WO2011107454A1 - Process for the preparation of a polymorph of strontium ranelate - Google Patents

Process for the preparation of a polymorph of strontium ranelate Download PDF

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Publication number
WO2011107454A1
WO2011107454A1 PCT/EP2011/052980 EP2011052980W WO2011107454A1 WO 2011107454 A1 WO2011107454 A1 WO 2011107454A1 EP 2011052980 W EP2011052980 W EP 2011052980W WO 2011107454 A1 WO2011107454 A1 WO 2011107454A1
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Prior art keywords
strontium
ranelate
polymorph
strontium ranelate
anhydrous
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PCT/EP2011/052980
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French (fr)
Inventor
Marco Baratella
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Chemelectiva Srl
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Priority to EP11708013A priority Critical patent/EP2542546A1/en
Priority to CN2011800124456A priority patent/CN102791700A/en
Priority to BR112012022442A priority patent/BR112012022442A2/en
Publication of WO2011107454A1 publication Critical patent/WO2011107454A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid

Definitions

  • the present invention relates to a stable of strontium ranelate polymorph, to a process for its preparation, to pharmaceutical compositions containing it and to its 5 use as a medicament.
  • the present invention also relates to a new ranelate salt useful as intermediate for the preparation of said stable strontium ranelate polymorph.
  • Osteoporosis is a systemic skeletal disease characterized by bone tissue microarchitecture deterioration. The bones become more fragile and are exposed to 10 an increased risk of fracture. Postmenopausal women are the most affected by this disease.
  • the basic therapy for the prevention and treatment of osteoporosis is provided by taking calcium supplement and vitamin D.
  • Some divalent metal salts such as strontium lactate, gluconate and carbonate are
  • strontium ranelate demonstrates higher bioavailability in comparison with the above listed salts and thus allows a lower dosage for the treatment of osteoporosis.
  • Strontium ranelate is a compound of formula
  • EP 0 415 850 discloses the octahydrate, eptahydrate and tetrahydrate forms of strontium ranelate. These hydrated forms are prepared from the tetraethyl ester of ranelic acid by hydrolysis to ranelic acid and salification with a strontium salt in aqueous medium. Alternatively, the tetraethyl ester of ranelic acid is treated at warm with a mixture of sodium hydroxide and ethanol to obtain the sodium salt of ranelic acid which is then converted into strontium ranelate by treatment with an aqueous solution of strontium chloride. Strontium ranelate can also be obtained directly from the corresponding tetraethyl ester by heating under reflux with strontium hydroxide in hydro-alcoholic medium.
  • WO2007/020527 discloses a process for the synthesis of strontium ranelate by reacting a tetraester of ranelic acid with an inorganic acid strontium salt in the presence of a lithium base in a solvent.
  • EP 2 042 497 discloses a process for the synthesis of strontium ranelate, which consists in reacting the tetramethylbenzidine ester of ranelic acid with sodium or potassium hydroxide in water or in a water/organic solvent mixture at a temperature between 0°C and 100°C to obtain the corresponding sodium or potassium salt which is subsequently reacted with strontium chloride in water or in a water/organic solvent mixture at 0-100°C.
  • CN 100554263C and CN 1995034A disclose a process for the preparation of strontium ranelate heptahydrate and tetrahydrate, respectively.
  • WO2010/034806 relates to anhydrate and hydrate forms of strontium ranelate having a water content of less than 5.5% w/w.
  • Some hydrate crystalline forms of strontium ranelate, namely form I , form II and form I II , as well as an anhydrate amorphous form of strontium ranelate are exemplified in WO2010/034806.
  • Form a Another strontium ranelate polymorph, called Form a, is disclosed in patent application EP 1 642 897.
  • Said form a is a crystalline nonahydrate form prepared by heating under reflux a solution of strontium ranelate octahydrate in water, cooling up to crystallization and filtering.
  • the form a is easily reproducible and has interesting characteristics of filtration and ease of formulation.
  • Polymorphism is the property of the molecules in the solid state to take more than one crystalline or amorphous form. Some substances are known to exist in one crystalline or amorphous form; others may have two or more crystalline forms. The polymorphs are distinct solids, with the same molecular formula but with different physical properties, which may be advantageous or disadvantageous when compared to other forms within the same family of polymorphs.
  • the morphology of the chemical organic active ingredients is important for their chemical and pharmaceutical development.
  • a crystalline form compared to other crystalline forms, can provide significant advantages.
  • An appropriate process to make a crystalline form may give to the producers of active ingredients several advantages, such as the use of low cost or low environmental impact steps or solvents, higher yields and purity of the desired product.
  • the polymorphism the number of crystalline forms of a chemical organic compound, their stability, their behavior in a living organism are never predictable.
  • Various polymorphs of a substance possess different energies of the crystal lattice thus showing different physical properties of the solid state (such as the form, the density, the melting point, the color, the stability, the dissolution rate, the ease of grinding, the granulation, etc.).
  • the dissolution rate of an active ingredient in the gastric fluid of a patient may have therapeutic consequences, since it determines the maximum concentration which may be reached in the blood by the orally administered active ingredient.
  • Other important properties of the polymorphic forms affect the ease of formulating the active ingredient in suitable pharmaceutical dosage forms, the flowing capability of a granulated or powdered form and the surface properties that determine whether the crystals of the form will adhere one another once compressed into a tablet.
  • a polymorph may have a thermal behavior different from that of an amorphous form or any other polymorphs.
  • the thermal behavior can be measured in laboratory through techniques such as capillary melting point, differential scanning calorimetry (DSC) and can be used to distinguish the various polymorphs.
  • a polymorph may show distinct spectroscopic properties detectable by X-ray diffraction (X-Ray Powder Diffraction, XRPD).
  • anhydrous strontium ranelate polymorph characterized by an XRPD comprising peaks at about 8.3, 8.6, 13.5, 19.3, 23.7, 25.7 ⁇ 0.2° 2 ⁇ or in accordance with Figure 1 .
  • the anhydrous polymorph according to the present invention has a water content generally between 0.13% and 0.15%.
  • the term "anhydrous" strontium ranelate means non-hydrate strontium ranelate, i.e. a strontium ranelate polymorph substantially free of water in its crystal lattice. It is clear to the skilled in the art that the anhydrous strontium ranelate object of the present invention can eventually absorb some water from the environment if stored in the presence of humidity. This absorbed water does not usually exceed 1 1 % w/w and does not represent crystallization water.
  • the eventual absorbed water present in the anhydrous strontium ranelate according to the present invention can be easily removed by heating the wet compound at about 50°C.
  • the eventual absorption of water and its subsequent removal by heating as above reported do not affect the polymorphic characteristics of the anhydrous strontium ranelate according to the present invention.
  • the new strontium ranelate polymorph has been also characterized by differential scanning calorimetry (DSC) and infrared absorption spectroscopy (FT-IR), in Figure 2 and Figure 3 respectively.
  • DSC differential scanning calorimetry
  • FT-IR infrared absorption spectroscopy
  • the compound of formula (III) is characterized by an XRPD comprising peaks at about 9.5, 14.1 , 16.6, 18.8, 22.2, 25.4 ⁇ 0.2° 2 ⁇ or in accordance with Figure 4.
  • the compound of formula (III) has been also characterized by differential scanning calorimetry (DSC) and infrared absorption spectroscopy (FT-IR), in Figure 5 and Figure 6 respectively.
  • polar solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, and tert- butanol; or a polarized solvent, such as, for example, an ester, for example, ethyl acetate, and butyl acetate; a nitrile, for example acetonitrile; an ether, for example tetrahydrofuran, and dioxane; an amide, for example, dimethylformamide, and dimethylacetamide; a sulfoxide, for example dimethyl sulfoxide; and analogues, and mixtures thereof.
  • an alcohol for example, methanol, ethanol, propanol, iso-propanol, butanol, and tert- butanol
  • a polarized solvent such as, for example, an ester, for example, ethyl acetate
  • Ranelic acid of formula (II) is a known compound, described for instance in the aforementioned EP 0 415 850.
  • the acid (II) is converted into the corresponding ammonium salt (III) by treatment with ammonia in a polar solvent.
  • a polar solvent Any polar solvent known by the skilled person can be used in this step of the process object of the present invention, but preferably the salification is carried out in an alcoholic medium, more preferably in methanol.
  • the reaction temperature is generally between room temperature and the reflux temperature of the solvent, preferably between room temperature and 60°C.
  • the resultant ammonium salt of formula (III) precipitates and is filtered from the reaction mixture.
  • the compound of formula (III) is dissolved in water and a strontium salt, such as for example, strontium acetate, strontium hydroxide, or strontium chloride, is added to the resultant solution at a suitable temperature.
  • a strontium salt such as for example, strontium acetate, strontium hydroxide, or strontium chloride
  • Strontium acetate is preferably added.
  • the reaction temperature for the anhydrous strontium ranelate form is generally between room temperature and the reflux temperature of the solvent, preferably between 60°C and 90°C.
  • the anhydrous strontium ranelate form obtained by the process of the present invention is filtered and dried in an oven, providing a new polymorphic form without requiring further purification and/or isolation steps, such as crystallization, dissolution in another solvent, etc.
  • the anhydrous strontium ranelate polymorph according to the present invention has the same therapeutic effectiveness of the form currently used in therapy and furthermore is stable, non-hygroscopic, particularly suitable for the preparation of pharmaceutical dosage forms.
  • a further object of the present invention is the use of the anhydrous crystalline strontium ranelate for the preparation of a medicament.
  • Still another object of the present invention is a pharmaceutical composition containing an anhydrous crystalline strontium ranelate in admixture with one or more pharmaceutically acceptable excipients.
  • the XRPD diffraction patterns were carried out through APD 2000 Ital Structures diffractometer at room temperature, using a tube Cuka (40 kV, 30 mA) as X-ray source. Data were collected through a 2 ⁇ continuous scan, at a scan speed of 0.027s in the range 3°-40° 2 ⁇ .
  • Thermic analysis DSC was carried out through differential scanning calorimeter Perkin Elmer Pyris 1 (4.8 mg, scan 20-400°C, 10°C/min) with perforated baskets.
  • the DRIFT analysis was carried out through a Perkin Elmer, Spectrum-One instrument.
  • ranelic acid 29.8 g, 0.087 mol
  • hot methanol 60 ml
  • NH 3 33% w/w was added up to basic pH.
  • the suspension was allowed to cool, filtered on Buckner and washed with methanol, obtaining 30.1 g (75% yield) of ammonium ranelate.
  • ranelate ammonium (26.4 g, 0.064 mol), prepared as described in example 2, was dissolved in water (130 ml) under reflux.
  • Strontium acetate (26.5 g, 0.128 mol) was added and a white solid precipitate was hot filtered and dried in oven at 60°C to obtain 33.4 g of strontium ranelate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An anhydrous strontium ranelate polymorph, a method for its preparation, pharmaceutical compositions containing it and its use as a medicament are described. The invention also relates to a new ranelate salt, useful as an intermediate in the preparation of strontium ranelate.

Description

PROCESS FOR THE PREPARATION OF A POLYMORPH OF STRONTIUM RANELATE
The present invention relates to a stable of strontium ranelate polymorph, to a process for its preparation, to pharmaceutical compositions containing it and to its 5 use as a medicament. The present invention also relates to a new ranelate salt useful as intermediate for the preparation of said stable strontium ranelate polymorph.
Osteoporosis is a systemic skeletal disease characterized by bone tissue microarchitecture deterioration. The bones become more fragile and are exposed to 10 an increased risk of fracture. Postmenopausal women are the most affected by this disease.
The basic therapy for the prevention and treatment of osteoporosis is provided by taking calcium supplement and vitamin D.
Unfortunately, some recent studies proved that this therapy has little effect on
15 reducing the risk of bone fractures.
On the other hand, the use of bisphosphonates, generally considered the first-line therapy in patients with osteoporosis, is limited because of their side effects on the gastrointestinal system: dyspepsia, abdominal pain, gastritis.
Some divalent metal salts, such as strontium lactate, gluconate and carbonate are
20 known in the literature for their therapeutic properties in treating bone diseases. In fact, the possibility of replacing calcium with strontium in bones now seems an effective alternative to other little or poorly tolerated drugs. Specifically, strontium ranelate demonstrates higher bioavailability in comparison with the above listed salts and thus allows a lower dosage for the treatment of osteoporosis.
25 Strontium ranelate is a compound of formula
Figure imgf000002_0001
coo- chemically known as distrontium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3-(2- oxido-2-oxoethyl)thiophene-2-carboxylate, described in EP 0 415 850 and on the market under the trademark Protelos®.
EP 0 415 850 discloses the octahydrate, eptahydrate and tetrahydrate forms of strontium ranelate. These hydrated forms are prepared from the tetraethyl ester of ranelic acid by hydrolysis to ranelic acid and salification with a strontium salt in aqueous medium. Alternatively, the tetraethyl ester of ranelic acid is treated at warm with a mixture of sodium hydroxide and ethanol to obtain the sodium salt of ranelic acid which is then converted into strontium ranelate by treatment with an aqueous solution of strontium chloride. Strontium ranelate can also be obtained directly from the corresponding tetraethyl ester by heating under reflux with strontium hydroxide in hydro-alcoholic medium.
WO2007/020527 discloses a process for the synthesis of strontium ranelate by reacting a tetraester of ranelic acid with an inorganic acid strontium salt in the presence of a lithium base in a solvent.
The synthesis of the octahydrate form of strontium ranelate is exemplified through the preparation of ranelic acid lithium salt as intermediate.
EP 2 042 497 discloses a process for the synthesis of strontium ranelate, which consists in reacting the tetramethylbenzidine ester of ranelic acid with sodium or potassium hydroxide in water or in a water/organic solvent mixture at a temperature between 0°C and 100°C to obtain the corresponding sodium or potassium salt which is subsequently reacted with strontium chloride in water or in a water/organic solvent mixture at 0-100°C.
CN 100554263C and CN 1995034A disclose a process for the preparation of strontium ranelate heptahydrate and tetrahydrate, respectively.
WO2010/034806 relates to anhydrate and hydrate forms of strontium ranelate having a water content of less than 5.5% w/w. Some hydrate crystalline forms of strontium ranelate, namely form I , form II and form I II , as well as an anhydrate amorphous form of strontium ranelate are exemplified in WO2010/034806.
Another strontium ranelate polymorph, called Form a, is disclosed in patent application EP 1 642 897. Said form a is a crystalline nonahydrate form prepared by heating under reflux a solution of strontium ranelate octahydrate in water, cooling up to crystallization and filtering. The form a is easily reproducible and has interesting characteristics of filtration and ease of formulation.
Polymorphism is the property of the molecules in the solid state to take more than one crystalline or amorphous form. Some substances are known to exist in one crystalline or amorphous form; others may have two or more crystalline forms. The polymorphs are distinct solids, with the same molecular formula but with different physical properties, which may be advantageous or disadvantageous when compared to other forms within the same family of polymorphs.
The morphology of the chemical organic active ingredients is important for their chemical and pharmaceutical development. A crystalline form, compared to other crystalline forms, can provide significant advantages. An appropriate process to make a crystalline form may give to the producers of active ingredients several advantages, such as the use of low cost or low environmental impact steps or solvents, higher yields and purity of the desired product.
The polymorphism, the number of crystalline forms of a chemical organic compound, their stability, their behavior in a living organism are never predictable. Various polymorphs of a substance possess different energies of the crystal lattice thus showing different physical properties of the solid state (such as the form, the density, the melting point, the color, the stability, the dissolution rate, the ease of grinding, the granulation, etc.). These differences may have dramatic effects on the flowing of ground solid (flowing affects the ease of treatment of the material during processing into a pharmaceutical product), on transport and storage stability of different forms of administration, on the ability to produce different forms of administration, on solubility in polar or non polar, protic or aprotic solvents, on aqueous solubility, on the solubility in gastric juices, on the solubility in blood and finally on the bioavailability.
The dissolution rate of an active ingredient in the gastric fluid of a patient may have therapeutic consequences, since it determines the maximum concentration which may be reached in the blood by the orally administered active ingredient. Other important properties of the polymorphic forms affect the ease of formulating the active ingredient in suitable pharmaceutical dosage forms, the flowing capability of a granulated or powdered form and the surface properties that determine whether the crystals of the form will adhere one another once compressed into a tablet.
A polymorph may have a thermal behavior different from that of an amorphous form or any other polymorphs. The thermal behavior can be measured in laboratory through techniques such as capillary melting point, differential scanning calorimetry (DSC) and can be used to distinguish the various polymorphs. A polymorph may show distinct spectroscopic properties detectable by X-ray diffraction (X-Ray Powder Diffraction, XRPD).
The achievement of new polymorphs of a pharmaceutical compound gives a further opportunity to improve the characteristics of this product by increasing the number of options available to an expert in pharmaceutical technology to design a dosage form with a targeted release profile or with other characteristics, such as the fluidity and dissolution rate in aqueous liquids.
Therefore, it is useful to have a new crystalline form of strontium ranelate that, while maintaining the efficacy of the known form, is stable and not hygroscopic and can be prepared with a simple and reproducible method, with high yields and easy industrialization.
We have now found a new anhydrous strontium ranelate polymorph, which has the desired characteristics of stability and non-hygroscopicity, which can be prepared with a simple, reproducible, and easily industrialized method, with high yields, and which is particularly suitable for the preparation of stable pharmaceutical formulations.
It is therefore an object of the present invention an anhydrous strontium ranelate polymorph characterized by an XRPD comprising peaks at about 8.3, 8.6, 13.5, 19.3, 23.7, 25.7 ± 0.2° 2Θ or in accordance with Figure 1 .
The anhydrous polymorph according to the present invention has a water content generally between 0.13% and 0.15%. When referred to the polymorph according to the present invention, the term "anhydrous" strontium ranelate means non-hydrate strontium ranelate, i.e. a strontium ranelate polymorph substantially free of water in its crystal lattice. It is clear to the skilled in the art that the anhydrous strontium ranelate object of the present invention can eventually absorb some water from the environment if stored in the presence of humidity. This absorbed water does not usually exceed 1 1 % w/w and does not represent crystallization water. The eventual absorbed water present in the anhydrous strontium ranelate according to the present invention can be easily removed by heating the wet compound at about 50°C. The eventual absorption of water and its subsequent removal by heating as above reported do not affect the polymorphic characteristics of the anhydrous strontium ranelate according to the present invention.
The new strontium ranelate polymorph has been also characterized by differential scanning calorimetry (DSC) and infrared absorption spectroscopy (FT-IR), in Figure 2 and Figure 3 respectively.
It is a further object of the present invention a process for preparing the anhydrous strontium ranelate polymorph (I), comprising:
(a) the salification of the ranelic acid of formula (II)
Figure imgf000006_0001
by treatment with ammonia to obtain ammonium ranelate of formula (III)
Figure imgf000006_0002
(b) the subsequent reaction with a strontium salt in a polar medium to give anhydrous strontium ranelate.
The compound of formula (III), ammonium ranelate,
Figure imgf000007_0001
is a new compound, useful as an intermediate for the preparation of strontium ranelate, and is a further object of the present invention.
The compound of formula (III) is characterized by an XRPD comprising peaks at about 9.5, 14.1 , 16.6, 18.8, 22.2, 25.4 ± 0.2° 2Θ or in accordance with Figure 4. The compound of formula (III) has been also characterized by differential scanning calorimetry (DSC) and infrared absorption spectroscopy (FT-IR), in Figure 5 and Figure 6 respectively.
All terms used in this description and in the claims which follows, unless otherwise specified, must be understood in their common meaning as known by the skilled person.
The term "polar solvent" refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, iso-propanol, butanol, and tert- butanol; or a polarized solvent, such as, for example, an ester, for example, ethyl acetate, and butyl acetate; a nitrile, for example acetonitrile; an ether, for example tetrahydrofuran, and dioxane; an amide, for example, dimethylformamide, and dimethylacetamide; a sulfoxide, for example dimethyl sulfoxide; and analogues, and mixtures thereof.
More information on non-polar or polar solvents can be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., John A. Riddick, et al., Vol II, in "Techniques of Chemistry Series", John Wiley & Sons, NY, 1986. These solvents are known to the person skilled in the art, and it is also clear to the person skilled in the art that the different solvents or mixtures thereof can be preferred depending on the specific compounds and reaction conditions, being their choice influenced, for example, by solubility and reactivity of the reagents, by the preferred temperature ranges, etc.
The term "about" includes the experimental error that can occur in any measurement.
The process for preparing an anhydrous strontium ranelate polymorph is depicted in the following scheme 1 .
Scheme 1
Figure imgf000008_0001
NH3
Figure imgf000008_0002
Figure imgf000008_0003
Ranelic acid of formula (II) is a known compound, described for instance in the aforementioned EP 0 415 850.
The acid (II) is converted into the corresponding ammonium salt (III) by treatment with ammonia in a polar solvent. Any polar solvent known by the skilled person can be used in this step of the process object of the present invention, but preferably the salification is carried out in an alcoholic medium, more preferably in methanol. The reaction temperature is generally between room temperature and the reflux temperature of the solvent, preferably between room temperature and 60°C.
The resultant ammonium salt of formula (III) precipitates and is filtered from the reaction mixture.
The compound of formula (III) is dissolved in water and a strontium salt, such as for example, strontium acetate, strontium hydroxide, or strontium chloride, is added to the resultant solution at a suitable temperature. Strontium acetate is preferably added. The reaction temperature for the anhydrous strontium ranelate form is generally between room temperature and the reflux temperature of the solvent, preferably between 60°C and 90°C. The anhydrous strontium ranelate form obtained by the process of the present invention is filtered and dried in an oven, providing a new polymorphic form without requiring further purification and/or isolation steps, such as crystallization, dissolution in another solvent, etc.
The anhydrous strontium ranelate polymorph according to the present invention has the same therapeutic effectiveness of the form currently used in therapy and furthermore is stable, non-hygroscopic, particularly suitable for the preparation of pharmaceutical dosage forms.
A further object of the present invention is the use of the anhydrous crystalline strontium ranelate for the preparation of a medicament.
Still another object of the present invention is a pharmaceutical composition containing an anhydrous crystalline strontium ranelate in admixture with one or more pharmaceutically acceptable excipients.
Although the present invention has been described in its characterizing features, the equivalents and modifications obvious to the skilled in the art are included in the present invention.
In order to better illustrate the present invention without limiting it, the following examples are now given. The XRPD diffraction patterns were carried out through APD 2000 Ital Structures diffractometer at room temperature, using a tube Cuka (40 kV, 30 mA) as X-ray source. Data were collected through a 2Θ continuous scan, at a scan speed of 0.027s in the range 3°-40° 2Θ.
Thermic analysis DSC was carried out through differential scanning calorimeter Perkin Elmer Pyris 1 (4.8 mg, scan 20-400°C, 10°C/min) with perforated baskets. The DRIFT analysis was carried out through a Perkin Elmer, Spectrum-One instrument.
Example 1
In a 100 ml one neck round flask ranelic acid (29.8 g, 0.087 mol) was dissolved in hot methanol (60 ml) and NH3 33% w/w was added up to basic pH. After precipitation of ammonium ranelate, the suspension was allowed to cool, filtered on Buckner and washed with methanol, obtaining 30.1 g (75% yield) of ammonium ranelate.
Example 2
In a 250-ml round flask ranelate ammonium (26.4 g, 0.064 mol), prepared as described in example 2, was dissolved in water (130 ml) under reflux. Strontium acetate (26.5 g, 0.128 mol) was added and a white solid precipitate was hot filtered and dried in oven at 60°C to obtain 33.4 g of strontium ranelate.

Claims

1 ) An anhydrous strontium ranelate polymorph characterized by an XRPD comprising peaks at about 8.3, 8.6, 13.5, 19.3, 23.7, 25.7 ± 0.2° 2Θ.
2) A process for the preparation of an anhydrous strontium ranelate polymorph (I), comprising:
(a) the salification of the ranelic acid of formula (II)
Figure imgf000011_0001
by treatment with ammonia to obtain ammonium ranelate formula (III)
Figure imgf000011_0002
(b) the subsequent reaction with a strontium salt in a polar medium to give anhydrous strontium ranelate.
3) A process according to claim 2 wherein the salification is carried out in an alcoholic solvent.
4) A process according to claim 3 wherein the alcoholic solvent is methanol.
5) A process according to claim 2 wherein the strontium salt is selected among strontium acetate, strontium hydroxide and strontium chloride.
6) A process according to claim 5 wherein the strontium salt is strontium acetate.
7) A compound of formula (III)
Figure imgf000011_0003
coo- 8) A compound of formula (III) according to claim 7 characterized by an XRPD comprising peaks at about 9.5, 14.1 , 16.6, 18.8, 22.2, 25.4 ± 0.2° 2Θ.
9) Use of an anhydrous strontium ranelate polymorph for the preparation of a medicament.
10) A pharmaceutical composition containing an anhydrous strontium ranelate polymorph in admixture with one or more pharmaceutically acceptable excipients.
PCT/EP2011/052980 2010-03-05 2011-03-01 Process for the preparation of a polymorph of strontium ranelate WO2011107454A1 (en)

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CN2011800124456A CN102791700A (en) 2010-03-05 2011-03-01 Process for the preparation of a polymorph of strontium ranelate
BR112012022442A BR112012022442A2 (en) 2010-03-05 2011-03-01 process for the preparation of a strontium ranelate polymorph

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Publication number Priority date Publication date Assignee Title
EP2641905A1 (en) 2012-03-23 2013-09-25 Urquima S.A. Solid forms of strontium ranelate and processes for their preparation

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