WO2009003001A2

WO2009003001A2 - Preparation of risedronate sodium hemi-pentahydrate

Info

Publication number: WO2009003001A2
Application number: PCT/US2008/068110
Authority: WO
Inventors: Vijaya Bhaskar Bolugoddu; Srinivasa Reddy Bhimavarapu; Alekhya Donthula; Shakil Sait; Naresh Tondepu; Chandra Sekhar Ravi Ram Elati; Vara Prasad Sree Naga Venkata Lakshmi Vakamudi
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2007-06-27
Filing date: 2008-06-25
Publication date: 2008-12-31
Anticipated expiration: 2009-12-27
Also published as: WO2009003001A3

Abstract

Processes for the preparation of risedronate sodium hemi-pentahydrate.

Description

PREPARATION OF RISEDRONATE SODIUM HEMI-PENTAHYDRATE

INTRODUCTION TO THE INVENTION

The present patent application relates to processes for preparing risedronic acid or its sodium salt. More specifically, the present application relates to processes for the preparation of risedronate sodium hemi-pentahydrate.

A chemical name for risedronic acid is [1 -hydroxy-2-(3- pyhdinyl)ethylidene]bis(phosphonic acid). The monosodium salt (hereinafter referred to by the officially adopted name "risedronate sodium") that is currently approved for use is a hemi-pentahydrate, which is structurally represented by

Formula I. There typically is also a small monohydrate compound content.

Formula I Risedronate sodium hemi-pentahydrate is prescribed for the treatment and prevention of osteoporosis in postmenopausal women and is available commercially in products sold as ACTONEL^®. ACTONEL^® is also indicated for treatment to increase bone mass in men with osteoporosis, glucocorticoid-induced osteoporosis in men and women, and Paget's disease of bone in men and women. Each ACTONEL^® tablet contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium.

U.S. Patent No. 5,583,122 discloses risedronic acid, salts or esters thereof, pharmaceutical compositions, and their use. Risedronic acid or its salts are generally prepared by the bisphosphonation of 3-pyridylacetic acid, followed by treating with an appropriate base. U.S. Patent No. 6,410,520 discloses a process for preparation of risedronate sodium hemi-pentahydrate, or monohydrate, or their mixtures. U.S. Patent No. 7,002,014 discloses a process for the preparation of risedronate sodium in hemi-pentahydrate crystal form. W. R. Gossman et al., "Three hydrates of the bisphosphonate risedronate, consisting of one molecular and two ionic structures," Acta Crystallographica, (2003), C59, m33-m36, discloses processes for preparing three different hydrates (namely, risedronate monohydrate, risedronate sodium dihydrate and risedronate sodium hemi-pentahydrate) and their single crystal structures. U.S. Patent Application Publication No.

2003/0195170 A1 discloses risedronate sodium polymorphs, pseudopolymorphs, and processes for their preparation. International Application Publication No. WO 2006/051553 A1 describes processes for preparing two crystalline risedronate sodium monohydrate and hemi-pentahydrate forms. International Application Publication No. WO 2008/004000 A1 describes risedronate sodium hemi-pentahydrate with a HPLC purity of more than 99.5% and a process for its preparation. International Application Publication No. WO 2008/044245 A2 describes a process for the preparation of risedronate sodium hemi-pentahydrate comprising a treatment of risedronic acid with sodium hydroxide in the presence of a mixture of water and dimethylsulfoxide.

Although processes for preparing risedronate sodium hemi-pentahydrate are described in the art, they are not commercially viable because of the use of large volumes of solvent or formation of other hydrated forms as impurities. Thus, there is a continuing need for cost-effective and efficient processes for preparing pure risedronate sodium hemi-pentahydrate.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides processes for the preparation of risedronate sodium in the crystalline hemi-pentahydrate form, an embodiment comprising:

(a) providing a combination of risedronic acid and a solvent;

(b) treating the combination obtained in step (a) with a sodium base; and

(c) forming risedronate sodium hemi-pentahydrate; wherein a solvent comprises an alcohol, water or mixtures thereof. In an aspect, the invention provides risedronate sodium hemi-pentahydrate prepared according to the processes.

In a further aspect, the invention provides pharmaceutical compositions comprising risedronate sodium hemi-pentahydrate prepared according to the processes. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray powder diffraction (XRPD) pattern of a sample of risedronate sodium hemi-pentahydrate, as prepared in Example 5. Fig. 2 is a thermogravimetric analysis (TGA) curve of a sample of risedronate sodium hemi-pentahydrate.

Fig. 3 is a differential scanning calorimetry (DSC) curve of a sample of risedronate sodium hemi-pentahydrate.

Fig. 4 is a Fourier-transform infrared (FTIR) absorption spectrum of a sample of risedronate sodium hemi-pentahydrate.

Fig. 5 is an XRPD pattern of risedronic acid, as prepared in Example 2.

DETAILED DESCRIPTION All percentages and ratios recited herein are by weight of the total composition and all measurements made are at 25°C and normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open-ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, "comprising" includes the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having," "including," and "include" are also to be construed as open-ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on prior art. This includes, at least, the degree of expected experimental error, technical error and instrumental error for a given technique used to measure a value.

When a molecule or other material is identified herein as "pure," it generally means, unless specified otherwise, that the material is about 99% pure or higher. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities and unreacted starting materials. "Substantially" pure means the same as "pure," except that the material is about 95% pure or higher. "Essentially" pure means the same as "substantially" pure except that the material is about 90% pure or higher.

The present inventors found that the use of alcohols at low temperatures for isolation of risedronate sodium produces pure risedronate sodium hemi- pentahydrate with good yields.

An embodiment of a process for the preparation of risedronate sodium hemi-pentahydrate according to the present invention comprises:

(a) providing a combination of risedronic acid and a solvent;

(b) treating the combination obtained in step (a) with a sodium base; and (c) forming risedronate sodium hemi-pentahydrate; wherein a solvent comprises an alcohol, water or mixtures thereof.

Step a) involves providing a combination of risedronic acid and a solvent. The combination comprising risedronic acid may be obtained by combining risedronic acid with a solvent, or the combination may be obtained directly from a reaction in which risedronic acid is formed.

Solvents that may be utilized for this step include but are not limited to: water; and mixtures of water with CrC₄ alcohols such as methanol, ethanol, isopropanol, n-butanol, and 2-butanol, or glycols such as ethylene glycol and propylene glycol, in various proportions. Step a) may be performed at temperatures from about 10⁰C to about 40⁰C, or from about 15°C to about 35°C, or from about 20⁰C to about 30°C.

The relative amounts of solvent may be adjusted to ensure the success of the subsequent process steps. The solvent used in this step may range from about 3 to about 25, or about 3 to about 15, milliliters per gram of risedronic acid. Step b) involves treatment of the combination provided in step (a) with a sodium base. This step involves adjustment of the pH of the reaction mass with a sodium base. Suitable sodium bases that may be utilized for adjusting the pH of the reaction mass may be any inorganic bases such as sodium carbonate, sodium hydroxide and sodium bicarbonate, either as solids or their aqueous solutions. The pH is adjusted to be within a range of about 4 to 6, or about 4.4 to about 5.2, or about 4.5 to about 5.1 , or about 4.6 to about 5.

The combination may be cooled to about 0⁰C to about 30⁰C, or about 5°C to about 25°C, or about 10⁰C to about 20°C, before the addition of sodium base. After the pH adjustment, the resulting solution may optionally be treated with carbon and filtered to produce a particle-free solution.

Step c) involves the precipitation of risedronate sodium hemi-pentahydrate. To initiate crystallization of solid from the solution in step b), an anti-solvent can be added at about 0⁰C to about 30⁰C, or about 5°C to about 25°C, or about 10⁰C to about 20°C.

The anti-solvents that may be utilized for this step are same as the solvents that are used in step a), except water. The quantity of anti-solvent used in this step may range from about 1 to 20 milliliters, per gram of hsedronic acid. The mass after the addition of anti-solvent may be stirred for any desired time period, such as about 1 -4 hours, or about 1 -3 hours, or about 1 -2 hours. Longer times are also useful.

Optionally, a small quantity of seed crystals may be added to the mass to generate the desired crystalline form. The mass may be further cooled to between about -10⁰C to about 10⁰C, or between about 0⁰C to about 5°C. An anti-solvent may be additionally added to the mass to enhance the crystallization of risedronate sodium. The anti-solvents that may be utilized for this are same as those solvents that are used in step a), except water. The quantity of anti-solvent used in this step may range from about 3 to 20, or from about 5 to 15, milliliters per gram of risedronic acid.

The mass after the addition of additional anti-solvent may be stirred for about 1 -10 hours, or about 1 -5 hours, or about 1 -3 hours. Longer times also may be used.

In embodiments, the ratios of anti-solvent to water in the mass before separation of a solid product may range from about 25:75 to about 75:25, by volume.

The methods by which a solid product can be recovered from the final mixture can be any of techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing impurities, and the crystals may be washed with the anti-solvent to reduce the impurity concentrations.

If desired, the recovered product may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures from about 25°C to about 50⁰C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. The drying may be carried out for any desired time periods to achieve the desired product purity, such as from about 1 hour to about 15 hours, or longer. If desired, risedronate sodium hemi-pentahydrate obtained above may be further purified by slurrying or recrystallizing in a solvent or mixture of solvents. The solvents that can be utilized for this purification step include, but are not limited to: CrC₄ alcohols such as methanol, ethanol, isopropanol, n-butanol, and 2-butanol; glycols such as ethylene glycol and propylene glycol; and their mixtures with water in various proportions. The purification of risedronate sodium hemi- pentahydrate may enhance the chemical and polymorphic purities.

The material that is subjected to purification may be either in a wet form or in a dry form.

Purification by slurrying may be performed at temperatures ranging from about -10⁰C to about 40⁰C, or from about 0°C to about 30⁰C, or from about 10°C to about 20°C. The slurrying may be carried out for about 5 minutes to about 5 hours, or about 5 minutes to about 3 hours, or about 10 minutes to about 1 hour. Longer time periods also are useful.

The purification by recrystallization may be performed by dissolving risedronate sodium hemi-pentahydrate in the solvent and isolating the product by cooling the reaction mass.

The dissolution step may be performed at temperatures ranging from about 30°C to about the reflux temperature of the solvent. The solution may be cooled to between about -10°C and about 30°C, or between about 0°C and about 20°C, or between about 0⁰C and about 10⁰C.

The product after purification may be isolated and dried using the methods described above.

Risedronate sodium hemi-pentahydrate obtained by the processes of the present invention contains less than about 5%, or less than about 2%, or less than about 0.5% of risedronate sodium monohydrate. In certain instances, the risedronate sodium monohydrate content is below the limit of detection. Methods known to persons skilled in the art may be used for the determination of risedronate sodium monohydrate in risedronate sodium hemi- pentahydrate. The general methods that are useful for the quantification of one polymorphic form in another form include XRPD, FTIR, Raman spectroscopy, solid state NMR, DSC, etc. Any of these methods may be used for the quantification of risedronate sodium monohydrate in risedronate sodium hemi- pentahydrate.

Risedronate sodium hemi-pentahydrate of the present application may contain less than about 0.5% of total impurities, as determined by high performance liquid chromatography (HPLC). In embodiments, the total impurities are less than about 0.2%, or less than about 0.1 %, or less than about 0.05%.

An example of a HPLC method that can be used for the analysis includes an lnertsil ODS 3V, 250*4.6 mm, 5 μm or equivalent column. Additional method parameters are given in the table below:

Typically, risedronate sodium hemi-pentahydrate obtained by processes of the present invention has a particle size distribution where D(0.9) is less than about 250 microns, often less than about 150 microns. D(0.9) is a particle size value, for which 90 percent of the particles in a mixture are smaller. A desired particle size distribution may be obtained directly from the process or may be obtained by using techniques known to persons skilled in the art, such as milling, grinding, spray-drying, etc. The techniques that may be used for the determination of particle sizes include sieve analysis, sedimentation, electrozone sensing (Coulter™ counter), microscopy, and low angle laser light scattering (LALLS). Methods most commonly used in the pharmaceutical industry include laser diffraction and sieve analysis.

Risedronic acid used for the preparation of risedronate sodium hemi- pentahydrate may have a crystalline or amorphous form, may be a mixture of forms.

The starting material, i.e., risedronic acid, used herein may be prepared by any process, including the processes described in documents mentioned above or the process described hereinbelow.

Risedronic acid may be prepared by the reaction of 3-pyridylacetic acid with phosphorous acid and a halophosphorous compound, in the presence of diethyl carbonate as a solvent and methanesulfonic acid as co-diluent. The halophosphorous compound may comprise any of PCI₃, PCI₅, POCI₃, PBr₃, POBr₃ and PBr₅.

3-Pyridylacetic acid, phosphorous acid and diethyl carbonate may be added in any order followed by addition of a halophosphorous compound. Methanesulfonic acid may be added before or after the addition of a halophosphorous compound.

The reaction may be carried out at temperatures of about 40°C to about 100°C, or about 60⁰C to about 80⁰C. The reaction may be carried out for a period of about 1 -15 hours, or about 2-10 hours, or about 3-8 hours. Longer time periods may also be used.

The phosphorous acid is used in amounts of about 1 to 10 moles, or about 1 to 5 moles, per mole of 3-pyridylacetic acid. The halophosphorous compound is used in amounts of about 1 to 10 moles, or about 1 to 5 moles, per mole of 3- pyridylacetic acid. The methanesulfonic acid is used in amounts of about 0.5 to 10 times, or about 1 to 5 times, by volume to the weight of 3-pyridylacetic acid. The diethyl carbonate is used in an amount of about 1 to 10 times, or about 1 to 5 times, by volume to the weight of 3-pyridylacetic acid.

The reaction mass obtained as described above is diluted with water and the layers obtained may be separated. The aqueous layer may be further heated to temperatures about 60⁰C to about the reflux temperature and maintained for about 1 -20 hours, or longer. An inorganic acid such as hydrochloric acid may be added to the aqueous layer before heating. The reaction mass may then be cooled to about 0⁰C to about 30⁰C, or, about 10⁰C to about 20°C, and pH of the reaction mass adjusted to between 1 -2 using a base such as sodium hydroxide or potassium hydroxide.

A solvent may be added to the reaction mass before or after the pH adjustment with a base. Solvents that may be added to the reaction mass include but are not limited to: water; d-C₄ alcohols such as methanol, ethanol, isopropanol, n-butanol, and 2-butanol; glycols such as ethylene glycol and propylene glycol; and mixtures thereof in various proportions.

The method by which a solid product is recovered from the final mixture can be any of techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities, and the crystals may be washed with a solvent to get rid of the impurities.

If desired, the recovered product may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures from about 25°C to about 80°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon, and helium. The drying may be carried out for any desired time periods to achieve the desired product purity, from about 1 hour to about 15 hours, or longer.

If desired, risedronic acid obtained above may be further purified by slurrying in a solvent or mixture of solvents.

The material obtained above is subjected to purification may be either in wet form or in dry form. This step may be performed at temperatures ranging from about -10⁰C to about 4O⁰C or from about 0⁰C to about 20⁰C, or from about 0⁰C to about 10⁰C.

Solvents that may be used for this purification by slurrying include but are not limited to: water; CrC₄ alcohols such as methanol, ethanol, isopropanol, n- butanol, and 2-butanol; glycols such as ethylene glycol and propylene glycol; and mixtures thereof in various proportions.

The product obtained after the purification may be isolated and dried by any of the methods described above. Risedronic acid so prepared may contain less than about 2% of total impurities, as determined by HPLC. In instances, the total impurities are less than about 1 %, or less than about 0.5%.

Pharmaceutical compositions comprising hsedronate sodium hemi- pentahydrate along with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms including, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms including but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations including but not limited to solutions, dispersions, and freeze dried compositions.

The above-prepared formulations may be in the form of immediate release, delayed release or modified release. Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations. Modified release compositions may include hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. The compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that find use in the present patent application include, but are 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, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, 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; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. The X-ray powder diffraction patterns described herein were determined using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K- alpha radiation source. The X-ray powder diffraction patterns were also obtained by methods known in the art using a Bruker X-Ray powder diffractometer, goniometer model 1050/70 at a scanning speed of 1 degree per minute, with Cu radiation of λ=1.5418 A.

DSC analysis was performed with a Perkin Elmer, Pyris 6 DSC instrument. Sample masses for analysis were 1 to 3 mg, weighed into aluminum sample pans. The samples were encapsulated into closed aluminum pans and subsequently crimped to ensure a tight seal. The thermograms were recorded from 40 to 25O⁰C under a nitrogen atmosphere of 50 mL/minute, at a heating rate of 10°C/minute. TGA analysis was carried out on a TGA Q500 from TA Instruments. The sample mass was placed in a platinum pan with nitrogen gas purge at a flow rate of 40 mL/minute for balance and 60 mL/minute for sample. The TG analysis was recorded with a ramp rate of 10°C/minute up to 250⁰C. FTIR analysis was performed with a Perking Elmer Spectrum One FTIR spectrometer. The spectrum was collected in the scan range of 400-4000 cm^"1 and the samples were in KBr pellets.

While particular embodiments of the present invention have been illustrated and described, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. The following examples of certain specific aspects and embodiments are provided to aid in a more complete understanding of the invention but are not intended to, and should not be construed to limit its scope in any way.

EXAMPLE 1 : Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid).

3-pyridylacetic acid (50 g), methanesulfonic acid (50 ml), phosphorous acid (89.7 g) and diethyl carbonate (150 ml) were charged into a flask and stirred for 5 minutes. Phosphorous trichloride (100.3 g) was added slowly at 34°C. The reaction mass was then heated to 69°C and stirred for about 6 hours at 69-71⁰C and water (250 ml) was added to the reaction mass slowly. The reaction mass was again heated to reflux and stirred for about 5V₂ hours, with solvent collected during reflux. The reaction mass was cooled to 7O⁰C, isopropanol (250 ml) was added, and then the mass was cooled. The pH of the reaction mass was adjusted to 1.8 by addition of caustic lye solution (47-50% w/w NaOH, 183 ml) at 10-15⁰C and maintained at the same temperature for about 1 hour. The formed solid was filtered and washed with isopropanol (50 ml). The obtained solid was dried under vacuum at 66°C to a constant weight, to afford 100 g of the title compound. HPLC purity: 99.28%.

EXAMPLE 2: Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid).

3-pyridylacetic acid (50 g), diethyl carbonate (150 ml), phosphorous acid (65.8 g) and methanesulfonic acid (50 ml) were charged into a flask and stirred for 10 minutes. Phosphorous trichloride (48 ml) was added slowly at 37°C. The reaction mass was then heated to 70⁰C and stirred for 6 hours at 70-75⁰C and water (250 ml) was added to the reaction mass slowly. Separated the aqueous layer and the reaction mass was again heated to reflux and stirred for about 4 hours. The reaction mass was cooled to 6O⁰C, isopropanol (250 ml) was added, and then the mass was cooled. The pH of the reaction mass was adjusted to 1.8 by addition of aqueous sodium hydroxide solution (81 ml of caustic lye solution diluted with 81 ml of water) at 8-13⁰C and maintained at the same temperature for about 2 hours. The formed solid was filtered and washed with isopropanol (50 ml). The obtained solid was dried under vacuum at 50-58⁰C to a constant weight, to afford 92.1 g of the title compound.

The crystalline form of risedronic acid obtained by the above process is characterized by its XRPD pattern having characteristic peaks at approximately 8.5, 10.4, 12.4, 13.0, 16.6, 17.8, 20.4, 21 .2, 26.1 , and 28.8, ± 0.2 degrees two- theta. The crystalline form of risedronic acid is also characterized by its XRPD pattern, substantially in accordance with the pattern of Fig. 5. EXAMPLE 3: Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid).

3-pyridylacetic acid (50 g) and diethyl carbonate (150 ml) were charged into a round bottom flask and stirred for 5 minutes and then phosphorous acid (44.9 g) was added. Phosphorous trichloride (96 ml) was added to the reaction mass and then the mass was heated. Methanesulfonic acid (75 ml) was added to the reaction mass slowly between 43-45⁰C. The reaction mass was maintained at 60- 62⁰C for about 1 hour and then maintained at 70-72⁰C for about 5 hours. Chilled water (50 ml) was added to the reaction mass at 70-79⁰C and then the mass was cooled. Water (300 ml) was added to the reaction mass at 5O⁰C and stirred for 35 minutes. The aqueous and organic layers were separated and the aqueous layer was charged into a round bottom flask followed by 33% aqueous hydrochloric acid (48 ml). The reaction mass was heated to reflux and maintained at the same temperature for about 8V2 hours and then cooled, lsopropanol (250 ml) was charged into the reaction mass at 28⁰C. The reaction mass was further cooled to 9⁰C and the pH was adjusted to 1.64 with aqueous sodium hydroxide solution (115 ml of caustic lye solution diluted with 115 ml of water).

The reaction mass was further cooled to and maintained at 3-4⁰C for 2 hours. The reaction mass was filtered and the solid was suction-dried. The wet solid and water (175 ml) were charged into a round bottom flask, stirred for about 30 minutes at 25-26⁰C and filtered. The wet cake was washed with a chilled mixture of water (25 ml) and isopropanol (25 ml) and suction dried. The wet material was dried in an oven at 53⁰C to a constant weight to obtain 98.3 g of risedronic acid. Yield: 95.2%. The loss on drying (LOD) at 140⁰C (infrared moisture balance, 10 minutes) was found to be 0.6% w/w. HPLC purity: 99.59%.

EXAMPLE 4: Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid) monosodium hemi-pentahydrate.

Risedronic acid (10 g) was charged into a vessel containing water (124 ml) and isopropanol (16 ml) and stirred for 5 minutes. The mass was then cooled to 15°C and 10 ml of sodium hydroxide solution (1 .5 g of sodium hydroxide flakes dissolved in 20 ml water) were added and stirred for about 2/4 hours at 15-18°C. Isopropanol (100 ml) was added slowly to the reaction mass, which was then cooled to 5°C and stirred for about 2 hours for solid formation. The solid was filtered and washed with isopropanol (10 ml). The obtained solid was dried at 35°C under vacuum to afford 10.7 g of the title compound. HPLC purity: 99.83%. Fig. 4 is a FTIR spectrum for this product.

EXAMPLE 5: Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid) monosodium hemi-pentahydrate.

Risedronic acid (10 g) was charged into a vessel containing water (134 ml) and isopropanol (16 ml) and stirred for 25 minutes. The mass was then cooled to 15°C, 10 ml of 15% aqueous sodium hydroxide solution was added and stirred for about 2 hours at 15-18°C. The reaction mass was further cooled to 5°C and isopropanol (160 ml) was added slowly into the reaction mass and stirred at 1 -5°C for about 2 hours for solid formation. The solid was filtered and washed with isopropanol (5 ml). The obtained solid was dried at 30⁰C under vacuum to afford 10.5 g of the title compound. HPLC purity: 99.83%. To the filtrate, 100 ml of isopropanol was added and then cooled to 5°C.

The mass was maintained at the same temperature for about 2 hours and filtered. The solid was suction dried and then dried under vacuum to afford 0.4 of the title compound as a second crop.

A crystalline form of hsedronate sodium hemi-pentahydrate obtained by the above process is characterized by its XRPD pattern having characteristic peaks at approximately 8.9, 12.2, 12.9, 13.5, 15.3, 15.7, 19.7, 24.5, 27.8, 31 .1 , and 36.5, ± 0.2 degrees two-theta. A crystalline form of risedronate sodium hemi- pentahydrate is also characterized by its XRPD pattern, substantially in accordance with the pattern of Fig. 1 . Fig. 2 is a TGA curve for the product, and Fig. 3 is its DSC curve.

EXAMPLE 6: Preparation of [1 -Hydroxy-2-(3-pyridinyl)ethylidene]bis(phosphonic acid) monosodium hemi-pentahydrate.

Anhydrous risedronic acid (70 g) and water (798 ml) were charged into a round bottom flask and stirred for 5 minutes. The mass was cooled to 15°C and pH was adjusted to 4.85 using sodium hydroxide solution (10.5 g sodium hydroxide flakes dissolved in 70 ml water) at the same temperature. The mass was stirred for 15 minutes at 16°C. Carbon (3.5 g) was added and stirred at the same temperature for 20 minutes. The suspension was filtered through a Hyflow (flux-calcined diatomaceous earth) bed and washed with water (140 ml). The filtrate was placed in a round bottom flask and cooled to 16⁰C, and isopropanol (112 ml) was added to the reaction mass over about 10 minutes at the same temperature. The reaction mass was maintained at 16-17°C for about 2 hours. The reaction mass was further cooled and maintained for about 1 hour at 0-4°C. Chilled isopropanol (700 ml) was added to the reaction mass over 35 minutes at 0-4⁰C and the reaction mass was maintained at the same temperature for about 1-1.5 hours. The formed solid was filtered. The wet solid obtained was placed into a fresh round bottom flask containing water (385 ml) and isopropanol (315 ml) at 16°C. The mass was stirred at 16-17°C for 40 minutes and filtered, washed with a chilled mixture of water (35 ml) and isopropanol (35 ml) and suction dried. The wet material was dried in an oven under vacuum at 43°C to afford 66.2 g of title compound. Yield: 76.4%. HPLC purity: 99.99%.

Claims

CLAIMS:

1 . A process for preparing risedronate sodium hemi-pentahydrate, comprising:

(a) providing a combination of hsedronic acid and a solvent;

(b) treating the combination obtained in step (a) with a sodium base; and

(c) forming risedronate sodium hemi-pentahydrate; wherein a solvent comprises an alcohol or glycol, water, or a mixture thereof.

2. The process of claim 1 , wherein a solvent comprises water.

3. The process of claim 1 , wherein a solvent comprises a mixture of water and an alcohol.

4. The process of any of claims 1-3, wherein a solvent comprises one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol.

5. The process of any of claims 1 -3, wherein a solvent comprises isopropanol.

6. The process of any of claims 1 -5, wherein a sodium base comprises one or more of sodium carbonate, sodium hydroxide, and sodium bicarbonate.

7. The process of any of claims 1 -6, wherein a sodium base is added in an amount to adjust pH to values from about 4.2 to about 5.2.

8. The process of any of claims 1 -7 wherein b) is conducted below about 20⁰C.

9. The process of any of claims 1 -8, wherein risedronate sodium hemi- pentahydrate is formed by adding an anti-solvent.

10. The process of claim 9, wherein an anti-solvent comprises an alcohol.

1 1 . The process of any of claims 1 -10, further comprising purifying risedronate sodium hemi-pentahydrate formed in c).

12. The process of claim 11 , wherein purifying is carried out by recrystallizing or slurrying risedronate sodium hemi-pentahydrate in a solvent.

13. The process of claim 12, wherein a solvent for purifying comprises an alcohol or glycol, or a mixture thereof with water.

14. The process of claim 12, wherein a solvent for purifying comprises one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol.

15. Risedronate sodium hemi-pentahydrate prepared according to the process of any of claims 1 -14 and having less than about 0.5 percent by weight of impurities, as determined by high performance liquid chromatography.

16. Risedronate sodium hemi-pentahydrate prepared according to the process of any of claims 1 -14 and having less than about 0.2 percent by weight of impurities, as determined by high performance liquid chromatography.

17. Risedronate sodium hemi-pentahydrate prepared according to the process of any of claims 1 -14 and having less than about 0.1 percent by weight of impurities, as determined by high performance liquid chromatography.

18. Risedronate sodium hemi-pentahydrate prepared according to the process of any of claims 1 -14 and having less than about 0.05 percent by weight of impurities, as determined by high performance liquid chromatography.

19. A pharmaceutical composition containing risedronate sodium hemi- pentahydrate of any of claims 15-18 and one or more pharmaceutically acceptable excipients.