Multicomponent system of rosuvastatin calcium salt and sorbitol

Patent metadata

Field	Value
Publication number	US-9249108-B2
Application number	US-201113574005-A
Country	US
Kind code	B2
Filing date	Nov 21, 2011
Priority date	Nov 22, 2010
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

A novel solid form of Rosuvastatin comprises as the active ingredient a salt of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] and sorbitol. The crystal comprising the two components, and minor amounts of water, shows improved properties such as crystallization behavior and stability.

First claim

The invention claimed is:

1. A single phase solid form of a bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] salt comprising sorbitol, which is a co-crystal.

2. Solid form of claim 1 wherein the salt of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] is a calcium salt.

3. Solid form according to claim 1 wherein sorbitol is D-sorbitol.

4. Solid form according to claim 1 containing 0.3 to 1.5 molar parts, preferably 0.3 to 1.1 molar parts, of D-sorbitol on 1 molar unit of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid].

5. Solid form according to claim 1 , consisting essentially of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, D-sorbitol, and water as minor component by weight.

6. Solid form according to claim 1 , which is a crystalline form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with D-sorbitol, and/or hydrates thereof, exhibiting a X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å): 4.85 (s), 4.75 (s), 4.70 (s), 4.59 (s), 4.49 (vs), 4.33 (s), 4.23 (s), 4.00 (s), 3.86 (vs), 3.75 (s), 3.64 (s), 3.60 (s), 3.33 (s), 3.24 (s), 3.04 (s), 2.91 (s), 2.82 (s).

7. Solid form according to claim 1 , which is a crystalline form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt with D-sorbitol, and/or hydrates thereof, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) as shown in the below table:

d value

[Angstroem]
Intensity

25.4
W

18.1
S

12.7
M

10.6
M

9.6
S

8.5
M

7.7
S

6.3
S

5.65
S

5.44
M

5.14
M

4.95
M

4.85
S

4.75
S

4.70
S

4.59
S

4.49
vs

4.33
S

4.23
S

4.00
S

3.86
vs

3.75
S

3.64
S

3.60
S

3.43
M

3.33
S

3.24
S

3.09
M

3.04
S

2.96
M

2.91
S

2.82
S

2.72
M

2.57
 M.

8. Solid form according to claim 1 , comprising a crystalline form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt with D-sorbitol, and/or hydrates thereof, which exhibits a characteristic X-ray powder diffraction pattern essentially as exhibited in FIG. 1 .

9. Process for the preparation and/or purification of a solid form according to claim 1 , which process comprises the steps of
a) providing a solution of D-sorbitol in water,
b) providing a solution of Rosuvastatin calcium in a suitable solvent,
c) combining the solutions provided in steps (a) and (b), and
d) separating the precipitate and drying.

10. Pharmaceutical composition comprising the solid form according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

11. A therapeutic method for producing an HMG-CoA reductase inhibiting effect in a mammal, which method comprises administering to a mammal in need of such therapy, an effective amount of a solid form according to claim 1 .

12. A method of delivering a solid form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt and/or hydrates thereof, which method comprises administering to a host an effective amount of a solid form according to claim 1 .

Assignees

• Hafner Andreas
• Blatter Fritz
• Szelagiewicz Martin
• Siebenhaar Bernd
• Basf Se

Inventors

• Hafner Andreas
• Blatter Fritz
• Szelagiewicz Martin
• Siebenhaar Bernd

Classifications

• A61K47/6941

  the form being a granulate or an agglomerate · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• C07C29/00

  Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring · CPC title