PREPARATION OF IBANDRONATE SODIUM CRYSTALLINE FORM B
INTRODUCTION

Aspects of the present application relate to processes for preparing crystalline Form B of ibandronate sodium.

The drug compound having the adopted name "ibandronate sodium" is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. A chemical name for ibandronate sodium is 3-(A/-methyl-A/-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate, and the anhydrous compound is represented by the chemical structure of formula I.

Ibandronate sodium is useful in the treatment of bone disorders such as hypocalcemia of malignance, osteolysis, Paget's disease, osteoporosis and metastatic bone diseases and is available in the market under the trade name BONIVA™. It is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Gall et al. in U.S. Patent No. 4,927,814 describe Ibandronic acid, its analogues and physiologically acceptable salts thereof. The patent also discloses a pharmaceutical composition and its use in the treatment of prophylaxis of calcium metabolism disturbance or disease.

Eiermann et al. in U.S. Patent Application Publication No. 2006/0172975 Al describe a crystalline form of ibandronate sodium monohydrate, designated as crystalline Form A, and a process for its preparation which involves crystallizing ibandronate monosodium salt or a monohydrate, a polymorph or a polymorph mixture thereof at temperatures of 50°C to 70°C in a polar solvent, and adding a polar aprotic solvent for inducing crystallization. One of the disclosed processes involves dissolving ibandronate sodium in water at 60°C, maintaining the solution at 55°C and adding acetone over a period of 1 hour, followed by maintaining the mixture at the same temperature for 2 hours. The obtained precipitate is cooled to
15-20°C, isolated by filtration and dried in a vacuum from 150 to 20 mbar at 40°C for 14 hours, and then at 60°C for 24 hours to give crystalline Form A.

Eiermann et al. in U.S. Patent Application Publication No. 2006/0172976 A1 describe another crystalline form of ibandronate sodium monohydrate, designated as crystalline Form B, along with process for its preparation which involves crystallizing ibandronate monosodium salt or a monohydrate, a polymorph or a polymorph mixture thereof at temperatures of 10°C to 45°C in a polar solvent, and adding a polar aprotic solvent (such as aliphatic ketones or cyclic ethers) to initialize the crystallization. One of the disclosed processes involves dissolving ibandronate sodium in water, partially distilling water, cooling the solution to 35°C, and adding acetone over a period 20 minutes, followed by cooling the reaction mass to <25°C under stirring to obtain a complete crystallization. The obtained product was separated, washed with acetone/water, and dried in a vacuum of 150 to 20 mbar for 12 hours at 40°C, and 24 hours at 60°C, to give crystalline Form B.

There remains a need for improvements in the processes for the preparation of crystalline forms of ibandronate sodium.

SUMMARY
The present application relates to processes for preparing crystalline Form B of Ibandronate sodium.

In one aspect, the present application provides a process for preparing crystalline Form B of ibandronate sodium, comprising:

a) providing an aqueous solution of ibandronate sodium;

b) crystallizing the ibandronate sodium by combining the solution of step a) with an anti-solvent at temperatures less than l0°C; and

c) isolating a solid.

In another aspect, the present application provides processes for preparing crystalline Form B of Ibandronate sodium, an embodiment comprising:

a) providing an aqueous solution of ibandronate sodium;

b) crystallizing the ibandronate sodium by combining the solution of step a) with an anti-solvent at temperatures above 45°C; and

c) isolating a solid.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of an X-ray powder diffraction (XRPD) pattern of crystalline Form B of ibandronate sodium, obtained according to Example 1.

Fig. 2 is an example of an XRPD pattern of crystalline Form B of ibandronate sodium, obtained according to Example 2.

DETAILED DESCRIPTION

Aspects of the present application relate to processes for preparing crystalline Form B of ibandronate sodium.

In one aspect, the present application provides a process for preparing crystalline Form B of ibandronate sodium, comprising:

a) providing an aqueous solution of ibandronate sodium;

b) crystallizing the ibandronate sodium by combining the solution of step a) with an anti-solvent at temperatures less than 10°C; and

c) isolating a solid.
The steps for the process are described individually below.

Step a).
An aqueous solution of ibandronate sodium may be provided by dissolving ibandronate sodium in water, or may be obtained from a process by which ibandronate sodium is synthesized. Any form of ibandronate sodium, such as any crystalline or amorphous form, obtained by any method, is acceptable for providing the solution.

The concentration of ibandronate sodium in the solution is not critical as long as sufficient water is employed to ensure total dissolution. The amount of water employed is typically kept small, so as to avoid excessive product losses during crystallization and isolation.

The solution may be prepared by combining ibandronate sodium and water at room temperature and heating to the desired temperature of dissolution.
The solution may be prepared at temperatures ranging from about 10°C to about 90°C. Depending on the quantity of water used, solute may dissolve at 25 to 35°C, or the solution may need to be heated to higher, including reflux, temperatures.

Optionally, the solution may be distilled to partially remove water from the solution and increase the solute concentration.

The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used, the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid any premature crystallization.

Step b).
Step b) involves crystallizing the solid by adding an anti-solvent. Useful anti-solvents include, but are not limited to, ketones, esters, nitriles, alcohols, cyclic ethers, and N,N-dimethylformamide.

The solution of Ibandronate sodium obtained in a) is cooled to temperatures less than 10°C, or less than about 8°C, or preferably less than about 5°C, and is combined with an anti-solvent to initialize crystallization.

Suitable anti-solvents that may be used for initializing the crystallization include, but are not limited to, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; alcohols such as methanol, ethanol, n-propanol, isopropanol, and the like; cyclic ethers such as tetrahydrofuran; 1,4-dioxane, and the like; and aprotic compounds such as N,N-dimethylformamide.

In an embodiment, a ketone is used for crystallizing the solid from the solution of a).

In an embodiment, acetone is used for crystallizing the solid from the solution of a).

Optionally, a small amount of seed crystals of ibandronate sodium form B may also be added to the solution in b), before to the addition of the anti-solvent.

The suspension so obtained may be maintained at the same temperature under stirring until crystallization is complete, before the isolation takes place.

Step c).
The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with an anti-solvent, water, or mixtures thereof.

The isolated solid may optionally be dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at suitable temperatures.

In embodiments, the drying may be carried out at temperatures of about 25-55°C.

In embodiments, the product obtained is dried at 25-35°C at above 650 mm of Hg vacuum for about 1 hour or more, and then dried at 50-55°C at above 650 mm of Hg vacuum for about 2 hours or more.

In a preferred embodiment, the present application provides a process for preparing crystalline Form B of ibandronate sodium, comprising:

a) providing an aqueous solution of ibandronate sodium;

b) optionally distilling the solution of step a) to concentrate the reaction mass and diluting with water;

c) crystallizing the ibandronate sodium by combining the solution with an anti-solvent at temperatures less than 10°C; and

d) isolating the solid.

In another aspect, the present application provides processes for preparing crystalline Form B of Ibandronate sodium, an embodiment comprising:

a) providing an aqueous solution of ibandronate sodium;

b) crystallizing the ibandronate sodium by combining the solution of step a) with an anti-solvent at temperatures above 45°C; and

c) isolating a solid.
The steps for the process are described individually below.

Step a).
An aqueous solution of ibandronate sodium may be provided by dissolving ibandronate sodium in water, or may be obtained from a process by which ibandronate sodium is synthesized. Any form of ibandronate sodium, such as any crystalline or amorphous form, obtained by any method, is acceptable for providing the solution.

The concentration of ibandronate sodium in the solution is not critical as long as sufficient water is employed to ensure total dissolution. The amount of water employed is typically kept small, so as to avoid excessive product losses during crystallization and isolation.

The solution may be prepared by mixing ibandronate sodium and water at room temperature and heating to the desired temperature of dissolution.

The solution may be prepared at temperatures ranging from about 25°C to about 90°C. Depending on the quantity of water used, solute may dissolve at 25 to 35°C, or the solution may need to be heated to higher, including reflux, temperatures.

Optionally, the solution may be distilled to partially remove water and increase the solute concentration.

The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of clarifying agent such as Hyflow (flux-calcined diatomaceous earth). Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization.

Step b).
Step b) involves crystallizing a solid by combining the solution with an anti-solvent such as a ketone, ester, nitrile, alcohol, or N,N-dimethylformamide, at temperatures above 45°C.

The solution of ibandronate sodium obtained in a) is maintained at temperatures above 45°C and less than about 90°C, or at temperatures of about 50°C to about 55°C, and combined with an anti-solvent at the same temperature to initialize crystallization.

Useful anti-solvents that may be used for initializing the crystallization include, but are not limited to: ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, priopionitrile, and the like; alcohols such as methanol, ethanol, n-propanol, isopropanol, and the like; and aprotic compounds such as N,N-dimethylformamide..

In embodiments, a ketone is used for crystallizing the solid from the solution of a).

In an embodiment, acetone is used for crystallizing the solid from the solution of a).

Optionally, a small amount of seed crystals of ibandronate sodium form B may be added to the solution in b) before combination with the anti-solvent.

The suspension so obtained may be maintained at the same temperature under stirring until crystallization is complete before the isolation takes place.
Step c).

The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the solid may optionally be washed with an anti-solvent, water, or mixtures thereof.

The isolated solid may optionally be dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like and at suitable temperatures.

In embodiments, the drying may be carried out at temperatures of about 25-65°C. In embodiments, the product obtained is dried at 25-35°C at above 650 mm of Hg vacuum for about 1 hour or more, and then dried at 50-55°C at above 650 mm of Hg vacuum for about 2 hours or more.

In a preferred embodiment, the present application provides a process for preparing crystalline Form B of ibandronate sodium, comprising:

a) providing an aqueous solution of ibandronate sodium;

b) optionally distilling the solution of step a) to concentrate the reaction mass and diluting with water;

c) crystallizing the ibandronate sodium by combining the solution with an anti-solvent selected from ketone, ester, nitrile, alcohol or N,N-dimethylformamide, at temperatures above 45°C; and

d) isolating the solid.

The inventors of the present application have surprisingly found that crystalline Form B of ibandronate sodium can be obtained at temperatures less than 10°C and at temperatures above 45°C, from a mixture of water and a ketone solvent (which is a polar aprotic solvent), while according to the process disclosed U.S. Patent Application Publication No. 2006/0172975 A1 crystalline Form B is obtained only at temperatures ranging from 10-45°C, and according to the process disclosed in U.S. Patent Application Publication No. 2006/0172976 A1 crystalline form A is obtained at temperatures ranging from 55-60°C.

The ibandronate sodium obtained by the processes of the present application has a content of crystalline Form B of ibandronate sodium of at least about 95%, or at least about 99%, or at least about 99.7%, by weight.

XRPD data reported herein were obtained using a Bruker Axs D8 Advance Powder X-ray Diffractometer with copper Ka radiation.

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

EXAMPLES

EXAMPLE 1: Preparation of crystalline Form B of ibandronate sodium at a temperature less than 10°C.

Ibandronate sodium (48 g) and water (180 mL) were placed into a round bottom flask and heated to about 53°C to obtain a clear solution. Water (-90 mL) was distilled at about 65-70°C under vacuum. Added water (90 mL) to the concentrate and stirred for about 30 minutes at a temperature of 70-80°C. Cooled the mass to 0-5°C and added acetone (540 mL) over about 15 minutes. Stirred the mass at the same temperature for 1 hour, filtered the solid, washed the solid with acetone (32 mL), and dried the solid for 1 hour under vacuum. The solid material obtained was dried at 50-55°C for 7-8 hours.
Yield; 46 g.
XRPD pattern substantially in accordance with Fig. 1.

EXAMPLE 2: Preparation of crystalline Form B of Ibandronate sodium at a temperature above 45°C.

Ibandronate sodium (48 g) and water (180 mL) were placed into a round bottom flask and heated to about 64°C to obtain a clear solution. Water (-90 mL) was distilled at 65-70°C under vacuum. Added water (90 mL) to the concentrate, stirred for about 30 minutes at 75-80°C, and cooled the mass to 45-50°C. Added acetone (540 mL) slowly to the above solution at about 48-53°C and stirred at the same temperature for about 1 hour. Cooled the mass to 25-30°C, maintained for 30 minutes, filtered the solid, washed with acetone (32 mL), and suction dried the solid for about 1 hour under vacuum. The solid obtained was dried at 50-55°C under vacuum for 7-8 hours.
Yield: 44.0 g.
XRPD pattern substantially in accordance with Fig. 2.

Claims:
1. A process for preparing crystalline Form B of ibandronate sodium,
comprising:

a) providing an aqueous solution of ibandronate sodium;

b) optionally distilling the solution of step a) to concentrate the reaction mass and diluting with water;

c) crystallizing the ibandronate sodium by combining the solution with an anti-solvent at temperatures less than 10°C; and

d) isolating the solid.

2. A process for preparing crystalline Form B of ibandronate sodium, comprising:

a) providing an aqueous solution of ibandronate sodium;

b) optionally distilling the solution of step a) to concentrate the reaction mass and diluting with water;

c) crystallizing the ibandronate sodium by combining the solution with an anti-solvent selected from ketone, ester, nitrile, alcohol or N,N-dimethylformamide at temperatures above 45°C; and

d) isolating the solid.

2. The process of claims 1 and 2, wherein the solution of step a) may be prepared at temperatures ranging from about 10°C to about 90°C.

3. The process of claim 1, wherein the solution of step b) is cooled to a temperature less than 10°C.

4. The process of claim 2, wherein the solution of step b) is maintained at a temperature above 45°C.

5. The process of claim 1, wherein the solution of ibandronate sodium is combined with an anti-solvent at a temperature less than 5°C.

6. The process of claim 1, wherein the antisolvent of step c) is selected from the group consisting of ketone, ester, nitrile, alcohol, ether and N,N-dimethyl foumamide.

7. The process of claim 6, wherein the ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; ester is selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; nitrile is selected from acetonitrile, propionitrile; alcohol is selected from methanol, ethanol, n-propanol, isopropanol; cyclic ether is selected from tetrahydrofuran; 1,4-dioxane.

8. The process of claim 2, wherein the solution of ibandronate sodium is combined with an anti-solvent at a temperature above 45°C.

9. The process of claim 2, wherein the ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; ester is selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; nitrile is selected from acetonitrile, propionitrile; alcohol is selected from methanol, ethanol, n-propanol, isopropanol.