New polymorphic form of crystalline Rosuvastatin Calcium & novel processes for crystalline as well as amorphous Rosuvastatin Calcium
FIELD OF INVENTION:
The present invention relates to new polymorphic of crystalline Rosuvastatin calcium, furthermore the present invention also reports a novel processes for crystalline as well as amorphous form of Rosuvastatin calcium which are used to treat a disease condition wherein inhibition of HMG CO A reductase is beneficial.
BACKGROUD OF INVENTION:
Rosuvastatin calcium is known by its chemical name as 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt of formula I as given below.
(Formula Removed)
which is known to inhibit the HMG-CoA reductase, and subsequently suppress the bio synthesis of cholesterol. Rosuvastatin calcium is useful in the treatment of hyper cholesterolemia, hyperlipoproteinemia, and atherosclerosis. Rosuvastatin calcium may form hydrates with a varying content of water.
EP-A1-0521471 describes in the preparation of Rosuvastatin calcium in powder form. Rosuvastatin sodium is dissolved in water at room temperature and an aqueous calcium chloride solution is added dropwise. The collected precipitate is an amorphous powder. U.S.Pat. No 6,777,552 discloses the preparation of Rosuvastatin calcium through hydrolysis of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy-(E)-6-heptanoate with calcium hydroxide in a water / ethanol solution.
WO 00/42024 discloses a crystalline form, hereafter referred to as Form A of -[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxy-hept-6-enoic acid calcium salt and hydrates thereof, which are prepared by dissolving amorphous Rosuvastatin calcium form in a mixture of water and an organic solvent such as acetone or acetonitrile under heating and then cooling the solution to precipitate crystalline Form A.
WO 2005/023779 discloses another crystalline form, hereafter referred to as Form B of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt which is prepared by slurrying of Amorphous Rosuvastatin calcium in water at 40 °C to get crystalline Form B. US20080194604 describes another new process for the preparation.
US 20080194604 discloses another crystalline form, hereafter referred to as Form C of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid calcium salt
Crystalline forms often show desired different physical and/or biological characteristics which may assist in the manufacturing or formulation of the active compound, to the purity levels and uniformity required for regulatory approval. Crystalline forms of such active compounds may also possess improved pharmacological characteristics, for example, improved bioavailability, and therefore, novel crystalline forms offer enhanced possibilities to modulate and design improved drug products. As crystalline forms A, B, C etc of Rosuvastatin calcium have high water content which can affect the stability of the product, therefore there was a need for other crystalline forms of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-
methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid calcium salt or Rosuvastatin Calcium having low water content, to have a sufficient diversity on crystalline materials to optimize manufacture, formulation and biological efficiency.
SUMMARY OF INVENTION:
This invention provides a novel highly pure crystalline form hereinafter referred to as form M of -[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt or Rosuvastatin calcium and process for its manufacturing. Furthermore the invention also reports the novel process for the preparation of amorphous Rosuvastatin calcium as confirmed by XRD analysis.
DETAILED DESCRIPTION OF THE INVENTION:
The main aspect of the present invention is to provide a new crystalline polymorphic form of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt (Rosuvastatin Calcium) of high purity which exhibits a characteristic X-Ray diffraction pattern with characteristic peaks expressed in 2 values & relative intensity as given below in tabular form), hereinafter designated as form M. XRD diffractogram of Rosuvastatin calcium form M is attached as figure I.
(Table Removed)
According to another aspect of the present invention, a process for highly pure novel crystalline form M of Rosuvastatin Calcium of formula I which comprises:
a) Hydrolysis of Rosuvastatin tert butyl or methyl ester of formula II in presence of aq. Caustic solution in methanol.
(Formula Removed)
Chemical Name: tert-Buty or methyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)
amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate Formula II
b) Washing of reaction mass with methyl tert butyl ether.
c) treatment of aq, layer with hydrochloric acid followed by addition of calcium chloride to the reaction mass.
d) isolation of Rosuvastatin calcium by filtration & optionally drying.
e) dissolution of Rosuvastatin calcium (dry or wet) material in an aliphatic ketone.
f) crystallization of material by adding water.
g) filtration of resulting solid followed by drying to get new polymorphic form of Crystalline Rosuvastatin calcium designated as form M.
According to yet another aspect, the ketone used is selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof.
According to still another aspect of the present invention, a novel process for preparation of amorphous Rosuvastatin Calcium which comprises:
a) dissolution of any crystalline form of Rosuvastatin calcium in a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
b) partial recovery of halogenated hydrocarbon.
c) lowering of temperature of organic layer to 10-20 °C.
d) addition of an aliphatic ether as antisolvent for crystallization of material.
e) further stirring for complete crystallization of material at 10-20 °C.
f) isolation of material by filtration followed by drying at 50-60 °C for 30-40 hours to get amorphous Rosuvastatin calcium as confirmed by XRD pattern in figure II.
According to yet another aspect of present invention the aliphatic ether used is selected from Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture thereof.
According to still another aspect of the present invention, a novel process for preparation of amorphous Rosuvastatin Calcium which comprises:
a) dissolution of any crystalline form of Rosuvastatin calcium in a aliphatic ketone.
b) partial recovery of the aliphatic ketone.
c) lowering of temperature of organic layer to 10-20 °C.
d) addition of an aliphatic ether as antisolvent for crystallization of material.
e) further stirring for complete crystallization of material at 10-20 °C.
isolation of material by filtration followed by drying at 50-60 °C for 30-40 hours to get amorphous Rosuvastatin calcium as confirmed by XRD pattern in figure II.
According to another aspect the aliphatic ketone used is selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and aliphatic ether used is selected from Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or mixture thereof.
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
Preparation of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt
100 g of tert-Butyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate) was dissolved 1.0 liter of methanol. The resulting solution was stirred for 10-30 min followed by addition of 10% of caustic solution. The reaction mass is stirred for 3-4 hours followed by reaction monitoring by HPLC / TLC . The solvent was recovered under vaccum to give crude
product. Water 1.0 L added to the resulting crude and stirred reaction mass. Methyl tertiary butyl ether 400 ml is added & reaction mass is stirred for 15-20 minutes. The layer is separated and aqueous layer is filtered through celite bed followed by addition of 20% calcium chloride solution (100 ml). The resulting suspension is stirred for 3-4 hours filtered & washed with water. The material is dried at 50-60 °C to afford 90.0 g of Rosuvastatin Calcium.
Example 2:
Preparation of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt Polymorphic form M
To 90 g of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-
yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt prepared in example 1 is dissolved in 900 ml
acetone followed by its filration via hyflow bed. The resulting mass is taken a clean and dried round bottom flask. Water 500 ml is added to the filtered mass. The resulting mass is stirred for 6-10 hours. The resulting suspension is filtered and dried at 50-60 °C to afford 63.0 g of 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-
enoic acid Calcium salt Polymorphic form M. (water content = 3.18% & HPLC Purity = 99.79%).
Example 3:
Example no 1 & 2 are repeated using 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino) pyrimidine-5-yl]-(3R,5S)-dihydroxy-5-oxo(E)-6-heptenate as starting raw material to get new polymorphic form M of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt or Rosuvastatin calcium. (Water content = 4.42% & HPLC purity = 99.76%)
Example 4:
100 gm of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin -5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt Polymorphic form M is dissolved in 2.0 Liter of Methylene dichloride at 35-40 °C. The solvent is recovered at atmospheric pressure to be left with 500 ml followed by filtration through celite bed. The filtered layer is clean and dry round bottom flask and material is crystallized by the addition of methyl tertiary butyl ether. The material is filtered and dried under vaccum at 50-60 °C to afford 84.0 grams of amorphous Rosuvastatin calcium as a white to off-white solid.
Example 5:
100 gm of 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin -5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt Polymorphic form M is dissolved in 2.0 Liter of Methylene dichloride at 35-40 °C. The solvent is recovered at atmospheric pressure to be left with 500 ml followed by filtration through celite bed. The filtered layer is clean and dry round bottom flask and material is crystallized by the addition of diisopropyl ether. The material is filtered and dried under vaccum at 50-60 °C to afford 85.1 grams of amorphous Rosuvastatin calcium as a white to off-white solid.

We claim:
1. A novel polymorphic crystalline form for the compound 7-[4-(4-flurophenyl)-6-
isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]- (3R,5S) -dihydroxy-
hept-6-enoic acid Calcium salt, designated as form 'M' of Rosuvastatin calcium of
formula I or hydrates thereof.
(Formula Removed)
2. Polymophic crystalline form M of Rosuvastatin Calcium having characteristic peaks as given
below
(Table Removed)
3. A novel process for the preparation of crystalline form 'M' of the compound 7-[4-(4-
flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-pyrimidin-5-yl]-
(3R,5S) -dihydroxy-hept-6-enoic acid Calcium salt or hydrates thereof according to claim
1, which comprises
i) Hydrolysis of tert-Butyl or methyl-(6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5 -yl] -(3 R,5 S)-3,5 -dihydroxyhept-6-enoate or Rosuvastatin tert butyl / methyl ester in an aliphatic alcohol such as methanol with aq. Caustic solution.
ii) Isolation of Rosuvastatin calcium by addition of calcium chloride.
iii) Recrystallization of resulting Rosuvastatin Calcium (wet or dry) using an aliphatic ketone such as acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof & water.
iv) Isolation of novel Rosuvastatin calcium crystalline form M by routine filtration & drying.
4. A novel process for the preparation of amorphous Rosuvastatin Calcium for the
compound 7-[4-(4-flurophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonyl amino)-
pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid Calcium salt which comprises
i) Dissolution of new polymorphic form 'M' of Rosuvastatin calcium in halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or
mixture therof or an aliphatic ketone such as acetone, ethyl methyl ketone,
diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture
thereof, ii) Recovery of solvent from reaction mass of step (i) to left approximately 5 times
the volume w.r.t. the starting material or Rosuvastatin calcium, iii) Crystallization of amorphous Rosuvastatin Calcium salt by addition of an
aliphatic ether used is selected from Diisopropylether, methyl tert butyl ether,
dimethyl ether, diethyl ether or mixture thereof, iv) Isolation & drying of filtered material to get amorphous Rosuvastatin calcium.