WO2011124992A1

WO2011124992A1 - Substantially pure strontium ranelate

Info

Publication number: WO2011124992A1
Application number: PCT/IB2011/001727
Authority: WO
Inventors: Sonny Sebastian; Seetha Rama Sarma Peri; Prashant Jagadale; Nitin Sharadchandra Pradhan
Original assignee: Actavis Group Ptc Ehf
Priority date: 2010-03-24
Filing date: 2011-03-23
Publication date: 2011-10-13

Abstract

Provided herein is an improved, commercially viable and industrially advantageous process for the preparation of strontium ranelate, and its intermediates, in high yield and purity. Provided further herein is a highly pure strontium ranelate substantially free of impurities, and pharmaceutical compositions comprising highly pure strontium ranelate substantially free of impurities.

Description

SUBSTANTIALLY PURE STRONTIUM RANELATE

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to Indian provisional application No. 795/CHE/2010, filed on March 24, 2010, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

[0001] Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of strontium ranelate, and its intermediates, in high yield and purity. Disclosed further herein is a highly pure strontium ranelate substantially free of impurities, and pharmaceutical compositions comprising highly pure strontium ranelate substantially free of impurities.

BACKGROUND

[0002] Strontium ranelate, distrontium salt of 5-[bis(carboxymethyl)amino]-3- carboxymethyl-4-cyano-2-thiophenecarboxylic acid, 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 represented by the following structure of formula 1 :

and its first synthesis was disclosed in EP 0415850 and related U.S. Patent No. 5,128,367 (hereinafter referred to as the '367 patent). Strontium ranelate is sold under the brand name PROTELOS™ for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. It is administered as granules for oral suspension containing 2 g of strontium ranelate.

[0003] The '367 patent describes three methods for the synthesis of divalent metal salts of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid, for example, strontium ranelate. According to a first synthetic process, strontium ranelate is prepared by heating the tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3- cyano-4-carboxymethylthiophene-5-carboxylic acid at reflux in an aqueous alcoholic medium in the presence of sodium hydroxide solution, followed by hydro lyzing in an acidic medium to give 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid, which is then reacted with strontium hydro xide.8H₂0 in an aqueous medium to produce octahydrate of strontium ranelate. The octahydrate of strontium ranelate is then converted into heptahydrate by drying the octahydrate of strontium ranelate under a stream of dry air, which is further converted into corresponding tetrahydrate by drying the heptahydrate under reduced pressure (10 mm) at 55°C.

[0004] According to a second synthetic process, strontium ranelate is prepared by heating the tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid at reflux in a mixture of sodium hydroxide solution and ethanol to produce a reaction mass, followed by distillation in vacuo in a water bath to remove the ethanol and the majority of the water. The resulting oil is precipitated with ethanol and the sodium salt obtained is filtered and then dried in vacuo at 50°C. The resulting tetrasodium salt is dissolved in water, the filtered solution is added to a solution of strontium chloride in water and the resulting mixture is rapidly homogenized and then left to stand for 24 hours. The distrontium salt formed, in the form of octahydrate, is separated by filtration.

[0005] According to a third synthetic process, strontium ranelate is prepared by heating a mixture of tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid, strontium hydroxide, water and ethanol at reflux for 1 hour and followed by distillation of ethanol. The resulting aqueous solution is heated to 100°C, followed by filtration. The resulting residue is washed with water and the octahydrate of strontium ranelate obtained is separated by filtration.

[0006] However, the process for the preparation of tetraethyl ester of 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid is not described in the '367 patent.

[0007] Bull. Soc. Chim. France 1975, pages 1786-1792 describes a process for the preparation of tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid by reacting diethyl 3-oxoglutarate with malononitrile and sulphur in ethanol in the presence of morpholine or diethyl amine to produce ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate, which is then reacted with ethyl bromoacetate in the presence of potassium carbonate in acetone to produce the tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid.

[0008] Strontium ranelate and its intermediates obtained by the processes described in the above mentioned prior art do not have satisfactory purity. Unacceptable amounts of impurities are generally formed during the synthesis of strontium ranelate. Moreover, the processes described in the prior art suffer from the disadvantages like generation of large amount of aqueous saline waste, prolonged maintenance of reactions (about 5 days), use of higher volumes of solvents and lower product yields. The prior art processes do not mention or describe about the formation and removal of the potential impurities formed during the synthesis of strontium ranelate.

[0009] It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in strontium ranelate or any active pharmaceutical ingredient (API) are undesirable and might be harmful.

[0010] Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible.

[0011] The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.

[0012] Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate). Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the "retention time" ("Rt"). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use "relative retention time" ("RRt") to identify impurities. The RRt of an impurity is its retention time divided by the retention time of a reference marker.

[0013] It is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

[0014] A need remains for an improved, commercially viable and industrially advantageous process of preparing a highly pure strontium ranelate substantially free of impurities, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include shorter reaction times, environmentally friendly reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product.

SUMMARY

[0015] The following seven impurities are formed during the synthesis of strontium ranelate disclosed herein:

i) Impurity-A: Ethyl 5-amino-3-methyl-4-cyano-2-thiophenecarboxylate, which has the following structural formula:

Impurity-A ii) Impurity-B: Ethyl 5-[2-[5-[bis(ethoxycarbonylmethyl)]-amino-4-cyano-2-

(ethoxycarbonyl) thiophen-3-yl]acetamido]-4-cyano-3-(ethoxycarbonylmethyl)- thiophene-2-carboxylate, which has the following structural formula:

iii) Impurity-C: 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid triethyl ester, which has the following structural formula:

Impurity-C iv) Impurity-D: 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5- carboxylic acid mono ethyl ester trisodium salt, which has the following structural formula:

Impurity-D v) Impurity-E: 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid tri sodium salt, which has the following structural formula:

Impurity-E vi) Impurity-F: 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid sesqui-strontium salt, which has the following structural formula:

vii) Impurity-G: 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5- carboxylic acid mono ethyl ester sesqui-strontium salt, which has the following structural formula:

Impurity-G

[0016] The present inventors have surprisingly found that some of the above impurities are formed during the synthesis of strontium ranelate intermediates, which are persistent impurities and cannot be removed at final stage. Hence, these impurities need to be strictly controlled or removed at intermediate stages. Among these seven impurities, the impurities B, D, E, F and G are novel, which had not been reported or identified in the prior art processes, and thus forms part of the present invention.

[0017] In one aspect, provided herein is an improved, efficient, commercially viable and environment friendly process for the preparation of highly pure strontium ranelate, distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2- thiophenecarboxylic acid, of formula 1 substantially free of impurities. Advantageously, the process involves shorter reaction times and produces the product with higher yields.

[0018] In another aspect, provided also herein are processes for purification of strontium ranelate and its intermediates to reduce or completely eliminate the potential impurities, which are formed during the synthesis of strontium ranelate and its intermediates.

[0019] The strontium ranelate obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.95%, and most specifically greater than about 99.99% as measured by HPLC.

[0020] In another aspect, provided herein is a highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G.

[0021] In another aspect, provided herein is a pharmaceutical composition comprising highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G, and one or more pharmaceutically acceptable excipients.

[0022] In still another aspect, provided herein is a pharmaceutical composition comprising highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.

[0023] In still further aspect, encompassed is a process for preparing a pharmaceutical formulation comprising combining highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G with one or more pharmaceutically acceptable excipients.

[0024] In another aspect, the highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G disclosed herein for use in the pharmaceutical compositions has a D 0 particle size of less than or equal to about 300 microns, specifically about 1 micron to about 200 micron, and most specifically about 10 microns to about 100 microns.

DETAILED DESCRIPTION

[0025] Extensive experimentation was carried out by the present inventors to reduce the level of the impurities A, B, C, D, E, F and G formed during the synthesis of strontium ranelate. As a result, it has been found that the impurities A, B, C, D, E, F and G formed in the preparation of the strontium ranelate can be reduced or completely removed by the purification processes disclosed herein.

[0026] According to another aspect, there is provided an impurity of strontium ranelate, wherein the impurity is selected from ethyl 5-[2-[5-[bis(ethoxycarbonylmethyl)]- amino-4-cyano-2-(ethoxycarbonyl)thiophen-3-yl]acetamido]-4-cyano-3- (ethoxycarbonylmethyl)-thiophene-2-carboxylate impurity (impurity-B), 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5-carboxylic acid mono ethyl ester trisodium salt (impurity-D), 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- methylthiophene-5-carboxylic acid tri sodium salt impurity (impurity-E), 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid sesqui-strontium salt impurity (impurity-F), and 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid mono ethyl ester sesqui-strontium salt impurity (impurity- G). [0027] According to one aspect, there is provided a highly pure strontium ranelate substantially free at least one, or two, or more, specifically all, of the impurities A, B, C, D, E, F and G.

[0028] According to another aspect, there is provided a highly pure strontium ranelate substantially free one, or both, of the impurities F and G.

[0029] As used herein, "highly pure strontium ranelate substantially free of at least one, or two, or more, of the impurities A, B, C, D, E, F and G" refers to strontium ranelate comprising one, or two, or more, of the impurities A, B, C, D, E, F and G, each one, in an amount of less than about 0.2 area-% as measured by HPLC. Specifically, the strontium ranelate, as disclosed herein, contains less than about 0.1 area-%, more specifically less than about 0.05 area-%, still more specifically less than about 0.02 area-%> of one, or two, or more, of the impurities A, B, C, D, E, F and G, and most specifically is essentially free of one, or two, or more, of the impurities A, B, C, D, E, F and G.

[0030] In one embodiment, the highly pure strontium ranelate disclosed herein comprises one, or two, or more, of the impurities A, B, C, D, E, F and G each in an amount of about 0.01 area-%) to about 0.15 area-%, specifically in an amount of about 0.01 area-% to about 0.05 area-%, as measured by HPLC.

[0031] In another embodiment, the highly pure strontium ranelate disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure strontium ranelate is about 99% to about 99.9%, or about 99.5% to about 99.99%.

[0032] In another embodiment, the highly pure strontium ranelate disclosed herein is essentially free of one, or more, of the impurities A, B, C, D, E, F and G.

[0033] The term "strontium ranelate essentially free of one, or more, of the impurities A, B, C, D, E, F and G" refers to strontium ranelate contains a non-detectable amount of one, or more, of the impurities A, B, C, D, E, F and G as measured by HPLC.

[0034] According to another aspect, there is provided a process for preparing highly pure strontium ranelate of formula 1:

substantially free of the impurities A, B, C, D, E, F and G, comprising:

a) reacting diethyl 3-oxoglutarate of formula 5 :

with malononitrile and sulphur in the presence of a base in a polar aprotic solvent to produce a reaction mass containing crude ethyl 5-amino-3-ethoxycarbonylmethyl-4- cyano-2-thiophenecarboxylate of formula 4:

b) isolating the crude compound of formula 4 from the reaction mass obtained in step-(a); c) recrystallizing the crude compound of formula 4 obtained in step-(b) using a first solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an ester solvent and wherein the anti-solvent is an aliphatic hydrocarbon, to produce pure compound of formula 4;

d) reacting the pure compound of formula 4 obtained in step-(c) with ethyl bromoacetate in the presence of a base in a solvent to produce a reaction mass containing crude 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester of formula 3 :

isolating the crude tetraethyl ester compound of formula 3 from the reaction mass obtained in step-(d);

recrystallizing the crude compound of formula 3 obtained in step-(e) using a second solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an amide solvent and wherein the anti-solvent is an alcohol solvent, to produce pure tetraethyl ester compound of formula 3; g) reacting the pure tetraethyl ester compound of formula 3 obtained in step-(f) with sodium hydroxide in a solvent to produce a reaction mass containing crude 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt of formula 2:

h) isolating the crude tetrasodium salt compound of formula 2 from the reaction mass obtained in step-(g);

i) recrystallizing the crude tetrasodium salt compound of formula 2 obtained in step-(h) using a third solvent medium comprising a solvent and an anti- solvent, wherein the solvent is water or an alcohol solvent and wherein the anti-solvent is an amide solvent, to produce pure compound of formula 2;

j) dissolving the pure tetrasodium salt compound of formula 2 obtained in step-(i) in water to provide a solution;

k) optionally, subjecting the solution obtained in step- j) to carbon treatment or silica gel treatment;

1) combining the solution obtained in step- j) or step-(k) with strontium chloride to produce a reaction mass containing strontium rane late of formula 1; and

m) isolating and/or recovering the highly pure strontium ranelate of formula 1 from the reaction mass obtained in step-(l).

[0035] Exemplary polar aprotic solvents used in step-(a) include, but are not limited to, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. A most specific polar aprotic solvent is N,N-dimethylformamide.

[0036] In one embodiment, the base used in step-(a) is an organic base. Specific organic bases are triethylamine, tributylamine, diisopropylethylamine, diethylamine, tert- butyl amine, morpholine, N-methylmo holine, pyridine and 4-(N,N- dimethylamino)pyridine. A most specific organic base is morpholine.

[0037] In one embodiment, the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to about 60°C, and more specifically at a temperature of about 25°C to about 55°C. The reaction time may vary between about 1 hour to about 20 hours, specifically between about 2 hours to about 15 hours, and more specifically about 4 hours to about 10 hours. In another embodiment, the reaction mass may be quenched with water after completion of the reaction.

[0038] The reaction mass containing the crude ethyl 5-amino-3- ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate of formula 4 obtained in step-(a) may be subjected to usual work up such as a washing, a filtration, an extraction, an evaporation, a pH adjustment, or a combination thereof.

[0039] In one embodiment, the isolation of the crude compound of formula 4 in step- (b) is carried out by methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

[0040] Exemplary ester solvents used in step-(c) include, but are not limited to, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, and mixtures thereof. The term solvent also includes mixtures of solvents. A specific ester solvent is ethyl acetate.

[0041] Exemplary anti-solvents used in step-(c) include, but are not limited to, n- pentane, n-hexane, n-heptane, cyclohexane, and mixtures thereof. A most specific anti- solvent is cyclohexane.

[0042] The term "anti-solvent" refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance.

[0043] In one embodiment, the recrystallization in step-(c) is carried out by a process comprising providing a solution of crude compound of formula 4 in the ester solvent, optionally, subjecting the solution to carbon treatment or silica gel treatment; combining the solution with the anti-solvent at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to about 100°C; and isolating and/or recovering the pure compound of formula 4 from the resulting mass by the methods as described above.

[0044] In another embodiment, the isolation is carried out by cooling the reaction mass while stirring at a temperature of below 30°C for at least 15 minutes, specifically at a temperature of about 0°C to about 30°C for about 20 minutes to about 20 hours, and most specifically at about 20°C to about 30°C for about 1 hour to about 5 hours.

[0045] In another embodiment, the recovery of pure compound of formula 4 is accomplished by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, the pure compound of formula 4 is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

[0046] Exemplary solvents used in step-(d) include, but are not limited to, water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, a nitrile, an ester, an ether, a polar aprotic solvent, and mixtures thereof. The term solvent also includes mixtures of solvents.

[0047] In one embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloro ethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof; more specifically, the solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and a most specific solvent is acetone.

[0048] In one embodiment, the base used in step-(d) is an inorganic base. Exemplary inorganic bases include, but are not limited to, ammonia; hydroxides, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metals. Specific inorganic bases are ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide, potassium tert-butoxide, and mixtures thereof; and more specifically sodium hydroxide and potassium hydroxide.

[0049] In one embodiment, the reaction in step-(d) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to about 70°C, and more specifically at a temperature of about 40°C to about 60°C. The reaction time may vary between about 1 hour to about 20 hours, specifically between about 2 hours to about 15 hours, and more specifically about 6 hours to about 12 hours.

[0050] The reaction mass containing the crude 2-[N,N-di(carboxymethyl)amino]-3- cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester of formula 3 obtained in step-(d) may be subjected to usual work up methods as described above.

[0051] In one embodiment, the isolation of the crude compound of formula 3 in step- (e) is carried out by the methods as described above. [0052] Exemplary amide solvents used in step-(f) include, but are not limited to, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, and mixtures thereof. A specific amide solvent is N,N-dimethylformamide.

[0053] Exemplary anti-solvents used in step-(f) include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof. A most specific anti-solvent is isopropanol.

[0054] In one embodiment, the recrystallization in step-(f) is carried out by a process comprising providing a solution of crude compound of formula 3 in the amide solvent, optionally, subjecting the solution to carbon treatment or silica gel treatment; combining the solution with the anti-solvent at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 60°C to about 90°C; and isolating and/or recovering the pure compound of formula 3 from the resulting mass by the methods as described above.

[0055] In another embodiment, the isolation is carried out by cooling the reaction mass while stirring at a temperature of below 30°C for at least 15 minutes, specifically at a temperature of about 0°C to about 30°C for about 20 minutes to about 20 hours, and most specifically at about 0°C to about 10°C for about 1 hour to about 5 hours.

[0056] In another embodiment, the recovery of pure compound of formula 3 is accomplished by the methods as described above.

[0057] Exemplary solvents used in step-(g) include, but are not limited to, water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, a nitrile, an ester, an ether, a polar aprotic solvent, and mixtures thereof. The term solvent also includes mixtures of solvents.

[0058] In one embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloro ethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof; more specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof; and most specifically a mixture of water and ethanol. [0059] In one embodiment, the reaction in step-(g) is carried out at a temperature of below about 60°C, specifically at a temperature of about 15°C to about 50°C, and more specifically at a temperature of about 20°C to about 30°C. The reaction time may vary between about 5 hours to about 25 hours, specifically between about 8 hours to about 20 hours, and more specifically about 10 hours to about 15 hours.

[0060] The reaction mass containing the crude 2-[N,N-di(carboxymethyl)amino]-3- cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt of formula 2 obtained in step-(g) may be subjected to usual work up methods as described above.

[0061] In one embodiment, the isolation of the crude compound of formula 2 in step- (h) is carried out by the methods as described above.

[0062] Exemplary solvents used in step-(i) include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof. A most specific solvent is water.

[0063] Exemplary anti-solvents used in step-(i) include, but are not limited to, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, and mixtures thereof. A most specific anti- solvent is N,N-dimethylformamide.

[0064] In one embodiment, the recrystallization in step-(i) is carried out by a process comprising providing a solution of crude compound of formula 2 in the solvent, optionally, subjecting the solution to carbon treatment or silica gel treatment; combining the solution with the anti-solvent at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 50°C to about 60°C; and isolating and/or recovering the pure compound of formula 2 from the resulting mass by the methods as described above.

[0065] In another embodiment, the isolation is carried out by cooling the reaction mass while stirring at a temperature of below 30°C for at least 15 minutes, specifically at a temperature of about 0°C to about 30°C for about 20 minutes to about 20 hours, and most specifically at about 20°C to about 30°C for about 1 hour to about 5 hours.

[0066] In another embodiment, the recovery of pure compound of formula 2 is accomplished by the methods as described above.

[0067] In one embodiment, the pure tetrasodium salt compound of formula 2 in step- j) is dissolved in water at a temperature of about 0°C to about 100°C, specifically at about 20°C to about 60°C, and still more specifically at about 25°C to about 35°C.

[0068] The carbon treatment or silica gel treatment in step-(k) is carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 15 minutes, specifically at a temperature of about 20°C to about 40°C for at least 30 minutes; and filtering the resulting mixture through hyflo to obtain a filtrate by removing charcoal or silica gel. Specifically, the finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

[0069] Combining of the solution with strontium chloride in step-(l) is done in a suitable order, for example, the solution is added to the strontium chloride, or alternatively, the strontium chloride is added to the solution. In one embodiment, the strontium chloride is used in the form of an aqueous solution. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of below 25 °C for at least 15 minutes and more specifically at a temperature of about 5°C to about 15°C for about 20 minutes to about 2 hours. After completion of the addition process, the resulting mixture is stirred for at least 30 minutes, more specifically for about 1 hour to about 10 hours, and most specifically for about 2 hours to about 4 hours, at a temperature of about 10°C to about 15°C to produce the reaction mass.

[0070] The isolation of highly pure strontium ranelate of formula 1 substantially free of impurities in step-(m) is carried out by the methods as described above.

[0071] In another embodiment, the recovery of pure strontium ranelate of formula 1 is accomplished by the methods as described above.

[0072] The highly pure strontium ranelate obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

[0073] In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.

[0074] Further encompassed herein is the use of the highly pure strontium ranelate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and G for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

[0075] A specific pharmaceutical composition of highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G is selected from a solid dosage form and an oral suspension.

[0076] In one embodiment, the highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G has a D₉₀ particle size of less than or equal to about 300 microns, specifically about 1 micron to about 200 micron, and most specifically about 10 microns to about 100 microns.

[0077] In another embodiment, the particle sizes of the highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G are produced by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

[0078] According to another aspect, there is provided a method for treating a patient suffering with osteoporosis, comprising administering a therapeutically effective amount of the highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G, or a pharmaceutical composition that comprises a therapeutically effective amount of highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G, along with pharmaceutically acceptable excipients.

[0079] According to another aspect, there is provided pharmaceutical compositions comprising highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

[0080] Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrup, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

[0081] The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.

[0082] In one embodiment, capsule dosage forms contain highly pure strontium ranelate substantially free of at least one, or more, of the impurities A, B, C, D, E, F and G within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

[0083] Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered cellulose, micro crystalline cellulose, microfme cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin. [0084] Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

EXPERIMENTAL:

HPLC method for measuring chemical purity:

Water's HPLC system having alliance 2695 model pump and 2487 (UV) detector with Empower chromatography software or its equivalent.

Chromatographic Parameters:

Synergi polar - RP 80 A° (250 x 4.6) mm, 4μ

Make: Phenomenex, Part No: 00G-4336-E0

Detector UV at 236 nm

Flow rate 1.0 ml / min

Injection volume 10.0 μΐ

Oven temperature Ambient

Run time 60 minutes

Refrigerated auto sampler temperature : 4°C

Elution : Gradient

Diluent preparation:

0.1% (v/v) Orthophosphoric acid solution preparation: 1.0 ml of Orthophosphoric acid is added to 1000 ml of water, followed by mixing well.

Diluent: Mix, 0.1 % (v/v) Orthophosphoric acid: Acetonitrile (90: 10) (v/v)

Buffer preparation:

2.72 g of Potassium hydrogen phosphate is taken in 1000 ml of water, followed by adjusting the pH to 2.50 (±0.05) using dilute orthophosphoric acid solution and then filtering through

0.22 μ porosity membrane and degas.

Mobile phase preparations:

Mobile phase - A : Buffer (100 %)

Mobile phase - B : Methanol: Acetonitrile (50:50) (v/v) [0085] The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

EXAMPLES

Example 1

Preparation of pure Distrontium salt of 5-[Bis(carboxymethyl)amino]-3-carboxymethyl-4- cyano-2-thiophenecarboxylic acid (Strontium Ranelate)

Step-I: Preparation of crude Ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2- thiophenecarboxylate

A solution of morpholine (76.9 g) in dimethylformamide (175 ml) was added to a solution of diethyl 3-oxoglutarate (175 g) and malononitrile (59.46 g) in dimethylformamide (262 ml) for 30-45 minutes while maintaining the temperature at below 35°C. The reaction mass was cooled to 25-30°C and stirred for 2 to 3 hours. A mixture of sulfur powder (30.56 g) in dimethylformamide (87.5 ml) was added to the reaction mass at 25-30°C, followed by heating the mass at 50-55°C and maintaining for 2 to 4 hours. Water (1750 ml) was added to the hot reaction mixture at 50-55°C for 30 to 45 minutes. The reaction mass was then cooled to 25-30°C and stirred for 3 to 4 hours. The precipitated product was filtered, washed with water (2 x 700 ml) and then dried at 50-60°C in air oven for 4 to 5 hours to produce 201.5 g of crude ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate [Yield: 82.5%; Purity by HPLC: 92.3%; Content of ethyl 5-amino-3-methyl-4-cyano-2- thiophenecarboxylate (Impurity- A): 6.9%].

Step-II: Purification of crude Ethyl 5-amino-3-ethoxycarbonylmethyl-4-cyano-2- thiophenecarboxylate

Ethyl acetate (50 ml) was added to the crude ethyl 5-amino-3-ethoxycarbonylmethyl-4- cyano-2-thiophenecarboxylate (25 g, obtained in step-I) and the reaction mixture was heated at reflux for 30 minutes. Cyclohexane (150 ml) was added to the hot solution and the reaction mixture was cooled to 25-30°C. The separated solid was filtered, washed with cyclohexane (50 ml) and then dried the product at 50-60°C to produce 21.2 g of pure ethyl 5- amino-3-ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate [Yield: 85%, Purity by HPLC: 99.5%, Content of ethyl 5-amino-3-methyl-4-cyano-2-thiophenecarboxylate (Impurity- A): 0.26 %].

Step-Ill: Preparation of crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxy methylthiophene-5-carboxylic acid tetraethyl ester Potassium carbonate powder (107.8 g) was added to a solution of ethyl 5-amino-3- ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate (50 g, obtained in step-II) in acetone (400 ml) at 25-30°C. The reaction mass was heated at 40-45°C, followed slow addition of a solution of ethyl bromoacetate in acetone (65.2 g in 50 ml of acetone) over a period of 30-60 minutes. The temperature of the reaction mass was raised to 55-60°C and maintained for 6 to 8 hours. The reaction mass was cooled to 25-30°C, filtered out the inorganic solids and washed with acetone (250 ml). The filtrate was concentrated and the residue was dissolved in acetone (80 ml). Water (200 ml) was slowly added to the reaction mass at 25-30°C and stirred for 2 to 3 hours. The precipitated product was filtered, washed with water (3 x 100 ml) and then dried to produce 74 g of crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid tetraethyl ester (Yield: 91.9%; Purity by HPLC: 92.7%).

Content of Impurities:

1) Ethyl 5-[2-[5-[bis(ethoxycarbonylmethyl)]-amino-4-cyano-2-(ethoxycarbonyl)thiophen- 3-yl]acetamido]-4-cyano-3-(ethoxycarbonylmethyl)-thiophene-2-carboxylate (Impurity- B): 2.39%;

2) 2-[N,N-Di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid triethyl ester (Impurity-C): 3.4%.

Step-IV: Purification of crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxy methylthiophene-5-carboxylic acid tetraethyl ester

Dimethylformamide (37.5 ml) was added to the crude 2-[N,N-di(carboxymethyl)amino]-3- cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester (25 g, obtained in step- III), followed by heating the mixture at 75-80°C for 30 minutes to get clear solution. Isopropanol (125 ml) was added to the resulting solution over a period of 30 minutes. The reaction mixture was initially cooled to 25-30°C and then further cooled to 0-5°C. The separated solid was filtered, the solid was washed with a mixture of isopropanol (25 ml) and water (50 ml), and then dried at 50-60°C to produce 20.5 g of pure 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5-carboxylic acid tetraethyl ester (Yield: 82%; Purity by HPLC: 97.4%).

Content of Impurities:

1) Ethyl 5-[2-[5-[bis(ethoxycarbonylmethyl)]-amino-4-cyano-2-(ethoxycarbonyl)thiophen- 3-yl]acetamido]-4-cyano-3-(ethoxycarbonylmethyl)-thiophene-2-carboxylate (Impurity- B): 1.3%; 2) 2-p f,N-Di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid triethyl ester (Impurity-C): 0.19%.

Step-V: Preparation of crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5-carboxylic acid tetrasodium salt

2-[N,N-Di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester (65 g, obtained in step-IV) was dissolved in ethanol (325 ml) and the solution was cooled to 15-20°C. The solution was followed by the addition of a solution of sodium hydroxide (25.7 g) in water (325 ml) at 15-20°C. The temperature of the reaction mixture was raised to 25-30°C and then stirred for 10 to 12 hours. The reaction mass was extracted with ethyl acetate (2 x 260 ml) and then collected the aqueous layer. The aqueous layer was slowly added to methanol (780 ml) and stirred for 2 to 3 hours. The precipitated product was filtered and washed with methanol (135 ml) and then dried to produce 57.9 g of crude 2- [N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt (Yield: 94%; Purity by HPLC: 98.09%).

Content of Impurities:

1) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid mono ethyl ester trisodium salt (Impurity-D): 0.71%;

2) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid tri sodium salt (Impurity-E): 0.47%.

Step-VI: Purification of crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5-carboxylic acid tetrasodium salt

Water (120 ml) was added to the crude 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxy methylthiophene-5-carboxylic acid tetrasodium salt (60g, obtained in step-V) at 25-30°C and the resulting mixture was heated at 50-55°C for 30 minutes. Dimethylformamide (300 ml) was added drop wise to the above hot solution over a period of 30 minutes. The resulting mixture was cooled to 25-30°C to separate the solid. The separated solid was filtered, washed with methanol (180 ml), followed by drying at 50-60°C to produce 48.5 g of pure 2- [N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt (Yield: 80.8%; and Purity by HPLC: 99.84%).

Content of Impurities:

1) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid mono ethyl ester trisodium salt (Impurity-D): 0.13%;

2) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid tri sodium salt (Impurity-E): 0.02%. Step-VII: Preparation of pure Strontium Ranelate

2-[N,N-Di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt (140g, obtained in step-VI) was dissolved in water (560 ml) at 25-30°C. Charcoal (14 g) was added to the resulting solution and then stirred for 30 to 45 minutes at 25-30°C. The solution was filtered and washed with water (70 ml). The filtrate was cooled to 10-15°C, followed by the addition of a solution of strontium chloride (173.5 g) in water (700 ml) at 10-15°C over a time period of 45 to 60 minutes. The reaction mass was stirred for 2 to 3 hours at 10-15°C. The precipitated product was filtered, washed with water (3 x 700 ml) and then dried at 25-30°C in air oven to produce 157 g of strontium ranelate as an octahydrate (Yield 73.4%; and purity by HPLC: 99.85%).

Content of Impurities:

1) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid sesqui- strontium salt (Impurity- F): 0.02%>;

2) 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid mono ethyl ester sesqui-strontium salt (Impurity-G): 0.02%.

[0086] Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

[0087] The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

[0088] The term "pharmaceutical composition" is intended to encompass a drug product including 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 or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

[0089] The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. [0090] The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

[0091] The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

[0092] The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

[0093] The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC(™) F68, PLURONIC(™) F127), collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, micro crystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

[0094] The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, micro crystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

[0095] The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

[0096] The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

[0097] The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, micro crystalline cellulose (e.g., Avicel(™)), carsium (e.g., Amberlite(™)), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

[0098] The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN(™)s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

[0099] As used herein, the term, "detectable" refers to a measurable quantity measured using an HPLC method having a detection limit of 0.01 area-%.

[0100] As used herein, in connection with amount of impurities in strontium rane late, the term "not detectable" means not detected by the herein described HPLC method having a detection limit for impurities of 0.01 area-%. [0101] As used herein, "limit of detection (LOD)" refers to the lowest concentration of analyte that can be clearly detected above the base line signal, is estimated is three times the signal to noise ratio.

[0102] The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.

[0103] As used herein, the term "micron" or "μηι" both are same refers to "micrometer" which is lxlO^"6 meter.

[0104] As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates.

[0105] As used herein, "Particle Size Distribution (PSD)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent. "Mean particle size distribution, i.e., (D₅₀)" correspondingly, means the median of said particle size distribution.

[0106] The important characteristics of the PSD are the (D90), which is the size, in microns, below which 90% of the particles by volume are found, and the (D50), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D₉₀ or d(0.9) of less than 300 microns means that 90 volume -percent of the particles in a composition have a diameter less than 300 microns.

[0107] All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

We claim:

1. Strontium ranelate, as being greater than 99% pure, comprising at least one, or both, of a 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid sesqui-strontium salt impurity (impurity-F) and a 2-[N,N-di(carboxymethyl)amino]-3-cyano- 4-carboxymethylthiophene-5-carboxylic acid mono ethyl ester sesqui-strontium salt impurity (impurity-G), each, in an amount of less than about 0.2 area-% as measured by HPLC.

2. Strontium ranelate of claim 1, comprising one, or both, of the impurity-F and impurity-G each in an amount of about 0.01 area-% to about 0.15 area-%; and wherein the strontium ranelate has a purity of about 99.5% to about 99.99% as measured by HPLC.

3. Strontium ranelate of claim 1, further comprising one, or more, of an ethyl 5- amino-3-methyl-4-cyano-2-thiophenecarboxylate impurity (impurity-A), an ethyl 5-[2-[5- [bis(ethoxycarbonylmethyl)]-amino-4-cyano-2-(ethoxycarbonyl)thiophen-3-yl]acetamido]-4- cyano-3-(ethoxycarbonylmethyl)-thiophene-2-carboxylate impurity (impurity-B), a 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid triethyl ester impurity (impurity-C), a 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5-carboxylic acid mono ethyl ester trisodium salt impurity (impurity-D) and a 2- [N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid tri sodium salt impurity (impurity-E), each, in an amount of less than about 0.2 area-% as measured by HPLC.

4. Strontium ranelate of claim 3, comprising one, or more, of the impurity-A, impurity-B, impurity-C, impurity-D and impurity-E, each, in an amount of about 0.01 area-% to about 0.15 area-%.

5. Strontium ranelate of claim 3, having a non-detectable amount of one, or more, of the impurity-A, impurity-B, impurity-C, impurity-D and impurity-E as measured by HPLC.

6. A process for the preparation of the highly pure strontium ranelate of claim 1, comprising:

a) reacting diethyl 3-oxoglutarate of formula 5 :

b) isolating the crude compound of formula 4 from the reaction mass obtained in step-

(a);

c) recrystallizing the crude compound of formula 4 obtained in step-(b) using a first solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an ester solvent and wherein the anti-solvent is an aliphatic hydrocarbon, to produce pure compound of formula 4;

d) reacting the pure compound of formula 4 obtained in step-(c) with ethyl bromoacetate in the presence of a base in a solvent to produce a reaction mass containing crude 2- [N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester of formula 3 :

e) isolating the crude tetraethyl ester compound of formula 3 from the reaction mass obtained in step-(d);

f) recrystallizing the crude compound of formula 3 obtained in step-(e) using a second solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an amide solvent and wherein the anti- solvent is an alcohol solvent, to produce pure tetraethyl ester compound of formula 3;

g) reacting the pure tetraethyl ester compound of formula 3 obtained in step-(f) with sodium hydroxide in a solvent to produce a reaction mass containing crude 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetrasodium salt of formula 2:

i) recrystallizing the crude tetrasodium salt compound of formula 2 obtained in step-(h) using a third solvent medium comprising a solvent and an anti-solvent, wherein the solvent is water or an alcohol solvent and wherein the anti-solvent is an amide solvent, to produce pure compound of formula 2;

k) optionally, subjecting the solution obtained in step-(j) to carbon treatment or silica gel treatment;

1) combining the solution obtained in step-(j) or step-(k) with strontium chloride to produce a reaction mass containing strontium ranelate of formula 1 :

7. The process of claim 6, wherein the polar aprotic solvent used in step-(a) is selected from the group consisting of Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof; wherein the ester solvent used in step-(c) is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, and mixtures thereof; wherein the anti-solvent used in step-(c) is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, and mixtures thereof; wherein the solvent used in step-(d) is selected from the group consisting of water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, a nitrile, an ester, an ether, a polar aprotic solvent, and mixtures thereof; wherein the amide solvent used in step-(f) is selected from the group consisting of Ν,Ν-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof; wherein the anti-solvent used in step-(f) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof; wherein the solvent used in step-(g) is selected from the group consisting of water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, a nitrile, an ester, an ether, a polar aprotic solvent, and mixtures thereof; wherein the solvent used in step-(i) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof; and wherein the anti-solvent used in step-(i) is selected from the group consisting of N,N- dimethylformamide, Ν,Ν-dimethylacetamide, and mixtures thereof.

8. The process of claim 7, wherein the polar aprotic solvent used in step-(a) is Ν,Ν-dimethylformamide; wherein the ester solvent used in step-(c) is ethyl acetate; wherein the anti-solvent used in step-(c) is cyclohexane; wherein the solvent used in step-(d) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; wherein the amide solvent used in step-(f) is N,N-dimethylformamide; wherein the anti-solvent used in step-(f) is isopropanol; wherein the solvent used in step-(g) is selected from the group consisting of water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, and mixtures thereof; wherein the solvent used in step-(i) is water; and wherein the anti-solvent used in step-(i) is N,N-dimethylformamide.

9. The process of claim 6, wherein the base used in step-(a) is an organic base selected from the group consisting of triethylamine, tributylamine, diisopropylethylamine, diethylamine, tert-butyl amine, morpholine, N-methylmorpholine, pyridine and 4-(N,N- dimethylamino)pyridine; and wherein the base used in step-(d) is an inorganic base selected from the group consisting of ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide, potassium tert-butoxide, and mixtures thereof.

10. The process of claim 9, wherein the base used in step-(a) is morpholine; and wherein the base used in step-(d) is sodium hydroxide or potassium hydroxide.

11. The process of claim 6, wherein the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used; wherein the reaction in step-(d) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used; and wherein the reaction in step-(g) is carried out at a temperature of below about 60°C.

12. The process of claim 11, wherein the reaction in step-(a) is carried out at a temperature of about 20°C to about 60°C; wherein the reaction in step-(d) is carried out at a temperature of about 20°C to about 70°C; and wherein the reaction in step-(g) is carried out at a temperature of about 15°C to about 50°C.

13. An impurity of strontium ranelate, wherein the impurity is selected from ethyl 5-[2-[5-[bis(ethoxycarbonylmethyl)]-amino-4-cyano-2-(ethoxycarbonyl)thiophen-3- yl]acetamido]-4-cyano-3-(ethoxycarbonylmethyl)-thiophene-2-carboxylate impurity (impurity-B), 2- N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyl thiophene-5- carboxylic acid mono ethyl ester trisodium salt (impurity-D), 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5-carboxylic acid tri sodium salt impurity (impurity-E), 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-methylthiophene-5- carboxylic acid sesqui-strontium salt impurity (impurity-F), and 2-[N,N- di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid mono ethyl ester sesqui-strontium salt impurity (impurity-G).

14. A pharmaceutical composition comprising the highly pure strontium ranelate of claim 1, and one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition of claim 14, wherein the strontium ranelate has a D90 particle size of less than or equal to about 300 microns.

16. The pharmaceutical composition of claim 15, wherein the D90 particle size is about 1 micron to about 200 microns.

17. A method for treating a patient suffering with osteoporosis, comprising administering the pharmaceutical composition comprising highly pure strontium ranelate of claim 14.