FORM 2
THE PATENT ACT. 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL POLYMORPHIC FORM OF STRONTIUM RANELATE OCTAHYDRATE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at I7th FIoor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
i. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL POLYMORPHIC FORM OF STRONTIUM RANELATE OCTAHYDRATE

FIELD OF THE INVENTION:

The present invention relate to a novel polymorphic form of strontium ranelate octahydrate designated herein as beta crystalline form. The invention further relate to methods of preparing beta crystalline form of strontium ranelate octahydrate and pharmaceutical composition comprising strontium ranelate octahydrate.

BACKGROUND OF THE INVENTION:

Strontium ranelate is chemically Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate and is known from U.S Patent No. 5,128,367 and is represented by compound of structural 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.
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% weight/weight.

Chinese Patent No. 100554263 discloses crystalline form of strontium ranelate heptahydrate which is characterized by powder X-ray diffraction pattern and having a water content of from 19.0 to 20.4% weight/weight.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

Accordingly there is a need in the art to develop a new form of strontium ranelate octahydrate.

SUMMARY OF THE INVENTION:

A first aspect of the present invention is to provide a novel polymorphic form of strontium ranelate octahydrate designated herein as beta crystalline form.

A second aspect of the present invention is to provide a process for preparing beta crystalline form of strontium ranelate octahydrate comprising the steps of:
a. reacting a compound of structural formula II with alkali metal hydroxide in an organic solvent selected from the group comprising of n-butanol, n-pentanol, tertiary butanol, dimethylformamide, N,N-dimethyl acetamide, methyl acetate, ethyl acetate, n-butyl acetate, iso-butyl acetate, tertiary butyl acetate, methyl isobutyl ketone, diethyl ether, methyl tertiary butyl ether, dipropyl ether, dichloromethane, ethylenedichloride of 1,4 dioxane to get a compound of structural formula III

wherein R is C1-C6 alkyl group
b. reacting a compound of structural formula III with a source of strontium to get a compound of formula I and

c. isolating beta crystalline form of strontium ranelate octahydrate.

Another aspect of the present invention is to provide pharmaceutical compositions comprising beta crystalline form of strontium ranelate octahydrate in combination with one or more pharmaceutically acceptable, inert and non-toxic carriers.

Another aspect of the present invention is to provide pharmaceutical compositions comprising beta crystalline form of strontium ranelate octahydrate in admixture or association with an appropriate pharmaceutical excipient, such as, for example, distilled water, glucose, lactose, starch, talc, ethyl cellulose, magnesium stearate or cocoa butter.

Another aspect of the present invention is to provide a method of treating a living animal body, including a human, afflicted with osteoporosis, comprising the step of administering to the living animal body, including a human, an amount of beta crystalline form of strontium ranelate octahydrate which is effective for alleviation of osteoporosis.

Another aspect of the present invention is to provide a method of treating a living animal body, including a human, afflicted with arthrosis, comprising the step of administering to the living animal body, including a human, an amount of beta crystalline form of strontium ranelate octahydrate which is effective for alleviation of arthrosis.

Another aspect of the present invention is to provide beta crystalline form of strontium ranelate octahydrate characterized by data selected from a group consisting of a powder X-ray diffraction pattern having peaks at 13.8, 15.2, 17.9, 19.1, 19.9, 21.3, 22.0, 25.2, 26.8, 33.9, 34.7, 35.0, 35.2, 35.5, 36.2, 36.8, 36.9, 38.1, 39.3 ± 0.2 degrees two-theta.

Another aspect of the present invention is to provide beta crystalline form of strontium ranelate octahydrate characterized by a powder X-ray diffraction pattern as depicted in Figure 1.

DETAIL DESCRIPTION OF THE INVENTION:

The beta crystalline form of strontium ranelate octahydrate has the following advantageous properties over alpha crystalline form of strontium ranelate octahydrate

1. Beta crystalline form of strontium ranelate octahydrate flows freely and may be readily compressed into tablets by direct compression in tablet-making machines.
2. Beta crystalline form of strontium ranelate octahydrate is having less electrostatic current as compared to alpha crystalline form of strontium ranelate octahydrate and therefore easy to handle during the preparation of formulation.
3. Beta crystalline form of strontium ranelate octahydrate is having small particle size compared to alpha crystalline form of strontium ranelate octahydrate and hence showing more therapeutic efficacy.

The beta crystalline form of strontium ranelate octahydrate may be characterized by powder X-ray diffraction pattern having following peaks:

Pos. [°2Th.] Height [cts] Area [cts*°2Th.] FWHM [°2Th.] d-spacing [Å] Rel. Int. [%]
7.6304 233.55 38.12 0.1224 11.57672 16.13
7.9943 104.56 22.75 0.1632 11.05050 7.22
8.3939 440.45 59.90 0.1020 10.52536 30.42
8.6486 670.72 54.73 0.0612 10.21591 46.32
8.9500 1448.12 196.94 0.1020 9.87259 100.00
10.9656 231.44 37.77 0.1224 8.06196 15.98
11.3050 114.30 12.44 0.0816 7.82067 7.89
12.0178 151.64 33.00 0.1632 7.35838 10.47
13.1797 481.19 52.35 0.0816 6.71219 33.23
13.8815 125.59 10.25 0.0612 6.37437 8.67
14.6923 141.44 15.39 0.0816 6.02440 9.77
14.9049 145.43 23.73 0.1224 5.93895 10.04
15.2777 738.41 60.25 0.0612 5.79483 50.99
15.8731 269.44 36.64 0.1020 5.57879 18.61
16.0828 170.50 18.55 0.0816 5.50653 11.77
16.7301 115.22 18.80 0.1224 5.29490 7.96
17.3339 144.75 19.69 0.1020 5.11179 10.00
17.9323 407.00 55.35 0.1020 4.94253 28.11
19.1298 300.53 65.40 0.1632 4.63576 20.75
19.9247 125.33 40.91 0.2448 4.45257 8.65
20.6969 409.16 44.52 0.0816 4.28815 28.25
21.3092 111.28 30.27 0.2040 4.16630 7.68
22.0490 89.79 8.08 0.0900 4.02815 6.20
22.7917 206.78 33.75 0.1224 3.89854 14.28
23.0872 212.01 34.60 0.1224 3.84931 14.64
24.0933 803.11 109.22 0.1020 3.69080 55.46
25.0052 442.59 48.15 0.0816 3.55822 30.56
25.2134 558.95 45.61 0.0612 3.52931 38.60
25.5126 473.24 102.98 0.1632 3.48860 32.68
25.9084 232.26 18.95 0.0612 3.43620 16.04
26.8938 334.79 45.53 0.1020 3.31249 23.12
28.1057 359.33 29.32 0.0612 3.17235 24.81
28.5601 221.05 30.06 0.1020 3.12290 15.26
29.6451 157.12 34.19 0.1632 3.01103 10.85
30.1689 177.91 24.20 0.1020 2.95993 12.29
31.9955 276.88 32.81 0.1185 2.79500 19.12
33.9109 163.70 17.81 0.0816 2.64137 11.30
34.7134 125.57 40.99 0.2448 2.58213 8.67
35.0355 158.63 17.26 0.0816 2.55912 10.95
35.2273 159.07 12.98 0.0612 2.54563 10.98
35.5932 140.49 15.29 0.0816 2.52029 9.70
36.2896 298.01 48.64 0.1224 2.47351 20.58
36.8044 240.81 19.65 0.0612 2.44009 16.63
36.9221 254.58 20.77 0.0612 2.43258 17.58
38.1741 243.56 15.37 0.0631 2.35562 16.82
39.3963 249.09 14.48 0.0581 2.28531 17.20

The compound of formula II may include following compounds of structural formula:

The compound of formula II may be prepared by any of the methods described in prior art references such as US Patent No. 5,128,367; 7,091,364; 7,105,683 and 7,214,805, which are incorporated herein by reference only.

The examples of alkali metal hydroxide may include sodium hydroxide, potassium hydroxide, lithium hydroxide or mixture(s) thereof.

The alkali metal hydroxide may be used as such or it may be used as an aqueous solution.

The concentration of aqueous solution of alkali metal hydroxide may be in the range of 10% to 20% weight / weight.

The reaction of a compound of structural formula II with alkali metal hydroxide in an organic solvent selected from the group comprising of n-butanol, n-pentanol, tertiary butanol, dimethylformamide, N,N-dimethyl acetamide, methyl acetate, ethyl acetate, n-butyl acetate, iso-butyl acetate, tertiary butyl acetate, methyl isobutyl ketone, diethyl ether, methyl tertiary butyl ether, dipropyl ether, dichloromethane, ethylenedichloride of 1,4 dioxane may be carried out at a temperature in the range of 0°C to 15°C for a period of 4 hours to 16 hours to get a compound of structural formula III.

The compound of structural formula III may be used as such for the next step of reaction.

The source of strontium may include strontium chloride, strontium hydroxide or strontium carbonate.

The reaction of a compound of structural formula III with a source of strontium may be carried out at a temperature in the range of 0°C to 30°C for a period of 6 hours to 24 hours to get a beta crystalline form of strontium ranelate octahydrate.

The beta crystalline form of strontium ranelate octahydrate may be isolated by filtration and then the wet cake of beta crystalline form of strontium ranelate octahydrate may be slurred with water at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 2 hours.

The beta crystalline form of strontium ranelate octahydrate may be further isolated by the steps of filtration, centrifugation, washing, drying and the combination thereof.

The beta crystalline form of strontium ranelate octahydrate may be dried at a temperature in the range of 30°C to 35°C for a period of 6 hours to 18 hours.

The beta crystalline form of strontium ranelate octahydrate may contain moisture content in the range of 20% weight / weight to 24% weight / weight.

The pharmaceutical composition may contain from 200 to 300 mg of beta crystalline form of strontium ranelate octahydrate and it may be formulated as tablets, dragees, gelatin-coated pills, drinkable solutions, injectable solutions, or suppositories and, depending on the case in question, may be administered orally, rectally or parenterally at a dose of from 200 to 300 mg from 2 to 4 times per day.

The pharmaceutical composition may contain 2 gm sachet of beta crystalline form of strontium ranelate octahydrate and pharmaceutical acceptable excipients.

The beta crystalline form of strontium ranelate octahydrate having a mean particle size in the range of 5 um to 10 um.

The particle size distribution data of beta crystalline form of strontium ranelate octahydrate may be as follows:
d (0.1) = 2.5 um;
d (0.5) = 5.8 um;
d (0.9) = 11.28 um

BRIEF DESCRIPTION OF THE DRAWING:

Figure 1 is a characteristic powder X-ray diffraction pattern of beta crystalline form of strontium ranelate octahydrate.
Figure 2 is a characteristic particle size distribution data of beta crystalline form of strontium ranelate octahydrate.

XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha [Å]: 1.54060

Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

The particle size of beta crystalline form of strontium ranelate octahydrate was measured using a Malvern Mastersizer Model MS1 particle size analyzer (Malvern Instruments Inc., 10 Southville Rd., Southborough, Mass. 01772) with a Small Volume Recirculating unit attached.

EXAMPLES:

In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example 1: Preparation of beta crystalline form of strontium ranelate octahydrate.

A solution of ethyl 5-(bis(2-ethoxy-2-oxoethyl)amino)-4-cyano-3-(2-ethoxy-2-oxoethyl)thiophene-2-carboxylate compound of structural formula V (100gm) in 1,4 dioxane (300ml) was added aqueous solution of sodium hydroxide (400ml, 15% weight / weight) at 5-10°C and resulting reaction mixture was stirred for 12 hours at 5-10°C. The strontium chloride solution (264gm dissolved in 600ml water) was added at 0-5°C and then the resulting reaction mixture was heated to 20-25°C and stirred for 18 hours. The solids obtained were filtered and washed with water (500ml). The wet solid was added water (500ml) and stirred for 1 hour at 20-25°C. The resulting solids were filtered, washed with (200ml) water and dried at 30-35°C for 10 hours to get title compound.
Yield: 88.5gm
Purity: 99.9% (By HPLC)
XRD: As depicted in Figure 1

Example 2: Preparation of beta crystalline form of strontium ranelate octahydrate.

A solution of methyl 5-(bis (2-methoxy-2-oxoethyl) amino)-4-cyano-3-(2-methoxy-2-oxoethyl) thiophene-2-carboxylate compound of structural formula IV (100gm) in 1,4 dioxane (300ml) was added aqueous solution of sodium hydroxide (400ml, 15% weight / weight) at 5-10°C and resulting reaction mixture was stirred for 12 hours at 5-10°C. The strontium chloride solution (264gm dissolved in 600ml water) was added at 0-5°C and the resulting reaction mixture was heated to 20-25°C and stirred for 18 hours. The solids obtained were filtered and washed with water (500ml). The wet solid was added water (500ml) and stirred for 1 hour at 20-25°C. The resulting solids were filtered, washed with (200ml) water and dried at 30-35°C for 10 hours to get title compound.
Yield: 77.5gm
Purity: 99.9% (By HPLC)
XRD: As depicted in Figure 1

WE CLAIM:

1. A compound which is beta crystalline form of strontium ranelate octahydrate having substantially the same X-ray diffraction pattern as shown in Figure 1.

2. The compound of claim no. 1 having X-ray diffraction pattern comprising the peaks at 13.8, 15.2, 17.9, 19.1, 19.9, 21.3, 22.0, 25.2, 26.8, 33.9, 34.7, 35.0, 35.2, 35.5, 36.2, 36.8, 36.9, 38.1, 39.3 ± 0.2 degrees two-theta.

3. The compound of claim no. 1 having a mean particle size in the range of 5 um to 10 um.

4. The compound of claim no. 1 having moisture content in the range of 20% weight / weight to 24% weight / weight.

5. A process for preparing beta crystalline form of strontium ranelate octahydrate comprising the steps of:
a. reacting a compound of structural formula II with alkali metal hydroxide in an organic solvent selected from the group comprising of n-butanol, n-pentanol, tertiary butanol, dimethylformamide, N,N-dimethyl acetamide, methyl acetate, ethyl acetate, n-butyl acetate, iso-butyl acetate, tertiary butyl acetate, methyl isobutyl ketone, diethyl ether, methyl tertiary butyl ether, dipropyl ether, dichloromethane, ethylenedichloride of 1,4 dioxane to get a compound of structural formula III

wherein R is C1-C6 alkyl group
b. reacting a compound of structural formula III with a source of strontium to get a compound of formula I and

c. isolating beta crystalline form of strontium ranelate octahydrate.

6. The process according to claim no. 5 wherein, reaction of a compound of structural formula II with alkali metal hydroxide is carried out at a temperature in the range of 0°C to 15°C for a period of 4 hours to 16 hours to get a compound of structural formula III.

7. The process according to claim nos. 5 and 6 wherein, the examples of alkali metal hydroxide is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide or mixture(s) thereof.

8. The process according to claim no. 5 wherein, reaction of a compound of structural formula III with a source of strontium such as strontium chloride, strontium hydroxide or strontium carbonate is carried out at a temperature in the range of 0°C to 30°C for a period of 6 hours to 24 hours to get a beta crystalline form of strontium ranelate octahydrate.

9. The process according to claim no. 5 wherein, beta crystalline form of strontium ranelate octahydrate is isolated by filtration and then the wet cake of beta crystalline form of strontium ranelate octahydrate may be slurred with water at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 2 hours followed by filtration, centrifugation, washing, drying at a temperature in the range of 30°C to 35°C for a period of 6 hours to 18 hours.

10. A pharmaceutical compositions comprising beta crystalline form of strontium ranelate octahydrate in admixture or association with an appropriate pharmaceutical excipient, such as, for example, distilled water, glucose, lactose, starch, talc, ethyl cellulose, magnesium stearate or cocoa butter.