WO2012038785A1 - Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt - Google Patents

Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt Download PDF

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WO2012038785A1
WO2012038785A1 PCT/IB2010/055058 IB2010055058W WO2012038785A1 WO 2012038785 A1 WO2012038785 A1 WO 2012038785A1 IB 2010055058 W IB2010055058 W IB 2010055058W WO 2012038785 A1 WO2012038785 A1 WO 2012038785A1
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calcium
crystalline form
degrees
values
polymorph
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PCT/IB2010/055058
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French (fr)
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Srinivas Pullela Venkata
Anegondi Sreenivasa Prasad
Thangarasu Ponnusamy
Rajat Chaudhary
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Biocon Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present disclosure relates to novel crystalline forms and amorphous form of Rosuvastatin Acetonide Calcium which is known by chemical name (3R,5S,6E)- 7 - [4- (4-Fluoro- phenyl) -6-isopropyl-2-(methanesulfony 1- methyl-amino ) - pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt further resulted with good 10 recovery and purity.
  • the crystallanity of compound- 1 is further characterized by well- established techniques like XRD and FTIR.
  • the present disclosure is related to the methods of purification which further results in substantially pure crystalline and amorphous forms of Rosuvastatin acetonide calcium.
  • WO 2010029561 which is herein incorporated by reference discloses few methods for 20 the preparation of Rosuvastatin acetonide calcium. STATEMENT OF DISCLOSURE:
  • Rosuvastatin Acetonide Calcium [(3R,5S,6E)- 7 - [4-(4-Fluoro- phenyl) -6-isopropyl-2-(methanesulfony 1- methyl-amino) - pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium] salt; a process for preparation of polymorphs of Rosuvastatin Acetonide Calcium salt comprising acts of :
  • Rosuvastatin Acetonide Calcium salt dissolving Rosuvastatin Acetonide Calcium salt in solvents selected from the group consisting of aliphatic alcohols, aromatic hydrocarbons, aliphatic ethers, water and mixtures thereof, stirring the contents with solvent mixture, isolating the solids by filtration and drying to obtain polymorphs of Rosuvastatin Acetonide Calcium salt; a pharmaceutical composition, comprising polymorphs of Rosuvastatin Acetonide Calcium and at least one pharmaceutically acceptable compound selected from a group including excipient, diluent, carrier, binder and coating material and use of polymorphs of Rosuvastatin acetonide calcium salt in a medicine.
  • Figure 1 X-ray diffractogram of form 1 of Rosuvastatin Acetonide calcium salt.
  • Figure 2 X-ray diffractogram of form 2 of Rosuvastatin Acetonide calcium salt.
  • Figure 3 X-ray diffractogram of form 3 of Rosuvastatin Acetonide calcium salt.
  • Figure 4 X-ray diffractogram of form 4 of Rosuvastatin Acetonide calcium salt.
  • Figure 5 X-ray diffractogram of form 5 of Rosuvastatin Acetonide calcium salt.
  • Figure 6 X-ray diffractogram of form 6 of Rosuvastatin Acetonide calcium salt.
  • the polymorph is crystalline form 1.
  • the polymorph is crystalline form 2.
  • the polymorph is crystalline form 3.
  • the polymorph is crystalline form 4.
  • the polymorph is crystalline form 5. In still another embodiment of the present invention, the polymorph is crystalline form 6.
  • the polymorph is an amorphous.
  • the form 1 has an X-ray powder diffraction pattern comprising 5.94, 8.904, 10.736, 1 1.956, 13.312, 14.894, 15.782,
  • the X-ray powder diffraction pattern further contains 17.9, 18.4, 18.943, 21.596, 23.575, 24.648, 25.303, 25.736, 26.982,
  • the form 2 has an X-ray powder diffraction pattern comprising 3.842, 5.339, 7.38, 7.662, 9.389, 10.734, 18.703, 19.166, ⁇ 0.2 degrees 2 ⁇ values.
  • the X-ray powder diffraction pattern further contains 8.568, 10.402, 1 1.251, 1 1.68, 12.239, 12.542, 13.581, 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91 , 19.495, 19.846, 20.1, 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ⁇ 0.2 degrees 2 ⁇ values.
  • the form 3 has an X-ray powder diffraction pattern comprising 3.54, 8.805, 10.458, 10.708, 17.672, 17.972, 18.432, 19.215, ⁇ 0.2 degrees 2 ⁇ values.
  • the X-ray powder diffraction pattern further contains 7.114, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481 , 37.151 , 38.893, 40.44, 44.613, 45.42, 56.375, ⁇ 0.2 degrees 2 ⁇ values.
  • the form 4 has an X-ray powder diffraction pattern comprising 3.662, 4.226, 7.645, 8.854, 9.427, 10.47, 17.082, 18.807, 19.209, ⁇ 0.2 degrees 2 ⁇ values.
  • the X-ray powder diffraction pattern further contains 5.937, 1 1.062, 12.763, 15.129, 20.151, 21.245, 21.612, 22.456 ⁇ 0.2 degrees 2 ⁇ values.
  • the form 5 has an X-ray powder diffraction pattern comprising 3.554, 8.779, 10.388, 10.715, 17.624, 19.157, 19.527, ⁇ 0.2 degrees 2 ⁇ values.
  • the X-ray powder diffraction pattern further contains 7.132 12.74,13.699, 15.051, 15.906, 16.628, 17.061, 17.963, 18.407, 18.666, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981 , 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ⁇ 0.2 degrees 2 ⁇ values.
  • the form 6 has an X-ray powder diffraction pattern comprising 4.605, 6.971, 9.706, 13.603, 18.202, 18.51, 19.683, ⁇ 0.2 degrees 2 ⁇ values.
  • the X-ray powder diffraction pattern further contains 6.286, 7.56, 8.0, 8.708, 9.217, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 14.284, 14.929, 16.656, 17.177, 17.709, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462, ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure is also in relation to a process for preparation of polymorphs of Rosuvastatin Acetonide Calcium salt comprising acts of:
  • the aliphatic alcohols are selected from a group comprising CI - C3 alcohols.
  • the C 1 -C3 alcohols are selected from a group comprising methanol, ethanol and propanol.
  • the aromatic hydrocarbons are selected from a group comprising benzene and toluene.
  • aliphatic ethers are selected from a group comprising tetrahydrofuran and methyl tertiary butyl ether.
  • the solvents are used as a binary, tertiary or quaternary mixture.
  • the stirring time is ranging from about lOhr to about 50 hr.
  • stirring time is ranging from about 25hr to about 30 hr.
  • drying is carried out at temperature ranging from about 25 to about 70 °C under vacuum, (please inform about the lower limit of the temperature).
  • the drying is carried out in a vacuum drier.
  • the vacuum drier is selected from a group comprising vacuum tray drier and rotary drier.
  • the present disclosure is also in relation to a pharmaceutical composition, comprising polymorphs of Rosuvastatin Acetonide Calcium according to any preceding claims and at least one pharmaceutically acceptable compound selected from a group including excipient, diluent, carrier, binder and coating material.
  • the composition is in a form selected from a group comprising tablets, cachets, capsules, powders, dispersible granules and pills.
  • the present disclosure is also in relation to use of polymorphs of Rosuvastatin acetonide calcium salt in a medicine.
  • the object of the present disclosure is directed to preparation of different crystalline forms and an amorphous form of Rosuvastatin acetonide calcium.
  • the process employs the solvents like aliphatic alcohols, aromatic solvents and aliphatic hydrocarbons.
  • An embodiment of the present disclosure provides a crystalline form (Form-1) of Compound- 1 having the X-ray diffraction pattern with peaks at 5.917, 7.607, 8.193, 8.88, 9.815, 10.11 , 1 1.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651 , 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-1) of Compound-1 with peaks at 3434, 2968, 1601, 1549, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 573, 529 cm “1 .
  • the present disclosure provides a crystalline form (Form-2) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.842, 5.339, 7.38, 7.662, 8.568, 9.389, 10.402, 10.734, 1 1.251, 1 1.68, 12.239, 12.542, 13.581, 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91, 18.703, 19.166, 19.495, 19.846, 20.1 , 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-2) of Compound-1 with peaks at 3429, 2968, 1601, 1550, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 568, 519 cm "1 .
  • the present disclosure provides a crystalline form (Form-3) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.54, 7.1 14, 8.805, 10.458, 10.708, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 17.672, 17.972, 18.432, 19.215, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481, 37.151, 38.893, 40.44, 44.613, 45.42, 56.375 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-3)of Compound-1 with peaks at 3429, 2968, 1601, 1550, 1510, 1438, 1382, 1337, 1230, 1199, 1 157, 966, 776, cm "1 .
  • the present disclosure provides a crystalline form (Form-4) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.662, 4.226, 5.937, 7.645, 8.854, 9.427, 10.47, 11.062, 12.763, 15.129, 17.082, 18.807, 19.209, 20.151, 21.245, 21.612, 22.456 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-4) of Compound-1 with peaks at 3434, 2968, 1601, 1549, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 573, 529 cm “1 .
  • the present disclosure provides a crystalline form (Form-5) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.554, 7.132, 8.779, 10.388, 10.715, 12.74, 13.699, 15.051, 15.906, 16.628, 17.061, 17.624, 17.963, 18.407, 18.666, 19.157, 19.527, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981, 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-5) of Compound-1 with peaks at 3436, 2966, 1548, 1511, 1437, 1381, 1337, 1230, 1199, 1155, 966, 845, 776, 572, 518 cm 1 .
  • the present disclosure provides a crystalline form (Form-6) of Compound- 1 having the X-ray diffraction pattern with peaks at 4.605, 6.286, 6.971, 7.56, 8.0, 8.708, 9.217, 9.706, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 13.603, 14.284, 14.929, 16.656, 17.177, 17.709, 18.202, 18.51, 19.683, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462 ⁇ 0.2 degrees 2 ⁇ values.
  • the present disclosure provides FTIR spectra of crystalline form (Form-6) of Compound-1 with peaks at 3436, 2966, 1548, 1511, 1437, 1381, 1337, 1230, 1199, 1155, 966, 845, 776, 572, 518 cm 1 .
  • the present disclosure provides a method to prepare (Compound- 1) in a substantially pure amorphous form using solvents from a group consisting of aliphatic esters, aliphatic ketones.
  • the present disclosure provides FTIR spectra of amorphous form of Compound-1 with peaks at 3433, 2971 , 1601, 1545, 1510, 1439, 1381, 1337, 1266, 1199, 1156, 963, 845, 776, 570, 520 cm "1 .
  • the present disclosure relates to the purification of Compound-1 and isolation of crystalline and amorphous forms of the same.
  • Compound-1 was prepared according to the known processes in the prior art application WO2010/029561.
  • the present disclosure provides a method for Purification and preparation of different polymorphs of compound-1 comprising the steps of:
  • solvents for purification are selected from a group comprising of CI- C3 aliphatic alcohols like methanol, ethanol and isopropanol.
  • Solvent is in an amount of 5-10 vol, most preferably 10.0 vol relative to Compound -1.
  • Solvents can be selected from a group consisting of aromatic hydrocarbons like Benzene, Toluene. Solvent is in an amount of 2-5 vol, relative to Compound -1.
  • Solvents can be selected from a group consisting of Tetrahydrofuran and Methyl tertiary butyl ether. Solvent is in an amount of 1.0-2.5 vol, relative to Compound - 1. In another embodiment, water can be selected in an amount of 1.0-2.5 vol, most preferably 1.5 vol relative to Compound -1.
  • solvents can be used as a binary mixture or quaternary mixture from the group of solvents mentioned above along with water in required proportions.
  • reactions stirring time is selected between 10 - 50 hrs, preferably 25-30 hrs which may vary depending on the reaction conditions.
  • the resulting crystalline solids from the above mentioned aspects are recovered by conventional techniques like filtration.
  • the crystals are then dried. Drying may be carried out at a temperature less than 50-55°C under vacuum in vacuum tray drier or rotary drier.
  • the disclosure encompasses a crystalline form (Form-1) of compound - 1 characterized by powder X-Ray diffraction pattern having prominent peaks at 5.94, 8.904, 10.736, 11.956, 13.312, 14.894, 15.782, 20.182 ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 17.9, 18.4, 18.943, 21.596, 23.575, 24.648, 25.303, 25.736, 26.982, 27.828, 29.8, 30.104, 32.668, 32.793, 33.296, 37.377, 38.742, 39.201 , 40.334, 41.21 1 , 48.204, 50.837, 54.196, ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline compound (Form-1) of the present disclosure shows main FTIR peaks at 3434, 2968, 1601 , 1549, 1510, 1437, 1382, 1337, 1267, 1 199, 1 156, 965, 845, 776, 573, 529 cm “1 .
  • the most intense peaks appear at 3434, 2968, 1601 ,1549, 1510,1437,1382, 1 156, 965, 845, 776, 573, 529 cm "1'
  • the disclosure encompasses a crystalline form (Form-2) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.842, 5.339, 7.38, 7.662, 9.389, 10.734, 18.703, 19.166, ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 8.568, 10.402, 1 1.251 , 1 1.68, 12.239, 12.542, 13.581 , 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91 , 19.495, 19.846, 20.1 , 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline intermediate of the present disclosure shows main FTIR peaks at 3429, 2968, 1601 , 1550, 1510, 1437, 1382, 1337, 1267, 1 199, 1 156, 965, 845, 776, 568, 519 cm "1 .
  • the most intense peaks appear at 3434, 2968, 1601 , 1550, 1382, 1 156, 966, 776 cm "1'
  • the disclosure encompasses a crystalline form (Form-3) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.54, 8.805, 10.458, 10.708, 17.672, 17.972, 18.432, 19.215, ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 7.114, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481 , 37.151 , 38.893, 40.44, 44.613, 45.42, 56.375, ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline compound (Form-3) of the present disclosure shows main FTIR peaks at 3429, 2968, 1601, 1550, 1510, 1438, 1382, 1337, 1230, 1 199, 1157, 966, 776, cm 1 .
  • the most intense peaks appear at 3434, 2968, 1601, 1550, 1438, 1382, 1157, 965, 845, 776, 573, 529 cm 1'
  • the disclosure encompasses a crystalline form (Form-4) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.662, 4.226, 7.645, 8.854, 9.427, 10.47, 17.082, 18.807, 19.209, ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 5.937, 11.062, 12.763, 15.129, 20.151, 21.245, 21.612, 22.456 ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline compound (Form-4) of the present disclosure shows main FTIR peaks at 3445, 2966, 1600, 1549, 1510, 1437, 1382, 1338, 1267, 1200, 1156, 963, 776, 573, 529 cm “1 .
  • the most intense peaks appear at 3445, 2966, 1600,1549,1437,1382, 1156, 963,776, 573, 529 cm "L
  • An embodiment of the present disclosure encompasses a crystalline form (Form- 5) of compound - 1 characterized by powder X-Ray Diffraction pattern having Prominent peaks at 3.554, 8.779, 10.388, 10.715, 17.624, 19.157, 19.527, ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 7.132 12.74,13.699, 15.051, 15.906, 16.628, 17.061, 17.963, 18.407, 18.666, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981, 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline compound (Form-5) of the present disclosure shows main FTIR peaks at 3436, 2966, 1548, 1511, 1437, 1381 , 1337, 1230, 1199, 1 155, 966, 845, 776, 572, 518 cm “1 .
  • the most intense peaks appear at 3436, 2966, 1548, 1381, 1337, 1155, 966 cm "1
  • the disclosure encompasses a crystalline form (Form-6) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 4.605, 6.971, 9.706, 13.603, 18.202, 18.51 , 19.683, ⁇ 0.2 degrees 2 ⁇ values.
  • the crystalline form may be further characterized by X-Ray powder diffraction peaks at about 6.286, 7.56, 8.0, 8.708, 9.217, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 14.284, 14.929, 16.656, 17.177, 17.709, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462, ⁇ 0.2 degrees 2 ⁇ values.
  • crystalline compound (Form-6) of the present disclosure shows main FTIR peaks at 3433, 2971 , 1601, 1545, 1510, 1439, 1381, 1337, 1266, 1 199, 1156, 963, 845, 776, 570, 520 cm “1 .
  • the most intense peaks appear at 3434, 2971 , 1545, 1510, 1381, 1156, 963, 845, 776, 570, 520 cm 1'
  • amorphous compound of the present disclosure shows main FTIR peaks at 3435, 2968, 1602, 1549, 1510, 1437, 1381, 1338, 1268, 1229,1199, 1156, 964, 844, 775, 573, 519 cm "1 .
  • the most intense peaks appear at 3434, 2968, 1602, 1549, 1510, 1437, 1381, 1338, 1 156, 964, 844, 775, 573, 529 cm "L
  • the polymorphs of Rosuvastatin acetonide Calcium salt is used for the treatment of hyperlipidemia.
  • pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include tablets, cachets, capsules, powders, dispersible granules or pills.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • Rosuvastatin Acetonide calcium is formulated by employing Microcrystalline cellulose, Lactose monohydrate, Tribasic calcium phosphate, Crospovidone, Magnesium stearate, Hydroxy propyl methyl cellulose, Triacetin, Titanium dioxide, Yellow ferric oxide and red ferric oxide as other ingradients.
  • Rosuvastatin intermediate of the present disclosure is characterized by X- Ray powder Diffraction (XRD), DSC analysis, and FTIR spectroscopy.
  • FTIR Spectrum was recorded on Perkin-Elmer spectrum- 1 spectrometer, Diffuse Reflectance Technique. The sample was finely ground with Potassium Bromide, and the spectrum was recorded using Potassium Bromide background in a Diffused reflectance accessory.
  • Reaction mass was filtered through celite bed and washed with 4mL methanol. Filtrate was concentrated under vacuum at 50°C Then stripped of with 5mL acetonitrile to get a solid. Added acetonitrile (10 mL) and filtered the insolubles. Concentrated the filtrate and added 40mL Water, 3mL Methanol & 6mL MTBE and separated the aqueous layer. Aqueous layer was washed with 6mL MTBE. Another 6mL MTBE Wash was given to the aqueous layer after adjusting the pH to 8.0- 8.2 using 0.5N HCL. Heated the aqueous layer to 40-45°C and stirred for 30 mins.
  • Example 1 Preparation of crystalline compound-1 using THF-Toluene-IPA-HiO
  • Example 7 Preparation of crystalline compound-1 using THF-Toluene-Petether- H 2 0
  • Example 8 Preparation of crystalline compound-1 using THF-Xylene-ACN-H 2 0
  • Compound-1 (lO.Og) was dissolved in THF (20ml) and added Xylene (20ml) and stir for 10 min. Added water (2.5ml) followed addition of ACN(lOml) for about 30 minute, reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (7.0 g) as a white crystalline solid.
  • Formula 3 3
  • Example 13 Preparation of crystalline compound-1 using Ethyl Acetate -ACN-H 2 0
  • Compound-1 (lO.Og) was dissolved in Ethyl Acetate (10ml) and added ACN (10ml) and stir for 10 min.
  • Added water (1 ml) reaction mass was stirred for 20-24hrs.
  • the separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (2.5 g) as a white crystalline solid.
  • Form-5 Form-5
  • Example 14 Preparation of crystalline compound-1 using THF-Cyclo hexene- Ethyl Acetate -H 2 0
  • Example 16 Preparation of crystalline compound-1 using THF-Cyclohexene- Toluene-H 2 0
  • Example 17 Preparation of crystalline compound-1 using THF-Xylene- Ethyl Acetate -H 2 0
  • Example 20 Preparation of amorphous compound-1 using THF-MTBE-IPA-H 2 0
  • Example 23 Preparation of amorphous compound-1 using MeOH- Pet ether -EA- Compound- 1 (10. Og) was dissolved in MeOH (30ml) and added pet ether (40ml) and stir for 10 min. Added water (1 ml) followed addition of EA (20ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white Amorphous solid.
  • Example 25 Preparation of amorphous compound-1 using IPA-ACN- Ethyl Acetate -MeOH
  • Example 26 Preparation of amorphous compound-1 using ACETONE- Pet ether - Ethyl Acetate -H 2 0
  • Example 27 Preparation of amorphous compound-1 using ACETONE- Pet ether - Ethyl Acetate -H 2 0

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Abstract

The present invention relates to crystalline forms and an amorphous form of Rosuvastatin Acetonide Calcium which is known by the systemic chemical name (3R,5S,6E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dipxan-4-yl) acetic acid calcium salt. The present invention also provides the processes for the preparation of the disclosed crystalline forms and amorphous form of Rosuvastatin Acetonide Calcium.

Description

POLYMORPHS OF ROSUVASTATIN ACETONIDE CALCIUM ((3R,5S,6E)-7-[4-(4- FLUOROPHENYL)-6-ISOPROPYL-2-(METHANESULFONYL-METHYL-AMINO)-PYRIMIDIN-5- YL)VTNYL)-2,2-DIMETHYL-l,3-DIOXAN-4-YL) ACETIC ACID CALCIUM SALT
5 TECHNICAL FIELD:
The present disclosure relates to novel crystalline forms and amorphous form of Rosuvastatin Acetonide Calcium which is known by chemical name (3R,5S,6E)- 7 - [4- (4-Fluoro- phenyl) -6-isopropyl-2-(methanesulfony 1- methyl-amino ) - pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt further resulted with good 10 recovery and purity. The crystallanity of compound- 1 is further characterized by well- established techniques like XRD and FTIR.
BACKGROUND:
Figure imgf000002_0001
15 Compound 1
Rosuvastatin Acetonide Calcium
The present disclosure is related to the methods of purification which further results in substantially pure crystalline and amorphous forms of Rosuvastatin acetonide calcium.
WO 2010029561 , which is herein incorporated by reference discloses few methods for 20 the preparation of Rosuvastatin acetonide calcium. STATEMENT OF DISCLOSURE:
Accordingly the present disclosure provides polymorphs of Rosuvastatin Acetonide Calcium [(3R,5S,6E)- 7 - [4-(4-Fluoro- phenyl) -6-isopropyl-2-(methanesulfony 1- methyl-amino) - pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium] salt; a process for preparation of polymorphs of Rosuvastatin Acetonide Calcium salt comprising acts of :
dissolving Rosuvastatin Acetonide Calcium salt in solvents selected from the group consisting of aliphatic alcohols, aromatic hydrocarbons, aliphatic ethers, water and mixtures thereof, stirring the contents with solvent mixture, isolating the solids by filtration and drying to obtain polymorphs of Rosuvastatin Acetonide Calcium salt; a pharmaceutical composition, comprising polymorphs of Rosuvastatin Acetonide Calcium and at least one pharmaceutically acceptable compound selected from a group including excipient, diluent, carrier, binder and coating material and use of polymorphs of Rosuvastatin acetonide calcium salt in a medicine.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS:
The features of the present disclosure will become more fully apparent from the following description taken in conjunction with the accompanying drawings. Understanding that the drawings depict only several embodiments in accordance with the disclosure and are therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings:
Figure 1: X-ray diffractogram of form 1 of Rosuvastatin Acetonide calcium salt.
Figure 2 : X-ray diffractogram of form 2 of Rosuvastatin Acetonide calcium salt.
Figure 3 : X-ray diffractogram of form 3 of Rosuvastatin Acetonide calcium salt.
Figure 4 : X-ray diffractogram of form 4 of Rosuvastatin Acetonide calcium salt.
Figure 5 : X-ray diffractogram of form 5 of Rosuvastatin Acetonide calcium salt.
Figure 6 : X-ray diffractogram of form 6 of Rosuvastatin Acetonide calcium salt. DETAILED DESCRIPTION OF DISCLOSURE:
The present disclosureis in relation to polymorphs of Rosuvastatin Acetonide Calcium
[(3R,5S,6E)- 7 - [4-(4-Fluoro- phenyl) -6-isopropyl-2-(methanesulfony 1-methyl-amino)
- pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium] salt.
In an embodiment of the present invention, the polymorph is crystalline form 1.
In another embodiment of the present invention, the polymorph is crystalline form 2.
In still another embodiment of the present invention, the polymorph is crystalline form 3.
In still another embodiment of the present invention, the polymorph is crystalline form 4.
In still another embodiment of the present invention, the polymorph is crystalline form 5. In still another embodiment of the present invention, the polymorph is crystalline form 6.
In still another embodiment of the present invention, the polymorph is an amorphous.
In still another embodiment of the present invention, the form 1 has an X-ray powder diffraction pattern comprising 5.94, 8.904, 10.736, 1 1.956, 13.312, 14.894, 15.782,
20.182 ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 17.9, 18.4, 18.943, 21.596, 23.575, 24.648, 25.303, 25.736, 26.982,
27.828, 29.8, 30.104, 32.668, 32.793, 33.296, 37.377, 38.742, 39.201, 40.334, 41.211,
48.204, 50.837, 54.196, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the form 2 has an X-ray powder diffraction pattern comprising 3.842, 5.339, 7.38, 7.662, 9.389, 10.734, 18.703, 19.166, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 8.568, 10.402, 1 1.251, 1 1.68, 12.239, 12.542, 13.581, 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91 , 19.495, 19.846, 20.1, 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ± 0.2 degrees 2Θ values. In still another embodiment of the present invention, the form 3 has an X-ray powder diffraction pattern comprising 3.54, 8.805, 10.458, 10.708, 17.672, 17.972, 18.432, 19.215, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 7.114, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481 , 37.151 , 38.893, 40.44, 44.613, 45.42, 56.375, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the form 4 has an X-ray powder diffraction pattern comprising 3.662, 4.226, 7.645, 8.854, 9.427, 10.47, 17.082, 18.807, 19.209, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 5.937, 1 1.062, 12.763, 15.129, 20.151, 21.245, 21.612, 22.456 ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the form 5 has an X-ray powder diffraction pattern comprising 3.554, 8.779, 10.388, 10.715, 17.624, 19.157, 19.527, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 7.132 12.74,13.699, 15.051, 15.906, 16.628, 17.061, 17.963, 18.407, 18.666, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981 , 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees 2Θ values. In still another embodiment of the present invention, the form 6 has an X-ray powder diffraction pattern comprising 4.605, 6.971, 9.706, 13.603, 18.202, 18.51, 19.683, ± 0.2 degrees 2Θ values.
In still another embodiment of the present invention, the X-ray powder diffraction pattern further contains 6.286, 7.56, 8.0, 8.708, 9.217, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 14.284, 14.929, 16.656, 17.177, 17.709, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462, ± 0.2 degrees 2Θ values.
The present disclosure is also in relation to a process for preparation of polymorphs of Rosuvastatin Acetonide Calcium salt comprising acts of:
a. dissolving Rosuvastatin Acetonide Calcium salt in solvents selected from the group comprising aliphatic alcohols, aromatic hydrocarbons, aliphatic ethers, water and mixtures thereof,
b. stirring the contents with solvent mixture,
c. isolating the Solids by filtration, d. drying to obtain polymorphs of Rosuvastatin Acetonide Calcium salt.
In still another embodiment of the present invention, the aliphatic alcohols are selected from a group comprising CI - C3 alcohols.
In still another embodiment of the present invention, the C 1 -C3 alcohols are selected from a group comprising methanol, ethanol and propanol.
In still another embodiment of the present invention, the aromatic hydrocarbons are selected from a group comprising benzene and toluene.
In still another embodiment of the present invention, aliphatic ethers are selected from a group comprising tetrahydrofuran and methyl tertiary butyl ether.
In still another embodiment of the present invention, the solvents are used as a binary, tertiary or quaternary mixture.
In still another embodiment of the present invention, the stirring time is ranging from about lOhr to about 50 hr.
In still another embodiment of the present invention, stirring time is ranging from about 25hr to about 30 hr.
In still another embodiment of the present invention, drying is carried out at temperature ranging from about 25 to about 70 °C under vacuum, (please inform about the lower limit of the temperature).
In still another embodiment of the present invention, the drying is carried out in a vacuum drier.
In still another embodiment of the present invention, the vacuum drier is selected from a group comprising vacuum tray drier and rotary drier. The present disclosure is also in relation to a pharmaceutical composition, comprising polymorphs of Rosuvastatin Acetonide Calcium according to any preceding claims and at least one pharmaceutically acceptable compound selected from a group including excipient, diluent, carrier, binder and coating material. In still another embodiment of the present invention, the composition is in a form selected from a group comprising tablets, cachets, capsules, powders, dispersible granules and pills.
The present disclosure is also in relation to use of polymorphs of Rosuvastatin acetonide calcium salt in a medicine.
The object of the present disclosure is directed to preparation of different crystalline forms and an amorphous form of Rosuvastatin acetonide calcium. The process employs the solvents like aliphatic alcohols, aromatic solvents and aliphatic hydrocarbons.
An embodiment of the present disclosure provides a crystalline form (Form-1) of Compound- 1 having the X-ray diffraction pattern with peaks at 5.917, 7.607, 8.193, 8.88, 9.815, 10.11 , 1 1.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651 , 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574 ± 0.2 degrees 2Θ values.
In yet another embodiment, the present disclosure provides FTIR spectra of crystalline form (Form-1) of Compound-1 with peaks at 3434, 2968, 1601, 1549, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 573, 529 cm"1.
In another embodiment, the present disclosure provides a crystalline form (Form-2) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.842, 5.339, 7.38, 7.662, 8.568, 9.389, 10.402, 10.734, 1 1.251, 1 1.68, 12.239, 12.542, 13.581, 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91, 18.703, 19.166, 19.495, 19.846, 20.1 , 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ± 0.2 degrees 2Θ values. In yet another embodiment the present disclosure provides FTIR spectra of crystalline form (Form-2) of Compound-1 with peaks at 3429, 2968, 1601, 1550, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 568, 519 cm"1. In yet another aspect, the present disclosure provides a crystalline form (Form-3) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.54, 7.1 14, 8.805, 10.458, 10.708, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 17.672, 17.972, 18.432, 19.215, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481, 37.151, 38.893, 40.44, 44.613, 45.42, 56.375 ± 0.2 degrees 2Θ values.
In yet another embodiment the present disclosure provides FTIR spectra of crystalline form (Form-3)of Compound-1 with peaks at 3429, 2968, 1601, 1550, 1510, 1438, 1382, 1337, 1230, 1199, 1 157, 966, 776, cm"1.
In another embodiment, the present disclosure provides a crystalline form (Form-4) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.662, 4.226, 5.937, 7.645, 8.854, 9.427, 10.47, 11.062, 12.763, 15.129, 17.082, 18.807, 19.209, 20.151, 21.245, 21.612, 22.456 ± 0.2 degrees 2Θ values.
In yet another embodiment the present disclosure provides FTIR spectra of crystalline form (Form-4) of Compound-1 with peaks at 3434, 2968, 1601, 1549, 1510, 1437, 1382, 1337, 1267, 1199, 1156, 965, 845, 776, 573, 529 cm"1. In another embodiment, the present disclosure provides a crystalline form (Form-5) of Compound- 1 having the X-ray diffraction pattern with peaks at 3.554, 7.132, 8.779, 10.388, 10.715, 12.74, 13.699, 15.051, 15.906, 16.628, 17.061, 17.624, 17.963, 18.407, 18.666, 19.157, 19.527, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981, 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574 ± 0.2 degrees 2Θ values. In yet another embodiment the present disclosure provides FTIR spectra of crystalline form (Form-5) of Compound-1 with peaks at 3436, 2966, 1548, 1511, 1437, 1381, 1337, 1230, 1199, 1155, 966, 845, 776, 572, 518 cm 1.
In another embodiment, the present disclosure provides a crystalline form (Form-6) of Compound- 1 having the X-ray diffraction pattern with peaks at 4.605, 6.286, 6.971, 7.56, 8.0, 8.708, 9.217, 9.706, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 13.603, 14.284, 14.929, 16.656, 17.177, 17.709, 18.202, 18.51, 19.683, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462 ± 0.2 degrees 2Θ values.
In yet another embodiment the present disclosure provides FTIR spectra of crystalline form (Form-6) of Compound-1 with peaks at 3436, 2966, 1548, 1511, 1437, 1381, 1337, 1230, 1199, 1155, 966, 845, 776, 572, 518 cm 1.
In another embodiment the present disclosure provides a method to prepare (Compound- 1) in a substantially pure amorphous form using solvents from a group consisting of aliphatic esters, aliphatic ketones.
In yet another embodiment the present disclosure provides FTIR spectra of amorphous form of Compound-1 with peaks at 3433, 2971 , 1601, 1545, 1510, 1439, 1381, 1337, 1266, 1199, 1156, 963, 845, 776, 570, 520 cm"1.
The present disclosure relates to the purification of Compound-1 and isolation of crystalline and amorphous forms of the same. Compound-1 was prepared according to the known processes in the prior art application WO2010/029561.
The present disclosure provides a method for Purification and preparation of different polymorphs of compound-1 comprising the steps of:
a) dissolving compound-1 in solvents from a group consisting of aliphatic alcohols, aromatic hydro carbons, aliphatic ethers, and water and mixtures there of.
b) stirring the contents for the sufficient period of time as required and c) isolating the Solid Compound- 1 by filtration.
In particular preferred embodiment, solvents for purification are selected from a group comprising of CI- C3 aliphatic alcohols like methanol, ethanol and isopropanol. Solvent is in an amount of 5-10 vol, most preferably 10.0 vol relative to Compound -1.
In another embodiment, Solvents can be selected from a group consisting of aromatic hydrocarbons like Benzene, Toluene. Solvent is in an amount of 2-5 vol, relative to Compound -1.
In another embodiment, Solvents can be selected from a group consisting of Tetrahydrofuran and Methyl tertiary butyl ether. Solvent is in an amount of 1.0-2.5 vol, relative to Compound - 1. In another embodiment, water can be selected in an amount of 1.0-2.5 vol, most preferably 1.5 vol relative to Compound -1.
In yet another embodiment, solvents can be used as a binary mixture or quaternary mixture from the group of solvents mentioned above along with water in required proportions.
In another aspect of the invention, reactions stirring time is selected between 10 - 50 hrs, preferably 25-30 hrs which may vary depending on the reaction conditions. The resulting crystalline solids from the above mentioned aspects are recovered by conventional techniques like filtration. The crystals are then dried. Drying may be carried out at a temperature less than 50-55°C under vacuum in vacuum tray drier or rotary drier.
In another embodiment, the disclosure encompasses a crystalline form (Form-1) of compound - 1 characterized by powder X-Ray diffraction pattern having prominent peaks at 5.94, 8.904, 10.736, 11.956, 13.312, 14.894, 15.782, 20.182 ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 17.9, 18.4, 18.943, 21.596, 23.575, 24.648, 25.303, 25.736, 26.982, 27.828, 29.8, 30.104, 32.668, 32.793, 33.296, 37.377, 38.742, 39.201 , 40.334, 41.21 1 , 48.204, 50.837, 54.196, ± 0.2 degrees 2Θ values. In another embodiment, crystalline compound (Form-1) of the present disclosure shows main FTIR peaks at 3434, 2968, 1601 , 1549, 1510, 1437, 1382, 1337, 1267, 1 199, 1 156, 965, 845, 776, 573, 529 cm"1.
In another embodiment of the invention, the most intense peaks appear at 3434, 2968, 1601 ,1549, 1510,1437,1382, 1 156, 965, 845, 776, 573, 529 cm"1'
In another embodiment, the disclosure encompasses a crystalline form (Form-2) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.842, 5.339, 7.38, 7.662, 9.389, 10.734, 18.703, 19.166, ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 8.568, 10.402, 1 1.251 , 1 1.68, 12.239, 12.542, 13.581 , 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66, 17.91 , 19.495, 19.846, 20.1 , 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ± 0.2 degrees 2Θ values.
In another embodiment, crystalline intermediate of the present disclosure shows main FTIR peaks at 3429, 2968, 1601 , 1550, 1510, 1437, 1382, 1337, 1267, 1 199, 1 156, 965, 845, 776, 568, 519 cm"1. In another embodiment, the most intense peaks appear at 3434, 2968, 1601 , 1550, 1382, 1 156, 966, 776 cm"1'
In another embodiment, the disclosure encompasses a crystalline form (Form-3) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.54, 8.805, 10.458, 10.708, 17.672, 17.972, 18.432, 19.215, ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 7.114, 12.805, 13.681, 15.036, 15.942, 16.626, 17.047, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481 , 37.151 , 38.893, 40.44, 44.613, 45.42, 56.375, ± 0.2 degrees 2Θ values.
In another embodiment, crystalline compound (Form-3) of the present disclosure shows main FTIR peaks at 3429, 2968, 1601, 1550, 1510, 1438, 1382, 1337, 1230, 1 199, 1157, 966, 776, cm 1. In still another embodiment, the most intense peaks appear at 3434, 2968, 1601, 1550, 1438, 1382, 1157, 965, 845, 776, 573, 529 cm 1'
In another embodiment, the disclosure encompasses a crystalline form (Form-4) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 3.662, 4.226, 7.645, 8.854, 9.427, 10.47, 17.082, 18.807, 19.209, ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 5.937, 11.062, 12.763, 15.129, 20.151, 21.245, 21.612, 22.456 ± 0.2 degrees 2Θ values. In another embodiment, crystalline compound (Form-4) of the present disclosure shows main FTIR peaks at 3445, 2966, 1600, 1549, 1510, 1437, 1382, 1338, 1267, 1200, 1156, 963, 776, 573, 529 cm"1.
In another embodiment of the present invention, the most intense peaks appear at 3445, 2966, 1600,1549,1437,1382, 1156, 963,776, 573, 529 cm"L
An embodiment of the present disclosure encompasses a crystalline form (Form- 5) of compound - 1 characterized by powder X-Ray Diffraction pattern having Prominent peaks at 3.554, 8.779, 10.388, 10.715, 17.624, 19.157, 19.527, ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 7.132 12.74,13.699, 15.051, 15.906, 16.628, 17.061, 17.963, 18.407, 18.666, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981, 44.745, 45.435, 56.424, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees 2Θ values. In another embodiment, crystalline compound (Form-5) of the present disclosure shows main FTIR peaks at 3436, 2966, 1548, 1511, 1437, 1381 , 1337, 1230, 1199, 1 155, 966, 845, 776, 572, 518 cm"1.
In another embodiment of the present invention, the most intense peaks appear at 3436, 2966, 1548, 1381, 1337, 1155, 966 cm"1
In another embodiment, the disclosure encompasses a crystalline form (Form-6) of compound - 1 characterized by powder X-Ray Diffraction pattern having prominent peaks at 4.605, 6.971, 9.706, 13.603, 18.202, 18.51 , 19.683, ± 0.2 degrees 2Θ values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 6.286, 7.56, 8.0, 8.708, 9.217, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 14.284, 14.929, 16.656, 17.177, 17.709, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462, ± 0.2 degrees 2Θ values. In another embodiment, crystalline compound (Form-6) of the present disclosure shows main FTIR peaks at 3433, 2971 , 1601, 1545, 1510, 1439, 1381, 1337, 1266, 1 199, 1156, 963, 845, 776, 570, 520 cm"1.
In another embodiment of the present invention, the most intense peaks appear at 3434, 2971 , 1545, 1510, 1381, 1156, 963, 845, 776, 570, 520 cm 1'
In another embodiment, amorphous compound of the present disclosure(Compound-l) shows main FTIR peaks at 3435, 2968, 1602, 1549, 1510, 1437, 1381, 1338, 1268, 1229,1199, 1156, 964, 844, 775, 573, 519 cm"1. In another embodiment of the present invention, the most intense peaks appear at 3434, 2968, 1602, 1549, 1510, 1437, 1381, 1338, 1 156, 964, 844, 775, 573, 529 cm"L
In still another embodiment, the polymorphs of Rosuvastatin acetonide Calcium salt is used for the treatment of hyperlipidemia. For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include tablets, cachets, capsules, powders, dispersible granules or pills. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
Tablet formulation: Rosuvastatin Acetonide calcium is formulated by employing Microcrystalline cellulose, Lactose monohydrate, Tribasic calcium phosphate, Crospovidone, Magnesium stearate, Hydroxy propyl methyl cellulose, Triacetin, Titanium dioxide, Yellow ferric oxide and red ferric oxide as other ingradients.
The disclosure is further illustrated by the following examples, which should not be construed to limit the scope of the disclosure in anyway.
Characterization
Rosuvastatin intermediate of the present disclosure(Compound-2) is characterized by X- Ray powder Diffraction (XRD), DSC analysis, and FTIR spectroscopy.
XRD:
XRD Diffracto grams were collected on Bruker AXS D-8 advance X- Ray powder diffract meter, Scintillation detector. Scanning Parameters : ScanType - Locked Coupled, Scan Mode -Continuous, Range (2 theta) - 3.0°- 60.0°, Rate - 3.6 min
FTIR Spectroscopy:
FTIR Spectrum was recorded on Perkin-Elmer spectrum- 1 spectrometer, Diffuse Reflectance Technique. The sample was finely ground with Potassium Bromide, and the spectrum was recorded using Potassium Bromide background in a Diffused reflectance accessory.
Examples
Preparation of Compound- 1
2.0g of(6- {2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino )- pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l ,3]dioxan-4-yl)-acetic acid tert-butyl ester was taken in 20mL Methanol, Tetrahydrofuran (10ml) and added 10 mL of 10% sodium hydroxide solution slowly under stirring. Heated to 35°C and maintained for 15hrs-16hrs. Adjusted the pH to 9.0-9.5 at 30°C using 0.5 N HCl. Reaction mass was filtered through celite bed and washed with 4mL methanol. Filtrate was concentrated under vacuum at 50°C Then stripped of with 5mL acetonitrile to get a solid. Added acetonitrile (10 mL) and filtered the insolubles. Concentrated the filtrate and added 40mL Water, 3mL Methanol & 6mL MTBE and separated the aqueous layer. Aqueous layer was washed with 6mL MTBE. Another 6mL MTBE Wash was given to the aqueous layer after adjusting the pH to 8.0- 8.2 using 0.5N HCL. Heated the aqueous layer to 40-45°C and stirred for 30 mins. Added Calcium acetate 0.54g dissolved in 2.7ml water slowly to the reaction mass. Stirred for 30mins at 40-45°C and then at 30°C for lh. Solid Rosuvastatin calcium with acetonide obtained was filtered and washed with water 6mL, dried under vacuum at 45-50°C to get white solid.
The disclosure is further described by the following examples which accompanied by figures 1 to 6 which are explained below. However it should not be construed to limit the scope of the invention.
Example 1: Preparation of crystalline compound-1 using THF-Toluene-IPA-HiO
Compound-1 (10. Og) was dissolved in THF (25ml) and added Toluene (50ml) and stir for 10 min. Added water (15 ml) followed addition of IP A (150ml) for about 30 min.The reaction mass was stirred for 20-30 hrs. The separated solid was filtered, washed with IPA and dried under vacuum for 10-15 hrs yielding compound - 1 (7.0 g) as a white crystalline solid. (Form-1)
Example 2: Preparation of crystalline compound-1 using THF-xylene-IPA-HiO
Compound- 1 (10. Og) was dissolved in THF (20ml) and added xylene (50ml) and stir for 10 min. Added water (20 ml) followed addition of IPA (120ml) for about 30 minute, reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form- 2)
Example 3: Preparation of crystalline compound-1 using THF-Toluene-Ethyl Acetate -H20
Compound-1 (10. Og) was dissolved in THF (30ml) and added Toluene (50ml) and stir for 10 min. Added water (5 ml) followed addition of EA (30ml) for about 30 minute, reaction mass was stirred for 45-48 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (8.0 g) as a white crystalline solid. (Form- 2)
Example 4: Preparation of crystalline compound-1 using THF-Cyclohexene- MTBE-H20
Compound-1 (10. Og) was dissolved in THF (20ml) and added Cyclo hexane (15ml) and stir for 10 min. Added water (2.5ml) followed addition of MTBE (20ml) for about 30 minute, reaction mass was stirred for 32-36 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (9.0 g) as a white crystalline solid. (Form-2)
Example 5: Preparation of crystalline compound-1 using THF-xylene-Petether-H20
Compound-1 (10. Og) was dissolved in THF (25ml) and added xylene (25ml) and stir for 10 min. Added water (2.5 ml) followed addition of PE (2.5ml) for about 30 minute, reaction mass was stirred for 32-36 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form- 2) Example 6: Preparation of crystalline compound-1 using IPA-ACN-Ethyl acetate- H20
Compound-1 (lO.Og) was dissolved in IPA (80ml) and added ACN(20ml) and stir for 10 min. Added water (100ml) followed addition of EA (5ml) for about 30 min.The reaction mass was stirred for 70-72hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (5.0g) as a white crystalline solid. (Form-2)
Example 7: Preparation of crystalline compound-1 using THF-Toluene-Petether- H20
Compound-1 (10. Og) was dissolved in THF (20ml) and added Toluene (40ml) and stir for 10 min. Added water (2.5 ml) followed addition of Petether (10ml) for about 30 minute, reaction mass was stirred for 32-36 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form- 3)
Example 8: Preparation of crystalline compound-1 using THF-Xylene-ACN-H20 Compound-1 (lO.Og) was dissolved in THF (20ml) and added Xylene (20ml) and stir for 10 min. Added water (2.5ml) followed addition of ACN(lOml) for about 30 minute, reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (7.0 g) as a white crystalline solid. (Form- 3)
Example 9: Preparation of crystalline compound-1 using MeOH- Pet ether - Toluene-H20
Compound-1 (10. Og) was dissolved in MeOH (20ml) and added Toluene (40ml) and stir for 10 min. Added water (2.5ml) followed addition of pet ether (20ml) for about 30 minute, then added EA(4ml), reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (7.0 g) as a white crystalline solid. (Form-3)
Example 10: Preparation of crystalline compound-1 using THF- Pet ether -IPA- H20 Compound-1 (10. Og) was dissolved in THF (10ml) and added pet ether (10ml) and stir for 10 min. Added water (2.5 ml) followed addition of IP A (20ml) for about 30 minute, reaction mass was stirred for 20-24 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form- 4)
Example 11: Preparation of crystalline compound-1 using Dioxane-ACN-HiO
Compound-1 (lO.Og) was dissolved in Dioxane (10ml) and added IPA (100ml) and stir for 10 min. Added water (10 ml). The reaction mass was stirred for 70-72hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (6.0 g) as a white Crystalline solid. (Form-4)
Example 12: Preparation of crystalline compound-1 using THF- Ethyl Acetate - H20
Compound-1 (10. Og) was dissolved in THF (10ml) and added (40ml) and stir for 10 min. Added water (1 ml) followed addition of Ethyl Acetate (10ml) for about 30 minute, reaction mass was stirred for 70-72hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (8.0 g) as a white crystalline solid. (Form- 5)
Example 13: Preparation of crystalline compound-1 using Ethyl Acetate -ACN-H20 Compound-1 (lO.Og) was dissolved in Ethyl Acetate (10ml) and added ACN (10ml) and stir for 10 min. Added water (1 ml), reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (2.5 g) as a white crystalline solid. (Form-5)
Example 14: Preparation of crystalline compound-1 using THF-Cyclo hexene- Ethyl Acetate -H20
Compound-1 (10. Og) was dissolved in THF (20ml) and added Cyclo hexane (30ml) and stir for 10 min. Added water (2.5ml) followed addition of Ethyl Acetate (10ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form-5)
Example 15: Preparation of crystalline compound-1 using MeOH-Toluene-IPA- H20
Compound-1 (lO.Og) was dissolved in MeOH (15ml) and added Toluene (20ml) and stir for 10 min. Added water (10ml) followed addition of IP A (100ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form- 5)
Example 16: Preparation of crystalline compound-1 using THF-Cyclohexene- Toluene-H20
Compound-1 (10. Og) was dissolved in THF (30ml) and added Cyclohexane (50ml) and stir for 10 min. Added water (5ml) followed addition of Toluene (40ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (8.0 g) as a white crystalline solid. (Form-5)
Example 17: Preparation of crystalline compound-1 using THF-Xylene- Ethyl Acetate -H20
Compound-1 (lO.Og) was dissolved in THF (10ml) and added Xylene (30ml) and stir for 10 min. Added water (2.5ml) followed addition of Ethyl Acetate (10ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white crystalline solid. (Form-5)
Example 18: Preparation of crystalline compound-1 using MeOH-Xylene- Ethyl Acetate -H20
Compound-1 (10. Og) was dissolved in MeOH (10ml) and added Xylene (15ml) and stir for 10 min. Added water (2.5 ml) followed addition of Ethyl Acetate (15ml) for about 30 min.The reaction mass was stirred for 20-24 hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (2.5g) as a white crystalline solid. (Form-6)
Example 19: Preparation of amorphous compound-1 using MeOH-MTBE-IPA- H20
Compound-1 (10. Og) was dissolved in MeOH (25ml) and added MTBE (50ml) and stir for 10 min. Added water (15 ml) followed addition of IP A (150ml) for about 30 min.The reaction mass was stirred for 20-30 hrs. The separated solid was filtered, washed with IPA and dried under vacuum for 10-15 hrs yielding compound - 1 (7.0 g) as a white Amorphous solid.
Example 20: Preparation of amorphous compound-1 using THF-MTBE-IPA-H20
Compound-1 (10. Og) was dissolved in THF(20ml) and added MTBE (100ml) and stir for 10 min. Added water (20 ml) followed addition of IPA (300ml) for about 30 min.The reaction mass was stirred for 35-40 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (4.0 g) as a white Amorphous solid.
Example 21: Preparation of amorphous compound-1 using IP A-H20
Compound-1 (10.0g) was dissolved in IPA(30ml) at 60-65°C stir for 10 min. Added water (100 ml)) for about 30 min at 60-65°C .The reaction mass was slowly cooled 25- 30°C in 60mins. The reaction mass was stirred for 30-40 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (8.0 g) as a white Amorphous solid.
Example 22: Preparation of amorphous compound-1 using MeOH-ACN-H20
Compound-1 (10.0g) was dissolved in MeOH (40ml) and added ACN (30ml) and stir for 10 min. Added water (120 ml),The reaction mass was stirred for 20-24hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (6.0 g) as a white Amorphous solid.
Example 23: Preparation of amorphous compound-1 using MeOH- Pet ether -EA- Compound- 1 (10. Og) was dissolved in MeOH (30ml) and added pet ether (40ml) and stir for 10 min. Added water (1 ml) followed addition of EA (20ml) for about 30 minute, reaction mass was stirred for 20-24hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white Amorphous solid.
Example 24: Preparation of amorphous compound-1 using MeOH-Xylene-IPA- H20
Compound-1 (10. Og) was dissolved in MeOH (10ml) and added Xylene (20ml) and stir for 10 min. Added water (2.5 ml) followed addition of IP A (60ml) for about 30 min.The reaction mass was stirred for 20-24 hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (8.0 g) as a white Amorphous solid.
Example 25: Preparation of amorphous compound-1 using IPA-ACN- Ethyl Acetate -MeOH
Compound-1 (10.0g) was dissolved in IPA (40ml) and added ACN(lOml) and stir for 10 min. Added MeOH (20ml) followed addition of Ethyl Acetate (20ml) for about 30 min.The reaction mass was stirred for 70-72hrs. The separated solid was filtered, dried under vacuum for 10-15 hrs yielding compound - 1 (8g) as a white Amorphous solid.
Example 26: Preparation of amorphous compound-1 using ACETONE- Pet ether - Ethyl Acetate -H20
Compound-1 (10. Og) was dissolved in Acetone (20ml) and added Pet ether (30ml) and stir for 10 min. Added water (1 ml) followed addition of Ethyl Acetate (20ml) for about 30 minute, reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white amorphous solid.
Example 27: Preparation of amorphous compound-1 using ACETONE- Pet ether - Ethyl Acetate -H20
Compound-1 (10. Og) was dissolved in Acetone (20ml) and added pet ether (30ml) and stir for 10 min. Added water (1 ml) followed addition of Ethyl Acetate (20ml) for about 30 minute, reaction mass was stirred for 70-72 hrs. The separated solid was filtered and dried under vacuum for 10-15 hrs yielding compound - 1 (5.0 g) as a white amorphous solid.

Claims

We Claim:
1. Polymorphs of Rosuvastatin Acetonide Calcium [(3R,5S,6E)- 7 - [^-^-Fluorophenyl) -6-isopropyl-2-(methanesulfony 1-methyl- amino) - pyrimidin-5-yl) vinyl)- 2,2-dimethyl-l ,3-dioxan-4-yl) acetic acid calcium] salt.
2. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 1.
3. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 2.
4. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 3.
5. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 4.
6. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 5.
7. The polymorph as claimed in claim 1 , wherein the polymorph is crystalline form 6.
8. The polymorph as claimed in claim 1, wherein the polymorph is an amorphous.
9. The crystalline form 1 of Rosuvastatin Acetonide Calcium as claimed in claim 2, wherein the form 1 has an X-ray powder diffraction pattern comprising 5.94, 8.904, 10.736, 1 1.956, 13.312, 14.894, 15.782, 20.182 ± 0.2 degrees 2Θ values.
10. The crystalline form 1 of Rosuvastatin Acetonide Calcium as claimed in claim 9, wherein the X-ray powder diffraction pattern further contains 17.9, 18.4, 18.943, 21.596, 23.575, 24.648, 25.303, 25.736, 26.982, 27.828, 29.8, 30.104, 32.668, 32.793, 33.296, 37.377, 38.742, 39.201 , 40.334, 41.21 1, 48.204, 50.837, 54.196, ± 0.2 degrees 2Θ values.
11. The crystalline form 2 of Rosuvastatin Acetonide Calcium as claimed in claim 3, wherein the form 2 has an X-ray powder diffraction pattern comprising 3.842, 5.339, 7.38, 7.662, 9.389, 10.734, 18.703, 19.166, ± 0.2 degrees 2Θ values.
12. The crystalline form 2 of Rosuvastatin Acetonide Calcium as claimed in claim 11 , wherein the X-ray powder diffraction pattern further contains 8.568, 10.402, 11.251, 11.68, 12.239, 12.542, 13.581, 14.103, 14.94, 15.34, 16.017, 16.988, 17.288, 17.66,
17.91, 19.495, 19.846, 20.1 , 20.693, 20.88, 21.519, 21.985, 22.376, 23.077, 23.768, 24.352, 24.637, 25.556, 26.075, 27.034, 27.404, 27.899, 30.096, 30.637, 31.554, 31.994, 34.012, 34.559,35.413,40.649 ± 0.2 degrees 2Θ values.
13. The crystalline form 3 of Rosuvastatin Acetonide Calcium as claimed in claim 4, wherein the form 3 has an X-ray powder diffraction pattern comprising 3.54, 8.805,
10.458, 10.708, 17.672, 17.972, 18.432, 19.215, ± 0.2 degrees 2Θ values.
14. The crystalline form 3 of Rosuvastatin Acetonide Calcium as claimed in claiml3, wherein the X-ray powder diffraction pattern further contains 7.114, 12.805, 13.681 , 15.036, 15.942, 16.626, 17.047, 19.542, 20.086, 21.566, 22.004, 22.985, 23.442, 24.142, 25.807, 26.874, 27.212, 27.934, 28.649, 28.95, 30.326, 31.707, 34.649, 35.705, 36.481, 37.151, 38.893, 40.44, 44.613, 45.42, 56.375, ± 0.2 degrees 2Θ values.
15. The crystalline form 4 of Rosuvastatin Acetonide Calcium as claimed in claim 5, wherein the form 4 has an X-ray powder diffraction pattern comprising 3.662, 4.226, 7.645, 8.854, 9.427, 10.47, 17.082, 18.807, 19.209, ± 0.2 degrees 2Θ values.
16. The crystalline form 4 of Rosuvastatin Acetonide Calcium as claimed in claim 15, wherein the X-ray powder diffraction pattern further contains 5.937, 11.062, 12.763, 15.129, 20.151, 21.245, 21.612, 22.456 ± 0.2 degrees 2Θ values.
17. The crystalline form 5 of Rosuvastatin Acetonide Calcium as claimed in claim 6, wherein the form 5 has an X-ray powder diffraction pattern comprising 3.554, 8.779, 10.388, 10.715, 17.624, 19.157, 19.527, ± 0.2 degrees 2Θ values.
18. The crystalline form 5 of Rosuvastatin Acetonide Calcium as claimed in claim 17, wherein the X-ray powder diffraction pattern further contains 7.132 12.74,13.699, 15.051, 15.906, 16.628, 17.061 , 17.963, 18.407, 18.666, 20.065, 20.901, 21.533, 21.998, 22.385, 23.355, 25.234, 25.656, 26.43, 26.733, 27.328, 28.0, 28.45, 28.877, 31.697, 34.615, 35.118, 36.508, 37.147, 38.981, 44.745, 45.435, 56.424, 33.962,
34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees 2Θ values.
19. The crystalline form 6 of Rosuvastatin Acetonide Calcium as claimed in claim 7, wherein the form 6 has an X-ray powder diffraction pattern comprising 4.605, 6.971, 9.706, 13.603, 18.202, 18.51 , 19.683, ± 0.2 degrees 2Θ values.
20. The crystalline form 6 of Rosuvastatin Acetonide Calcium as claimed in claim 19, wherein the X-ray powder diffraction pattern further contains 6.286, 7.56, 8.0, 8.708, 9.217, 10.493, 10.872, 11.423, 12.185, 12.565, 13.173, 14.284, 14.929, 16.656, 17.177, 17.709, 20.266, 21.235, 22.333, 22.928, 23.548, 25.467, 27.609, 30.05, 30.487, 31.861, 35.743, 36.462, ± 0.2 degrees 2Θ values.
21. A process for preparation of polymorphs of Rosuvastatin Acetonide Calcium salt comprising acts of : a. dissolving Rosuvastatin Acetonide Calcium salt in solvents selected from the group comprising aliphatic alcohols, aromatic hydrocarbons, aliphatic ethers, water and mixtures thereof,
b. stirring the contents with solvent mixture,
c. isolating the Solids by filtration,
d. drying to obtain polymorphs of Rosuvastatin Acetonide Calcium salt.
22. The process for preparation as claimed in claim 21, wherein the aliphatic alcohols are selected from a group comprising CI- C3 alcohols.
23. The process for preparation as claimed in claim 22, wherein C1-C3 alcohols are selected from a group comprising methanol, ethanol and propanol.
24. The process for preparation as claimed in claim 21 , wherein the aromatic hydrocarbons are selected from a group comprising benzene and toluene.
25. The process for preparation as claimed in claim 21, wherein aliphatic ethers are selected from a group comprising tetrahydrofuran and methyl tertiary butyl ether.
26. The process for preparation as claimed in claim 21, wherein the solvents are used as a binary, tertiary or quaternary mixture.
27. The process for preparation as claimed in claim 21, wherein the stirring time is ranging from about lOhr to about 50 hr.
28. The process for preparation as claimed in claim 27, wherein stirring time is ranging from about 25hr to about 30 hr.
29. The process for preparation as claimed in claim 21, wherein drying is carried out at temperature ranging from about 25 to about 70 °C under vacuum.
30. The process for preparation as claimed in claim 29, wherein drying is carried out in a vacuum drier.
31. The process for preparation as claimed in claim 30, wherein vacuum drier is selected from a group comprising vacuum tray drier and rotary drier.
32. A pharmaceutical composition, comprising polymorphs of Rosuvastatin Acetonide Calcium according to any preceding claims and at least one pharmaceutically acceptable compound selected from a group including excipient, diluent, carrier, binder and coating material.
33. The pharmaceutical composition as claimed in claim 32, wherein the composition is in a form selected from a group comprising tablets, cachets, capsules, powders, dispersible granules and pills.
34. Use of polymorphs of Rosuvastatin acetonide calcium salt as claimed in any preceding claims in a medicine.
PCT/IB2010/055058 2010-09-21 2010-11-08 Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt WO2012038785A1 (en)

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