CN105646603A - Crystal form A of ertugliflozin and preparation method - Google Patents
Crystal form A of ertugliflozin and preparation method Download PDFInfo
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- CN105646603A CN105646603A CN201610114024.9A CN201610114024A CN105646603A CN 105646603 A CN105646603 A CN 105646603A CN 201610114024 A CN201610114024 A CN 201610114024A CN 105646603 A CN105646603 A CN 105646603A
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- 239000013078 crystal Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims description 7
- MCIACXAZCBVDEE-CUUWFGFTSA-N Ertugliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl MCIACXAZCBVDEE-CUUWFGFTSA-N 0.000 title abstract description 4
- 229950006535 ertugliflozin Drugs 0.000 title abstract description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 10
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 6
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 6
- 230000005855 radiation Effects 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 6
- 230000009466 transformation Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- 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)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a crystal form A of ertugliflozin. The crystal form A is characterized in that Cu-K alpha radiation is used, X-RPD (X-ray powder diffraction) represented with the 2 theta angle has diffraction peaks at 5.0+/-0.2 degrees, 6.6+/-0.2 degrees, 7.5+/-0.2 degrees, 16.2+/-0.2 degrees, 18.5+/-0.2 degrees, 19.1+/-0.2 degrees, 19.7+/-0.2 degrees, 21.6+/-0.2 degrees, 22.2+/-0.2 degrees, 24.5+/-0.2 degrees, 24.8+/-0.2 degrees, 25.8+/-0.2 degrees, 26.8+/-0.2 degrees, 27.8+/-0.2 degrees and 29.5+/-0.2 degrees. The crystal form A has very good stability, the purity of HPLC (high performance liquid chromatography) is 99% or higher, and a crystal transformation phenomenon cannot occur. Besides, the solubility is high, the dissolution rate is good, and the bioavailability is high.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular it relates to the crystal formation that Ai Gelie is clean, and the preparation method of crystal formation.
Background technology
Ai Gelie clean (Ertugliflozin) be Pfizer with Mo Shadong cooperative research and development act on SGLT-2(sodium glucose co-transporter 2 white 2) type 2 diabetes mellitus medicine; SGLT-2 is nearest newfound treating diabetes novel targets; its mechanism of action is to suppress the kidney re-absorption to glucose specifically, and does not rely on the dysfunction of �� cell or the degree of insulin resistant. Its effect declines without exhaustion or severe insulin opposing along with �� cell function, will not produce the untoward reaction that conventional medicament brings, be the new way for the treatment of diabetes. Ai Gelie clean (Ertugliflozin) is also sent to great expectations. But compound finally successfully to be developed as oral drugs, bioavailability that dissolubility, dissolution are become reconciled and important.
Summary of the invention
It is desirable to provide the novel crystal forms A that a kind of Ai Gelie is clean, Heat stability is good, dissolubility is high and dissolution is good, and bioavailability is high.
The crystal form A that Ai Gelie of the present invention is clean, it is characterised in that use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 5.0 �� 0.2 ��, 6.6 �� 0.2 ��, 7.5 �� 0.2 ��, 16.2 �� 0.2 ��, 18.5 �� 0.2 ��, 19.1 �� 0.2 ��, 19.7 �� 0.2 ��, 21.6 �� 0.2 ��, 22.2 �� 0.2 ��, 24.5 �� 0.2 ��, 24.8 �� 0.2 ��, 25.8 �� 0.2 ��, 26.8 �� 0.2 ��, 27.8 �� 0.2 ��, there is diffraction maximum at 29.5 �� 0.2 �� of places.
Further, described crystal form A, use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is at 5.0 �� 0.2 ��, 5.5 �� 0.2 ��, 6.6 �� 0.2 ��, 7.5 �� 0.2 ��, 8.7 �� 0.2 ��, 16.2 �� 0.2 ��, 18.5 �� 0.2 ��, 19.1 �� 0.2 ��, 19.7 �� 0.2 ��, 20.6 �� 0.2 ��, 21.6 �� 0.2 ��, 22.2 �� 0.2 ��, 22.6 �� 0.2 ��, 24.0 �� 0.2 ��, 24.5 �� 0.2 ��, 24.8 �� 0.2 ��, 25.1 �� 0.2 ��, 25.8 �� 0.2 ��, 26.0 �� 0.2 ��, 26.1 �� 0.2 ��, 26.8 �� 0.2 ��, 27.2 �� 0.2 ��, 27.8 �� 0.2 ��, 28.5 �� 0.2 ��, 29.5 �� 0.2 ��, 29.9 �� 0.2 ��, 30.2 �� 0.2 ��, 30.6 �� 0.2 ��, 31.7 there is diffraction maximum at �� 0.2 �� of place.
The clean amorphous article of the preparation method of described crystal formation: Ai Gelie adds in acetate-methanol, and heating, to backflow, the methanol in progressively removing system, is cooled to 5 degree rapidly, insulated and stirred 2 hours, filters, and filter cake water rinses, and heating mill-drying obtains crystal form A.
Above-mentioned preparation method, Ai Gelie is clean and acetate-methanol addition is 1g:7mL:10mL. Cooling refers to and is cooled to 5 degree in 15min rapidly.
The present invention also provides for a kind of pharmaceutical composition, including described crystal form A and pharmaceutically acceptable excipient.
The present invention also provides for a kind of pharmaceutical composition, including the combination of described crystal form A and the second pharmacological active substance.
Crystal formation of the present invention has fabulous stability, HPLC high purity more than 99%, does not have and turns brilliant phenomenon. Additionally, dissolubility is high and dissolution is good, bioavailability is high.
Accompanying drawing explanation
Fig. 1 is the X-RPD collection of illustrative plates of crystal form A of the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition. Experiment material used in following example and reagent all can obtain from commercially available channel if no special instructions.
Embodiment 1
The clean amorphous article of 10g Ai Gelie adds in 70mL ethyl acetate-100mL methanol, and heating is to backflow, and the methanol in progressively removing system, 15min speed of having to go to the toilet is cooled to 5 degree, and insulated and stirred 2 hours filters, and filter cake water rinses, and heating mill-drying obtains crystal form A. Using Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is as it is shown in figure 1, HPLC purity is for 99.91%.
Mensuration about the crystal formation of embodiment 1 preparation:
1. stability test
When the clean crystal form A sample of Ai Gelie that Example 1 prepares is placed on 35 DEG C, investigating in the stability placing 1 month, 3 months, 6 months, result of the test is in Table 1. (method of concrete study on the stability is referred to the method for 2010 editions second annex XIXC of Chinese Pharmacopoeia; Purity detecting HPLC method, it is possible to reference to the method for 2010 editions second annex VD of Chinese Pharmacopoeia)
The stability test result of the clean crystal form A of table 1 Ai Gelie
| Purity % | Crystal formation | |
| 1 month | 99.91 | Same Fig. 1 |
| 3 months | 99.91 | Same Fig. 1 |
| 6 months | 99.90 | Same Fig. 1 |
2. solubility test
Measure the medium (phosphate buffer of water, 0.01mol/LHCl solution and pH6.8) of 10ml respectively in cillin bottle, add the excessive clean crystal form A of Ai Gelie, cillin bottle is sealed and puts 37 DEG C of constant temperature water baths stirrings 1 hour, through 0.45 ��m of membrane filtration, taking subsequent filtrate and measure absorbance respectively at the wavelength place of 284nm, result is in Table 2.
Table 2 Ai Gelie clean crystal form A dissolubility in different medium compares (�� g/ml)
| Water | 0.01mol/L HCl solution | The phosphate buffer of pH6.8 | |
| The clean crystal form A of Ai Gelie | 10.45 | 8.89 | 7.71 |
3. dissolution determination
Clean for Ai Gelie crystal form A being crossed 80 mesh sieves, weighs powder 10mg after sieving, according to two annex XC the second method (paddle method) devices of " Chinese Pharmacopoeia " version in 2010, dissolution medium is 500ml water respectively, rotating speed 100rpm, temperature 37 DEG C. Respectively at 10,15,30,45,60,90min sample 3ml, and fluid infusion 3ml in time, 0.22 ��m of filter membrane crossed by sample, and sample introduction, in HPLC, calculates dissolution. Result is in Table 3.
Table 3 Ai Gelie clean crystal form A dissolution percentage amounts/% in water
| Time (min) | The clean crystal form A of Ai Gelie |
| 10 | 15.23 |
| 15 | 23.66 |
| 30 | 36.95 |
| 45 | 41.09 |
| 60 | 45.26 |
| 90 | 46.00 |
Claims (7)
1. crystal form A clean for Ai Gelie, it is characterised in that use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 5.0 �� 0.2 ��, 6.6 �� 0.2 ��, 7.5 �� 0.2 ��, 16.2 �� 0.2 ��, 18.5 �� 0.2 ��, 19.1 �� 0.2 ��, 19.7 �� 0.2 ��, 21.6 �� 0.2 ��, 22.2 �� 0.2 ��, 24.5 �� 0.2 ��, 24.8 �� 0.2 ��, 25.8 �� 0.2 ��, 26.8 �� 0.2 ��, 27.8 �� 0.2 ��, there is diffraction maximum at 29.5 �� 0.2 �� of places.
2. crystal form A clean for Ai Gelie according to claim 1, it is characterized in that, use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is at 5.0 �� 0.2 ��, 5.5 �� 0.2 ��, 6.6 �� 0.2 ��, 7.5 �� 0.2 ��, 8.7 �� 0.2 ��, 16.2 �� 0.2 ��, 18.5 �� 0.2 ��, 19.1 �� 0.2 ��, 19.7 �� 0.2 ��, 20.6 �� 0.2 ��, 21.6 �� 0.2 ��, 22.2 �� 0.2 ��, 22.6 �� 0.2 ��, 24.0 �� 0.2 ��, 24.5 �� 0.2 ��, 24.8 �� 0.2 ��, 25.1 �� 0.2 ��, 25.8 �� 0.2 ��, 26.0 �� 0.2 ��, 26.1 �� 0.2 ��, 26.8 �� 0.2 ��, 27.2 �� 0.2 ��, 27.8 �� 0.2 ��, 28.5 �� 0.2 ��, 29.5 �� 0.2 ��, 29.9 �� 0.2 ��, 30.2 �� 0.2 ��, 30.6 �� 0.2 ��, 31.7 there is diffraction maximum at �� 0.2 �� of place.
3. the preparation method of crystal form A clean for Ai Gelie, it is characterised in that the clean amorphous article of Ai Gelie adds in acetate-methanol, heating is to refluxing, methanol in progressively removing system, is cooled to 5 degree rapidly, insulated and stirred 2 hours, filtering, filter cake water rinses, and heating mill-drying obtains crystal form A.
4. method according to claim 3, it is characterised in that described Ai Gelie is clean and acetate-methanol addition is 1g:7mL:10mL.
5. method according to claim 3, it is characterised in that cooling refers to and is cooled to 5 degree in 15min rapidly.
6. a pharmaceutical composition, including crystal form A described in claim 1 and pharmaceutically acceptable excipient.
7. a pharmaceutical composition, including the combination of crystal form A described in claim 1 and the second pharmacological active substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610114024.9A CN105646603A (en) | 2016-03-01 | 2016-03-01 | Crystal form A of ertugliflozin and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610114024.9A CN105646603A (en) | 2016-03-01 | 2016-03-01 | Crystal form A of ertugliflozin and preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105646603A true CN105646603A (en) | 2016-06-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610114024.9A Pending CN105646603A (en) | 2016-03-01 | 2016-03-01 | Crystal form A of ertugliflozin and preparation method |
Country Status (1)
| Country | Link |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018055496A1 (en) * | 2016-09-23 | 2018-03-29 | Granules India Limited | Crystalline ertugliflozin process |
| CN107857768A (en) * | 2018-01-04 | 2018-03-30 | 威海贯标信息科技有限公司 | A kind of net novel crystal forms of Ai Gelie |
| CN107898764A (en) * | 2017-12-12 | 2018-04-13 | 威海贯标信息科技有限公司 | A kind of net compositions of Ai Gelie |
| WO2019169988A1 (en) * | 2018-03-06 | 2019-09-12 | 广东东阳光药业有限公司 | Crystal forms of ertugliflozin and preparation method therefor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018055496A1 (en) * | 2016-09-23 | 2018-03-29 | Granules India Limited | Crystalline ertugliflozin process |
| CN107898764A (en) * | 2017-12-12 | 2018-04-13 | 威海贯标信息科技有限公司 | A kind of net compositions of Ai Gelie |
| CN107857768A (en) * | 2018-01-04 | 2018-03-30 | 威海贯标信息科技有限公司 | A kind of net novel crystal forms of Ai Gelie |
| WO2019169988A1 (en) * | 2018-03-06 | 2019-09-12 | 广东东阳光药业有限公司 | Crystal forms of ertugliflozin and preparation method therefor |
| CN111566112A (en) * | 2018-03-06 | 2020-08-21 | 广东东阳光药业有限公司 | Crystal form of eggliflozin and preparation method thereof |
| CN111566112B (en) * | 2018-03-06 | 2022-02-15 | 广东东阳光药业有限公司 | Crystal form of eggliflozin and preparation method thereof |
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