FORM. 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Titie of the invention
"A NON HYGROSCOPIC THERMODYNAMICALLY STABLE POLYMORPHIC FORM OF STRONTIUM RANELATE AND PROCESS FOR PREPARING THE SAME"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code; 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed,

A NON HYGROSCOPIC THERMODYNAMICALLY STABLE POLYMORPHIC FORM OF STRONTIUM RANELATE AND PROCESS FOR PREPARING THE SAME
FIELD OF THE INVENTION
The present invention relates to a non hygroscopic thermodynamically stable polymorphic form of strontium ranelate designated as "Form A" and process for preparing the same.
BACKGROUND OF THE INVENTION
Distrontium 5-[bis (2-oxido-2-oxoethyI) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is known from U.S Patent No. 5,128,367 and is represented by compound of formula I.

Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate have valuable therapeutic and pharmacological properties, especially remarkable anti-osteoporosis properties, as a result of which they can be used as medicaments especially in the treatment of bone diseases. They can also be used in the treatment of cutaneous and vascular ageing, hepatic diseases and dental diseases.
Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is indicated for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures.

Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is indicated for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures.
U.S Patent No. 5,128,367 describes strontium ranelate or hydrates thereof. Strontium ranelate octahydrate, strontium ranelate heptahydrate and strontium ranelate tetrahydrate are specifically described.
U.S Patent No. 7,459,568 discloses alpha crystalline form of strontium ranelate octahydrate, which is characterized by powder X-ray diffraction pattern and having a water content of from 22 to 24%.
Strontium ranelate octahydrate, strontium ranelate heptahydrate and strontium ranelate tetrahydrate are not suitable for preparing pharmaceutical formulation like granules and powder form due to their hygroscopic nature and high contents of water.
According])' there is a need in the art to develop a new form of strontium ranelate which overcomes the prior-art problems.
SUMMARY OF THE INVENTION
The first aspect of the present invention is to provide non hygroscopic thermodynamicaliy stable polymorphic form of strontium ranelate designated as "Form A".
Another aspect of the present invention is to provide a process for preparing non hygroscopic thermodynamicaliy stable polymorphic form of strontium ranelate designated as "Form A".
Another aspect of the present invention is to provide a process for preparing non hygroscopic thermodynamicaliy stable polymorphic form of strontium ranelate designated as "Form A" comprising azeotropic distillation of water from the solution of strontium ranelate hydrates in an organic solvent.

Another aspect of the present invention is to use non hygroscopic thermodynamically stable polymorphic form of strontium ranelate designated as "Form A" for preparing pharmaceutical composition.
Another aspect of the present invention is to provide a method for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures comprising administering a pharmaceutical composition of strontium ranelate "Form A" in patient.
DETAIL DESCRIPTION OF THE INVENTION
Form A of strontium ranelate obtained by the present invention is non hygroscopic and does not have a tendency to catch moisture content at 30°C temperature and 75% relative humidity.

Product Name Initial moisture Moisture content Moisture content Moisture content
content after 3 hours after 6 hours after 12 hours
(by KF method) (by KF method) (by KF method) (by KF method)
Strontium ranelate 22.10% 24.67% 26.35% 27.5%
octahydrate
Strontium ranelate 19.70 % 22.56% 24.96% 27.30%
heptahydrate
Strontium ranelate 12.29% 18.67% 23.56% 26.98%
tetrahydrate
Strontium ranelate 3.56% 3.59% 3.59% 3.60%
Form A
Moisture contents are calculated on the basis of weight / weight.
Form A of strontium ranelate obtained by the present invention is thermodynamically stable and does not convert into other strontium ranelate hydrates form.

Form A of strontium ranelate obtained by the present invention having good flow properties and so, the non hygroscopic thermodynamically stable polymorphic form of strontium ranelate designated as "Form A" is suitable for formulating strontium ranelate into granule form or powder form.
Form A of strontium ranelate may be characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at 8.7 ± 0.2, 12.5 ± 0.2, 18.4 ± 0.2, 22.9 ± 0.2, 26.8 ± 0.2, 27.4 ± 0.2, 29.4 ± 0.2, 31.5 ± 0.2, 35.6± 0.2, 37.0 ± 0.2, 38.0 ± 0.2 and 38.9 ± 0.2 degrees.
Form A of strontium ranelate may be characterized by an X-ray powder diffraction spectrum as described in figure 1.
The azeotropic distillation of water from the solution of strontium ranelate hydrates in an organic solvent may be carried out at a temperature in the range of 55°C to 120°C for 2 hours to 8 hours.
Examples of organic solvent may include but not limited to aromatic hydrocarbons, alcoholic and ketonic solvents.
Examples of aromatic hydrocarbons solvent may include but not limited to toluene, xylene or mixture(s) thereof.
Examples of alcoholic solvents may include but not limited to methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof.
Examples of ketonic solvents may include but not limited to acetone, methyl isobutyl ketone, diisopropyl ketone, methyl ethyl ketone, dibutyl ketone or mixture(s) thereof.
The organic solvent used for the azeotropic distillation of water from the solution of strontium ranelate hydrates in an organic solvent may be 10 volumes / weight to 25 volumes / weight of strontium ranelate hydrates.

After azeotropic distillation of water from the solution of strontium ranelate hydrates, the Form A of strontium ranelate may be isolated by the steps of filtration, centrifugafion, washing, drying and combinations thereof.
The Form A of strontium ranelate may be dried at a temperature in the range of 90°C to 100°C for 12 to 16 hours under reduced pressure.
The Form A of strontium ranelate may contain water content less than 5% water content measured by Karl-Fischer titration method.
The pharmaceutical composition of Form A of strontium ranelate may include granule and powder form.
Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is indicated for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING:
Figure 1 is x-ray powder diffraction spectrum of Form A of strontium ranelate
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 3 was obtained on D 8 -Advance, Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Ka (X= 1.5406 A) radiation with scanning range between 2.00-39.98°26 at scanning speed of 2°/min.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention
Example 1: Preparation of Form A of strontium ranelate
A solution of strontium ranelate octahydrate (10 gm) in toluene (100 ml) was heated to 100°C
and water (2ml) was removed from the reaction mixture by using Dean-Stark apparatus and
resulting solids were filtered and dried at 100°C for 12 hours under reduced pressure.
Yield: 8 gm
Purity: 99.96% (By HPLC)
Example 2: Preparation of Form A of strontium ranelate
A solution of strontium ranelate heptahydrate (10 gm) in xylene (100 ml) was heated to 110°C
and water (3.7ml) was removed from the reaction mixture by using Dean-Stark apparatus and
resulting solids were filtered and dried at 95 °C for 34 hours under reduced pressure.
Yield: 8.25 gm
Purity: 99.90% (By HPLC)
Example 3: Preparation of Form A of strontium ranelate
A solution of strontium ranelate tetrahydrate (10 gm) in acetone (100 ml) was heated to 55°C and
water (1.1ml) was removed from the reaction mixture by using Dean-Stark apparatus and
resulting solids were filtered and dried at 90°C for 16 hours under reduced pressure.
Yield: 8.75 gm
Purity: 99.87% (By HPLC)

WE CLAIM:
1. Crystalline Form A of strontium ranelate characterized by an X-ray powder diffraction spectrum having peaks expressed as 29 at 8.7 ± 0.2, 12.5 ± 0.2, 18.4 ± 0.2, 22.9 ± 0.2, 26.8 ± 0.2, 27.4 ± 0.2, 29.4 ± 0.2, 31.5 ± 0.2, 35.6± 0.2, 37.0 ± 0.2, 38.0 ± 0.2 and 38.9 ± 0.2 degrees.
2. Crystalline Form A of strontium ranelate characterized by an X-ray powder diffraction spectrum as described in figure 1.
3. A process for the preparation of crystalline Form A of strontium ranelate comprising azeotropic distillation of water from the solution of strontium ranelate hydrates in an organic solvent.
4. The process according to claim no. 3, wherein organic solvent is selected from the group comprising of aromatic hydrocarbon, alcoholic or ketonic solvents.
5. The process according to claim no. 4, wherein aromatic hydrocarbon solvent is selected from the group comprising of toluene, xylene or mixture(s) thereof.
6. The process according to claim no. 4, wherein alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propanol. isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof.
7. The process according to claim no. 4, wherein ketonic solvent is selected from the group comprising of acetone, methyl isobutyl ketone, diisopropyl ketone, methyl ethyl ketone, dibutyl ketone or mixture(s) thereof.
8. The process according to claim no. 3, wherein azeotropic distillation of water from the solution of strontium ranelate hydrates in an organic solvent is carried out at a temperature in the range of 55°C to 120°C for 2 hours to 8 hours.

9. A use of strontium ranelate crystalline Form A for the preparation of pharmaceutical composition comprising granule or powder form.
10. A method for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures comprising administering a pharmaceutical composition of strontium ranelate crystalline Form A in patient.