 37.3 ± 0.2, when 38.6 ± 0.2, there is characteristic peak.
Da Gelie is clean-preparation method of citric acid eutectic, comprise the steps:
1) by clean for Da Gelie be (0.9-1.1) in molar ratio with citric acid: (0.9-1.1) mixes;
2) only and in the mixture of citric acid add appropriate esters solvent to Da Gelie, make it be suspending system;
3) above-mentioned suspending system is fully stirred, crystallization, collect gained crystalline powder; Be drying to obtain arrival lattice and arrange clean-citric acid eutectic.
Preferably, in step 1) Da Gelie clean with citric acid in molar ratio for 1:1 mixes.
Preferably, step 2) in esters solvent be selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate.
Preferably, step 2) in esters solvent be isopropyl acetate.
Preferably, step 2) in the clean and citric acid of every 100mg Da Gelie mixture in add esters solvent amount be 0.2 ~ 2.5mL.
Preferably, step 2) in the clean and citric acid of every 100mg Da Gelie mixture in add esters solvent amount be 0.2 ~ 2.0mL.
Preferably, temperature when stirring in step 3) is 0 ~ 70 DEG C.
Preferably, temperature when stirring in step 3) is 25 ~ 50 DEG C.
Preferably, the time of stirring in step 3) is not less than 2h.
Preferably, the time of stirring in step 3) is 2h ~ 2d.
The present invention by clean for Da Gelie with citric acid in molar ratio (0.9-1.1): (0.9-1.1) mixes, and preferred mol ratio is 1:1, can prepare productive rate reach the Da Gelie of 90% only-citric acid eutectic; The institute Da Gelie that obtains is clean-and citric acid eutectic foreign matter content is low, and stability improves greatly, and water absorbability obviously reduces, and is conducive to carrying out smoothly of the clean production process of Da Gelie.From production angle, in order to cost-saving, advise that mol ratio with citric acid clean at Da Gelie is when 1:1 constant, increases raw material, prepare more Da Gelie only-citric acid eutectic.
The invention has the beneficial effects as follows:
The Da Gelie that the present invention prepares is clean-citric acid eutectic, its water absorbability is better than the clean and Da Gelie of Da Gelie clean-propylene glycol-water eutectic, be conducive to the stability improving medicine, and reduce its error produced in research, production because of moisture absorption, be conducive to carrying out smoothly of the clean production process of Da Gelie.
The Da Gelie of the present invention's design is clean-and citric acid eutectic is easy to preparation.The preparation method's reaction conditions that the present invention relates to is gentle, and simple to operate, favorable reproducibility, production cost is low.
Accompanying drawing explanation
Fig. 1 be Da Gelie clean-x-ray diffractogram of powder of citric acid eutectic;
Fig. 2 is the clean x-ray diffractogram of powder of Da Gelie;
Fig. 3 is the x-ray diffractogram of powder of citric acid;
Fig. 4 be Da Gelie clean-nucleus magnetic resonance (NMR) of citric acid eutectic detects figure;
Fig. 5 be Da Gelie clean-thermogravimetric analysis (TG) figure of citric acid eutectic;
Fig. 6 be Da Gelie clean-differential scanning calorimeter (DSC) figure of citric acid eutectic;
Fig. 7 is clean differential scanning calorimeter (DSC) figure of Da Gelie;
Fig. 8 is differential scanning calorimeter (DSC) figure of citric acid;
Fig. 9 be Da Gelie clean-infrared spectra (IR) figure of citric acid eutectic;
Figure 10 is that Da Gelie is clean, Da Gelie is clean-citric acid eutectic, Da Gelie be clean-and Dynamic Water Vapor Sorption instrument (DVS) the detected result comparison diagram of propylene glycol-water eutectic.
Embodiment
The clean molar mass of Da Gelie is 408.9g/mol, and the molar mass of citric acid is 192.1g/mol.
Below in conjunction with specific embodiment, the present invention is further illustrated, but be not limited thereto.
Embodiment 1
Take 122.4mg Da Gelie clean with 57.6mg citric acid in test tube, add 0.5mL ethyl formate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 157.6mg, productive rate 87.6%.
Embodiment 2
Take 122.4mg Da Gelie clean with 57.6mg citric acid in test tube, add 0.5mL methyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 143.9mg, productive rate 79.9%.
Embodiment 3
Take 122.4mg Da Gelie clean with 57.6mg citric acid in test tube, add 0.5mL ethyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 151.2mg, productive rate 84.0%.
Embodiment 4
Take 122.4mg Da Gelie clean with 57.6mg citric acid in test tube, add 0.5mL isopropyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 162.8mg, productive rate 90.4%.
Embodiment 5
Take 81.6mg Da Gelie clean with 38.4mg citric acid in test tube, add 0.5mL ethyl formate, seal, under 50 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 101.6mg, productive rate 84.7%.
Embodiment 6
Take 81.6mg Da Gelie clean with 38.4mg citric acid in test tube, add 0.5mL methyl acetate, seal, under 50 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 91.1mg, productive rate 75.9%.
Embodiment 7
Take 81.6mg Da Gelie clean with 38.4mg citric acid in test tube, add 0.5mL ethyl acetate, seal, under 50 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 97.2mg, productive rate 81.0%.
Embodiment 8
Take 81.6mg Da Gelie clean with 38.4mg citric acid in test tube, add 0.5mL isopropyl acetate, seal, under 50 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 106.1mg, productive rate 88.4%.
Embodiment 9
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL ethyl formate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 46.2mg, productive rate 77.0%.
Embodiment 10
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL methyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 29.8mg, productive rate 49.7%.
Embodiment 11
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL ethyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 38.0mg, productive rate 63.3%.
Embodiment 12
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL isopropyl acetate, seal, under 25 DEG C of conditions, stir 2d formed to there being mass crystallization white solid, collect products therefrom, ambient temperature in vacuum drying obtains white powdery solids 50.1mg, productive rate 83.5%.
Structural characterization is tested
The Da Gelie prepared embodiment is clean-and citric acid eutectic measures and characterizes, specific as follows:
After the clean and citric acid of Da Gelie forms eutectic, proterties has larger improvement.Da Gelie is clean-and citric acid eutectic is white powdery solids, is exposed to after in air, do not have significant change.And Da Gelie is particulate state amorphous solid only, is exposed in air moisture absorption gradually and becomes glutinous, finally become oily matter.
Adopt BrukerD2PHASER diffractometer measure Da Gelie clean-the X-ray powder diffraction figure of citric acid eutectic, condition determination is as follows: CuK α, and 30kV, 10mV are light source, step-length 0.12 °, sweep velocity 10 °/min, and sweep limit 7 ~ 40 °, carries out under room temperature.Embodiment 1 gained X-ray powder diffraction figure as shown in Figure 1.Fig. 2, Fig. 3 represent that Da Gelie is clean, the X-ray powder diffraction figure of citric acid respectively.Comparison diagram 1, Fig. 2, Fig. 3, the obtained product of known embodiment 1 is a new crystal material, namely Da Gelie clean-citric acid eutectic.According to Fig. 1, Da Gelie is clean-and the X-ray powder diffraction of citric acid eutectic at angle of diffraction 2 θ is: 8.9 ± 0.2, 12.2 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 15.3 ± 0.2, 16.2 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.4 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.9 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.6 ± 0.2, 29.2 ± 0.2, 30.0 ± 0.2, 32.0 ± 0.2, 32.8 ± 0.2, 33.2 ± 0.2, 33.9 ± 0.2, 35.5 ± 0.2, 36.1 ± 0.2, 37.3 ± 0.2, when 38.6 ± 0.2, there is characteristic peak.Under the characterization data of embodiment 1 is shown in:
Adopt BrukerAvanceIII nuclear magnetic resonance spectrometer measure Da Gelie clean-magnetic resonance detection of citric acid eutectic, magneticstrength: 9.39T, resonant frequency: 400MHz, uses solvent: deuterated DMSO.As shown in Figure 4, wherein, the clean peak of Da Gelie is δ: 7.37 (d, J=8.2Hz to embodiment 1 gained magnetic resonance detection result, 1H), 7.32 (d, J=1.8Hz, 1H), 7.23 (dd, J=8.2,1.9Hz, 1H), 7.09 (d, J=8.5Hz, 2H), 6.82 (d, J=8.6Hz, 2H), 4.94 (s, 2H), 4.82 (s, 1H), 4.43 (s, 1H), 4.06 ~ 3.88 (m, 5H), 3.69 (d, J=11.0Hz, 1H), 3.44 (dd, J=11.7,5.6Hz, 1H), 3.27 ~ 3.06 (m, 4H), 1.29 (t, J=7.0Hz, 3H).The peak of citric acid is δ: 2.71 (dd, J=41.4,15.4Hz, 4H).According to the known Da Gelie of the integral result at each peak clean-citric acid eutectic in Da Gelie be 1:1 with the ratio of the amount of substance of citric acid only.In addition, the blunt peak of δ: 5.15 (s, 1H), 13.32 (s, 3H) represents the reactive hydrogen of the clean and intermolecular formation hydrogen bond of citric acid two of Da Gelie.
Da Gelie is clean-thermogravimetric analysis (TG) result of citric acid eutectic as shown in Figure 5,169.2 DEG C time, Da Gelie is clean-citric acid eutectic starts to decompose; Da Gelie is clean-differential scanning calorimeter (DSC) result of citric acid eutectic as shown in Figure 6,147.8 DEG C time, Da Gelie is clean-and citric acid eutectic starts melting, in addition the display of DSC result only has the melting peak of an eutectic, and melting peak that is clean without Da Gelie or citric acid, illustrate that product is purer.Fig. 7, Fig. 8 are differential scanning calorimeter (DSC) figure of the clean and citric acid of Da Gelie respectively.According to Fig. 7, Fig. 8, the clean second-order transition temperature of Da Gelie is 56.3 DEG C, and the fusing point of citric acid is 152.5 DEG C.Therefore visible, Da Gelie is clean form eutectic with citric acid after, comparatively Da Gelie is only, citric acid changes to some extent for its melting process, illustrates and defines new crystallized form.
Da Gelie is clean-infrared spectrogram (IR) of citric acid eutectic as shown in Figure 9, its IR(KBr, cm
-1) wave number of characteristic peak is: 3545,3468,3401,2928,2620,2546,1720,1512,1407,1241,1115,1048,1025,833,798,593.
Da Gelie clean (DAP), Da Gelie be clean-and citric acid eutectic (DAP-CA), Da Gelie be clean-propylene glycol-water eutectic (DAP-PDO-H
2o) as shown in Figure 10, when humidity is elevated to 95%, the clean moisture absorption of Da Gelie is serious for Dynamic Water Vapor Sorption instrument comparison and detection result, and water suction weightening finish reaches 7.70%.Da Gelie is clean-propylene glycol-water eutectic water absorbability comparatively Da Gelie only decrease, when relative humidity is 95%, moisture absorption weightening finish is 1.85%.And Da Gelie clean-citric acid eutectic is when relative humidity is 95%, moisture absorption weightening finish only 1.12%, after illustrating that Da Gelie is clean and forming eutectic with citric acid, effectively can solve the problem that the clean water absorbability of Da Gelie is excessively strong, and be better than the clean commercialized product form of Da Gelie---Da Gelie only-propylene glycol-water eutectic.
Comparative example 1
Take the clean and 25mg citric acid of 40.8mg Da Gelie in test tube, add 0.5mL isopropyl acetate, sealing, stirs 2d and is formed to there being mass crystallization white solid under 25 DEG C of conditions, collect products therefrom, ambient temperature in vacuum drying obtains white powder Da Gelie clean-citric acid eutectic solid.Detect through PXRD, DSC, still there is more unreacted citric acid in product, have impact on the purity of product, be unfavorable for that raw material is for further production.
Comparative example 2
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL isopropyl acetate, sealing, stirs 2d under 80 DEG C of conditions, obtains muddy oily matter, and nodeless mesh white powder is formed, namely do not formed Da Gelie only-citric acid eutectic.
Comparative example 3
Take 40.8mg Da Gelie clean with 19.2mg citric acid in test tube, add 0.5mL methyl alcohol, sealing, stirs 2d under 25 DEG C of conditions, obtains muddy oily matter, without Da Gelie only-formation of citric acid eutectic.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. the clean eutectic formed with citric acid of Da Gelie, wherein Da Gelie only and the mol ratio of citric acid be 1:1.
2. eutectic according to claim 1, it is characterized in that: Da Gelie is clean-and the X-ray powder diffraction of citric acid eutectic at angle of diffraction 2 θ is: 8.9 ± 0.2, 12.2 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 15.3 ± 0.2, 16.2 ± 0.2, 17.8 ± 0.2, 18.2 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.4 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.9 ± 0.2, 24.8 ± 0.2, 25.8 ± 0.2, 26.6 ± 0.2, 29.2 ± 0.2, 30.0 ± 0.2, 32.0 ± 0.2, 32.8 ± 0.2, 33.2 ± 0.2, 33.9 ± 0.2, 35.5 ± 0.2, 36.1 ± 0.2, 37.3 ± 0.2, when 38.6 ± 0.2, there is characteristic peak.
3. Yi Zhong Da Gelie clean-preparation method of citric acid eutectic, comprise the steps:
1) by clean for Da Gelie be (0.9-1.1) in molar ratio with citric acid: (0.9-1.1) mixes;
2) only and in the mixture of citric acid add appropriate esters solvent to Da Gelie, make it be suspending system;
3) above-mentioned suspending system is fully stirred, crystallization, collect gained crystalline powder; Be drying to obtain arrival lattice and arrange clean-citric acid eutectic.
4. preparation method according to claim 3, is characterized in that: in step 1) Da Gelie clean with citric acid in molar ratio for 1:1 mixes.
5. preparation method according to claim 3, is characterized in that: step 2) in esters solvent be selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate.
6. preparation method according to claim 3, is characterized in that: step 2) in the clean and citric acid of every 100mg Da Gelie mixture in add esters solvent amount be 0.2 ~ 2.5mL.
7. preparation method according to claim 3, is characterized in that: step 2) in the clean and citric acid of every 100mg Da Gelie mixture in add esters solvent amount be 0.2 ~ 2.0mL.
8. preparation method according to claim 3, is characterized in that: temperature when stirring in step 3) is 0 ~ 70 DEG C.
9. the preparation method according to claim 3 or 6, is characterized in that: temperature when stirring in step 3) is 25 ~ 50 DEG C.
10. method according to claim 3, is characterized in that: the time of stirring in step 3) is not less than 2h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108863864A (en) * | 2018-08-16 | 2018-11-23 | 天津大学 | A kind of Florfenicol-citric acid eutectic and preparation method thereof |
| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
| CN114173766A (en) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | Solid compositions comprising a GLP-1 agonist, an SGLT2 inhibitor, and a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101479287A (en) * | 2006-06-28 | 2009-07-08 | 布里斯托尔-迈尔斯斯奎布公司 | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
| CN103502245A (en) * | 2011-05-09 | 2014-01-08 | 詹森药业有限公司 | L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r)-2-(3-((5- (4-fluorophenyl)thiophen-2-yl) methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
| WO2015198227A1 (en) * | 2014-06-23 | 2015-12-30 | Sun Pharmaceutical Industries Limited | Co-crystal of dapagliflozin with citric acid |
-
2016
- 2016-01-15 CN CN201610029562.8A patent/CN105503802A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101479287A (en) * | 2006-06-28 | 2009-07-08 | 布里斯托尔-迈尔斯斯奎布公司 | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
| CN103502245A (en) * | 2011-05-09 | 2014-01-08 | 詹森药业有限公司 | L-proline and citric acid co-crystals of (2s, 3r, 4r, 5s, 6r)-2-(3-((5- (4-fluorophenyl)thiophen-2-yl) methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol |
| WO2015198227A1 (en) * | 2014-06-23 | 2015-12-30 | Sun Pharmaceutical Industries Limited | Co-crystal of dapagliflozin with citric acid |
Non-Patent Citations (2)
| Title |
|---|
| 尼尔·G·安德森: "《实用有机合成工艺研发手册》", 31 January 2011, 科学出版社 * |
| 张昌军 等: "《有机化学实验》", 31 August 2006, 中国医药科技出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108863864A (en) * | 2018-08-16 | 2018-11-23 | 天津大学 | A kind of Florfenicol-citric acid eutectic and preparation method thereof |
| CN108863864B (en) * | 2018-08-16 | 2020-07-24 | 天津大学 | Florfenicol-citric acid eutectic crystal and preparation method thereof |
| CN114173766A (en) * | 2019-08-07 | 2022-03-11 | 诺和诺德股份有限公司 | Solid compositions comprising a GLP-1 agonist, an SGLT2 inhibitor, and a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid |
| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
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