Title of Invention

" , A PROCESS FOR PREPARATION OF ALPHA CRYSTALLINE FORM OF STRONTIUM RANELATE "

Abstract Process for the preparation of the alpha crystalline form of strontium ranelate of formula (I): characterised by a water content of from 22 to 24 % and by the following powder X-ray diffraction diagram measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height ("FWHM", expressed in degrees) and interplanar distance d (expressed in A).
Full Text The present invention relates to the alpha crystalline form of strontium ranelate, to a process for its preparation and to pharmaceutical compositions containing it.
Strontium ranelate, represented by formula (I)
(Formula Removed)
or the distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and its hydrates have very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making these compounds useful in the treatment and prevention of bone diseases.
Strontium ranelate and its hydrates also have properties making them useful in the treatment and prevention of arthrosis.
The preparation and therapeutic use of strontium ranelate and its tetrahydrate, heptahydrate and octahydrate have been described in the European Patent Specification EP 0 415 850.
The use of strontium ranelate in the prevention and treatment of arthrosis has been described in the European Patent Specification EP 0 813 869.
The Applicant has now found that strontium ranelate can be obtained in a well-defined crystalline form which is perfectly reproducible and which, by virtue of that fact, has valuable characteristics in terms of filtration and ease of formulation.
More specifically, the present invention relates to the alpha crystalline form of strontium ranelate, characterised by a water content of from 22 to 24 % and by the following powder X-ray diffraction diagram measured using a PANalytical X'Pert Pro diffractometer together

with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height ("FWHM", expressed in degrees) and interplanar distance d (expressed in A):
(Table Removed)
The invention relates also to a process for the preparation of the alpha crystalline form of strontium ranelate, characterised in that a solution of strontium ranelate or a hydrate thereof in water is heated to reflux and then cooled until crystallisation is complete, and the product is collected by filtration.
• In the preparation process according to the invention it is possible to use strontium
ranelate or a hydrate thereof obtained by any process, for example strontium ranelate
octahydrate obtained by the preparation process described in the Patent Specification
EP 0415 850.
• An advantage of obtaining the said crystalline form is to allow especially rapid and
efficient filtration and also the preparation of pharmaceutical formulations of consistent
and reproducible composition, which is especially advantageous when the formulations
are intended for oral administration.
• The form thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions in terms of temperature, light, humidity or oxygen levels.
The invention relates also to pharmaceutical compositions comprising as active ingredient the alpha crystalline form of strontium ranelate together with one or more appropriate, inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and chewing gums.
The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 0.2 to 10 g per day in one or more administrations.
The Examples that follow illustrate the invention.
The X-ray powder diffraction spectrum was measured under the following experimental conditions :
PANalytical X'Pert Pro diffractometer, X'Celerator detector,
- voltage 45 kV, intensity 40 mA,
- mounting θ-θ
- Kβ (Ni) filter,
incident-beam and diffracted-beam Seller slit: 0.04 rad,
- divergence slits : automatic, irradiated length: 10 mm,
mask : 10 mm,
- antiscatter slit: 1/2°,
measurement mode : continuous from 3° to 34°, in increments of 0.017°,
- measurement time per step : 31.1 s,
- total time : 8 min 07 s,
- measurement speed : 0.068°/s,
- spinner : turning at 1 revolution/s,
measurement temperature: ambient.
EXAMPLE 1 : Alpha crystalline form of strontium ranelate
200 g of strontium ranelate octahydrate obtained according to the process described in Patent Specification EP 0 415 850 are mixed with 2 litres of water and heated to reflux. The mixture is then cooled to 20°C. The solid obtained is collected by filtration.
The water content of the product obtained, determined by loss on drying, is from 22 to 24 %, which corresponds to from 8.1 to 9 molecules of water per molecule of strontium ranelate.
X-ray powder diffraction diagram :
The X-ray powder diffraction profile (diffraction angles) of the alpha form of strontium ranelate is given by the significant rays collated in the following table:
(Table Removed)
EXAMPLE 2 : Pharmaceutical composition
Formula for the preparation of 1000 tablets each containing 0.5 g of active ingredient:
Compound of Example 1 658 g
Sodium carboxymethyl starch 25.5 g
Microcrystalline cellulose 119.4 g

Povidone 38

g

Anhydrous colloidal silica 1.5 g
Magnesium stearate 7.6g







WE CLAIM:
1. Process for the preparation of the alpha crystalline form of strontium ranelate of formula (I):
(Formula Removed)
characterised by a water content of from 22 to 24% and by the powder X-ray diffraction diagram as described herein before characterised in that a solution of strontium ranelate or a hydrate thereof in water is heated to reflux and then cooled until crystallisation is complete, and the product is collected by filtration.


Documents:

1410-DEL-2005-Abstract-(03-07-2009).pdf

1410-del-2005-abstract.pdf

1410-DEL-2005-Claims (15-01-2010).pdf

1410-DEL-2005-Claims-(03-07-2009).pdf

1410-del-2005-claims.pdf

1410-DEL-2005-Correspondence-Others (15-01-2010).pdf

1410-del-2005-Correspondence-Others (25-11-2009).pdf

1410-del-2005-Correspondence-Others (26-11-2009).pdf

1410-DEL-2005-Correspondence-Others-(10-06-2009).pdf

1410-del-2005-correspondence-others.pdf

1410-DEL-2005-Corresponence-Others-(03-07-2009).pdf

1410-del-2005-description (complete).pdf

1410-del-2005-form-1.pdf

1410-del-2005-form-18.pdf

1410-DEL-2005-Form-2-(03-07-2009).pdf

1410-del-2005-form-2.pdf

1410-del-2005-Form-3 (25-11-2009).pdf

1410-DEL-2005-Form-3-(10-06-2009).pdf

1410-del-2005-form-3.pdf

1410-del-2005-form-5.pdf

1410-DEL-2005-GPA-(03-07-2009).pdf

1410-del-2005-gpa.pdf

1410-DEL-2005-Others-Documents-(10-06-2009).pdf

1410-DEL-2005-Petition-137-(10-06-2009).pdf

1410-DEL-2005-Petition-138-(10-06-2009).pdf

abstract.jpg


Patent Number 239616
Indian Patent Application Number 1410/DEL/2005
PG Journal Number 14/2010
Publication Date 02-Apr-2010
Grant Date 26-Mar-2010
Date of Filing 01-Jun-2005
Name of Patentee LES LABORATOIRES SERVIER
Applicant Address 12, PLACE DE LA DEFENSE, 92415 COURBEVOIE CEDEX, FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 STEPHANE HORVATH 35 ROUTE D'ORLEANS, 45380 LA CHAPELLE-SAINT-MESMIN, FRANCE.
2 ISABELLE DEMUYNCK 6, RUE DE LA BOURIE ROUGE, 45000 ORLEANS, FRANCE.
3 GERARD DAMIEN 31 BIS, AVENUE DU BLENOIS, 45130 MEUNG-SUR-LOIRE, FRANCE.
PCT International Classification Number C07D 333/38
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04.10335 2004-09-30 France