WO2012143932A1

WO2012143932A1 - Crystalline strontium ranelate form-s

Info

Publication number: WO2012143932A1
Application number: PCT/IN2011/000590
Authority: WO
Inventors: Vimal Kumar Shrawat; Veereshappa .; Prashant Purohit; Vinod Kumar Singh
Original assignee: Shilpa Medicare Limited
Priority date: 2011-04-21
Filing date: 2011-08-29
Publication date: 2012-10-26

Abstract

Crystalline strontium ranelate form-S and process for preparation thereof are provided. Also provided is a substantially pure crystalline product obtained by the process having characteristic XRPD peak set of 7.70, 15.33, 16.46, 19.55, 20.11, 22.08, 27.90, 29.47±0.10 20° and water content in the range of 20.5 to 23.0% w/w, which is therapeutically used for the treatment of bone diseases like osteoporosis.

Description

"CRYSTALLINE STRONTIUM RANELATE FORM-S"

FIELD OF THE INVENTION Particular aspects of the present application relate to the crystalline Strontium ranelate Form-S and process for its preparation.

BACKGROUND OF THE INVENTION

Strontium Ranelate is strontium salt of Ranelic acid and is represented by structural formula (I)-

C N

CH CH,

Ό ^{2 0}

s ^H'^c o- ^H0 H₂C

N Sr- HO

Q ^{S CH}2 ^C0° S CH₂ COOH

Strontium ranelate ( I ) Ranelic Acid

Its chemical name is distrontium 5-[bis(2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2- oxoethyl) thiophene-2-carboxylate.

Strontium Ranelate i.e. strontium (II) salt of ranelic acid is therapeutically used for the treatment of bone diseases like osteoporosis. It acts as a dual action bone agent i.e. increases deposition of new bone osteoblasts and reduces the resorption of bone by osteoclasts. It is currently sold in the form of sachets (2-gm) containing granules that are made up into an oral suspension, for the treatment of osteoporosis under the trade name- Protelos^®. First preparation and therapeutic use of strontium ranelate and its tetrahydrate, heptahydrate and octahydrate have been described in the European Patent Specification EP0415850Bland its equivalent US patent 5,128,367. It disclosed the preparation of divalent metal salts of 2-[N- N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid by three methods, which comprise the processes as summarized in the scheme-l.

The process involves the use of key starting material as tetra ester compound of formula-ll,

l CN

C₂H₅OOC

CH₂ COOC 2Hⁿ5

C₂H₅OOC N

(II) ^CH2 C ^OwOC^₂2Hⁿ ₅S

which by either of the three methods results in the formation of divalent metal salts of ranelic acid.

CH₂- COOC2H5

H

Scheme-I: Process for preparation of Strontium ranelate as per US5128367 (EP0415850B1) Vaysse-Ludot et al in US 7,214,805 disclosed a different process for the industrial synthesis of Strontium Ranelate and its octahydrate, however, process differs mainly till the tetraester compound (II) formation. Horvath et al. in US patent 7,745,482 and US 7,459,568 (Equivalent EP1642897B1) disclosed the alpha crystalline form of strontium Ranelate, characterized by having water content ranging between 22 to 24% w/w and having a powder X-ray diffraction pattern exhibiting main peaks at 7.6, 8.0, 8.6, 11.3, 12.0 and 13.5° 2Θ value. Albrecht et al. in WO2010/034806 Al disclosed the processes for the preparation of novel anhydrate and hydrate forms of strontium Ranelate. The hydrate form of strontium Ranelate has water content of about 1.5 wt % to about 5.5wt % and having a characteristic powder X-ray diffraction pattern exhibiting main peaks at 8.7, 10.5, 12.6, 13.7, 13.9, 17.5, 17.6, 19.7, 23.1, 27.5 ° ± 0.2 2Θ value.

Though there are various process disclosures including crystalline forms known till date, however, there still remains a need for new crystalline polymorphic form, which may be stable, easy to handle under normal conditions of the atmosphere as well as obtainable by industrially amenable process.

The present application addresses such need for the strontium ranelate by providing a crystalline strontium ranelate designated as Form-S and process for its preparation.

SUMMARY OF THE INVENTION

Particular aspects of the present application relate to the crystalline Strontium ranelate Form-S and process for its preparation.

Various inventive aspects of the present application are summarized herein below individually.

In one aspect, the present invention provides a substantially pure Crystalline Strontium ranelate designated as Form-S, which is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 7.70, 15.33, 16.46, 19.55, 20.11, 22.08, 27.90, 29.47 ± 0.10 2θ° and water content in the range of 20.5 to 23.0% w/w.

Form-S according to the present invention is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 80 to 89"C

b. Peak -2- Between 140 to 149°C

c. Peak -3- Between 180 to 189°C

d. Peak -4- Between 215 to 225°C

and TGA weight loss upto not more than 23% w/w, when carried out in the thermal range of 30-300°C with a heating rate of not more than 10°C/min.

In another aspect of the present application, the present invention provides a process for preparation of Crystalline Strontium ranelate Form-S comprising the steps of - a) . combining strontium hydroxide and water

b) . heating the combined mixture of step a) upto more than 75°C but less than 105°C.

c) . adding the compound of formula (II)

Eto o

CN

O A CH₂COOEt

^Et0 CH₂COOEt

Π

in 2-5 lots, while heating.

d) . removing the solvent from the system

e) . combining the mass from step d) with an aqueous acid solution

f) . reflux the mixture for 1-5 hours

g.) cool the matter of step f).

h.) isolating the crystalline form-S In a particular aspect of the present invention, substantially pure Crystalline Strontium ranelate Form-S obtained according to the process of the present invention results in matter purity by HPLC of more than 99% w/w. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an Illustration of an X-ray powder diffraction ("XRPD") pattern of Crystalline Strontium ranelate Form-S.

Fig. 2 is an Illustration of a differential scanning calorimetry ("DSC") curve of Crystalline

Strontium ranelate Form-S.

Fig. 3 is an Illustration of IR spectrum of Crystalline Strontium ranelate Form-S.

Fig. 4 is an Illustration of a thermo gravimetric analysis ("TGA") of Crystalline Strontium

ranelate Form-S. DETAILED DESCRIPTION OF THE INVENTION

As set forth herein, embodiments of the present invention relate to the crystalline Strontium ranelate Form-S and process for its preparation. Unless stated otherwise, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. For purposes of the present invention, the following terms are defined below. A "compound" is a chemical substance that includes molecules of the same chemical structure.

The term "isolating" is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of "isolating".

The term "substantially pure" in reference to a active pharmaceutical ingredient, as used herein, means that the substance detected for the respective purity in by methods known to those skilled in the art at the time of the filing of this application.

The term "crystalline Form S of Strontium ranelate" is used to refer to a new polymorphic form of Strontium ranelate possessing hydration not less than six molecules of water obtained by the inventors. The term "composition" includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof. The term composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. A "composition" may contain a single compound or a mixture of compounds.

The term "pharmaceutical composition" is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients.

"Pharmaceutically acceptable" means that- entity useful in preparing a pharmaceutical composition which is generally non-toxic, not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as fillers, diluents, carrier, and so on. The excipients that are useful in preparing a pharmaceutical composition are preferably in general safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient. The invention contemplates the actual substance of the crystalline Form S of Strontium ranelate regardless of its particle size, method of preparation and/or methods of analytical characterization.

Various embodiments of the invention according to the present application are detailed herein below individually.

In one embodiment of the present application, it provides a substantially pure Crystalline Strontium ranelate designated as Form-S, which is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 20° peaks selected from the XRPD peak set of 7.70, 15.33, 16.46, 19.55, 20.11, 22.08, 27.90, 29.47 ± 0.10 29° and water content in the range of 20.5 to 23.0% w/w.

Substantially pure Crystalline Strontium ranelate 'Form S^' exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1. The prominent and characteristic 2 9 ° and ^"d^* spacing values for the Form-S of the present invention, includes 7.70 (11.48 d value), 15.33 (5.77 d value), 16.46 (5.38 d value), 19.55 (4.55 d value), 20.11 (4.41 d value), 22.08 (4.02 d value), 27.90 (3.19 d value) and 29.47 (3.03 d value)± 0.1° 2 Θ. The Crystalline Strontium ranelate ^'Form S produced by the inventors of the present application was characterized by the 2 theta values (in degrees) in the X-ray diffractograms are shown in Table 1.

Table 1: Form-S characteristic X-ray diffractograms- 2 theta values (in degrees)

S.No. 2 θ° Peaks

27. 21.77

28. 22.09

29. 22.39

30. 22.78

31. 23.14

32. 23.62

33. 24.12

34. 24.84

35. 25.23

36. 25.77

37. 25.97

38. 26.44

39. 26.68

40. 27.15

41. 27.76

42. 27.91

43. 28.12

44. 28.39

45. 29.22

46. 29.47

47. 29.68

48. 30.26

49. 30.62

50. 31.00

51. 32.15

52. 32.70

53. 32.96

54. 33.49

55. 34.71

56. 35.00 S.No. 2 θ^β Peaks

57. 35.74

58. 36.37

59. 36.54

60. 37.58

61. 38.35

62. 38.71

63. 39.33

64. 40.96

65. 41.50

66. 42.01

67. 42.62

68. 43.62

69. 44.29

70. 47.01

71. 47.65

It should be kept in mind that typical minor variation in the observed 2 theta angles values may be expected based on the sample preparation, the analyst, the specific diffractometer employed and technique. Sometimes, more variation may also be expected for the relative peak intensities, which is largely affected often by the particle size of the sample. Thus, identification of the exact crystalline form of a compound should be based primarily on observed 2 theta angles with lesser importance attributed to relative peak intensities. D- spacing values are calculated with observed 2 theta angles and copper K(a) wavelength using the Bragg equation well known to those of skill in the art.

Characteristic XRPD based observed 2 theta angles and corresponding D-spacing values for the substantially pure Crystalline Strontium Ranelate Form-S of the present invention are tabulated in the Table-2- Table 2: Characteristics observed 2 theta angles and corresponding D-spacing values of Form-S S. No. 2 Θ° d(A")

1) 7.70 11.48

2) 15.33 5.77

3) 16.47 5.38

4) 19.56 4.55

5) 20.11 4.41

6) 22.09 4.02

7) 27.91 3.19

8) 29.47 3.03

In the crystalline form-S of the present application, some margin of error may be present in each of the 2 theta angle assignments reported herein. The assigned margin of error in the 2 theta angles for the crystalline Form-S of Strontium ranelate is approximately ± 0.10 29° for each of the peak assignments. In view of the assigned margin of error, in a preferred variant, the crystalline Form-S of Strontium ranelate may be characterized by an X-ray diffraction pattern, expressed in terms of 2 theta angles, that includes five or more peaks selected from the group consisting of 7.70 ± 0.10, 15.33 ± 0.10, 16.46 ± 0.10, 19.55 ± 0.10, 20.11 ± 0.10, 22.08 ± 0.10, 27.90 ± 0.10 and 29.47 ± 0.10 20°.

The samples of Strontium ranelate Form-S were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. The crystalline Form-S of Strontium ranelate is hydrated form. A sample of the crystalline Form- S prepared by the inventors of the present application had moisture content less than 22% by KF method, which confirmed the hydrated nature of the compound possessing hexahydrate or hemihexahydrate (6.5 Molecules of H₂0). While the invention is not limited to any specific theory, it should be understood however that the crystalline Form-S of Strontium ranelate may contain additional residual, unbound moisture without losing its hydrate character and/or its crystalline Form-S characteristics. In a particular embodiment, the water content measured by Karl Fischer method for crystalline Form-S was 21.78% w/w. It is believed that additional residual moisture may be present in the form of water molecules present in the channel of the crystals, rather than being bound and joined inside the crystal lattice as in hydrated forms. When the crystalline Form-S is wet, the entire crystalline lattice may expand due to the space occupied by the water molecules and hence the X-ray powder diffraction pattern of the wet hydrated crystalline form may also expand. In such case, the X-ray powder diffraction patterns of two different moisture trapped crystalline forms may not be perfectly overlapped. Nevertheless, one skilled in the art should be able to determine whether they are same crystalline forms or not, by looking at the overall view of the X-ray powder diffraction pattern optionally with help of other spectroscopy data such as Infrared spectroscopy (I ).

Crystalline Form-S is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 80 to 89°C

b. Peak -2- Between 140 to 149°C

c. Peak -3- Between 180 to 189°C

d. Peak -4- Between 215 to 225°C

The Differential scanning calorimetry (DSC) thermogram of crystalline form of Strontium ranelate obtained by the inventors is shown in Fig. 2. It exhibits a significant endo-exo pattern with 4 well identified peaks around 84.12°C, 143.09, 183.91 and 220.94 °C. The DSC thermal pattern was measured on a Perkin Elmer Pyris 7.0 instrument. It is known to one of skill in the art that the endothermic peak location may be affected by the heating rate in the DSC. Thus, slight variation of the peak may be acceptable. Thermo-gravimetric analysis (TGA) for the gradual weight loss of crystalline form-S of Strontium ranelate obtained by the inventors is shown in Fig. 4. It weight loss upto but not more than 23% w/w. The TGA thermal pattern was measured on a TA Instruments model Q5000.

The crystalline Form-S of Strontium ranelate prepared by the inventors was also characterized by IR as shown respectively in Fig. 3. In the IR spectrum, the peak locations of several distinctive peaks may help one of skill in the art to identify the crystalline form of the present invention. These peaks include main absorption bands at about 1183.6 cm^"1, 1317.27 cm^"1, about 1579.39 cm^"1, about 2207.12 cm^"1 and 3393.5 cm^"1. The IR spectrum was measured by KBr-pellet transmission method with Perkin Elmer FT-IR spectroscopy model Spectrum 100.

Illustrative examples of analytical data for the crystalline ^'Form S^' obtained in the Examples are set forth in the Figs. 1-4.

In a further embodiment, the invention also relates to a composition containing crystalline Strontium ranelate of which at least 80%, by total weight of the crystalline form of Strontium ranelate in the composition, is the crystalline Form-S. In the more preferred form of this composition, the crystalline Strontium ranelate is suitable for use as active ingredient in formulating pharmaceutical products. In an embodiment of the invention, the composition may comprise at least 90% of the crystalline Form-S of Strontium ranelate with respect to total weight of the Strontium ranelate in the composition. In another embodiment of the invention, the composition may comprise at least 95% of the Form-S of Strontium ranelate with respect to total weight of the Strontium ranelate in the composition. In yet another embodiment of the invention, the composition is substantially free of the Form-Alpha of Strontium ranelate.

X-ray diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline forms in a solid mixture. X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks, particularly long range peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture. The percent composition of crystalline Strontium ranelate in an unknown composition can be determined. Preferably, the measurements are made on solid powder Strontium ranelate. The X-ray powder diffraction patterns of an unknown composition can be compared to known quantitative standards containing the pure crystalline Form-S of Strontium ranelate to identify the percent ratio of a particular crystalline form. This may be done by comparing the relative intensities of the peaks from the diffraction pattern of the unknown solid powder composition with a calibration curve derived from the X- ray diffraction patterns of pure known samples. The curve can be calibrated based on the X-ray powder diffraction pattern for the strongest peak or any distinctive peak from a pure sample of the crystalline Form-S of Strontium ranelate. The calibration curve may be created in a manner known to those of skill in the art. For example, five or more artificial mixtures of crystalline forms of Strontium ranelate, at different amounts, may be prepared. In a non-limiting example, such mixtures may contain, 2%, 5%, 10% and 15% of the Form-S of Strontium ranelate. Then, X- ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured. The intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the crystalline form. The resulting plot is a calibration curve that allows determination of the amount of the crystalline form Form-S of Strontium ranelate in an unknown sample. For the unknown mixture of the crystalline forms of Strontium ranelate, the intensities of the selected characteristic peak(s) in the mixture, relative to an intensity of this peak in a calibration mixture, may be used to determine the percentage of the given crystalline form in the composition.

Similar quantitative analysis may be carried out using IR spectroscopy, particularly with attenuating total reflectance (ATR) technology.

In another embodiment of the present application, it provides a process preparation of Crystalline Strontium ranelate Form-S comprising the steps of - a). combining the strontium hydroxide and water

b). heating the combined mixture of step a) upto more than 75°C but less than 105-C.

c) . optionally adding the compound of formula (II) in 2-5 lots, while heating.

d) . removing the solvent from the system

e) . combining the mass from step d) with an aqueous acid solution

f). reflux the mixture for 1-5 hours

g. ) cool the matter of step f).

h. ) isolating the crystalline form-S

Individual steps of process preparation of Crystalline Strontium ranelate Form-S are detailed herein below with the specifics of the embodiment.

Step a) of the process involves the combining strontium hydroxide and water. Combining the strontium hydroxide and water comprise preparing solution of strontium hydroxide octahydrate with water. The solution is prepared by combining strontium hydroxide octahydrate with water upto the range between 8 to 15 times by weight of strontium hydroxide octahydrate. In a particular embodiment, strontium hydroxide octahydrate solution was prepared in pure water only by combining 270 gm of strontium hydroxide octahydrate with 2700 gm water (10 times).

Step b) of the process involves heating the combined mixture of step a) upto more than 75°C but less than 105°C.

This step of heating the combined mixture of step a) upto more than 75"C but less than 105°C comprise a slow and constant heating. A fast heating rate of more than 5 °C may be avoided in view of any inconsistency in the further steps. Step c) of the process involves adding the compound of formula (II) in 2-5 lots, while heating

EtO o

CN

O CH₂COOEt

s ^N

^Et0 CH₂COOEt

II

Adding the tetraester compound of formula-ll into a solution of Strontium hydroxide octahydrate [Sr(OH)2.8H20] prepared in water ( as per step a) for preparing Form-S comprise lot wise addition of the compound of formula-ll in two to five lots at a time interval of 15 to 45 mins. In one of the preferred embodiment, the time interval used was 30 minutes. Lot wise addition of compound of formula-ll was carried out at a temperature of not less than 50.

Tetraester compound of formula-ll may be taken 1 mole with respect to Strontium hydroxide octahydrate upto the range between 1.7 to 2.5 Moles. Preferably, formula-ll may be taken 1 mole with respect to Strontium hydroxide octahydrate of 2.3-2.4 Moles. In one of the particular embodiment, lot wise addition of compound of formula-ll was carried out at a temperature 75°C and three lots of 50% (lot-1), 30 (lot-2) and 20 (lot-1) of the total amount of the required tetraester compound of formula-ll. The combined mixture may be maintained for about 1-2 hrs, however, this time may be more, but, depending upon achieving the desired solution nature and equilibration to impurity profile compliance.

The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Strontium ranelate can be substantially removed by the process of the present invention resulting in the formation crystalline Form-S. In view of maintaining the equilibrium to the impurity profile compliance, the process requires quality checks, while raising the temperature, whenever required upto 70°C.

Step d) of the process involves removing the solvent from the system

The reaction mass may be subjected to removing the water solvent by concentrating the reaction mass adequate enough to get the crystallization. In a particular embodiment, the concentration was carried out till the removal of solvent water upto atleast 50% of the total amount added to it in the beginning. The removal of solvent water and ethanol formed in the process may be carried out under vacuum also.

Step e) of the process involves combining the mass from step d) with an aqueous acid solution

The concentrated mass can be combined with an aqueous acid solution, which often comprises an organic acid selected from C1-C3 carboxylic acid. The amount of organic acid may be upto the range between 0.8 to 1.2 Moles, however, in a particular embodiment, organic acid was taken as acetic acid and was taken nearly 1 mole per mole of the tetraester compound of formula-ll. This organic acid addition provides a pH level, which assists in isolating the product in the subsequent steps. Step f) of the process involves reflux the mixture for 1-5 hours

After adding organic acid as per step e), the process of step f) involves refluxing or conditioning the reaction mass for about 1-5 hours. In a particular and preferred embodiment, the refluxing is carried out for 2-3 hours.

Step g) of the process involves cool the matter of step f)

Reaction mass can be cooled upto 0 -30°C and subjected to stir for about 1-2 hrs. The product may be isolated from the reaction mass by concentrating the reaction mass adequate enough to get the crystallization. In a particular embodiment, the concentration was carried out till the removal of solvent water upto atleast 50% of the total amount added to it in the beginning.

Step h) of the process involves isolating the crystalline form-S.

Process of isolating Form-S comprise processes but not limited to conventional processes including filtering and optional drying, which may be carried out at room temperature for the suitable durations to retain the crystalline polymorphic form characteristics. Substantially pure Crystalline Strontium ranelate Form-S obtained according to the process of the present invention results in matter purity by HPLC of more than 99% w/w.

In a further embodiment, the invention provides a process of preparation of distrontium 5- [bis(2-oxido-2-oxoethyl)amino]-4-cyano-3-(2-oxido-2-oxoethyl)thiophene-2-carboxylate comprising the three stages, which are summarized as per scheme shown below:

EtO O

NC N

o o o CN

Malanonitrile, I Ι'Λ, diethyl amine

EtO O

Sulfur NH,

Stage I EtO

Intermediate- 1

1 ,3 acetone dicarboxylic acid diethyl ester

Kthylbromoacetate

Stage II

,C0₃ Acetone

IPA

EtO

O O

CN

2+ O Sr(Oi r)_2|n8I I₂0 CN

'^" CI COO

2+ Water O CI UCOOEt

Sr

I ucoo Stage III s N

Cl I₂COOEt

StrontiumRanelate lntermediate-2

Scheme-I: Preparation of Strontium Ranelate as per the present invention

The specifics of the process of preparing Strontium ranelate are detailed in the exam section.

In another embodiment, the crystalline "Form S" of Strontium ranelate obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin. The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Form-S of Strontium ranelate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of Crystalline Form-S of Strontium ranelate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Preparation of Strontium Ranelate;

The present invention for the preparation of Strontium Ranelate comprises the following examples which are given herein below- Stage I). Preparation of lntermediate-1: In a clean and dried reactor charge 320gm of IPA, 132gm of malanonitrile and 400 gm of diethyl 1,3-acetonedicarboxylate. Cool down the temperature below 10°C. Add the mixer of 146gm of diethyl amine and 160gm IPA drop wise in lhr, during the adding course, control the temperature below 20°C. After addition, raise the temperature upto 40°C and maintain the temperature for lhr and then add 64gm of sulfur powder, heat up to 55 to 60°C and maintain for 3hrs at 55 to 60°C. Then add 400gm of water, cool down the temperature to room temperature, filter, wash with water and dry the powder in the oven at 60°C to et about 335 m intermediate

1

Stage II). Preparation of lntermediate-2:

Add 335gm of intermediate l,397gm of K₂C0₃, 1576gm (2L) of acetone and 16.8gm of tetra butyl ammonium bromide into a reactor of 5L. Add 416.2gm of ethyl bromoacetate drop wise slowly, maintaining temperature between 20 to 25°C. After complete addition, heat upto reflux and keep refluxing for 18hrs. Then cool down the temperature to room temperature, filter to remove K₂C0₃, collect filtrate and distill acetone under vacuum to remove the complete acetone. Add 2400gm of IPA and heat to 60 to 70°C to dissolve the product cool down the temperature to 20-25°C to obtain the precipitation. Filter the product. Then again it is recrystallized with 3200gm of IPA. Filter and dry at 35 to 40^eC to get 350gm of intermediate 2.

Intermediate- 1

Stage III). Preparation of Strontium Ranelate:

StrontiumRanelate

Intermediate-2

350gm of strontium hydroxide and 4867gm of water are charged into a reactor. Heat up to gently reflux at 100 to 102 °C. Add 175.0 gm, 106.0 gm and 69.0gm of intermediate 2 every half an hour. At the same time, distill out the mixer of solvent formed in the reaction and water up to temperature 102°C. After addition of last lot of intermediate 2, distill out the solvent for more 2 hrs up to 102.0°C and then add 45.63 gm of acetic acid and water slowly. Reflux for about 2hrs, filter the mass at 70°C, wash with hot water. The product is back charged into a flask and added 4563.0 gm of water. Heat to reflux at 100 to 102°C for 1-2 hrs. Cool down the temperature slowly below 30°C and filter. Air dry the product to get of strontium ranelate (Yield= 340 gm).

Preparation of Crystalline Strontium ranelate Form-S

Example 1

In a process of preparation of Crystalline Strontium ranelate Form-S-

Eto o

CN

O CH₂COOEt

S ^N

^Et0 CH₂COOEt

II

Charge 270.0 gm of strontium hydroxide and 2700gm of water into a round bottom flask. Raise the temperature upto the reflux temperature. Add 135 gm, 82 gm and 53 gm of compound of formula II in every half an hour at 100-102 °C. At the same time, distill out the solvent simultaneously. After addition of the last lot, distill the solvent for two more hrs and then add 35 gm of acetic acid and water slowly with respect to distilled volume of solvent. Reflux for 2hrs, cool to 70 °C and filter then wash with 100 ml hot water. Again the product is put into a flask and 3500 gm of water is added. Raise the temperature to reflux at 100-102 °C and keep refluxing for lhr. Cool the reaction mass slowly to ambient temperature 25°C-30°C and stir for overnight. Filter. Dry the product at room temperature for 12-20 hr to isolate crystalline strontium ranelate form-S.

Yield 265.5 gm

Example 2 Charge 486.95 gm (1.83 M) of strontium hydroxide and 4867 gm of water into a round bottom flask. Raise the temperature slowly upto the reflux temperature i.e. 100 to 102 ^eC. Further add 175.0 gm, 106.0 gm and 69.0gm of compound of formula II (Total 350 gm as 0.77 M) in every half an hour. At the same time, distill out the mixer of solvent formed in the reaction and water up to temperature 102°C. After addition of last lot of intermediate II, distill out the solvent for more 2hrs up to 102"C and then add 45.63 gm of acetic acid and water slowly (refer to the solvent volume distilled out).Then reflux for 2hrs, filter the mass at 70°C, wash with hot water. The product is back charged into a flask and added 4563.0 gm of water. Raise the mass temperature upto the reflux temperature i.e.100 to 102 °C. Keep refluxing for lhr. Cool down the temperature slowly to ambient temperature and filter. Dry the product at room temperature to get the crystalline strontium ranelate form-S.

Yield 340 gm

Claims

CLAIMS We Claim:

1. A substantially pure Crystalline Strontium Ranelate Form-S characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 20° peaks selected from the XRPD peak set of 7.70, 15.33, 16.46, 19.55, 20.11, 22.08, 27.90, 29.47 ± 0.10 2Θ° and water content in the range of 20.5 to 23.0% w/w.

2. A substantially pure Crystalline Strontium Ranelate Form-S according to claim-l, comprising the peaks-

3. A substantially pure Crystalline Strontium ranelate Form-S according to claim-1, which is further characterized by DSC isotherm comprising at least three endothermic peaks ranging between- a. Peak -1- Between 80 to 89°C

b. Peak -2- Between 140 to 149°C

c. Peak -3- Between 180 to 189°C

d. Peak -4- Between 215 to 225°C

4. A substantially pure Crystalline Strontium ranelate Form-S according to claim-1 & 3, which is further characterized by TGA weight loss upto not more than 23% w/w, when carried out in the thermal range of 30-300°C with a heating rate of not more than 10°C/min.

5. Crystalline Strontium ranelate Form-S characterized by X-ray powder diffraction

pattern comprising at least 5 characteristic 20°peaks selected from the XRPD peak set of 7.70, 15.33, 16.46, 19.55, 20.11, 22.08, 27.90, 29.47 ± 0.10 26° and DSC isotherm comprising the endothermic peaks ranging between 80 to 89°C (Peak -1), 140 to 149°C (Peak -2), 180 to 189°C (Peak -3), 215 to 225°C (Peak - 4).

6. Crystalline Strontium ranelate Form-S according to proceeding claims, characterized by X-ray powder diffraction pattern substantially according to Fig-1.

7. Crystalline Strontium ranelate Form-S according to proceeding claims, characterized by DSC isotherm substantially according to Fig-2.

8. Crystalline Strontium ranelate Form-S according to proceeding claims, characterized by IR spectra substantially according to Fig-3.

9. Crystalline Strontium ranelate Form-S according to proceeding claims, characterized by TGA thermogram substantially according to Fig-4.

10. Substantially pure Crystalline Strontium ranelate Form-S according to proceeding claims, comprising the purity by HPLC is more than 99% w/w.

11. A process of preparation of Crystalline Strontium ranelate Form-S comprising the steps of - a) . combining the strontium hydroxide and water

c) . adding the compound of formula (II)

EtO n

CN

O CH₂COOEt

s ^N

^Et0 CH₂COOEt

II

in 2-5 lots, while heating.

d) . removing the solvent from the system

e) . combining the mass from step d) with an aqueous acid solution

f) . reflux the mixture for 1-5 hours

g. ) cool the matter of step f).

h. ) isolating the crystalline form-S

12. A process of preparation of Crystalline Strontium ranelate Form-S according to claim-11, wherein the ratio of water used in the step a) comprising in the range of 8-15 times of the strontium hydroxide utilized weight/weight.

13. A process of preparation of Crystalline Strontium ranelate Form-S according to claim-11, wherein the aqueous acid solution used in the step e) comprising an organic acid selected from C1-C3 carboxylic acid.

14. A process of preparation of Crystalline Strontium ranelate Form-S according to claim-11, wherein the cooling carried out in the step g) comprising a temperature ranging between 50-80°C.