CN104098572A - Eutectic form of Ticagrelor Brilinta - Google Patents
Eutectic form of Ticagrelor Brilinta Download PDFInfo
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- CN104098572A CN104098572A CN201310119094.XA CN201310119094A CN104098572A CN 104098572 A CN104098572 A CN 104098572A CN 201310119094 A CN201310119094 A CN 201310119094A CN 104098572 A CN104098572 A CN 104098572A
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- adz6140
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- powder diffraction
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- cocrystallizing type
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel eutectic form of Ticagrelor Brilinta (type I), wherein The eutectic compound is selected from L-proline or p-hydroxy benzoic acid, and pharmaceutical compositions containing these eutectic form and application thereof to manufacture of medicaments for preventing of arterial thrombotic complications for patients with coronary artery disease, cerebrovascular disease and peripheral vascular disease.
Description
Technical field
The invention provides the new cocrystallizing type of ADZ6140.
Background technology
[0002] ADZ6140 (compound shown in formula I), by Astrazeneca AB (AstraZeneca) research and development, obtains FDA approval for reducing the generation of acute coronary syndrome (ACS) patient Cardioversion on July 20th, 2011.ADZ6140 is a kind of novel, there is optionally anticoagulant, also be first reversible mating type P2Y12 adenosine diphosphate (ADP) acceptor (ADP) antagonist, purine 2 receptor subtype P2Y12 on vasoactive smooth muscle cell (VSMC) reversibly, the platelet aggregation that ADP is caused has obvious restraining effect, can effectively improve acute coronary patient's symptom.
（I）
WO2001/092262 discloses 4 kinds of crystal formations of ADZ6140, is respectively polymorphic I, polymorphic II, polymorphic III, polymorphic IV.Wherein the X-ray powder diffraction pattern of polymorphic I has special high strength peak at 2 θ of 5.3 ° (± 0.10 °), 20.1 ° (± 0.10 °), 20.7 ° (± 0.10 °), 21.0 ° (± 0.10 °) and 21.3 ° (± 0.10 °); Wherein the X-ray powder diffraction pattern of polymorphic II has special high strength peak at 2 θ of 5.5 ° (± 0.10 °), 13.5 ° (± 0.10 °), 18.3 ° (± 0.10 °), 22.7 ° (± 0.10 °) and 24.3 ° (± 0.10 °); Wherein the X-ray powder diffraction pattern of polymorphic III has special high strength peak at 2 θ of 14.0 ° (± 0.10 °), 17.4 ° (± 0.10 °), (± 0.10 °), 18.4 ° (± 0.10 °) 21.4 ° (± 0.10 °) and 24.1 ° (± 0.10 °); Wherein the X-ray powder diffraction pattern of polymorphic IV has special high strength peak at 2 θ of 4.9 ° (± 0.10 °), 9.2 ° (± 0.10 °), (± 0.10 °), 11.6 ° (± 0.10 °), 15.6 ° (± 0.10 °) and 16.4 ° (± 0.10 °).Summary of the invention
First object of the present invention is to provide the cocrystallizing type of a kind of ADZ6140 and L-PROLINE, and its X-ray powder diffraction pattern has absorption peak at 2 θ that comprise 6.08 ° (± 0.10 °), 11.26 ° (± 0.10 °), 17.06 ° (± 0.10 °).
Further, described ADZ6140 and the cocrystallizing type of L-PROLINE,, its X-ray powder diffraction pattern has absorption peak at 2 θ that comprise 6.08 ° (± 0.10 °), 11.26 ° (± 0.10 °), 13.62 ° (± 0.10 °), 17.06 ° (± 0.10 °), 18.19 ° (± 0.10 °) and 18.84 ° (± 0.10 °).
Further, described ADZ6140 and the cocrystallizing type of L-PROLINE, its X-ray powder diffraction pattern has absorption peak at 2 θ of 6.08 ° (± 0.10 °), 8.48 ° (± 0.10 °), 11.26 ° (± 0.10 °), 13.62 ° (± 0.10 °), 17.06 ° (± 0.10 °), 18.19 ° (± 0.10 °), 18.84 ° (± 0.10 °), 21.03 ° of (± 0.10 °) 23.77 ° (± 0.10 °).
Further, the dsc of the cocrystallizing type of ADZ6140 and L-PROLINE (DSC) analysis has been located absorption peak at approximately 156.57 ℃.
Further, the TGA of the cocrystallizing type of ADZ6140 and L-PROLINE analyzes demonstration, because of solvent, from crystal, separates out, and occurs approximately 1.06% weight loss gradient.
Described ADZ6140 and the cocrystallizing type of L-PROLINE are in organic solvent, to form saturated solution by ADZ6140 free alkali is dissolved in; Get supernatant liquor, add L-PROLINE, configuration saturated solution, crosses leaching supernatant liquor, and stirring and crystallizing obtains.Described organic solvent comprises: lower alcohol, lower paraffin hydrocarbons, acetone etc.; The mixed solvent of particular methanol and normal heptane, in described mixed solvent, the amount ratio of methyl alcohol and normal heptane is 1:1-10:1(V/V), preferred 3:1(V/V).Described stirring is at room temperature to stir.
Another object of the present invention, be to provide the cocrystallizing type of a kind of ADZ6140 and P-hydroxybenzoic acid, it is characterized in that X-ray powder diffraction pattern is comprising, 2 θ that 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 19.03 ° (± 0.10 °) are located have absorption peak.
Further, the X-ray powder diffraction pattern of described ADZ6140 and the cocrystallizing type of P-hydroxybenzoic acid comprising, 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 12.44 ° (± 0.10 °), 18.30 ° (± 0.10 °), 19.03 ° (± 0.10 °), 26.11 ° (± 0.10 °), 2 θ that locate have absorption peak.
Further, the X-ray powder diffraction pattern of described ADZ6140 and the cocrystallizing type of P-hydroxybenzoic acid is comprising, 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 9.81(± 0.10 °), 12.44 ° (± 0.10 °), 18.30 ° (± 0.10 °), 19.03 ° (± 0.10 °), 19.55(± 0.10 °), 24.24(± 0.10 °), 26.11 ° (± 0.10 °), 2 θ that locate have absorption peak.
Further, the dsc of the cocrystallizing type of ADZ6140 and L-PROLINE (DSC) analysis has been located absorption peak at approximately 125.48 ℃.
Further, the TGA of the cocrystallizing type of ADZ6140 and P-hydroxybenzoic acid analyzes demonstration, because of solvent, from crystal, separates out, and occurs approximately 0.345% weight loss gradient.
Described ADZ6140 and the cocrystallizing type of P-hydroxybenzoic acid are by ADZ6140 free alkali being dissolved in organic solvent and forming saturated solution, get supernatant liquor, adding P-hydroxybenzoic acid, and configuration saturated solution, crosses leaching supernatant liquor, and stirring and crystallizing obtains.Described organic solvent comprises: lower alcohol, lower paraffin hydrocarbons, acetone etc.; The mixed solvent of preferred acetone and normal heptane, in described mixed solvent, the amount ratio 1:1-10:1(V/V of acetone and normal heptane), be preferably 3:1(V/V).Described stirring is at room temperature to stir.
The cocrystallizing type of the new ADZ6140 that the present invention prepares has better solubleness and mobility with respect to the ADZ6140 crystal formation of free form, compares with existing crystal formation, is more suitable for the exploitation in solid preparation.
Further, the eutectic of ADZ6140 of the present invention and L-PROLINE, and the eutectic of ADZ6140 and P-hydroxybenzoic acid can be used for preventing or treating artery thrombosis and the complication thereof of the patient with coronary artery, the cerebrovascular or peripheral vascular disease.Described complication comprises unstable angina, arteriosclerosis, apoplexy, local asphyxia etc.
Further, the invention provides a kind of pharmaceutical composition of ADZ6140, said composition comprises the eutectic with L-PROLINE, or the eutectic of ADZ6140 and P-hydroxybenzoic acid and pharmaceutically acceptable carrier.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of the cocrystallizing type of ADZ6140 and L-PROLINE;
Fig. 2 is the thermogravimetric analysis figure of the cocrystallizing type of ADZ6140 and L-PROLINE;
Fig. 3 is the means of differential scanning calorimetry figure of the cocrystallizing type of ADZ6140 and L-PROLINE;
Fig. 4 is the X-ray powder diffraction figure of the cocrystallizing type of ADZ6140 and P-hydroxybenzoic acid;
Fig. 5 is the cocrystallizing type thermogravimetric analysis figure of ADZ6140 and P-hydroxybenzoic acid;
Fig. 6 is the cocrystallizing type means of differential scanning calorimetry figure of ADZ6140 and P-hydroxybenzoic acid.
Embodiment
Below will further set forth the present invention by specific embodiment, but be not limited to protection scope of the present invention.In following embodiment, except as otherwise noted, described test method is implemented according to the condition of normal condition or manufacturer's suggestion conventionally; Shown raw material, reagent all can obtain by the mode of commercially available purchase.
X-ray powder diffraction figure of the present invention gathers on Panalytical Empyrean x-ray powder diffraction instrument; Described means of differential scanning calorimetry figure gathers in TA Q200 differential scanning calorimeter; Described thermogravimetric analysis figure gathers on TA Q500 thermogravimetric analyzer.
Embodiment 1:
Get ADZ6140 crystal form II, the mixed solvent that adds pre-configured Methanol/n-Heptane (3/1), prepare the saturated solution of initial material, cross leaching supernatant liquor, add eutectic organizer L-PROLINE solid, prepare its saturated solution, cross leaching supernatant liquor, under room temperature, stir one day, solid collected by filtration is ADZ6140-L-PROLINE eutectic.As shown in Figure 1, as shown in Figure 2, means of differential scanning calorimetry figure as shown in Figure 3 for thermogravimetric analysis figure for its X-ray powder diffraction figure.
The special data of X-ray powder diffraction of ADZ6140 and L-PROLINE are as shown in table 1 below
Table 1
| Numbering | 2θ[°] | D-spacing [] | Relative intensity [%] |
| 1 | 6.08 | 14.54 | 100 |
| 2 | 8.48 | 10.42 | 11.58 |
| 3 | 11.26 | 7.86 | 22.21 |
| 4 | 13.62 | 6.50 | 16.41 |
| 5 | 17.06 | 5.20 | 47.94 |
| 6 | 18.19 | 4.88 | 17.31 |
| 7 | 18.84 | 4.71 | 20.00 |
| 8 | 21.03 | 4.23 | 12.87 |
| 9 | 23.77 | 3.74 | 10.62 |
Embodiment 2
Get ADZ6140 crystal form II, the mixed solvent that adds pre-configured acetone/normal heptane (3/1), prepare the saturated solution of initial material, cross leaching supernatant liquor, add eutectic organizer P-hydroxybenzoic acid solid, prepare its saturated solution, cross leaching supernatant liquor, under room temperature, stir one day, solid collected by filtration is ADZ6140-L-PROLINE eutectic.As shown in Figure 4, as shown in Figure 5, means of differential scanning calorimetry figure as shown in Figure 6 for thermogravimetric analysis figure for its X-ray powder diffraction figure.
The special data of X-ray powder diffraction of ADZ6140 and P-hydroxybenzoic acid are as shown in table 2 below
Table 2
| Numbering | 2θ[°] | D-spacing [] | Relative intensity [%] |
| 1 | 3.15 | 28.05 | 100.00 |
| 2 | 8.54 | 10.35 | 95.42 |
| 3 | 9.81 | 9.02 | 33.29 |
| 4 | 12.44 | 7.12 | 58.97 |
| 5 | 18.30 | 4.85 | 43.22 |
| 6 | 19.03 | 4.66 | 77.02 |
| 7 | 19.55 | 4.54 | 30.19 |
| 8 | 24.24 | 3.67 | 33.67 |
| 9 | 26.11 | 3.41 | 44.29 |
Claims (10)
1. a cocrystallizing type for ADZ6140 and L-PROLINE, is characterized in that, its X-ray powder diffraction pattern has absorption peak at 2 θ that comprise 6.08 ° (± 0.10 °), 11.26 ° (± 0.10 °), 17.06 ° (± 0.10 °).
2. cocrystallizing type according to claim 1, it is characterized in that, its X-ray powder diffraction pattern has absorption peak at 2 θ that comprise 6.08 ° (± 0.10 °), 11.26 ° (± 0.10 °), 13.62 ° (± 0.10 °), 17.06 ° (± 0.10 °), 18.19 ° (± 0.10 °) and 18.84 ° (± 0.10 °).
3. cocrystallizing type according to claim 2, it is characterized in that, its X-ray powder diffraction pattern has absorption peak at 2 θ of 6.08 ° (± 0.10 °), 8.48 ° (± 0.10 °), 11.26 ° (± 0.10 °), 13.62 ° (± 0.10 °), 17.06 ° (± 0.10 °), 18.19 ° (± 0.10 °), 18.84 ° (± 0.10 °), 21.03 ° of (± 0.10 °) 23.77 ° (± 0.10 °).
4. cocrystallizing type according to claim 1, is characterized in that, X-ray powder diffraction pattern substantially as shown in Figure 1.
5. a cocrystallizing type for ADZ6140 and P-hydroxybenzoic acid, is characterized in that X-ray powder diffraction pattern is comprising, 2 θ that 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 19.03 ° (± 0.10 °) are located have absorption peak.
6. cocrystallizing type according to claim 5, it is characterized in that X-ray powder diffraction pattern is comprising, 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 12.44 ° (± 0.10 °), 18.30 ° (± 0.10 °), 19.03 ° (± 0.10 °), 26.11 ° (± 0.10 °), 2 θ that locate have absorption peak.
7. cocrystallizing type according to claim 6, it is characterized in that X-ray powder diffraction pattern is comprising, 3.15 ° (± 0.10 °), 8.54 ° (± 0.10 °), 9.81(± 0.10 °), 12.44 ° (± 0.10 °), 18.30 ° (± 0.10 °), 19.03 ° (± 0.10 °), 19.55(± 0.10 °), 24.24(± 0.10 °), 26.11 ° (± 0.10 °), 2 θ that locate have absorption peak.
8. cocrystallizing type according to claim 5, is characterized in that, X-ray powder diffraction pattern substantially as shown in Figure 4.
9. a medicinal compositions, said composition comprises the cocrystallizing type of the ADZ6140 as described in claim 1 or 5 any one mixing mutually with pharmaceutically acceptable carrier.
10. the cocrystallizing type of the ADZ6140 described in claim 1 or 2 any one has patient's the artery thrombosis of coronary artery, the cerebrovascular or peripheral vascular disease and the purposes in the medicine of complication thereof for the preparation of prevention or treatment.
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| CN201310119094.XA CN104098572A (en) | 2013-04-08 | 2013-04-08 | Eutectic form of Ticagrelor Brilinta |
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| CN201310119094.XA CN104098572A (en) | 2013-04-08 | 2013-04-08 | Eutectic form of Ticagrelor Brilinta |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1432018A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Crystalline and amorphous form of triazolo (4,5-d) pyrimidine compound |
| CN101443328A (en) * | 2006-04-05 | 2009-05-27 | 安斯泰来制药有限公司 | Cocrystal of C-glycoside derivative and L-proline |
| CN102167715A (en) * | 2011-03-07 | 2011-08-31 | 上海惠斯生物科技有限公司 | Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals |
| WO2012164286A1 (en) * | 2011-06-01 | 2012-12-06 | Astrazeneca Ab | Novel ticagrelor co - crystal |
| CN102813664A (en) * | 2011-06-12 | 2012-12-12 | 王定豪 | Oral enteric preparation containing Grel drugs and aspirin |
-
2013
- 2013-04-08 CN CN201310119094.XA patent/CN104098572A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1432018A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Crystalline and amorphous form of triazolo (4,5-d) pyrimidine compound |
| CN101443328A (en) * | 2006-04-05 | 2009-05-27 | 安斯泰来制药有限公司 | Cocrystal of C-glycoside derivative and L-proline |
| CN102167715A (en) * | 2011-03-07 | 2011-08-31 | 上海惠斯生物科技有限公司 | Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals |
| WO2012164286A1 (en) * | 2011-06-01 | 2012-12-06 | Astrazeneca Ab | Novel ticagrelor co - crystal |
| CN102813664A (en) * | 2011-06-12 | 2012-12-12 | 王定豪 | Oral enteric preparation containing Grel drugs and aspirin |
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Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 Nano Technology Park building C25 Applicant after: Borui Pharmaceutical (Suzhou) Limited by Share Ltd Applicant after: Crystal Pharmatech Co., Ltd. Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 BioBAY building C27 Applicant before: Borui Bio-medical Technology (Jiangsu) Co., Ltd. Applicant before: Crystal Pharmatech Co., Ltd. |
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Application publication date: 20141015 |
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