CN105524033A - Fumaric acid eutectic of dapagliflozin, and preparation method and pharmaceutical composition thereof - Google Patents
Fumaric acid eutectic of dapagliflozin, and preparation method and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention discloses a fumaric acid eutectic of dapagliflozin. The eutectic has a structural formula as shown in the specification, wherein X is equal to 1 or 2. The invention also discloses a preparation method for the above-mentioned fumaric acid eutectic of dapagliflozin, and a pharmaceutical composition containing the eutectic which is used as one of active ingredients. A single or double fumaric acid eutectic of dapagliflozin is prepared by the method provided by the invention through dissolution and crystallization of dapagliflozin and fumaric acid; and compared with a marketed crystal form of dapagliflozin, the crystal form provided by the invention is easier to be absorbed by human body, has better stability in an environment with high humidity, high temperature and strong-light irradiation, and is more suitable for industrial preparation of preparations.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly relate to the clean fumaric acid cocrystal of SGLT2 inhibitor Da Gelie, its preparation method and contain this eutectiferous pharmaceutical composition.
Background technology
Da Gelie is a kind of selectivity SGLT2 inhibitor only, and it can suppress uriniferous tubules glucose reabsorption, and unnecessary blood sugar is discharged through urine, thus reduces blood sugar in diabetic patients.Da Gelie is used for the treatment of Adult type II diabetes by U.S. FDA approval only, and its structural formula is as follows:
Da Gelie the accounts show a surplus of at multiple polymorphic forms, is referred to the amorphous forms that Da Gelie is clean in patent WO03099836, but this unformed contain 0.11% ethyl acetate, this is obviously not suitable as medicinal forms.
The clean amino acid co-crystal forms of Da Gelie (proline(Pro) and phenylalanine eutectic) is referred in patent WO2008002824, these eutectic preparation process all need the participation of organic solvent, and this patent does not propose effectively to avoid organic solvent to participate in the scheme of eutectic, therefore there is the possibility that organic solvent exceedes residual limit, and dissolvent residual too much obviously can produce larger impact to Drug safety.
Patent CN101479287B is referred to the eutectic of clean and (the S)-1,2-PD of Da Gelie, and (S)-1,2-PD is expensive, and this brings larger economical load by patient undoubtedly.The eutectiferous fusing point of (S)-1,2-PD that Da Gelie is clean is simultaneously lower, and only have about 70 DEG C, this brings larger challenge for formulation process.
Summary of the invention
One of the technical problem to be solved in the present invention is to provide the clean fumaric acid cocrystal of a kind of Da Gelie, and it is safer, more economical, have more druggability.
For solving the problems of the technologies described above, the fumaric acid cocrystal that Da Gelie of the present invention is clean, has following structural formula:
Wherein, X=1 or 2.
Two of the technical problem to be solved in the present invention is to provide the preparation method of the clean fumaric acid cocrystal of above-mentioned Da Gelie.
For solving the problems of the technologies described above, the fumaric acid cocrystal (eutectic I, X=1, single fumaric acid) that the first Da Gelie of the present invention is clean, its preparation method comprises the following steps:
1) Da Gelie is clean and fumaric acid dissolves is in inert solvent;
2) crystallization 1 ~ 48 hour at-18 DEG C ~ 60 DEG C temperature, suction filtration, washing, dry.
Step 1), Da Gelie molar ratio that is clean and fumaric acid is preferably 1:1 ~ 1:1.5.
Step 1), preferred inert solvent comprises: water, first alcohol and water, second alcohol and water, tetrahydrofuran (THF) and water; The equivalent of inert solvent is preferably 1:10 ~ 1:50.
Step 2), recrystallization temperature is preferably 20 DEG C ~ 30 DEG C; The crystallization time is preferably 16 ~ 24 hours.
The fumaric acid cocrystal (eutectic II, X=2, two fumaric acid) that the second Da Gelie of the present invention is clean, its preparation method comprises the following steps:
1) Da Gelie is clean and fumaric acid dissolves is in inert solvent;
2) stir 2 ~ 3 hours at 40 DEG C ~ 60 DEG C temperature;
3) crystallization 1 ~ 48 hour at-18 DEG C ~ 60 DEG C temperature, suction filtration, washing, dry.
Step 1), Da Gelie molar ratio that is clean and fumaric acid is preferably 1:1.5 ~ 1:4.
Step 1), preferred inert solvent comprises: water, first alcohol and water, second alcohol and water, tetrahydrofuran (THF) and water; The equivalent of inert solvent is preferably 1:10 ~ 1:50.
Step 3), recrystallization temperature is preferably 20 DEG C ~ 30 DEG C; The crystallization time is preferably 16 ~ 24 hours.
Three of the technical problem to be solved in the present invention is to provide containing above-mentioned eutectic and this eutectic is the pharmaceutical composition of one of activeconstituents.
The present invention by the clean and fumaric acid dissolves crystallization by Da Gelie, the list that acquisition Da Gelie is clean or two fumaric acid cocrystal, compared with the crystal formation of listing that Da Gelie is clean, the clean fumaric acid cocrystal of Da Gelie of the present invention has the following advantages and beneficial effect:
1. fusing point is high, is applicable to the preparation of industrialized preparation.The fusing point of the fumaric acid cocrystal that Da Gelie of the present invention is clean is more than 200 DEG C, far exceed (S)-1,2-PD eutectic that the Da Gelie that gone on the market is clean, in tablet granulation, tableting processes, tablet not easily deforms, and is more suitable for the preparation of industrialized preparation.
2. be easily absorbed by the body.The clean solubleness of fumaric acid cocrystal in simulated gastric fluid and simulated intestinal fluid of Da Gelie of the present invention is obviously greater than clean (S)-1 of the Da Gelie that gone on the market, 2-propylene glycol eutectic, visible, the clean fumaric acid cocrystal of Da Gelie of the present invention is more conducive to the oral absorption of the clean medicine of Da Gelie.
3., in high humidity, high temperature, strong illumination environment, every physics of the fumaric acid cocrystal that Da Gelie of the present invention is clean, chemical property (the S)-1,2-PD eutectic cleaner than the Da Gelie gone on the market is more stable.
Accompanying drawing explanation
Fig. 1 is eutectic I
1hNMR schemes.
Fig. 2 is the XPRD figure of eutectic I.
Fig. 3 is eutectic II
1hNMR schemes.
Fig. 4 is the XPRD figure of eutectic II.
Fig. 5 is the stripping curve figure of prescription 1 in embodiment 13.
Fig. 6 is the stripping curve figure of prescription 2 in embodiment 13.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted concrete reaction conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
In all embodiments, thermometer does not correct, and yield all represents with molar yield;
1h-NMR VarianMercury400 nuclear magnetic resonance analyser record, chemical shift represents with δ (ppm); GC is Shimadzu system; Mass spectrum Agilent6120LC-MS LC-MS instrument measures.
The preparation of embodiment 1 eutectic I
1g Da Gelie is clean, 1.0g fumaric acid joins in 10ml dehydrated alcohol and 40ml water, stirs, and adds thermosol clear, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 0.85g white solid.
The preparation of embodiment 2 eutectic I
1g Da Gelie is clean, 1.0g fumaric acid joins in 10ml tetrahydrofuran (THF) and 40ml water, stirs, and adds thermosol clear, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 0.95g white solid.
The preparation of embodiment 3 eutectic I
1g Da Gelie is clean, 1.0g fumaric acid joins in 50ml purified water, heating, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 1.1g white solid.
The preparation of embodiment 4 eutectic I
1g Da Gelie is clean, 1.0g fumaric acid joins in 10ml methyl alcohol and 40ml purified water, heating, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 1.01g white solid.
The preparation of embodiment 5 eutectic I
1g Da Gelie is clean, 0.5g fumaric acid joins in 25ml purified water, heating, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 0.92g white solid.
The preparation of embodiment 6 eutectic I
1g Da Gelie is clean, 0.3g fumaric acid joins in 15ml purified water, heating, and backflow 2 ~ 3h, is cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h, suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 0.96g white solid.
The preparation of embodiment 7 eutectic II
1g Da Gelie is clean, 1.5g fumaric acid joins in 50ml purified water, heating, backflow 2 ~ 3h, is first cooled to 60 DEG C and stirs 2 ~ 3h, then be cooled to 20 ~ 30 DEG C, stirring and crystallizing 16 ~ 24h suction filtration, washing, and 60 DEG C of vacuum-dryings, to dry, obtain 1.02g white solid.
The preparation of embodiment 8 eutectic II
1g Da Gelie is clean, 1.5g fumaric acid joins in 10ml methyl alcohol and 40ml purified water, heating, backflow 2 ~ 3h, is first cooled to 60 DEG C and stirs 2 ~ 3h, be cooled to 20 ~ 30 DEG C again, stirring and crystallizing 16 ~ 24h, suction filtration, washing, 60 DEG C of vacuum-dryings, to dry, obtain 0.87g white solid.
The preparation of embodiment 9 eutectic II
1g Da Gelie is clean, 1.5g fumaric acid joins in 10ml ethanol and 40ml purified water, heating, backflow 2 ~ 3h, is first cooled to 60 DEG C and stirs 2 ~ 3h, be cooled to 20 ~ 30 DEG C again, stirring and crystallizing 16 ~ 24h, suction filtration, washing, 60 DEG C of vacuum-dryings, to dry, obtain 0.84g white solid.
The constitutional features of embodiment 10 eutectic I characterizes
1. nucleus magnetic hydrogen spectrum (
1hNMR)
Testing conditions:
Instrument: VarianINOVA-400 (400MHz)
Solvent: DMSO-d6
Interior mark: TMS
Measure temperature: 313.1K
Eutectic I
1as shown in Figure 1, spectrum elucidation result refers to table 1 to HNMR spectrogram.
Table 1 eutectic I
1hNMR spectral data and parsing
| Proton assignments | Chemical potential (ppm) | Multiplicity | Proton number |
| 11 | 7.36 | d | 1 |
| 13 | 7.31 | s | 1 |
| 12 | 7.22 | d | 1 |
| 15，16 | 7.09 | d | 2 |
| 17，18 | 6.82 | d | 2 |
| 21，22 | 6.63 | s | 2 |
| 14 | 4.92 | d | 2 |
| 20 | 3.07 | t | 3 |
1hNMR spectrogram indicating characteristic chemical shift (6.82ppm, 17,18 hydrogen) proton number at place and characteristic chemical shifts (6.63ppm, the ethylene linkage hydrogen of fumaric acid) ratio of proton number at place is 1:1, disclosing Da Gelie ratio that is clean and fumaric acid is 1:1, meets structure and the composition of eutectic I.
2. powder x-ray diffraction method (XPRD)
The XPRD of eutectic I uses BrukerD8 Powder X-ray Diffractometer, and test condition is: CuK α light source
operating voltage 40kV/40mA, step-length 0.02 °, sweep velocity 12.0 °/minute, sweep limit 3 ° to 40 °.
As shown in Figure 2, spectrum elucidation result refers to table 2 to the XPRD spectrogram of eutectic I:
The XPRD spectral data of table 2 eutectic I
| Peak sequence number | Angle 2 θ |
| 1 | 3.900 |
| 2 | 7.974 |
| 3 | 10.958 |
| 4 | 13.970 |
| 5 | 15.495 |
| 6 | 15.630 |
| 7 | 17.356 |
| 8 | 18.860 |
| 9 | 19.421 |
| 10 | 20.309 |
| 11 | 22.770 |
The constitutional features of embodiment 11 eutectic II characterizes
1. nucleus magnetic hydrogen spectrum (
1hNMR)
Testing conditions:
Instrument: VarianINOVA-400 (400MHz)
Solvent: DMSO-d6
Interior mark: TMS
Measure temperature: 313.1K
Eutectic II
1as shown in Figure 3, spectrum elucidation result refers to table 3 to HNMR spectrogram:
Table 3 eutectic II
1hNMR spectral data and parsing
| Proton assignments | Chemical potential (ppm) | Multiplicity | Proton number |
| 11 | 7.36 | d | 1 |
| 13 | 7.31 | s | 1 |
| 12 | 7.22 | d | 1 |
| 15，16 | 7.09 | d | 2 |
| 17，18 | 6.82 | d | 2 |
| 21，22 | 6.63 | s | 4 |
| 14 | 4.92 | d | 2 |
| 20 | 3.07 | t | 3 |
1hNMR spectrogram indicating characteristic chemical shift (6.82ppm, 17,18 hydrogen) proton number at place and characteristic chemical shifts (6.63ppm, the ethylene linkage hydrogen of fumaric acid) ratio of proton number at place is 1:2, disclosing Da Gelie ratio that is clean and fumaric acid is 1:2, meets structure and the composition of eutectic II.
2. powder x-ray diffraction method (XPRD)
The XPRD of eutectic II uses BrukerD8 Powder X-ray Diffractometer, and test condition is: CuK α light source
operating voltage 40kV/40mA, step-length 0.02 °, sweep velocity 12.0 °/minute, sweep limit 3 ° to 40 °.
As shown in Figure 4, spectrum elucidation result refers to table 4 to the XPRD spectrogram of eutectic II:
The XPRD spectral data of table 4 eutectic II
| Peak sequence number | Angle 2 θ |
| 1 | 21.220 |
| 2 | 22.878 |
| 3 | 24.447 |
| 4 | 28.952 |
Only go on the market embodiment 12 eutectic of the present invention and Da Gelie physics between form, chemical property compare
For all medicinal compounds or composition, the physical properties of medicinal thing and chemical stability particularly important in the business development process of medicine.This kind of character comprises: fusing point, solubleness, the stability under suitable temperature, humidity and illumination condition.
One, fusing point compares
Fusing point measures by " Chinese Pharmacopoeia " 2010 editions two annex VI C first methods.
Fusing point test result is in table 5:
Table 5 crystalline melting point compares
| Eutectic title | Eutectic I (single fumaric acid) | Eutectic II (two fumaric acid) | Listing form (S propylene glycol) |
| Fusing point (DEG C) | 201-202 | 230-232 | 71.8-73.4 |
As seen from Table 5, the clean eutectiferous fusing point of (S)-1,2-PD of Da Gelie is less than 100 degrees Celsius, and fusing point is too low, and in tablet granulation, tableting processes, tablet is yielding, causes waste paper rate high, is extremely unfavorable for industrial production.The fusing point of eutectic I and II, more than 200 DEG C, is more suitable for the preparation of industrialized preparation.
Two, solubleness compares
1. sample preparation:
1) preparation of saturated solution: get appropriate test sample in 5ml Rong Liang ping, add respectively and in simulated gastric fluid and simulated intestinal fluid, make supersaturated solution (put in water-bath 37 DEG C of shaking tables 24 hours), via hole diameter is organic membrane filtration twice of 0.22 μm, obtains saturated solution.
2) preparation of reference substance solution: precision takes test sample 20mg in 10ml Rong Liang ping, and solubilizer methyl alcohol, makes sample dissolution, is then settled to scale, shakes up, more accurate dilution 25 is doubly, obtains reference substance solution.
3) preparation of sample solution: precision pipettes in saturated solution 1ml to 25ml Rong Liang ping, and solubilizer methyl alcohol, is settled to scale, shakes up and get final product.
2. solubility test:
Be weighting agent with octadecylsilane chemically bonded silica, by chromatographic condition below, by sample solution and reference substance solution each sample introduction 10 μ l, test liquid chromatography.
Chromatographic condition: mobile phase A is buffering salt (0.01MNa
2hPO
4, pH=6.0 (H
3pO4)), Mobile phase B is acetonitrile; Flow rate of mobile phase 1.0ml/min, determined wavelength 260nm, the gradient of gradient elution is as follows:
Calculation of Solubility formula:
C
right: reference substance solution concentration
A
sample: sample solution main peak peak area
A
right: reference substance solution main peak peak area
N: saturated solution extension rate
Solubleness test result is see table 6:
The solubleness of table 6 crystal
Table 6 data presentation, eutectic I and the solubleness of eutectic II in simulated gastric fluid and simulated intestinal fluid are obviously greater than listing crystal formation, show that the clean fumaric acid cocrystal of Da Gelie of the present invention is more conducive to Oral drug absorption.
Three, stability compares
1. high humidity stability compares
Trial-product is put in constant humidity encloses container, in 25 DEG C, place 10 days under RH75% ± 5% condition, the 5th day and sampling detection in the 10th day, test result was in table 7:
Table 7 high humidity stability test data
2. high-temperature stability compares
Trial-product is put in sealing clean container, places 10 days under 60 DEG C of conditions, in the 5th day and sampling in the 10th day, detects related index.Test result is in table 8:
Table 8 high-temperature stability test data
3. light durability compares
Trial-product was put in lighting box that fluorescent lamp is housed or other suitable illumination container, places 10 days under illumination 4500Lx ± 500Lx condition, the 5th day and sampling detection in the 10th day.The results are shown in Table 9:
Table 9 light durability test result
The data presentation of above-mentioned table 7 ~ 9, eutectic I of the present invention and eutectic II are in strong illumination test, high temperature test (60 DEG C), high wet test (humidity 75%), outward appearance and content have no significant change, eutectic I of the present invention and eutectic II stable in properties are described, particularly have the chemical property more stable than listing form crystal under the high temperature conditions.
The clean tablet of embodiment 13 Da Gelie
Above-mentioned eutectic I or eutectic II can form medicinal compositions with pharmaceutical excipient, according to disease to be treated and object, by oral way, once a day or repeatedly per daily dose (per daily dose is about 5 ~ 10mg eutectic I or eutectic II) administration.Be preferably composition for oral liquid, particularly oral tablet, capsule or granule.
The present embodiment provides two kinds of clean tablet formulations of Da Gelie, and prescription is specifically filled a prescription see table 10:
The prescription of the clean tablet of table 10 Da Gelie
The usage ratio of being pressed by above-mentioned supplementary material in table 10 weighs, and mix, direct compression, gained tablet coating powder carries out dressing and get final product.The stripping curve result of two prescriptions is see table 11,12, and stripping curve figure is see Fig. 5,6.From dissolution results, two prescriptions all can reach more than 85% at 15 minutes stripping quantities, and dissolved corrosion is better.
Table 11 prescription 1 stripping curve result
Table 12 prescription 2 stripping curve result
Claims (10)
1. the fumaric acid cocrystal that Da Gelie is clean, is characterized in that, has following structural formula:
Wherein, X=1 or 2.
2. the preparation method of the fumaric acid cocrystal that Da Gelie is clean, is characterized in that, step comprises:
1) Da Gelie is clean and fumaric acid dissolves is in inert solvent;
2) crystallization 1 ~ 48 hour at-18 DEG C ~ 60 DEG C temperature, suction filtration, washing, dry.
3. method according to claim 2, is characterized in that, step 1), Da Gelie molar ratio that is clean and fumaric acid is 1:1 ~ 1:1.5.
4. method according to claim 2, is characterized in that, step 1), described inert solvent comprises: water, first alcohol and water, second alcohol and water, tetrahydrofuran (THF) and water; The equivalent of inert solvent is 1:10 ~ 1:50.
5. method according to claim 2, is characterized in that, step 2), recrystallization temperature is 20 DEG C ~ 30 DEG C; The crystallization time is 16 ~ 24 hours.
6. the preparation method of the fumaric acid cocrystal that Da Gelie is clean, is characterized in that, step comprises:
1) Da Gelie is clean and fumaric acid dissolves is in inert solvent;
2) stir 2 ~ 3 hours at 40 DEG C ~ 60 DEG C temperature;
3) crystallization 1 ~ 48 hour at-18 DEG C ~ 60 DEG C temperature, suction filtration, washing, dry.
7. method according to claim 6, is characterized in that, step 1), Da Gelie molar ratio that is clean and fumaric acid is 1:1.5 ~ 1:4.
8. method according to claim 6, is characterized in that, step 1), described inert solvent comprises: water, first alcohol and water, second alcohol and water, tetrahydrofuran (THF) and water; The equivalent of inert solvent is 1:10 ~ 1:50.
9. method according to claim 6, is characterized in that, step 3), recrystallization temperature is 20 DEG C ~ 30 DEG C; The crystallization time is 16 ~ 24 hours.
10. containing eutectic described in claim 1 and this eutectic is the pharmaceutical composition of one of activeconstituents.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
| KR102111248B1 (en) * | 2019-12-30 | 2020-05-14 | 유니셀랩 주식회사 | New Empagliflozin cocrystal |
| WO2021105779A1 (en) * | 2019-11-27 | 2021-06-03 | Alparis, S.A. De C.V. | New solid forms of dapagliflozin |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
| CN114085203A (en) * | 2021-12-17 | 2022-02-25 | 宁波高新区美诺华医药创新研究院有限公司 | Dapagliflozin composition |
| WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
| WO2021105779A1 (en) * | 2019-11-27 | 2021-06-03 | Alparis, S.A. De C.V. | New solid forms of dapagliflozin |
| KR102111248B1 (en) * | 2019-12-30 | 2020-05-14 | 유니셀랩 주식회사 | New Empagliflozin cocrystal |
| WO2021137369A1 (en) * | 2019-12-30 | 2021-07-08 | 유니셀랩 주식회사 | Novel cocrystal of empagliflozin |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
| WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
| CN114085203A (en) * | 2021-12-17 | 2022-02-25 | 宁波高新区美诺华医药创新研究院有限公司 | Dapagliflozin composition |
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