WO2018178997A1 - Novel crystalline form of ticagrelor - Google Patents
Novel crystalline form of ticagrelor Download PDFInfo
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- WO2018178997A1 WO2018178997A1 PCT/IN2017/050244 IN2017050244W WO2018178997A1 WO 2018178997 A1 WO2018178997 A1 WO 2018178997A1 IN 2017050244 W IN2017050244 W IN 2017050244W WO 2018178997 A1 WO2018178997 A1 WO 2018178997A1
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- ticagrelor
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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
Definitions
- the present invention relates to novel crystalline form Form N of Ticagrelor and process for preparation of the same.
- Ticagrelor which is (15,25,3i?,55)-3-[7- ⁇ [(li?,25)-2-(3,4-Difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, having the structure
- Ticagrelor is approved under the trademark "BRILINTA" by US Food and Drug Administration for indicated for the prevention of thrombotic events.
- the U.S. patent Nos. 7265124 discloses four crystalline forms (I, II, III and IV) and amorphous (Form a) of Ticagrelor, process for their preparation, and characterizes the polymorphs by powder X-ray diffraction (XRPD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
- XRPD powder X-ray diffraction
- DSC differential scanning calorimetry
- the Ticagrelor crystalline Form-I can be prepared by two methods.
- Ticagrelor Form-I was prepared by heating and cooling of Ticagrelor Form II using DSC at temperatures 35 to 143 to 35 to 148 to 35 to 148 to 35° C.
- Ticagrelor Form-I was prepared by dissolving Ticagrelor in methanol and water mixture (5:7.3 ratio ml/g) followed by added seed of Ticagrelor Form-I.
- the Ticagrelor Form-Ill prepared by seed crystals of mixture of polymorphs of Form-II&III and was prepared by crystallization of Ticagrelor from ethanol overnight.
- the resulted seed crystals of mixture polymorph was added to the slurry of Ticagrelor Form-II suspended in 50% aqueous isopropanol and this slurry was stir for 2 days to afford Ticagrelor polymorphic Form-Ill.
- a novel crystalline Form- N of Ticagrelor wherein the ratio of intensities of the significant 2 ⁇ angles (XRPD, Fig.l) peaks of 5.5 ⁇ 0.2 (I) and 13.9 ⁇ 0.2 (I 0 ) is about 3.5 (I/ I 0 ).
- a novel crystalline Form-N of Ticagrelor further characterized by differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
- a novel crystalline Form- N of Ticagrelor further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
- a novel crystalline Form-N of Ticagrelor further characterized by IR spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521, 1451, 1328, 1091, 1052, 881, & 771 ⁇ 1.
- novel crystalline Form-N of Ticagrelor characterized by insignificant weight loss by thermogravimetric analysis.
- a crystal morphology that, the crystal morphology of novel crystalline Form-N of Ticagrelor indicates the product exists as monoclinic micro needles.
- a process for the preparation of novel crystalline Form-N of Ticagrelor comprising:
- Fig, 1 XRPD diffractogram of novel crystalline Form-N of Ticagrelor.
- Fig, 2 DSC thermogram of novel crystalline Form-N of Ticagrelor
- Fig. 3 Raman spectrum of novel crystalline Form-N of Ticagrelor.
- Fig, 4 infrared spectrum of novel crystalline Form-N of Ticagrelor.
- Fig. 5 Thermograviraetric analysis of novel crystalline Forrn-N of Ticagrelor.
- Fig, 6 Crystal morphology of novel crystalline Form-N of Ticagrelor.
- a novel crystalline Form-N of Ticagrelor having XPRD 20-reflections (°) at about 6.9 ⁇ 0.2.
- the novel crystalline Form-N of Ticagrelor is characterized by XRPD, wherein the ratio of intensities of the significant 2 ⁇ angles peaks of 5.5 ⁇ 0.2 (I) and 13.9 ⁇ 0.2 (Io) is about 3.5 (1/ 1 0 ).
- the novel crystalline Form-N of Ticagrelor is further characterized by a differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
- the novel crystalline Form-N of Ticagrelor is further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
- the novel crystalline Form-N of Ticagrelor is further characterised by having an infrared spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521 , 1451 , 1328, 1091 , 1052, 881, & 771 ⁇ 1.
- the novel crystalline Form-N of Ticagrelor is confirmed by thermogravimetric analysis as it is substantially anhydrous in nature.
- the crystal morphology of novel crystalline Form-N of Ticagrelor is shown to be monoclinic micro needles.
- Ticagrelor or Ticagrelor solvate is selected from Ticagrelor Form-I, Form-II, amorphous form or Ticagrelor DMF solvate preferably Ticagrelor DMF solvate.
- the polar solvent or mixture is selected from acetonitrile, propionitrile, methanol, isopropyl alcohol, ethanol, 1-propanol, butanol or its mixture, preferably mixture of acetonitrile-isopropyl alcohol.
- the ratio of acetonitrile and isopropyl alcohol is 7:3, 8:2 or 9: 1, preferably 9: 1.
- the dissolution temperature at which Ticagrelor or Ticagrelor solvate is dissolved in the range of 50-70°C preferably 65-70°C.
- the solution is optionally clarified over activated carbon, and filtrate is gradually cooled to 0-20°C preferably cooled to 0-5°C.
- the wet Ticagrelor Form-N thus obtained is dried at 40-60°C, preferably at 50-60°C
- the process of the present invention is feasible to produce novel crystalline polymorph, Form-N of Ticagrelor on commercial scale.
- Novel crystalline polymorph, Form-N of Ticagrelor is stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.
- the process of the present invention is suitable to convert Ticagrelor (technical grade) Ticagrelor Form-I, Form-II, amorphous form and Ticagrelor DMF solvate to novel crystalline Ticagrelor polymorph, Form-N.
- Novel crystalline polymorph, Form-N is stable at ambient temperature and also at elevated temperatures (60°C).
- Form-N of Ticagrelor is non-hygroscopic and is compatible for further pharmaceutical processing operations.
- Example 1 Process for the preparation of novel crystalline polymorph, Form-N of Ticagrelor.
- the Ticagrelor DMF solvate (150 g) was dissolved in 1200 ml of acetonitrile (1080 mL)-isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution, the solution was treated with activated carbon (15g) and filtered. The filtrate was again heated to 65-70°C and maintained for ⁇ 2h and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
- Crystal morphology Crystal morphology of Form-N of ticagrelor exhibits monoclinic microneedles
- Example 2 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-I
- the Ticagrelor Form-I (lOg) was dissolved in 80 ml of acetonitrile (72 mL)-isopropyl alcohol (8 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70° and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
- Example 3 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-II
- the Ticagrelor Form-II (150g) was dissolved in 1200 mL of acetonitrile (1080 mL)- isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70°C and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form-N dried under vacuum at 55-60°C.
- Example 4 Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Amorphous form
- the Ticagrelor amorphous form (25g) was dissolved in 200 ml of acetonitrile (180 mL)-isopropyl alcohol (20 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70° and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C. Yield: 21.5g; 86% by theory; HPLC Purity: >99.8%
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Abstract
The present invention relates to novel crystalline form, Form N of Ticagrelor and process for preparation of the same.
Description
NOVEL CRYSTALLINE FORM OF TICAGRELOR
FIELD OF THE INVENTION
The present invention relates to novel crystalline form Form N of Ticagrelor and process for preparation of the same.
BACKGROUND OF THE INVENTION
Ticagrelor which is (15,25,3i?,55)-3-[7- {[(li?,25)-2-(3,4-Difluorophenyl)cyclopropyl] amino} -5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, having the structure
HO OH
TICAGRELOR
Ticagrelor is approved under the trademark "BRILINTA" by US Food and Drug Administration for indicated for the prevention of thrombotic events.
The U.S. patent Nos. 7265124 discloses four crystalline forms (I, II, III and IV) and amorphous (Form a) of Ticagrelor, process for their preparation, and characterizes the polymorphs by powder X-ray diffraction (XRPD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
According to the U.S. patent Nos. 7265124 the Ticagrelor crystalline Form-I can be prepared by two methods. In the first method, Ticagrelor Form-I was prepared by heating and cooling of Ticagrelor Form II using DSC at temperatures 35 to 143 to 35 to 148 to 35 to 148 to 35° C. In the second method, Ticagrelor Form-I was prepared
by dissolving Ticagrelor in methanol and water mixture (5:7.3 ratio ml/g) followed by added seed of Ticagrelor Form-I.
The said U.S. patent Nos. 7265124 also described the process of crystalline Form-II from Ticagrelor by crystallization from chloroform.
According to the U.S. patent Nos. 7265124 the Ticagrelor Form-Ill prepared by seed crystals of mixture of polymorphs of Form-II&III and was prepared by crystallization of Ticagrelor from ethanol overnight. The resulted seed crystals of mixture polymorph was added to the slurry of Ticagrelor Form-II suspended in 50% aqueous isopropanol and this slurry was stir for 2 days to afford Ticagrelor polymorphic Form-Ill.
In our hands, by the following the disclosed process for Ticagrelor Form-Ill, we could not get mixture of polymorphs II & III as expected and also formation of crystalline product was not observed at all. Hence the reported process is not reproducible.
Consequently, there is still a need for an improved and reliable polymorphic form which would be reproducible on large scale, stable at standard pharmaceutical operations such as, filtration, drying, milling, stable at ambient storage conditions and prepared by a convenient process affording high yields and high purity.
SUMMARY OF THE I VENTION
In the course of our investigations on industrially feasible crystallization procedures for Ticagrelor, we surprisingly found a novel crystalline form of Ticagrelor, which will obviate the above difficulties in isolating the required polymorph.
During our continuous efforts in research & development, we have come across a novel crystalline form of Ticagrelor which is consistently reproducible, does not have the tendency to convert to other forms, and found to be more stable under standard
pharmaceutical operation conditions such as drying, milling, compression, granulation and blending with excipients.
In one aspect of the present invention, there is provided a novel crystalline Form-N of Ticagrelor having XPRD 20-reflections (°) at about 6.9±0.2
In a second aspect of the present invention, there is provided a novel crystalline Form- N of Ticagrelor, wherein the ratio of intensities of the significant 2Θ angles (XRPD, Fig.l) peaks of 5.5±0.2 (I) and 13.9±0.2 (I0) is about 3.5 (I/ I0).
In a third aspect of the present invention, there is provided a novel crystalline Form-N of Ticagrelor further characterized by differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
In a fourth aspect of the present invention, there is provided a novel crystalline Form- N of Ticagrelor further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
In a fifth aspect of the present invention, there is provided a novel crystalline Form-N of Ticagrelor further characterized by IR spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521, 1451, 1328, 1091, 1052, 881, & 771±1.
In a sixth aspect of the present invention, there is provided novel crystalline Form-N of Ticagrelor characterized by insignificant weight loss by thermogravimetric analysis.
In a seventh aspect of the present invention, there is provided a crystal morphology that, the crystal morphology of novel crystalline Form-N of Ticagrelor indicates the product exists as monoclinic micro needles.
In an eighth aspect of the present invention, there is provided a process for the preparation of novel crystalline Form-N of Ticagrelor comprising:
i. dissolve the Ticagrelor or Ticagrelor solvate in a polar solvent or mixture thereof;
ii. heat the reaction mixture to dissolve completely;
iii. cool the reaction mass to the desired temperature to obtain crystalline product. iv. filter the product and washing with solvent.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig, 1 : XRPD diffractogram of novel crystalline Form-N of Ticagrelor.
Fig, 2: DSC thermogram of novel crystalline Form-N of Ticagrelor,
Fig. 3: Raman spectrum of novel crystalline Form-N of Ticagrelor.
Fig, 4: infrared spectrum of novel crystalline Form-N of Ticagrelor.
Fig. 5: Thermograviraetric analysis of novel crystalline Forrn-N of Ticagrelor.
Fig, 6: Crystal morphology of novel crystalline Form-N of Ticagrelor.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment of the present invention, there is provided there is provided a novel crystalline Form-N of Ticagrelor having XPRD 20-reflections (°) at about 6.9±0.2.
In a Second embodiment of the present invention, the novel crystalline Form-N of Ticagrelor is characterized by XRPD, wherein the ratio of intensities of the significant 2Θ angles peaks of 5.5±0.2 (I) and 13.9±0.2 (Io) is about 3.5 (1/ 10).
In a third embodiment of the present invention, the novel crystalline Form-N of Ticagrelor is further characterized by a differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
In a fourth embodiments of the present invention, the novel crystalline Form-N of Ticagrelor is further characterized by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm-1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
In a fifth embodiment of the present invention, the novel crystalline Form-N of Ticagrelor is further characterised by having an infrared spectrum comprising absorbances at the following wavenumbers (cm-1): 3292. 1624, 1590, 1521 , 1451 , 1328, 1091 , 1052, 881, & 771±1.
In a sixth embodiment of the present invention, the novel crystalline Form-N of Ticagrelor, is confirmed by thermogravimetric analysis as it is substantially anhydrous in nature.
In a seventh embodiment of the present invention, the crystal morphology of novel crystalline Form-N of Ticagrelor is shown to be monoclinic micro needles.
In an eighth embodiment of the present invention, there is provided a process for the preparation of novel crystalline Form-N of Ticagrelor comprising:
i. dissolve the Ticagrelor or Ticagrelor solvate in a polar solvent or mixture thereof;
ii. heat the reaction mixture to dissolve completely;
iii. cool the reaction mass to the desired temperature to obtain crystalline product. iv. filter the product and washing with solvent.
Ticagrelor or Ticagrelor solvate is selected from Ticagrelor Form-I, Form-II, amorphous form or Ticagrelor DMF solvate preferably Ticagrelor DMF solvate.
The polar solvent or mixture is selected from acetonitrile, propionitrile, methanol, isopropyl alcohol, ethanol, 1-propanol, butanol or its mixture, preferably mixture of acetonitrile-isopropyl alcohol.
The ratio of acetonitrile and isopropyl alcohol is 7:3, 8:2 or 9: 1, preferably 9: 1.
The dissolution temperature at which Ticagrelor or Ticagrelor solvate is dissolved in the range of 50-70°C preferably 65-70°C.
After complete dissolution, the solution is optionally clarified over activated carbon, and filtrate is gradually cooled to 0-20°C preferably cooled to 0-5°C. The wet Ticagrelor Form-N thus obtained is dried at 40-60°C, preferably at 50-60°C
Advantages of the present invention
1. The process of the present invention is feasible to produce novel crystalline polymorph, Form-N of Ticagrelor on commercial scale.
2. Novel crystalline polymorph, Form-N of Ticagrelor is stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.
3. The process of the present invention is suitable to convert Ticagrelor (technical grade) Ticagrelor Form-I, Form-II, amorphous form and Ticagrelor DMF solvate to novel crystalline Ticagrelor polymorph, Form-N.
4. Novel crystalline polymorph, Form-N is stable at ambient temperature and also at elevated temperatures (60°C).
5. Form-N of Ticagrelor is non-hygroscopic and is compatible for further pharmaceutical processing operations.
The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention.
EXAMPLES
Example 1: Process for the preparation of novel crystalline polymorph, Form-N of Ticagrelor.
The Ticagrelor DMF solvate (150 g) was dissolved in 1200 ml of acetonitrile (1080 mL)-isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution, the solution was treated with activated carbon (15g) and filtered. The filtrate was again heated to 65-70°C and maintained for ~2h and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
Yield: 102. lg; 77.6% by theory; HPLC purity: 99.82%
DSC: Peak melting point 133.68°C (Fig. l)
XRPD (2Θ, °): ratio of intensities of the significant 2 theta angles peaks of 5.5±0.2 (I) and 13.9±0.2 (I0) is about 3.5 (1/ 10).
IR ^ cm"1): 3292, 2933, 1625, 1589, 1521, 1451, 1426, 1329, 1275, 1210, 1107, 1091, 1052, 881, 790, 771.
Raman (λ, cm"1): 2920(m), 1583(m), 1451(m), 1331(s), 1241(m), 1222(m), 1063(m),
TGA: No significant weight loss observed
Crystal morphology: Crystal morphology of Form-N of ticagrelor exhibits monoclinic microneedles
Example 2: Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-I
The Ticagrelor Form-I (lOg) was dissolved in 80 ml of acetonitrile (72 mL)-isopropyl alcohol (8 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70° and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with
acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C.
Yield: 8.1g; 81% by theory; HPLC Purity: >99.8%
XRPD (2Θ, °): ratio of intensities of the significant 2 theta angles peaks of 5.5±0.2 (I) and 13.9±0.2 (Io) is about 3.5 (1/ Io).
lR , cm"1): 3292, 1625, 1589, 1520, 1451, 1426, 1329, 1275, 1210, 1107, 1091, 1051, 881, 790, 771.
TGA: No significant weight loss observed
Example 3: Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Form-II
The Ticagrelor Form-II (150g) was dissolved in 1200 mL of acetonitrile (1080 mL)- isopropyl alcohol (120 mL) (9: 1) mixture. The reaction mixture was heated to 65-70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70°C and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form-N dried under vacuum at 55-60°C.
Yield: 131g; 87.3% by theory; HPLC Purity: >99.8%
XRPD (2Θ, °): ratio of intensities of the significant 2 theta angles peaks of 5.5±0.2 (I) and 13.9±0.2 (Io) is about 3.5 (1/ Io).
IR ^ cm"1): 3292, 2933, 1625, 1589, 1520, 1451, 1426, 1329, 1275, 1210, 1107, 1091, 1051, 881, 790, 771.
TGA: No significant weight loss observed
Example 4: Process for the preparation of crystalline polymorph, Form-N of Ticagrelor from Amorphous form
The Ticagrelor amorphous form (25g) was dissolved in 200 ml of acetonitrile (180 mL)-isopropyl alcohol (20 mL) (9: 1) mixture. The reaction mixture was heated to 65- 70°C to dissolve completely. After complete dissolution maintained for 2h at 65-70°
and the solution was gradually cooled to 0-5°C. The resulting product was filtered washed with acetonitrile to obtain the Ticagrelor crystalline polymorph, Form-N. The wet Ticagrelor crystalline polymorph, Form -N dried under vacuum at 55-60°C. Yield: 21.5g; 86% by theory; HPLC Purity: >99.8%
XRPD (2Θ, °): ratio of intensities of the significant 2 theta angles peaks of 5.5±0.2 (I) and 13.9±0.2 (Io) is about 3.5 (1/ Io).
lR , cm"1): 3292, 1625, 1589, 1520, 1450, 1426, 1329, 1275, 1210, 1107, 1091, 1051, 880, 790, 771
TGA: No significant weight loss observed
Claims
A crystalline form N of Ticagrelor which has an X-ray diffraction pattern as shown in Fig 1.
A crystalline form N of Ticagrelor having XPRD 20-reflections (°) at about 6.9±0.2.
The crystalline form N of Ticagrelor according to claim 1, wherein the ratio of the ratio of intensities of the significant 2Θ value at 5.5±0.2 (I) and 13.9±0.2 (Io) is about 3.5 (I/ Io).
The crystalline form N of Ticagrelor of according to claim 1, further characterised by a differential scanning calorimetry curve to have an onset of melting which is in the range 133-134° C.
The crystalline form N of Ticagrelor according to claim 1, further characterised by Raman spectra having the following characteristic absorption bands, expressed in wave number (cm"1): 2920, 1583, 1451, 1331, 1241, 1222, 815, 771.
The crystalline form N of Ticagrelor according to claim 1, further characterised by having an infrared spectrum comprising absorbances at the following wavenumbers (cm"1): 3292. 1624, 1590, 1521, 1451, 1328, 1091, 1052, 881, & 771±1.
The crystalline form N of Ticagrelor according to claim 1, having a purity of greater than or equal to about 99% as measured by HPLC.
The crystalline form N of Ticagrelor according to claim 1 is in substantially anhydrous form.
A process for the preparation of crystalline Form-N of Ticagrelor comprising:
i. dissolve the Ticagrelor or Ticagrelor solvate in a polar solvent or mixture thereof;
ii. heat the reaction mixture to dissolve completely;
iii. cool the reaction mass to the desired temperature to obtain crystalline product.
iv. filter the product and washing with solvent.
The Ticagrelor or Ticagrelor solvate according to claim 7, selected from Ticagrelor Form-I, Form-II, amorphous form or Ticagrelor DMF solvate. The polar solvent or mixture according to claim 7, selected from acetonitrile, propionitrile, methanol, isopropyl alcohol, ethanol, 1-propanol, butanol or mixtures thereof.
The polar solvent mixture according to claim 10, wherein the polar solvent mixture is acetonitrile and isopropyl alcohol in the ratio of 7:3, 8:2 or 9: 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201741011565 | 2017-03-31 | ||
| IN201741011565 | 2017-03-31 |
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| WO2018178997A1 true WO2018178997A1 (en) | 2018-10-04 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7265124B2 (en) | 2000-06-02 | 2007-09-04 | Astrazeneca Ab | Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound |
| WO2014000719A1 (en) * | 2012-06-29 | 2014-01-03 | Zentiva, K.S. | Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol |
-
2017
- 2017-06-19 WO PCT/IN2017/050244 patent/WO2018178997A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7265124B2 (en) | 2000-06-02 | 2007-09-04 | Astrazeneca Ab | Cristalline and amorphous form of a triazolo (4,5-D) pyridimine compound |
| WO2014000719A1 (en) * | 2012-06-29 | 2014-01-03 | Zentiva, K.S. | Novel pharmaceutical solid forms of (1s,2s,3r,5s)-3-[7-[(1r,2s)-2-(3,4difluorophenyl)cyclopropylamino]-5-(propylthio)-3h-[1,2,3]triazolo[4,5-d]pyrimidin-3yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol |
Non-Patent Citations (1)
| Title |
|---|
| CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163 - 208, XP008166276, ISSN: 0340-1022 * |
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