A NEW POLYMORPHIC FORM OF STRONTIUM RANELATE MONOHYDRATE

FIELD OF THE INVENTION

The present invention relates to a new crystalline polymorphic form of strontium ranelate monohydrate and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Osteoporosis is most common in women after menopause, but may also develop in men, and also may occur in anyone in the presence of particular hormonal disorders and other chronic diseases. Strontium ranelate is the known medicament for the treatment of osteoporosis to reduce the risk of vertebral and hip fractures and marketed as protelos. Strontium ranelate is the only an anti-osteoporotic agent which is having dual effective action, increases the bone formation and also reduces the bone resorption, thus it gained importance in the treatment of bone diseases.

Strontium ranelate is a bivalent strontium salt and having the chemical name as distrontium5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophene carboxylic acid. The chemical structure of strontium ranelate is represented by formula-I.
The therapeutic use of strontium ranelate and treatment of osteoporosis has been described in the European patent EP 0813869.

Strontium ranelate is existed in different hydrate forms like tetrahydrate, heptahydrate and octahydrate and preparation of these hydrates have been described in European patent No. EP 0415850.

US Patent No. 7459568 discloses the process for the preparation of alpha crystalline form of strontium ranelate, which involves refluxing strontium ranelate octahydrate in water, followed by filtration and drying to give a crystalline strontium ranelate.

In recent PCT Publication No. WO 2010/034806 preparations of anhydrate and monohydrate forms of strontium ranelate have been described. This publication provides process for the preparation of an anhydrate/amorphous and monohydrate form of strontium ranelate, which involves suspending a known hydrate -tetrahydrate or octahydrate form of strontium ranelate in an organic solvent, heating the suspension under reflux, cooling the suspension, recovering the solid and drying the solid to obtain crystalline strontium ranelate, and optionally converting the crystalline form into an amorphous form of strontium ranelate. The water content of the resulting hydrates is measured by loss on drying (LOD) analysis and the crystalline and amorphous forms are identified by X-ray powder diffraction measurements. But product purity, impurity and residual solvent levels are not mentioned which are very essential quality factors for active pharmaceutical agent.

Several processes have been reported for the preparation of strontium ranelate or pharmaceutically acceptable salts and their polymorphs in the prior art and still there is a possibility to exist a new polymorphic form of strontium ranelate. The high water content of higher hydrates of strontium ranelate like octahydrate, heptahydrate and tetrahydrate forms are hygroscopic in nature and also unstable, therefore the higher hydrates are not suitable for formulation. Therefore an attempt is made to overcome the prior art problems by developing a novel method for making a decreased water content strontium ranelate - a new crystalline monohydrate form.

The present invention relates to the process for preparation of a new crystalline strontium ranelate monohydrate form by careful dehydration process of octahydrate of strontium ranelate. The dehydration process carried out by heating the strontium ranelate octahydrate at about 80-120°C and more specifically at 90-100°C under vacuum in a rotocone dryer to provide a crystalline strontium ranelate monohydrate. In the preparation of this crystalline strontium ranelate monohydrate, strontium ranelate octahydrate obtained by a novel process, developed in our laboratory has been used.

The strontium ranelate monohydrate obtained in the present invention is having excellent stability and high in purity and also less hygroscopic. Therefore the obtained product by the present invention can advantageously be used in pharmaceutical compositions due to its high quality factors.

Surprisingly, in addition to the excellent quality factors, the strontium ranelate monohydrate obtained in the present invention is found to be a new crystalline polymorphic form of monohydrate of strontium ranelate. This new crystalline polymorph is characterized by X-ray powder diffraction pattern (XRD) and thermo gravimetric analysis (TGA). The XRD pattern of strontium ranelate monohydrate obtained by the present invention is different from that of mentioned in the prior art, disclosed in PCT Publication No.WO2010/034806, therefore considered as a new polymorph of crystalline strontium ranelate monohydrate, designated as Polymorph-F, which is represented by formula-II.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a new polymorphic Form-F of crystalline strontium ranelate monohydrate.

Another aspect of the present invention, strontium ranelate monohydrate has a water content of about 3.0 wt % to of about 4.5 wt %. There are known methods in the art to determine the water content of a chemical substance such as for example the Karl-Fischer (KF) titration method, the loss on drying (LOD) method and thermogravimetric analysis (TGA) method. For the present invention thermogravimetric analysis (TGA) method is adopted for the determination of water content.

Another aspect of the present invention provides a process for the preparation of crystalline strontium ranelate monohydrate Form-F with a water content of about 3.0 to 4.5%, which is related to a monohydrate.

Another aspect of the present invention provides strontium ranelate monohydrate having purity more than 99.85% as measured by HPLC

The present invention further provides strontium ranelate monohydrate obtained by the process herein described has negligible residual organic solvents or organic volatile impurities, which are below than amount recommended for active pharmaceutical ingredients as set forth in ICH guidelines.

The present invention process comprises,

a) drying strontium ranelate octahydrate in a rotocone vacuum dryer,

b) collecting strontium ranelate monohydrate.

Yet another aspect of the present invention provides a process for the preparation of strontium ranelate monohydrate, which comprises,

a) drying strontium ranelate octahydrate in a rotocone vacuum dryer to give strontium ranelate tetrahydrate,

b) optionally further drying strontium ranelate tetrahydrate obtained in step a) or prolonging the drying process in step a) to give strontium ranelate monohydrate,

c) collecting strontium ranelate monohydrate.

BRIEF DESCRIPTION OF THE FIGURES

Figure-1 depicts X-ray powder pattern diffractogram (XRPD) of Form-F of crystalline strontium ranelate monohydrate.

Figure-2 depicts thermogram of (TGA) of Form-F of crystalline strontium ranelate monohydrate.

Powder XRD of the samples were determined by using X-ray Difractometer, PANanytical, X'pert PRO, X'celerator, X-ray tube with Cu target anode, Divergence
slits 15, Receiving slit 0.10mm, Scatter slit 1°, Power: 45 KV, 40 mA, Scanning speed: 2.122 deg/min,Wave length: 1.5406A.

TGA of the samples were determined by using Instrument: TA Instruments, TGA Q500.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention provides a process to obtain a new polymorphic Form-F of crystalline strontium ranelate monohydrate in well defined crystalline form which can be reproduced.

Another aspect of the present invention relates to a new crystalline Form-F of strontium ranelate monohydrate characterized by a water content of 4.41% measured by TGA. Preferably the monohydrate of strontium ranelate has a water content of about 3.0% to about 4.5%.

The crystalline Form-F of strontium ranelate monohydrate of the present invention having characteristic X-ray powder diffraction pattern, shown in Figure-1, having peaks with the following characteristic peak values (20): 26.82, 25.59,27.29, 9.29, 16.34, 10.48, 13.32, 17.41, 18.54, 24.74, 29.08, 29.59, 33.00, 35.12 and 13.77± 0.2.

Preferably the crystalline Form-F of strontium ranelate monohydrate has an X-ray powder diffraction pattern corresponding to Figure-1 the diffraction angles and the relative intensities are given in the table.

TABLE

Another aspect of the present invention relates to a process for the preparation of a new polymorph of crystalline strontium ranelate monohydrate, Form-F, which comprises,

a) charging the strontium ranelate octahydrate in to a rotocone vacuum dryer,
b) heating the product preferably at 90-100°C under vacuum,
c) cooling the product to 25-30°C, and
d) recovering the crystalline strontium ranelate monohydrate.

In the present invention, strontium ranelate octahydrate to be used as starting material is obtained by a novel process developed in our laboratory.

Another embodiment of the present invention, involving drying strontium ranelate octahydrate in rotocone vacuum dryer is carried at about 50°C to about 120°C, preferably at about 80°C to about 110° C and more preferably at about 90°C to about 100°C.

Yet another embodiment of the present invention, further involves drying strontium ranelate octahydrate in rotocone vacuum dryer until the loss on drying (LOD) of strontium ranelate reaches to about 3.0 to about 4.5%.

In another embodiment of the present invention, further involves cooling the obtained strontium ranelate having LOD of about 3.0 to about 4.5% to 25-30°C.
In another embodiment of the present invention, strontium ranelate monohydrate prepared by the method is crystalline monohydrate having moisture content in the range of about 3.0 to about 4.5% as measured by TGA.

Yet another aspect of the present invention provides a process for the preparation of a new polymorph of crystalline strontium ranelate monohydrate, Form-F, which comprises,

a) drying strontium ranelate octahydrate in a rotocone vacuum dryer to provide a new polymorph of crystalline strontium ranelate monohydrate,

b) collecting strontium ranelate monohydrate.

EXAMPLE

Preparation of crystalline strontium ranelate monohydrate, Form-F.

Strontium ranelate octahydrate (150 g) was charged into a rotocone vacuum dryer at
room temperature and rotated the dryer under high vacuum at 95-100°C for 25 h, the
dryer was cooled to 25-30°C and material was collected.

Yield: 115 g

Purity: 99.87% (HPLC)

The XRD pattern is as shown in Figure-1.

Loss on drying by TGA: 4.41% in Figure-2.

CLAIMS

1. A new polymorphic Form-F of crystalline strontium ranelate monohydrate.

2. A new polymorph of strontium ranelate monohydrate, Form-F, characterized by an X-ray powder diffractogram having peaks expressed as 29 angle positions at about 26.82, 25.59, 27.29, 9.29, 16.34, 10.48, 13.32, 17.41, 18.54, 24.74,29.08, 29.59, 33.00, 35.12 and 13.77± 0.2 degrees.

3. A crystalline form of strontium ranelate monohydrate, Form-F, characterized by an XRD pattern as depicted in Figure-1.

4. A crystalline form of strontium ranelate monohydrate, Form-F, as claimed in claim 1 is further characterized by having a water content of 3.0 to 4.5% as measured by TGA.

5. A crystalline form of strontium ranelate monohydrate, Form-F, as claimed in claim 1, wherein the strontium ranelate monohydrate is further characterized by thermogravimetric analysis (TGA) thermogram as shown in figure-2.

6. A process for the preparation of crystalline strontium ranelate monohydrate, Form-F, which comprises,

a) drying strontium ranelate octahydrate in rotocone vacuum dryer,

b) collecting strontium ranelate monohydrate.

7. A process for the preparation of strontium ranelate monohydrate Form-F according to claim 6, wherein drying strontium ranelate octahydrate in rotocone vacuum dryer is carried out at about 80°C to about 110°C.

8. A process for the preparation of strontium ranelate monohydrate Form-F according to claim 6, wherein the process involves drying strontium ranelate octahydrate in rotocone vacuum dryer is carried out at about 90°C to about 100°C.

9. A process for the preparation of strontium ranelate monohydrate Form-F according to claim 7, wherein drying strontium ranelate octahydrate in rotocone vacuum dryer is carried until the loss on drying of strontium ranelate reaches to about 3.0 to about 4.5%.