WO2010034806A1 - Anhydrate and hydrate forms of strontium ranelate - Google Patents

Anhydrate and hydrate forms of strontium ranelate Download PDF

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WO2010034806A1
WO2010034806A1 PCT/EP2009/062439 EP2009062439W WO2010034806A1 WO 2010034806 A1 WO2010034806 A1 WO 2010034806A1 EP 2009062439 W EP2009062439 W EP 2009062439W WO 2010034806 A1 WO2010034806 A1 WO 2010034806A1
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Prior art keywords
strontium ranelate
strontium
ranelate
drying
ray powder
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PCT/EP2009/062439
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French (fr)
Inventor
Wolfgang Albrecht
Gertrud Auer
Christian Janssen
Ramesh Matioram Gidwani
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Ratiopharm Gmbh
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Priority to CN2009801474430A priority Critical patent/CN102227419A/en
Priority to EP09783416A priority patent/EP2346846A1/en
Publication of WO2010034806A1 publication Critical patent/WO2010034806A1/en
Priority to IL212024A priority patent/IL212024A0/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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table

Definitions

  • the present invention relates to novel anhydrate and hydrate forms of strontium ranelate, processes for the preparation thereof and pharmaceutical compositions containing said strontium ranelate. Furthermore, the invention relates to by-products obtained in the synthesis of the novel forms of strontium ranelate.
  • Strontium ranelate having the chemical name 5-[bis(carboxymethyl)-amino]-2-carboxy-4- cyano-3-thiopheacetic acid di strontium salt has the following chemical structure:
  • Strontium ranelate the bis-strontium (II) salt of ranelic acid
  • Strontium ranelate comprises strontium, which is a bone-seeking element. It is suggested to act through dual effects on bone metabolism, by increased bone formation and decreased bone resorption, resulting in a rebalance of bone turnover in favour of bone formation.
  • Strontium ranelate has very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making this compound useful in the treatment of bone diseases.
  • Strontium ranelate is freely soluble in aqueous media of low pH ( ⁇ pH 2), but only slightly soluble in neutral aqueous media. Strontium ranelate is practically insoluble in most organic solvents.
  • Several crystalline forms of strontium ranelate are known in the art.
  • EP 415 850 A1 discloses octahydrate, heptahydrate and tetrahydrate forms of strontium ranelate.
  • WO 2006/035122 A1 discloses a nonahydrate form of strontium ranelate.
  • These known crystalline forms of strontium ranelate are, however, hygroscopic and thus unstable, rendering the preparation of pharmaceutical compositions difficult and disadvantageous.
  • strontium ranelate in a form which does not show the problems of the known forms of strontium ranelate, and in particular is non-hygroscopic, stable and nevertheless is sufficiently soluble in water, in particular more soluble than the known forms of strontium ranelate.
  • strontium ranelate having a decreased content of water compared to the known forms. Further it has been found that these forms of strontium ranelate can be obtained by heating strontium ranelate suspended in an organic solvent under reflux, and recovering the solid, reacting strontium salts with ranelic acid in certain solvents, or drying strontium ranelate hydrates under certain conditions. The obtained forms of strontium ranelate are less hygroscopic, more stable and more soluble than the crystalline forms of strontium ranelate known in the art.
  • the present invention therefore relates to strontium ranelate having a water content of less than about 5.5 wt.%.
  • the hydrate form of strontium ranelate has a water content of about 1.5 wt.% to about 5.5 wt.%.
  • the hydrate form of strontium ranelate according to the present invention has a water content of about 2.5 wt.% to about 4.5 wt.%, in particular about 3.3 wt.% to about 3.5 wt.%, such as about 3.4 wt.%.
  • a water content of about 2.5 wt.% to about 4.5 wt.%, in particular about 3.3 wt.% to about 3.5 wt.%, such as about 3.4 wt.%.
  • methods known in the art to determine the content of water of a chemical substance are for example the Karl-Fischer- titration or the "loss-on-drying" analysis (LOD, drying loss).
  • LOD loss-on-drying
  • the water content is preferably determined, according to the present invention, according to the loss-on-drying analysis (LOD).
  • LOD loss-on-drying analysis
  • Loss-on-drying is a known laboratory method of measuring the level of moisture in solid or semi-solid materials and it is known in the art how to conduct this method. Typically, a sample of material is weighed, heated in an oven for an appropriate period optionally under reduced pressure (e.g. at 180 0 C over night at 30 mbar), cooled, optionally in the dry atmosphere of a desiccator (exsiccator) and then re-weighed. If the volatile content of the solid is primary water, the LOD technique gives a good measure of moisture content.
  • the water content of the strontium ranelate is most preferably determined as LOD (180 0 C, 30 mbar, 12 hours), i.e. heating over 12 hours at a temperature of 180 0 C and at a pressure of 30 mbar.
  • the hemihydrate of strontium ranelate theoretically has a water content of about 1.7 wt.%, the monohydrate of 3.4 wt.%, and the sesquihydrate of about 5 wt.%. All these forms are therefore encompassed by the present invention.
  • strontium ranelate of the present invention can be in amorphous or crystalline form.
  • the anhydrate form of strontium ranelate preferably is in amorphous form.
  • the crystalline and amorphous forms of strontium ranelate can be identified according to their X-ray powder diffraction patterns (XRD).
  • XRD X-ray powder diffraction patterns
  • the samples were analyzed on a Bruker-axs D8 Advance powder X-ray diffractometer (Bruker-AXS, Düsseldorf, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during measurement.
  • the measurement conditions were as follows: Radiation: Cu Ka, Source 40 kV / 40 mA, divergence slit 0.6 mm, antiscattering slit 5.59 mm, detector slit 10.28 mm, start angle 2 °, end angle 55°, Step 0.016° 2 ⁇ .
  • the first crystalline form of strontium ranelate according to the present invention (form I) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 17.6 ⁇ 0.2, 23.1 ⁇ 0.2 and 27.5 ⁇ 0.2, more preferably of 12.6 ⁇ 0.2, 17.6 ⁇ 0.2, 23.1 ⁇ 0.2 and 27.5 ⁇ 0.2, in particular it has the most significant peaks at 2-Theta angle values of 8.7 ⁇ 0.2, 12.6 ⁇ 0.2, 17.6 ⁇ 0.2, 20.3 ⁇ 0.2, 23.1 ⁇ 0.2, 26.3 ⁇ 0.2, 27.5 ⁇ 0.2 and 29.5 ⁇ 0.2.
  • the crystalline form I of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
  • the crystalline form I of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 1.
  • the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 1.
  • the second crystalline form of strontium ranelate according to the present invention (form II) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 8.7 ⁇ 0.2, 13.7 ⁇ 0.2 and 17.5 ⁇ 0.2, more preferably of 8.7 ⁇ 0.2, 9.2 ⁇ 0.2, 13.7 ⁇ 0.2 and 17.5 ⁇ 0.2, in particular it has the most significant peaks at 2-Theta angle values of 8.7 ⁇ 0.2, 9.2 ⁇ 0.2, 10.4 ⁇ 0.2, 13.7 ⁇ 0.2, 17.5 ⁇ 0.2, 19.7 ⁇ 0.2, 25.5 ⁇ 0.2 and 27.1 ⁇ 0.2.
  • the crystalline form Il of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
  • the crystalline form Il of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 2.
  • the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 2.
  • the third crystalline form of strontium ranelate according to the present invention (form III) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 10.5 ⁇ 0.2, 13.9 ⁇ 0.2 and 19.7 ⁇ 0.2, more preferably of 9.2 ⁇ 0.2, 10.5 ⁇ 0.2, 13.9 ⁇ 0.2 and 19.7 ⁇ 0.2, in particular it has the most significant peaks at 2-Theta angle values of 9.2 ⁇ 0.2, 10.5 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 19.7 ⁇ 0.2, 26.8 ⁇ 0.2 and 27.2 ⁇ 0.2.
  • the crystalline form III of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
  • the crystalline form III of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 3.
  • the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 3.
  • the present invention further relates to a first process for the preparation of the anhydrate or hydrate forms of strontium ranelate as described above, which comprises the steps of
  • step a) suspending crude strontium ranelate in an organic solvent, in particular toluene, b) heating the suspension of step a) under reflux, c) cooling the suspension, d) recovering the solid and drying the solid to obtain crystalline strontium ranelate, and e) optionally converting the crystalline form into an amorphous form of strontium ranelate.
  • each strontium ranelate can be applied, preferably the known tetrahydrate, heptahydrate or octahydrate form, as described in the art, e.g. in EP 415 850 A1 , or the nonahydrate of strontium ranelate, as described in the art, e.g. in WO 2006/035122 Al
  • the crude strontium ranelate is suspended in step a) in an organic solvent.
  • organic solvent can be used, which is suitable to form a suspension with strontium ranelate, and which is further suitable for the removal of water under reflux.
  • the organic solvent is an aromatic solvent, such as for example benzene, toluene, ethylbenzene, xylenes, trimethylbenzene, 1 ,2-dichlorobenzene or mixtures thereof, preferably toluene or 1 ,2-dichlorobenzene.
  • the organic solvent is an a-protic aliphatic solvent, such as for example cyclohexane.
  • form Il of crystalline strontium ranelate can be obtained.
  • the organic solvent is a protic aliphatic solvent, such as for example alcohols, in particular methanol, ethanol, iso-butanol and mixtures thereof, such as a mixture of methanol and iso-butanol.
  • a protic aliphatic solvent such as for example alcohols, in particular methanol, ethanol, iso-butanol and mixtures thereof, such as a mixture of methanol and iso-butanol.
  • step b) the suspension obtained under step a) is heated under reflux.
  • the temperature necessary to obtain a sufficient reflux depends on the organic solvent used. If toluene is used as organic solvent, the suspension is heated to about 130 0 C to ensure sufficient reflux. If the organic solvent is cyclohexane the temperature can be about 140 0 C. If the organic solvent is ethanol the temperature can be about 110 0 C. If the heating temperature is above the boiling point of the solvent, the temperature is the temperature of the heating device, such as the heating bath. Optionally an additional amount of the organic solvent, which is preferably the same organic solvent as used in step a), such as toluene, can be added during the heating in step b).
  • step c) the suspension is cooled down, preferably to room temperature, or below, e.g. to about 25 0 C, 20 0 C or 4 0 C.
  • step d) the solid is recovered and dried to obtain crystalline strontium ranelate according to the present invention.
  • strontium ranelate is practically insoluble in most organic solvents, a high yield of recovering can be achieved.
  • the drying in step d) is conducted at room temperature at a pressure of about 5 mbar or lower, i.e. under vacuum.
  • step d) the drying is conducted at a temperature of about 30 0 C to about 60 °C, in particular about 50 0 C to about 60 0 C, at a pressure of about 5 mbar or lower.
  • step d) the drying is conducted at a temperature of about 70 0 C to about 90 0 C, in particular about 80 0 C, at a pressure of about 5 mbar or lower, such as about 1 mbar.
  • the drying in step d) is conducted at a temperature of about 30 °C to about 60 0 C, in particular of about 50 0 C to about 60 °C, at a pressure of about 100 mbar or lower, preferably about 100 mbar to 5 mbar, in particular 50 mbar to 5 mbar.
  • form Il of crystalline strontium ranelate can be prepared by a process comprising the step of drying strontium ranelate octahydrate or strontium ranelate tetrahydrate at a temperature of about 130 0 C to about 150 0 C, such as about 140 0 C, at about room pressure.
  • form III of crystalline strontium ranelate can be prepared by reacting a strontium salt, in particular strontium isopropoxide, with ranelic acid in ethylene glycol.
  • This reaction can for example be carried out by stirring a solution of strontium isopropoxide and ranelic acid in ethylene glycol at room temperature for a prolonged time, such as about 72 hours, and recovering the precipitate.
  • Amorphous strontium ranelate according to the present invention can for example also be prepared from crystalline strontium ranelate according to the present invention by methods known in the art, for example by rapidly cooling a melt of the strontium ranelate.
  • an anhydrate amorphous form of strontium ranelate can be prepared by drying a strontium ranelate hydrate at a temperature above about 160 0 C, such as about 180 0 C. The drying can be carried out for 2 hours or more, such as about 3 hours to about 6 hours. The drying can be carried out a room pressure or reduced pressure, such as about 30 mbar or below.
  • the present invention further relates to the hydrate form of strontium ranelate obtainable by the processes as described above.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the strontium ranelate according to the present invention as described above.
  • the pharmaceutical composition further comprises suitable pharmaceutically acceptable excipients and/or adjuvants as known in the art.
  • the pharmaceutical composition is preferably suitable for oral administration and is in particular a tablet or dragee, sachet, granules, sublingual tablet, capsule or any further oral dosage forms as known in the art.
  • the useful dosage can be varied as known in the art and can be, e.g., from about 0.2 to about 10 g per day, such as a 2 g daily dose.
  • the present invention further relates to the use of strontium ranelate as described above for the preparation of a medicament for the treatment of bone diseases, in particular osteoporosis.
  • Des-carboxy ranelic acid has the following structural formula:
  • strontium ranelate As strontium ranelate is used as pharmaceutically active ingredient it is important to verify the amount of unwanted by-products in the final strontium ranelate. For determining the amounts of by-products in strontium ranelate probes of the by-products are required as standards. Therefore, des-carboxy ranelic acid and the strontium salt of des-carboxy ranelic acid have been isolated using preparative HPLC. These compounds are provided by the present invention to be used as standards for determining the purity of strontium ranelate.
  • the crystalline and amorphous forms of strontium ranelate according to the present invention can be advantageously obtained by a processes according to the present invention. Examples for the processes according to the present invention can be found in Examples 1 to 5 and 11 to 19.
  • the crystalline form of strontium ranelate as described above is prepared starting from a strontium ranelate tetrahydrate, e.g. prepared according to EP 415 850 A1
  • the strontium ranelate is obtained starting from a strontium ranelate octahydrate, e.g. prepared according to EP 415 850 A1.
  • the strontium ranelate as described above can advantageously be used in pharmaceutical compositions, as it is less hygroscopic than the known crystalline forms.
  • Example 10 wherein the dynamic vapour sorption, i.e. the desorption and absorption of water of samples of strontium ranelate octahydrate is compared to those of the strontium ranelate according to the present invention.
  • the octahydrate can be easily converted into the tetrahydrate by decreasing the humidity and by the following increase of the humidity the heptahydrate and the nonahydrate can be obtained.
  • the strontium ranelate according to the present invention which comprises e.g.
  • the monohydrate releases water only by less than 2% of its total weight.
  • the water uptake with increasing humidity is also very low with the strontium ranelate according to the present invention.
  • the mass increase is only about 2% of the total weight at the strontium ranelate according to the present invention. This shows that between the broad range of 0% to 80% relative humidity the strontium ranelate according to the present invention is excellently stable.
  • the strontium ranelate according to the present invention is excellently soluble in aqueous media, in particular water.
  • the strontium ranelate according to the present invention designated as "strontium ranelate monohydrate" shows a good solubility compared to the known crystalline forms, i.e. the tetrahydrate, nonahydrate and octahydrate of strontium ranelate.
  • the saturation solubility of strontium ranelate according to the present invention in water is higher than those of the crystalline forms of strontium ranelate as known in the art, i.e. the tetrahydrate, octahydrate and nonahydrate of strontium ranelate.
  • strontium ranelate can be identified by XRD-measurements, Raman and infrared spectroscopy as shown in Examples 7 to 9.
  • Figure 1 shows an X-ray powder diffraction pattern of the strontium ranelate form I.
  • Figure 2 shows an X-ray powder diffraction pattern of the strontium ranelate form II.
  • Figure 3 shows an X-ray powder diffraction pattern of the strontium ranelate form III.
  • Figure 4 shows a superposition of five Raman spectra of samples of strontium ranelate, which are from below to top: 1 : strontium ranelate of Example 1 ; 2: strontium ranelate of Example 2; 3: strontium ranelate tetrahydrate, prepared according to EP 415 850 A1 ; 4: strontium ranelate nonahydrate, obtained from strontium ranelate octahydrate (prepared according to EP 415 850 A1) according to Example 1 of WO 2006/035122 A1 ; 5: octahydrate (prepared according to EP 415 850 A1).
  • Figure 5 shows an infrared spectrum of strontium ranelate form I.
  • Figure 6 shows dynamic vapour sorption diagrams of strontium ranelate octahydrate (left) and strontium ranelate according to the present invention (right) (a detailed description of the diagram is given in Example 10).
  • Figure 7 shows an infrared spectrum of strontium ranelate form II.
  • Figure 8 shows an infrared spectrum of strontium ranelate form III.
  • the XRD was identical with that of Example 1.
  • the IR spectra is shown in Figure 2 (second from the bottom); LOD: 4.3% (180 °C, 30 mbar, over night).
  • strontium ranelate according to the present invention was dissolved using the following parameters:
  • the strontium ranelate according to the present invention designated as "Ranelate Monohydrate” shows an improved dissolution compared to the tetrahydrate, nonahydrate or octahydrate crystalline forms, in particular after 60, 90 and 120 minutes.
  • the most significant reflexes are at 8.7, 12.6, 17.6, 20.3, 23.1 , 26.3, 27.5 and 29.5 ° 2-theta (the most characteristic being at 17.6, 23.1 and 27.5).
  • Example 8 Raman spectra of crystalline forms of strontium ranelate
  • Raman spectra have been acquired from five samples of strontium ranelate, and are shown superimposed in Figure 4. From bottom to top Figure 4 indicates the Raman spectra of 1 : strontium ranelate of Example 1 ; 2: strontium ranelate of Example 2; 3: strontium ranelate tetrahydrate (e.g. prepared according to EP 415 850 A1); 4: nonahydrate, obtained from strontium ranelate octahydrate (e.g. prepared according to EP 415 850 A1) according to Example 1 of WO 2006/035122 A1 ; 5: strontium ranelate octahydrate (e.g. prepared according to EP 415 850 A1).
  • the spectra acquired from the octahydrate and the nonahydrate are equivalent.
  • the spectra obtained from the tetrahydrate shows high conformity with those of the octahydrate and nonahydrate.
  • the peak at 1380 cm '1 is specific for the tetrahydrate.
  • the spectra of the strontium ranelate as obtained from Examples 1 and 2 differ from the tetrahydrate, octahydrate and nonahydrate at least by the presence of the peak at about 1570 cm “1 and about 1330 cm “1 .
  • the crystalline form of strontium ranelate according to the present invention does not show a broad peak at about 3200 cm "1 (OH-peak). Further the significant differences are in the range of 2200 cm "1 .
  • the tetrahydrate typically shows a double peak at about 2193 and about 2210 cm '1 , in comparison to a peak at about 2203 cm "1 present at the octahydrate.
  • the strontium ranelate according to the present invention shows a significant peak at about 2207 to about 2212 cm "1 .
  • strontium ranelate shows four characteristic peaks at about 1622, 1555, 1538 and 1508 cm “1 .
  • the IR-spectra of octahydrate and nonahydrate show only two significant peaks (octahydrate at 1551 and 1516 cm “1 ; tetrahydrate at 1567 and 1515 cm “1 ).
  • Example 10 Dynamic vapour sorption
  • the dynamic vapour sorption experiments were conducted by exposing the sample to changing relative humidities. In the beginning the relative humidity was 50%, then decreased to nearly 0%, and then increased to 95% (indicated by the V-shaped curve corresponding to the right scale). At the same time, the mass difference of the sample is determined (U-shaped curve in the left diagram, starting at 100%, and the flat curve in the right diagram, also starting at 100%; left scale in both diagrams).
  • the sorption diagram for the octahydrate shows that with decreasing humidity starting from the octahydrate water is removed to give a tetrahydrate via an intermediate heptahydrate. With increasing humidity the tetrahydrate is very fast converted into a nonahydrate.
  • the strontium ranelate according to the present invention In contrast with decreasing humidity the strontium ranelate according to the present invention (shown in right diagram of Figure 6) releases water only by less than 2% of its total weight. The water uptake with increasing humidity is also very low. At about 80% humidity the weight increase is only about 2% of the total weight. This shows that between 0% and 80% relative humidity the strontium ranelate according to the present invention is stable.
  • ranelic acid dissolved in 10 ml ethylene glycol in a 50 ml round bottom flask was added a solution of 114 mg (0.56 mmol) strontium isopropoxide in 5 ml ethylene glycol.
  • the initially clear solution was stirred at room temperature for 72 h.
  • the milky precipitate formed was allowed to settle and the supernatant was removed with a pipette.
  • the precipitate was re-slurried in 15 ml dichloromethane, allowed to settle and the supernatant was removed with a pipette. This washing was repeated until the precipitate became flakier.
  • the precipitate was filtered off, washed with dichloromethane and dried on the rotavap (60 °C/1 mbar) for 3 h.
  • strontium isopropylate [Sr(OiPr) 2 ] were dissolved in refluxing methanol. To this solution 1.2 mmol of ranelic acid were added and the mixture was stirred at reflux temperature for 1 h. The solid precipitate was collected and dried at 60 0 C for 1 h.

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Abstract

The present invention relates to novel anhydrate and hydrate forms of strontium ranelate, processes for the preparation thereof and a pharmaceutical composition comprising said strontium ranelate.

Description

Anhydrate and Hydrate Forms of Strontium Ranelate
The present invention relates to novel anhydrate and hydrate forms of strontium ranelate, processes for the preparation thereof and pharmaceutical compositions containing said strontium ranelate. Furthermore, the invention relates to by-products obtained in the synthesis of the novel forms of strontium ranelate.
Strontium ranelate, having the chemical name 5-[bis(carboxymethyl)-amino]-2-carboxy-4- cyano-3-thiopheacetic acid di strontium salt has the following chemical structure:
Figure imgf000002_0001
Strontium ranelate, the bis-strontium (II) salt of ranelic acid, is a known medication for the treatment of osteoporosis, e.g. marketed as Protelos® or Protos® by Servier. Strontium ranelate comprises strontium, which is a bone-seeking element. It is suggested to act through dual effects on bone metabolism, by increased bone formation and decreased bone resorption, resulting in a rebalance of bone turnover in favour of bone formation. Strontium ranelate has very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making this compound useful in the treatment of bone diseases.
Strontium ranelate is freely soluble in aqueous media of low pH (< pH 2), but only slightly soluble in neutral aqueous media. Strontium ranelate is practically insoluble in most organic solvents. Several crystalline forms of strontium ranelate are known in the art. EP 415 850 A1 discloses octahydrate, heptahydrate and tetrahydrate forms of strontium ranelate. WO 2006/035122 A1 discloses a nonahydrate form of strontium ranelate. These known crystalline forms of strontium ranelate are, however, hygroscopic and thus unstable, rendering the preparation of pharmaceutical compositions difficult and disadvantageous.
Therefore, there is a need in the art for strontium ranelate in a form which does not show the problems of the known forms of strontium ranelate, and in particular is non-hygroscopic, stable and nevertheless is sufficiently soluble in water, in particular more soluble than the known forms of strontium ranelate.
It now has been found that the problems of the prior art can be overcome by anhydrate and hydrate forms of strontium ranelate having a decreased content of water compared to the known forms. Further it has been found that these forms of strontium ranelate can be obtained by heating strontium ranelate suspended in an organic solvent under reflux, and recovering the solid, reacting strontium salts with ranelic acid in certain solvents, or drying strontium ranelate hydrates under certain conditions. The obtained forms of strontium ranelate are less hygroscopic, more stable and more soluble than the crystalline forms of strontium ranelate known in the art.
The present invention therefore relates to strontium ranelate having a water content of less than about 5.5 wt.%. Preferably, the hydrate form of strontium ranelate has a water content of about 1.5 wt.% to about 5.5 wt.%.
Preferably the hydrate form of strontium ranelate according to the present invention has a water content of about 2.5 wt.% to about 4.5 wt.%, in particular about 3.3 wt.% to about 3.5 wt.%, such as about 3.4 wt.%. There are several methods known in the art to determine the content of water of a chemical substance. Such methods are for example the Karl-Fischer- titration or the "loss-on-drying" analysis (LOD, drying loss). For the present invention, the determination of the water content according to a Karl-Fischer titration can be disadvantageous, as the compound has to be completely dissolved in an organic solvent. Therefore, the water content is preferably determined, according to the present invention, according to the loss-on-drying analysis (LOD). Loss-on-drying is a known laboratory method of measuring the level of moisture in solid or semi-solid materials and it is known in the art how to conduct this method. Typically, a sample of material is weighed, heated in an oven for an appropriate period optionally under reduced pressure (e.g. at 180 0C over night at 30 mbar), cooled, optionally in the dry atmosphere of a desiccator (exsiccator) and then re-weighed. If the volatile content of the solid is primary water, the LOD technique gives a good measure of moisture content. As used herein the water content of the strontium ranelate is most preferably determined as LOD (180 0C, 30 mbar, 12 hours), i.e. heating over 12 hours at a temperature of 180 0C and at a pressure of 30 mbar.
The hemihydrate of strontium ranelate theoretically has a water content of about 1.7 wt.%, the monohydrate of 3.4 wt.%, and the sesquihydrate of about 5 wt.%. All these forms are therefore encompassed by the present invention.
The strontium ranelate of the present invention can be in amorphous or crystalline form. The anhydrate form of strontium ranelate preferably is in amorphous form.
The crystalline and amorphous forms of strontium ranelate can be identified according to their X-ray powder diffraction patterns (XRD). The samples were analyzed on a Bruker-axs D8 Advance powder X-ray diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during measurement. The measurement conditions were as follows: Radiation: Cu Ka, Source 40 kV / 40 mA, divergence slit 0.6 mm, antiscattering slit 5.59 mm, detector slit 10.28 mm, start angle 2 °, end angle 55°, Step 0.016° 2Θ. Raw data were evaluated by using the program EVA (Bruker-AXS, Karlsruhe, Germany). Further methods and devices to conduct the measurement of the X-ray powder diffraction pattern are known in the art, and it can e.g. be referred to WO 2006/035122.
The first crystalline form of strontium ranelate according to the present invention (form I) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 17.6 ± 0.2, 23.1 ± 0.2 and 27.5 ± 0.2, more preferably of 12.6 ± 0.2, 17.6 ± 0.2, 23.1 ± 0.2 and 27.5 ± 0.2, in particular it has the most significant peaks at 2-Theta angle values of 8.7 ± 0.2, 12.6 ± 0.2, 17.6 ± 0.2, 20.3 ± 0.2, 23.1 ± 0.2, 26.3 ± 0.2, 27.5 ± 0.2 and 29.5 ± 0.2.
Preferably the crystalline form I of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
Figure imgf000005_0001
In one embodiment the crystalline form I of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 1. In a further embodiment the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 1.
The second crystalline form of strontium ranelate according to the present invention (form II) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 8.7 ± 0.2, 13.7 ± 0.2 and 17.5 ± 0.2, more preferably of 8.7 ± 0.2, 9.2 ± 0.2, 13.7 ± 0.2 and 17.5 ± 0.2, in particular it has the most significant peaks at 2-Theta angle values of 8.7 ± 0.2, 9.2 ± 0.2, 10.4 ± 0.2, 13.7 ± 0.2, 17.5 ± 0.2, 19.7 ± 0.2, 25.5 ± 0.2 and 27.1 ± 0.2.
Preferably the crystalline form Il of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
Figure imgf000006_0001
In one embodiment the crystalline form Il of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 2. In a further embodiment the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 2. The third crystalline form of strontium ranelate according to the present invention (form III) is preferably such having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 10.5 ± 0.2, 13.9 ± 0.2 and 19.7 ± 0.2, more preferably of 9.2 ± 0.2, 10.5 ± 0.2, 13.9 ± 0.2 and 19.7 ± 0.2, in particular it has the most significant peaks at 2-Theta angle values of 9.2 ± 0.2, 10.5 ± 0.2, 13.9 ± 0.2, 14.2 ± 0.2, 19.7 ± 0.2, 26.8 ± 0.2 and 27.2 ± 0.2.
Preferably the crystalline form III of strontium ranelate has an X-ray powder diffraction pattern, wherein the peaks are at the following 2-Theta angle values and having approximately the following relative intensities:
Figure imgf000007_0001
In one embodiment the crystalline form III of strontium ranelate according to the present invention has the X-ray powder diffraction pattern corresponding to the one shown in Figure 3. In a further embodiment the present invention provides a solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 3.
The present invention further relates to a first process for the preparation of the anhydrate or hydrate forms of strontium ranelate as described above, which comprises the steps of
a) suspending crude strontium ranelate in an organic solvent, in particular toluene, b) heating the suspension of step a) under reflux, c) cooling the suspension, d) recovering the solid and drying the solid to obtain crystalline strontium ranelate, and e) optionally converting the crystalline form into an amorphous form of strontium ranelate.
As crude strontium ranelate of step a) of the above-described process each strontium ranelate can be applied, preferably the known tetrahydrate, heptahydrate or octahydrate form, as described in the art, e.g. in EP 415 850 A1 , or the nonahydrate of strontium ranelate, as described in the art, e.g. in WO 2006/035122 Al
The crude strontium ranelate is suspended in step a) in an organic solvent. Each organic solvent can be used, which is suitable to form a suspension with strontium ranelate, and which is further suitable for the removal of water under reflux. In one embodiment the organic solvent is an aromatic solvent, such as for example benzene, toluene, ethylbenzene, xylenes, trimethylbenzene, 1 ,2-dichlorobenzene or mixtures thereof, preferably toluene or 1 ,2-dichlorobenzene. For example, by using toluene form I of crystalline strontium ranelate can be obtained, by using 1 ,2-dichlorobenzene amorphous strontium ranelate can be obtained. In a second embodiment the organic solvent is an a-protic aliphatic solvent, such as for example cyclohexane. In this embodiment form Il of crystalline strontium ranelate can be obtained.
In a third embodiment the organic solvent is a protic aliphatic solvent, such as for example alcohols, in particular methanol, ethanol, iso-butanol and mixtures thereof, such as a mixture of methanol and iso-butanol. In this embodiment form III of crystalline strontium ranelate can be obtained.
In step b) the suspension obtained under step a) is heated under reflux. The temperature necessary to obtain a sufficient reflux depends on the organic solvent used. If toluene is used as organic solvent, the suspension is heated to about 130 0C to ensure sufficient reflux. If the organic solvent is cyclohexane the temperature can be about 140 0C. If the organic solvent is ethanol the temperature can be about 110 0C. If the heating temperature is above the boiling point of the solvent, the temperature is the temperature of the heating device, such as the heating bath. Optionally an additional amount of the organic solvent, which is preferably the same organic solvent as used in step a), such as toluene, can be added during the heating in step b).
In step c) the suspension is cooled down, preferably to room temperature, or below, e.g. to about 25 0C, 20 0C or 4 0C.
In step d) the solid is recovered and dried to obtain crystalline strontium ranelate according to the present invention. As strontium ranelate is practically insoluble in most organic solvents, a high yield of recovering can be achieved. Preferably, the drying in step d) is conducted at room temperature at a pressure of about 5 mbar or lower, i.e. under vacuum.
In another embodiment of the process according to the present invention in step d) the drying is conducted at a temperature of about 30 0C to about 60 °C, in particular about 50 0C to about 60 0C, at a pressure of about 5 mbar or lower.
In another embodiment of the process according to the present invention in step d) the drying is conducted at a temperature of about 70 0C to about 90 0C, in particular about 80 0C, at a pressure of about 5 mbar or lower, such as about 1 mbar. In one embodiment of the process according to the present invention the drying in step d) is conducted at a temperature of about 30 °C to about 60 0C, in particular of about 50 0C to about 60 °C, at a pressure of about 100 mbar or lower, preferably about 100 mbar to 5 mbar, in particular 50 mbar to 5 mbar.
Alternatively, form Il of crystalline strontium ranelate can be prepared by a process comprising the step of drying strontium ranelate octahydrate or strontium ranelate tetrahydrate at a temperature of about 130 0C to about 150 0C, such as about 1400C, at about room pressure.
Alternatively, form III of crystalline strontium ranelate can be prepared by reacting a strontium salt, in particular strontium isopropoxide, with ranelic acid in ethylene glycol. This reaction can for example be carried out by stirring a solution of strontium isopropoxide and ranelic acid in ethylene glycol at room temperature for a prolonged time, such as about 72 hours, and recovering the precipitate.
The processes as described above can be used to obtain the crystalline and amorphous forms of strontium ranelate according to the present invention. Amorphous strontium ranelate according to the present invention can for example also be prepared from crystalline strontium ranelate according to the present invention by methods known in the art, for example by rapidly cooling a melt of the strontium ranelate.
Alternatively, an anhydrate amorphous form of strontium ranelate can be prepared by drying a strontium ranelate hydrate at a temperature above about 160 0C, such as about 180 0C. The drying can be carried out for 2 hours or more, such as about 3 hours to about 6 hours. The drying can be carried out a room pressure or reduced pressure, such as about 30 mbar or below.
The present invention further relates to the hydrate form of strontium ranelate obtainable by the processes as described above.
The present invention further relates to a pharmaceutical composition comprising the strontium ranelate according to the present invention as described above. The pharmaceutical composition further comprises suitable pharmaceutically acceptable excipients and/or adjuvants as known in the art. The pharmaceutical composition is preferably suitable for oral administration and is in particular a tablet or dragee, sachet, granules, sublingual tablet, capsule or any further oral dosage forms as known in the art. The useful dosage can be varied as known in the art and can be, e.g., from about 0.2 to about 10 g per day, such as a 2 g daily dose.
The present invention further relates to the use of strontium ranelate as described above for the preparation of a medicament for the treatment of bone diseases, in particular osteoporosis.
It has further been found that if ranelic acid or strontium ranelate are heated, such as in the processes of the present invention, des-carboxy ranelic acid and the strontium salt of des- carboxy ranelic acid can be formed as unwanted by-products. Des-carboxy ranelic acid has the following structural formula:
Figure imgf000011_0001
As strontium ranelate is used as pharmaceutically active ingredient it is important to verify the amount of unwanted by-products in the final strontium ranelate. For determining the amounts of by-products in strontium ranelate probes of the by-products are required as standards. Therefore, des-carboxy ranelic acid and the strontium salt of des-carboxy ranelic acid have been isolated using preparative HPLC. These compounds are provided by the present invention to be used as standards for determining the purity of strontium ranelate.
The crystalline and amorphous forms of strontium ranelate according to the present invention can be advantageously obtained by a processes according to the present invention. Examples for the processes according to the present invention can be found in Examples 1 to 5 and 11 to 19. In Examples 1 to 3 the crystalline form of strontium ranelate as described above is prepared starting from a strontium ranelate tetrahydrate, e.g. prepared according to EP 415 850 A1 , and in Examples 4 and 5 the strontium ranelate is obtained starting from a strontium ranelate octahydrate, e.g. prepared according to EP 415 850 A1.
The strontium ranelate as described above can advantageously be used in pharmaceutical compositions, as it is less hygroscopic than the known crystalline forms. This can be seen from Example 10, wherein the dynamic vapour sorption, i.e. the desorption and absorption of water of samples of strontium ranelate octahydrate is compared to those of the strontium ranelate according to the present invention. As it is shown in Example 10, the octahydrate can be easily converted into the tetrahydrate by decreasing the humidity and by the following increase of the humidity the heptahydrate and the nonahydrate can be obtained. In contrast thereto, when decreasing humidity the strontium ranelate according to the present invention, which comprises e.g. the monohydrate, releases water only by less than 2% of its total weight. The water uptake with increasing humidity is also very low with the strontium ranelate according to the present invention. At about 80% relative humidity the mass increase is only about 2% of the total weight at the strontium ranelate according to the present invention. This shows that between the broad range of 0% to 80% relative humidity the strontium ranelate according to the present invention is excellently stable.
Additionally to the excellent stability within a broad range of relative humidity the strontium ranelate according to the present invention is excellently soluble in aqueous media, in particular water. As it can be seen from Example 6, the strontium ranelate according to the present invention, designated as "strontium ranelate monohydrate", shows a good solubility compared to the known crystalline forms, i.e. the tetrahydrate, nonahydrate and octahydrate of strontium ranelate. Further the saturation solubility of strontium ranelate according to the present invention in water is higher than those of the crystalline forms of strontium ranelate as known in the art, i.e. the tetrahydrate, octahydrate and nonahydrate of strontium ranelate.
The crystalline form of strontium ranelate can be identified by XRD-measurements, Raman and infrared spectroscopy as shown in Examples 7 to 9.
Figure 1 shows an X-ray powder diffraction pattern of the strontium ranelate form I.
Figure 2 shows an X-ray powder diffraction pattern of the strontium ranelate form II. Figure 3 shows an X-ray powder diffraction pattern of the strontium ranelate form III.
Figure 4 shows a superposition of five Raman spectra of samples of strontium ranelate, which are from below to top: 1 : strontium ranelate of Example 1 ; 2: strontium ranelate of Example 2; 3: strontium ranelate tetrahydrate, prepared according to EP 415 850 A1 ; 4: strontium ranelate nonahydrate, obtained from strontium ranelate octahydrate (prepared according to EP 415 850 A1) according to Example 1 of WO 2006/035122 A1 ; 5: octahydrate (prepared according to EP 415 850 A1).
Figure 5 shows an infrared spectrum of strontium ranelate form I.
Figure 6 shows dynamic vapour sorption diagrams of strontium ranelate octahydrate (left) and strontium ranelate according to the present invention (right) (a detailed description of the diagram is given in Example 10).
Figure 7 shows an infrared spectrum of strontium ranelate form II.
Figure 8 shows an infrared spectrum of strontium ranelate form III.
The present invention will now be further illustrated by the following Examples.
Example 1 : Preparation of strontium ranelate
2.0 g of strontium ranelate tetrahydrate (e.g. prepared according to EP 415 850 A1) is weighed and suspended in 35 ml of toluene. The suspension is heated to 130 °C. After some of the toluene is collected in the water separator additional 10 ml of toluene are added. The suspension is further heated under reflux over night using a water separator. The reaction mixture is cooled to room temperature and a white solid is separated. The solid is washed with 5 ml of toluene and dried under vacuum at room temperature. Yield: 1.58 g
Analysis: XRD (shown in Figure 1), IR (lowest graph in Figure 2); LOD: 3.0% (180 0C, 30 mbar, over night). Example 2: Preparation of strontium ranelate
The preparation of strontium ranelate is repeated as described in Example 1.
The XRD was identical with that of Example 1. The IR spectra is shown in Figure 2 (second from the bottom); LOD: 4.3% (180 °C, 30 mbar, over night).
Example 3: Preparation of strontium ranelate
14.8 g of strontium ranelate tetrahydrate (e.g. prepared according to EP 415 850 A1) is weighed and suspended in 300 ml of toluene. The suspension is heated to 130 0C. After some of the toluene is collected in the water separator additional 50 ml of toluene are added. The suspension is further heated under reflux over night using a water separator. The reaction mixture is cooled to room temperature and a white solid is separated. The solid is dried under vacuum at 50 0C. Yield: 12.8 g Analysis: XRD (identical to Example 1), LOD: 3.9% (180 0C, 30 mbar, over night).
Example 4: Preparation of strontium ranelate
75 g of strontium ranelate octahydrate (e.g. prepared according to EP 415 850 A1) is weighed and is suspended in 1250 ml of toluene. The suspension is heated to 130 0C under reflux over night using a water separator. The reaction mixture is cooled to room temperature and the white solid is separated. The solid is dried in a drying chamber at 60
0C at 50 mbar.
Yield: 62.5 g
Analysis: XRD (identical to Example 1), LOD: 3.6% (180 0C, 30 mbar, over night).
Example 5: Preparation of strontium ranelate
100 g strontium ranelate octahydrate (prepared according to EP 415 850 A1) is weighed and is suspended in 1400 ml of toluene. The suspension is heated to 130 0C under reflux over night using a water separator. The reaction mixture is cooled to room temperature and a white solid is separated. The solid is dried in a drying chamber at 60 0C at 50 mbar. Yield: 79.96 g Analysis: XRD (identical to Example 1), LOD: 4.6% (180 0C, 30 mbar, over night) (contains residual amount of solvents).
Summary of Examples 1 to 5
The amounts of starting ingredients, obtained yields and the residual amounts of water determined by LOD (180 "C1 30 mbar, over night) are summarized in the following table:
Figure imgf000015_0001
Example 6: Dissolution of strontium ranelate
The strontium ranelate according to the present invention was dissolved using the following parameters:
Figure imgf000015_0002
Figure imgf000016_0001
As can be seen from the above results, the strontium ranelate according to the present invention, designated as "Ranelate Monohydrate" shows an improved dissolution compared to the tetrahydrate, nonahydrate or octahydrate crystalline forms, in particular after 60, 90 and 120 minutes.
The saturation solubility of strontium ranelate in water was determined at a temperature of 37 0C. The determination of solubility was done by UV and HPLC methods. The results are summarised in the following table:
Figure imgf000016_0002
As can be seen from the above table, the solubility of the strontium ranelate according to the present invention, designated as "strontium ranelate monohydrate" is significantly improved over the solubilities of the known tetrahydrate, octahydrate and nonahydrate crystalline forms of strontium ranelate. Example 7: XRD of the strontium ranelate as obtained in Example 1
An X-ray powder diffraction pattern was determined from the strontium ranelate as obtained in Example 1 , which is shown in Figure 1.
The following table summarises the significant peaks:
Figure imgf000017_0001
The most significant reflexes are at 8.7, 12.6, 17.6, 20.3, 23.1 , 26.3, 27.5 and 29.5 ° 2-theta (the most characteristic being at 17.6, 23.1 and 27.5).
Example 8: Raman spectra of crystalline forms of strontium ranelate
Raman spectra have been acquired from five samples of strontium ranelate, and are shown superimposed in Figure 4. From bottom to top Figure 4 indicates the Raman spectra of 1 : strontium ranelate of Example 1 ; 2: strontium ranelate of Example 2; 3: strontium ranelate tetrahydrate (e.g. prepared according to EP 415 850 A1); 4: nonahydrate, obtained from strontium ranelate octahydrate (e.g. prepared according to EP 415 850 A1) according to Example 1 of WO 2006/035122 A1 ; 5: strontium ranelate octahydrate (e.g. prepared according to EP 415 850 A1).
The spectra acquired from the octahydrate and the nonahydrate are equivalent. The spectra obtained from the tetrahydrate shows high conformity with those of the octahydrate and nonahydrate. The peak at 1380 cm'1 is specific for the tetrahydrate.
The spectra of the strontium ranelate as obtained from Examples 1 and 2 differ from the tetrahydrate, octahydrate and nonahydrate at least by the presence of the peak at about 1570 cm"1 and about 1330 cm"1.
Example 9: Infrared spectra
An infrared spectrum of the strontium ranelate as obtained in Example 1 was recorded and is shown in Figure 5.
In contrast to the infrared spectra of the known crystalline forms of strontium ranelate, i.e. tetrahydrate, octahydrate and nonahydrate (IR-spectra not shown) the crystalline form of strontium ranelate according to the present invention does not show a broad peak at about 3200 cm"1 (OH-peak). Further the significant differences are in the range of 2200 cm"1. The tetrahydrate typically shows a double peak at about 2193 and about 2210 cm'1, in comparison to a peak at about 2203 cm"1 present at the octahydrate. The strontium ranelate according to the present invention shows a significant peak at about 2207 to about 2212 cm"1.
Further differences between the known crystalline forms of strontium ranelate and those according to the present invention can be seen in the range between about 1650 and about 1500 cm"1. In particular the strontium ranelate according to the present invention shows four characteristic peaks at about 1622, 1555, 1538 and 1508 cm"1. In comparison thereto the IR-spectra of octahydrate and nonahydrate show only two significant peaks (octahydrate at 1551 and 1516 cm"1; tetrahydrate at 1567 and 1515 cm"1). Example 10: Dynamic vapour sorption
The desorption and absorption of water was evaluated with samples of strontium ranelate octahydrate and strontium ranelate according to the present invention. At a temperature of 25 0C the relative humidity was changed at a rate of 5% per hour. The minimum humidity of 0% and the maximum humidity of 95% were kept for 3 hours, respectively. The detailed results are indicated in Figure 6.
The dynamic vapour sorption experiments were conducted by exposing the sample to changing relative humidities. In the beginning the relative humidity was 50%, then decreased to nearly 0%, and then increased to 95% (indicated by the V-shaped curve corresponding to the right scale). At the same time, the mass difference of the sample is determined (U-shaped curve in the left diagram, starting at 100%, and the flat curve in the right diagram, also starting at 100%; left scale in both diagrams).
The sorption diagram for the octahydrate (left diagram of Figure 6) shows that with decreasing humidity starting from the octahydrate water is removed to give a tetrahydrate via an intermediate heptahydrate. With increasing humidity the tetrahydrate is very fast converted into a nonahydrate.
In contrast with decreasing humidity the strontium ranelate according to the present invention (shown in right diagram of Figure 6) releases water only by less than 2% of its total weight. The water uptake with increasing humidity is also very low. At about 80% humidity the weight increase is only about 2% of the total weight. This shows that between 0% and 80% relative humidity the strontium ranelate according to the present invention is stable.
Example 11 : Preparation of Form Il using Cyclohexane
To 530 mg (0.81 mmol) strontium ranelate octahydrate in a 50 ml round bottom flask was added 30 ml cyclohexane. The mixture was refluxed using a water separator in an oil bath at 140 0C for 5 h. After cooling to room temperature, the product was filtered off and washed with hexane. Drying was performed on the rotavap at 60 0C for 3 h. DSC: 173, 107 0C (both endothermic) Example 12: Preparation of Form Il by Drying
2.00 g (3.42 mmol) strontium ranelate tetrahydrate was weighted into a 20 ml LOD bottle (inner diameter: 45 mm) and dried at atmospheric pressure and 140 0C for 3 h. DSC: 173, 107 0C (both endothermic)
Example 13: Preparation of Form III using Ethanol
To 4.0 g (6.09 mmol) strontium ranelate octahydrate in a 500 ml two-neck round bottom flask was added 100 ml ethanol. A distillation assembly was connected to one neck and the volatiles were distilled out at atmospheric pressure using an oil bath (bath temperature 11O 0C). After 45 min distillation, another 150 ml ethanol was added and distillation continued for another 45 min after which another 150 ml ethanol was added. Distillation continued until a dry residue was left in the flask. Drying at 80 °C/1 mbar for a total of 12 h. DSC: 161 , 112 0C (both endothermic)
Example 14: Scale-up of Preparation of Form III using Ethanol
To 27.0 g (0.041 mol) strontium ranelate octahydrate in a 2 I two-neck round bottom flask was added 1500 ml ethanol. A distillation assembly was connected to one neck and a mechanical stirrer to the other neck. The volatiles were distilled out at atmospheric pressure using an oil bath at 110 0C. After 8 h of distillation, another 500 ml ethanol was added and distillation continued for another 5 h. Another 500 ml ethanol was added and distillation continued for 6 h. An aliquot was taken from the reaction mixture and dried on the rotavap (60 0C, 1 mbar, 2 h). DSC of this sample was equivalent to that of the desired form. The reaction mixture was concentrated in vacuo at 60 0C. The product was transferred to a drying pistol and dried at 60 °C/1 mbar for a total of 8 h. DSC: 161 , 112 0C (both endothermic)
Example 15: Preparation of Form III using Methanol/lsobutanol
To 2.5 g (3.80 mmol) strontium ranelate octahydrate in a 500 ml round bottom flask was added 100 ml methanol. The suspension was refluxed for 3 h after which 100 ml isobutanol was added. The volatiles were removed on the rotavap at 60 0C. The product was dried at 60 °C/1 mbar for 2 h and then at 80 °C/1 mbar for 1 h. DSC: 165, 110 0C (both endothermic) Example 16: Preparation of Form III starting from Strontium Isopropoxide
To 96 mg (0.28 mmol) ranelic acid dissolved in 10 ml ethylene glycol in a 50 ml round bottom flask was added a solution of 114 mg (0.56 mmol) strontium isopropoxide in 5 ml ethylene glycol. The initially clear solution was stirred at room temperature for 72 h. The milky precipitate formed was allowed to settle and the supernatant was removed with a pipette. The precipitate was re-slurried in 15 ml dichloromethane, allowed to settle and the supernatant was removed with a pipette. This washing was repeated until the precipitate became flakier. The precipitate was filtered off, washed with dichloromethane and dried on the rotavap (60 °C/1 mbar) for 3 h.
Example 17: Preparation of amorphous strontium ranelate
252 mg of Sr-Ranelate octahydrate were suspended in 1 ,2-dichloro-benzene. The mixture was refluxed for at 240 0C for 2h. The product filtered off dried at 60 0C for 3h. The DSC of the product indicates amorphous behaviour with no peaks typical for crystalline behaviour.
Example 18: Preparation of amorphous strontium ranelate
0.5 mmol strontium isopropylate [Sr(OiPr)2] were dissolved in refluxing methanol. To this solution 1.2 mmol of ranelic acid were added and the mixture was stirred at reflux temperature for 1 h. The solid precipitate was collected and dried at 60 0C for 1 h.
The previous experiment was repeated dissolving the ranelic acid first and adding the strontium isopropylate afterwards.
Example 19: Preparation of des-carboxy ranelic acid
2g of Sr-Ranelate octahydrate were suspended in 40 ml of toluene in a 100 ml round- bottom flask. The suspension was stirred for 5 d at 145 0C using a water separator and afterwards filtered. The solid was washed with 5-10 ml toluene and dried at 50 °C / 45 mbar for 2h. The solid was dissolved in water and the pH was adjusted to 1. The aqueous phase was extracted with ethyl acetate (2 x 15 ml) and the organic phases were evaporated. The residue was re-dissolved in water at a concentration of about 1 g / 10 ml and the title compound isolated using preparative HPLC. 1 H NMR: δ = 3.56 (s, 2H, CH2 ), 4.36 (s, 4H, NCH2), 6.46 (s, 1 H, CH) ppm. HPLC-MS: 299.1 (M+).

Claims

Claims
1. Strontium ranelate, having a water content of less than about 5.5 wt.%.
2. Strontium ranelate according to claim 1 , having a water content of about 1.5 wt.% to about 5.5 wt.%.
3. Strontium ranelate according to claim 1 or 2, which is in amorphous form.
4. Strontium ranelate according to claim 2, which is in crystalline form.
5. Crystalline form I of strontium ranelate according to claim 4 having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 12.6 ± 0.2, 17.6 ± 0.2, 23.1 ± 0.2 and 27.5 ± 0.2.
6. Crystalline form I of strontium ranelate according to claims 4 or 5 having an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 1.
7. Crystalline form Il of strontium ranelate according to claim 4 having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 8.7 ± 0.2, 13.7 ± 0.2 and 17.5 ± 0.2.
8. Crystalline form Il of strontium ranelate according to claims 4 or 7 having an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 2.
9. Crystalline form III of strontium ranelate according to claim 4 having significant X-ray powder diffraction pattern peaks at 2-Theta angle values of 10.5 ± 0.2, 13.9 ± 0.2 and 19.7 ± 0.2.
10. Crystalline form III of strontium ranelate according to claims 4 or 9 having an X-ray powder diffraction pattern corresponding to the pattern shown in Figure 3.
11. Amorphous form of strontium ranelate according to claim 3, which is anhydrous.
12. Process for the preparation of an anhydrate or hydrate form of strontium ranelate, which comprises the steps of
a) suspending crude strontium ranelate in an organic solvent, b) heating the suspension of step a) under reflux, c) cooling the suspension, d) recovering the solid and drying the solid to obtain crystalline strontium ranelate, and e) optionally converting the crystalline form into an amorphous form of strontium ranelate.
13. Process according to claim 12, wherein the organic solvent is an aromatic solvent, such as toluene or 1 ,2-dichlorobenzene, an a-protic aliphatic solvent, such as cyclohexane, or a protic aliphatic solvent, such as an alcohol.
14. Process according to claims 12 or 13, wherein the drying in step d) is conducted at room temperature at a pressure of about 5 mbar or lower.
15. Process according to any of the claims 12 or 13, wherein the drying in step d) is conducted at a temperature of about 30 0C to about 60 0C at a pressure of about 100 mbar or lower.
16. Process according to claim 15, wherein the drying is conducted at a pressure of about 5 mbar or lower.
17. Process according to any of the claims 12 or 13, wherein the drying in step d) is conducted at a temperature of about 70 0C to about 90 0C at a pressure of about 5 mbar or lower.
18. Process for the preparation of form Il of strontium ranelate, which comprises the step of drying strontium ranelate octahydrate or strontium ranelate tetrahydrate at a temperature of about 130 0C to about 150 0C at about room pressure.
19. Process for the preparation of form III of strontium ranelate, which comprises the step of reacting a strontium salt with ranelic acid in ethylene glycol.
20. Process for the preparation of an anhydrate form of strontium ranelate, which comprises the step of drying a strontium ranelate hydrate at a temperature above about 160 0C.
21. Hydrate form of strontium ranelate obtainable by a process according to any one of claims 12 to 19.
22. Anhydrate form of strontium ranelate obtainable by a process according to claim 20.
23. Solid state structure of strontium ranelate characterized in that the structure gives an X-ray powder diffraction pattern corresponding to the pattern shown in Figures 1 , 2 or 3.
24. Pharmaceutical composition comprising strontium ranelate according to any of claims 1 to 11 or 21 to 23 and suitable pharmaceutically acceptable excipients and/or adjuvants.
25. Use of strontium ranelate according to any of claims 1 to 11 or 21 to 23 for the preparation of a medicament for the treatment of osteoporosis.
26. Des-carboxy ranelic acid of the formula:
Figure imgf000024_0001
27. Strontium salt of des-carboxy ranelic acid according to claim 26.
28. Use of des-carboxy ranelic acid according to claim 26 or a strontium salt of des- carboxy ranelic acid according to claim 27 as standard for determining the amount of by-products in strontium ranelate.
PCT/EP2009/062439 2008-09-29 2009-09-25 Anhydrate and hydrate forms of strontium ranelate WO2010034806A1 (en)

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ITMI20100355A1 (en) * 2010-03-05 2011-09-06 Chemelectiva S R L PROCESS FOR THE PREPARATION OF A POLIMORFO
CN102321068A (en) * 2011-08-01 2012-01-18 山东铂源化学有限公司 Method for preparing strontium ranelate
WO2012046251A2 (en) * 2010-10-08 2012-04-12 Glenmark Generics Limited Novel form of ranelic acid
WO2012143932A1 (en) * 2011-04-21 2012-10-26 Shilpa Medicare Limited Crystalline strontium ranelate form-s
WO2012163309A1 (en) 2011-05-30 2012-12-06 Zentiva, K.S. Stable crystalline form x of strontium ranelate
EP2641905A1 (en) 2012-03-23 2013-09-25 Urquima S.A. Solid forms of strontium ranelate and processes for their preparation
US8569514B1 (en) 2012-05-17 2013-10-29 Divi's Laboratories, Ltd. Process for the preparation of strontium ranelate
WO2013175270A1 (en) * 2012-05-25 2013-11-28 Fleming Laboratories Limited Improved process for the preparation of strontium ranelate hydrates and new polymorphic form of monohydrate

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ITMI20100355A1 (en) * 2010-03-05 2011-09-06 Chemelectiva S R L PROCESS FOR THE PREPARATION OF A POLIMORFO
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WO2012046251A2 (en) * 2010-10-08 2012-04-12 Glenmark Generics Limited Novel form of ranelic acid
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WO2012143932A1 (en) * 2011-04-21 2012-10-26 Shilpa Medicare Limited Crystalline strontium ranelate form-s
WO2012163309A1 (en) 2011-05-30 2012-12-06 Zentiva, K.S. Stable crystalline form x of strontium ranelate
CN102321068A (en) * 2011-08-01 2012-01-18 山东铂源化学有限公司 Method for preparing strontium ranelate
CN102321068B (en) * 2011-08-01 2013-01-23 山东铂源药业有限公司 Method for preparing strontium ranelate
EP2641905A1 (en) 2012-03-23 2013-09-25 Urquima S.A. Solid forms of strontium ranelate and processes for their preparation
US8569514B1 (en) 2012-05-17 2013-10-29 Divi's Laboratories, Ltd. Process for the preparation of strontium ranelate
WO2013175270A1 (en) * 2012-05-25 2013-11-28 Fleming Laboratories Limited Improved process for the preparation of strontium ranelate hydrates and new polymorphic form of monohydrate

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