Field of Invention :

The present invention discloses a novel polymorph of strontium ranelate having water content of 1.5 to 2.5% and a process for its preparation.

Background of the Invention :

Strontium ranelate is the distrontium salt of 5-[bis ( carboxymethyl ) amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid and is represented by Formula I.

Strontium ranelate is used in treating osteoporosis and other bone diseases. It increases bone formation and also reduces bone resorption, resulting in a rebalance of bone turnover in favor of bone formation.

Description of the Prior Art:

Strontium salts such as lactate, gluconate, and carbonate were known to be useful in the
treatment of bone diseases such as osteoporosis (J'roc. Staff. Meetings Mayo Clinic, 1960, 35, 105-111; Can. Med. Assoc. 1981, 125, 703-712; Trace Subst. Environ. Health 1984, 18, 3-23). However strontium salt of ranelate was found to have distinct advantage over other salts because of its superior bioavailability (US Patent 5,128,367).

The preparation and the therapeutic uses of strontium ranelate are described in the US Patent 5,128,367. The'367 patent describes three methods to prepare strontium ranelate. In the first method, ethyl tetraester of Formula II was hydrolyzed to get free acid and the acid was dissolved in water and treated with strontium hydroxide.

The crystals of strontium ranelate were obtained as octahydrate. In the second method the tetraester was hydrolyzed to sodium salt of the acid and its aqueous solution was treated with strontium chloride. The strontium ranelate crystallized out as octahydrate. In the third method, the tetraester was directly hydrolyzed with strontium hydroxide in an aqueous solution to obtain octahydrate of strontium ranelate.

US Patent 7,459,568B2 describes an alpha crystalline form of strontium ranelate and a process for its preparation. The process consists of dissolving strontium ranelate octahydrate in water followed by refluxing the solution and cooling to obtain alpha crystalline form of strontium ranelate. It has water content of 22-24% which accounts for its octahydrate nature. The alpha crystalline form has been further characterized by powdered X-ray diffraction.

WO 2007/020527 A2 application describes a process for preparing strontium ranelate octahydrate from tetra ester through lithium base.

A Chinese patent, CN 101108845 (A) describes a method to prepare strontium ranelate heptahydrate where the tetra ester was hydrolyzed using aqueous alcoholic solution of sodium hydroxide and the sodium salt freated with strontium chloride. The heptahydrate obtained by this method had 19 to 20.4 % water content.

Strontium ranelate is available in the market as "PROTELOS", which is a 2 g sachet containing granules of strontium ranelate. The granules are to be added to water, stirred and taken orally as a suspension. The daily recommended dose is 2 g as a single dose.
The marketed "PROTELOS" contains sfrontium ranelate as its octahydrate. High moisture content of strontium ranelate, to the extent of about 22% indicates that only about 78% drug is available per unit weight. Since the dose is large, the bulk of the formulation is very large.

Those in the art would like to have strontium ranelate with lower moisture content so that the size of the formulation can be minimized. There is thus a need for a compact form of strontium ranelate with low moisture content, which could be used in formulations.

SUMMARY OF THE INVENTION

The present invention provides a novel form of strontium ranelate having much reduced water content, of about 1.5 to 2.5%, allowing for a smaller size formulation.
This novel strontium ranelate is a stable crystalline polymorph having characteristic powdered X-ray diffraction pattern as shown in Figure-1.

The invention also provides a process for the preparation of strontium ranelate having 1.5 to 2.5% water content and having characteristic powdered X-ray diffraction pattern as shown in Figure-1.

Detailed Description of the Invention :

In the present invention, we describe a new crystalline form of strontium ranelate with 1.5-2.5% water content. This new polymorph has been designated as Form A. It is stable and can be characterized by any five or more peaks in the powdered X-ray diffraction pattern given in Figure 1 including, but not limited to, 8.71, 17.48, 22.37, 23.03, 25.13, 26.20, 27.34, 29.43, and 35.44 degrees 2-theta and infi-ared absorption spectrum as given in Figure 2 including, but not limited to 3413.6, 2209,8, 1622.9, 1558.1, 1398.8, 1295.7, and 1246.9 cm''.

The present invention also describes a process for the preparation of Form A which comprises of azeotropic drying of strontium ranelate octahydrate by refluxing in a suitable solvent or antisolvent using Dean-Stark or any other apparatus to trap the released water. The preferred solvent to carryout the present invention is toluene. However, other solvents with high boiling point can also be used. After refluxing, the reaction mixture is cooled, filtered and further dried under vacuum to obtain a product with a moisture content of 1.5 to 2.5%. This product shows the characteristic peaks in powdered X-ray diffraction and infrared spectrum. The starting material, strontium ranelate octahydrate used in the process can be prepared by a process described in US Patent 5,128,367 or by any other method.
The main advantage of strontium ranelate form A is its very low water content (1.5 to
2.5%) compared to 22% in octahydrate or 19-20 % in heptahydrate forms. The
formulations prepared using Form A will have higher API content on weight by weight
basis. Because of low water content, the stability of the formulation will also improve to
a significant extent.

Example

Strontium ranelate octahydrate (20 g) was suspended in 250 ml of toluene and refluxed in
a Dean-Stark apparatus for 8 hours and collected water removed. The reaction mixture
was cooled to room temperature and filtered. The filtered solid was further dried under
vacuum to obtain 15.5 g of the product (98% yield, 99.6% purity by HPLC) with a
moisture content of 1.8 % w/w. It showed the characteristic powdered X-ray diffraction
pattern as in Figure 1 and IR pattern as in Figure 2.

1. Strontium ranelate of formula 1 having a water content of 1.5 to 2.5% w/w.

2. A crystalline polymorph of strontium ranelate of claim 1 that exhibits a powdered
X-ray diffraction pattern having characteristic peaks expressed in degrees 2 theta
at approximately 8.71, 17.48, 22.37,23.03,25.13,26.20, 27.34,29.43, and 35.44.

3. A crystalline polymorph of strontium ranelate of claim 1 that exhibits an infrared
absorption spectrum in KBr having characteristic absorption bands approximately
at, 3413.6,2209,8, 1622.9, 1558.1, 1398.8,1295.7, and 1246.9 cm.

4. A process for the preparation of the crystalline polymorph of the strontium
ranelate as in claim 1,2 or 3, which comprises suspending strontium ranelate or
its hydrate in a suitable solvent and refluxing the suspension to remove water by
azeotropic distillation.

5. The process of Claim 4, wherein the solvent used for the suspension of strontium
ranelate is toluene.