WO2009072769A2

WO2009072769A2 - Process for preparing risedronate sodium as anhydrous and hydrate forms

Info

Publication number: WO2009072769A2
Application number: PCT/KR2008/006912
Authority: WO
Inventors: Jae-Yeon Shin; Young-Deuck Kim
Original assignee: Dongwoo Syntech Co Ltd
Current assignee: Dongwoo Syntech Co Ltd
Priority date: 2007-12-07
Filing date: 2008-11-24
Publication date: 2009-06-11
Anticipated expiration: 2010-06-07
Also published as: WO2009072769A3; KR100925835B1; JP2011506310A; KR20090059635A; EP2229397A2; EP2229397A4

Abstract

Disclosed herein is a novel method for preparing risedronate sodium anhydrous and hydrates from risedronate sodium 2.5 hydrates as a starting material.

Description

PROCESS FOR PREPARING RISEDRONATE SODIUM AS ANHYDROUS AND HYDRATE FORMS

Technical Field

The present invention relates to a process for preparation of risedronate sodium in anhydrous and hydrate forms.

Osteoporosis is a disease causing gradual loss of bone minerals. Treatments for osteoporosis are designed to improve absorption of calcium while reducing urinary calcium excretion. A technical object of the present invention is bisphosphonate such as 2-(3-pyridyl)-l-hydroxyethane-l,l-bis-phosphonic acid (risedronic acid) represented by the following Formula I which is favorably used in treatment of bone diseases and calcium metabolic diseases. In particular, Paget' s disease and heterotropic ossification are known to be treated by both ethane- 1 -hydroxy- 1 , 1 -diphosphonic acid and risedronate sodium (I) .

Background Art

Risedronic acid (II) was disclosed in US Patent No. 5,583,122 published on December 10, 1996 in the name of Benedict et al., and assigned to The Procter & Gamble Co. and a Journal "An American Conference, Bisphophonates: Current status and future prospects" The Royal College of Physicians, London, England, May 21-22, 1990, compiled by IBC Technical Services.

Korean Patent Application No. 10-2002-7009790 describes a process for selective crystallization of risedronate sodium in a mono-hydrate or hemipenta- hydrate form wherein risedronate sodium is present in the form of mono-hydrate and/or hemipenta-hydrate and such hydrate form is selectively determined according to crystallization conditions. However, the above process has problems in controlling nucleation temperature and crystallization rate during mass production of the compound and requires not only pure water but also an additional solvent in large quantities, for example, 30 times that used in the present invention, in order to obtain a particular type hydrate.

Korean Patent Application No. 10-2004-7016268 proposes a variety of hydrate forms of risedronate sodium such as A (hemipenta hydrate), B (mono hydrate), BB, Bl, C, D (anhydrous form), E, F, G, H, etc. and their preparation methods, and demonstrates thermogravimetric analysis (TGA) and Fourier Transform Infrared Spectroscopy (FT-IR) results thereof. However, this patent also involves some problems that prolonged reflux is required, production yield is decreased, a desired reflux temperature must be maintained for a long time during which a hemi-penta hydrate type risendronate sodium is used as a starting material, and an additional solvent is required in an amount of at least 2 times that used in the present invention.

Accordingly, the present invention suggests use of risedronate sodium hemipenta hydrate (sometimes, referred to as "2.5 hydrate") as a starting material to produce a novel hydrate with improved characteristics, compared to conventional methods using risedronic acid as a starting material. The starting material, that is, risedronate sodium 2.5 hydrate according to the present invention may be easily prepared as described in the following exemplary embodiments.

Disclosure Technical Problem

Accordingly, in order to solve the problems in conventional processes described above, an object of the present invention is to provide a process for preparing risedronate sodium in a particular hydrate form with high yield in a short time, including: using risedronate sodium 2.5 hydrate as a starting material; and mixing the starting material with water and a small amount of an additional solvent in a predetermined mixing ratio thereof.

More specifically, the present invention provides a novel process for selectively preparing risedronate sodium in hydrate forms available commercially, wherein environmental problems can be eliminated, production yield can be improved and production time can be reduced, by using a small amount of the additional solvent and water in a desired relative ratio. A process for preparing, the starting material as used herein, "risedronate sodium 2.5 hydrate" is disclosed in detail in KR Patent No. 0775440 issued to the present applicant.

Technical Solution

The present invention is directed to a novel method for preparing risedronate sodium anhydrous, 1 hydrate and 1.5 hydrate from a mixture consisting of risedronate sodium 2.5 hydrate, an organic solvent and water in a specific ratio.

The method enables preparation of high yield risedronate sodium hydrates in a simple manner and is thus commercially available.

The preparation of risedronate sodium hydrate according to the present invention may be carried out by the following process.

1. Preparation of risedronate sodium 1 hydrate a) A mixture of a suitable organic solvent and water is added to risedronate sodium 2.5 hydrate. b) The solution is stirred at reflux temperature. c) The reaction solution is cooled, filtered and dried to prepare risedronate sodium 1 hydrate.

Organic solvents useful for step (a) include ethanol, methanol, isopropanol, acetonitrile 1,4-dioxane. Preferably, ethanol and isopropanol may be used. Also, in step (a), a mixing ratio of the organic solvent and water may be in the range of 6:4 to 9: 1 , preferably about 7:3.

In step (b), the reflux time may be 3 to 7 hours, preferably 5 hours.

In step (c), the cooling temperature may be 15 to 25°C and the cooling time may be 2 to 3 hours. The drying may be carried out under vacuum or hot air at 50⁰C.

2. Preparation of risedronate sodium 1.5 hydrate a) A mixture of a suitable organic solvent and water are added to risedronate sodium 2.5 hydrate. b) The solution is stirred at an elevated temperature. c) The reaction solution is cooled, filtered and dried to prepare a risedronate sodium 1.5 hydrate.

The solvent useful for step (a) may be methanol, ethanol and isopropanol, preferably isopropanol.

Also, a mixing ratio of the solvent and water in step (a) may be in the range of 5:5 to 6:4, preferably 6:4.

In step (b), the reaction temperature may be 50 to 70⁰C, preferably 6O⁰C.

Also, in step (b), the reaction time may be 6 to 8 hours, preferably 7 hours.

In step (c), the cooling may be carried out at a temperature of 15 to 25⁰C for 2 to 3 hours, and the drying may be carried out by hot air drying at 4O⁰C.

3. Preparation of risedronate sodium anhydrous a) A suitable organic solvent is added to risedronate sodium 2.5 hydrate. b) The solution is stirred at a reflux temperature. c) The reaction solution is cooled, filtered and dried to prepare risedronate sodium anhydrous.

In step (a), the solvent may preferably be methanol.

In step (b), the reflux time may be 7 to 20 hours, preferably 12 hours.

In step (c), the cooling may be carried out at a temperature of 15 to 25°C for 2 to 3 hours, and the drying may be carried out under vacuum at 50⁰C. The risedronate sodium prepared by the method is crystalline 1 hydrate,

1.5 hydrate or anhydrous. The moisture content is in the range of 5.5 to 7.5% (by TGA) for 1 hydrate, in the range of 9.0 to 11.0% (by TGA) for 1.5 hydrate, and 1.0% or less (by TGA) for anhydrous. Table 1 shown below shows a variety of analysis data according to a mixing ratio of a solvent and water and reaction temperature.

The X-ray diffraction data described herein was obtained by powder diffraction. The X-ray powder diffraction data is obtained by a method well- known in the art using a model provided with a solid detector, PANalytical, X'pert-Pro. X-ray diffraction patterns of the risedronate sodium 1 hydrate are x- ray diffraction peaks plot at 2Θ of 6.0°, 14.3°, 16.5°, 19.6°, 21.8°, 22.8° and 25.4° and X-ray diffraction patterns of the risedronate sodium 1.5 hydrate are x-ray diffraction peaks plot at 20 of 5.9°, 8.8°, 12.2°, 19.7° and 24.5°, and X-ray diffraction patterns of the risedronate sodium anhydrous are X-ray diffraction peaks at 20 of 9.8°, 17.1°, 22.6°, 27.7° and 29.1°. The TGA weight loss as used herein is obtained by calculating a weight loss at a bent of a weight loss curve (See drawings) in the range of at most about 200 ^°C to about 220 ^°C . Thermogravimetric analysis (TGA) is a thermal analysis method well-known in the art, which measures variations in weight of a sample as a function of temperature. This method is particularly suitable for, for example, decomposition and desolvation. TGA results reported herein were obtained using a TA Instrument, TGA 2950HR. A sample weight as herein used was about 5 mg to about 15 mg.

The sample was analyzed by heating at 25 °C to 250⁰C at a heating rate of 10°C/min. An oven was purged with nitrogen gas at a flow rate of 40 rnL/min. The weight loss thus obtained is greater than the level estimated, based on a theoretical moisture content. This is based on the fact that the TGA weight loss process involves decomposition steps.

TABLE 1

Description of Drawings

The above and other aspects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. 1 illustrates X-ray powder diffraction of risedronate sodium 1 hydrate prepared using ethanol as a solvent in Example 2;

FIG. 2 illustrates a TGA curve of risedronate sodium 1 hydrate prepared using ethanol as a solvent in Example 2;

FIG. 3 illustrates X-ray powder diffraction of risedronate sodium anhydrous prepared using ethanol as a solvent in Example 4; and

FIG. 4 illustrates a TGA curve of risedronate sodium anhydrous prepared in Example 4.

Best Mode

Hereinafter, preferred embodiments and examples of the present invention will be described in detail. However, these examples are given for the purpose of illustration and are not intended to limit the invention.

Example 1 : Preparation of risedronate sodium 2.5 hydrate 60 mL of distilled water and 1.41 g of sodium hydroxide were added to 10.0 g of 2-(3-pyridyl)-l-hydroxyethane-l,l-bis-phosphonic acid (risedronic acid) and the mixture was heated to 65 °C . After dissolution, the solution was cooled to 25 ^°C over 3 hours, and the resulting crystal was filtered and dried to obtain risedronate sodium 2.5 hydrate (8.0 g, 64.7% of a theoretical value, LOD (by TGA): = 13.2%)

Example 2: Preparation of risedronate sodium 1 hydrate a. Using ethanol as a solvent

30 mL of ethanol and 20 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 5 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and air-dried at 40 ^°C to obtain risedronate sodium 1 hydrate (4.5 g, 97.5% of a theoretical value, LOD (by TGA) = 7.2%) b. Using isopropanol as a solvent

40 mL of isopropanol and 10 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 5 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and vacuum-dried at 50°C to obtain risedronate sodium 1 hydrate (4.5 g, 97.5% of a theoretical value, LOD (by TGA) = 7.4%). c. Using methanol as a solvent 45 mL of methanol and 5 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 5 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and vacuum-dried at 50 ^°C to obtain risedronate sodium 1 hydrate (4.6 g, 99.7% of a theoretical value, LOD (by TGA) = 7.4%). d. Using acetonitrile as a solvent

30 mL of acetonitrile and 20 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 5 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and vacuum-dried at 50^°C to obtain risedronate sodium 1 hydrate (4.5 g, 97.5% of a theoretical value, LOD (by TGA) = 7.4%). e. Using 1,4-dioxane as a solvent

35 mL of 1 ,4-dioxane and 15 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 5 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and vacuum-dried at 50 ^"C to obtain risedronate sodium 1 hydrate (4.5 g, 97.5% of a theoretical value, LOD (by TGA) = 7.1%).

Example 3: Preparation of risedronate sodium 1.5 hydrate 30 mL of isopropanol and 20 mL of distilled water were added to 5.0 g of risedronate sodium 2.5 hydrate, and the mixture was refluxed at an elevated temperature of 60 "C for 7 hours. The reaction mixture was cooled to 20 ^°C over 2 hours, and the resulting crystal was filtered and air-dried at 40 ^°C to obtain risedronate sodium 1.5 hydrate (4.6 g, 97.0% of a theoretical value, LOD by TGA = 10.0%)

Example 4: Preparation of risedronate sodium anhydrous 50 mL of methanol was added to 5.0 g of risedronate sodium 2.5 hydrate and the mixture was refluxed at an elevated temperature for 12 hours. The reaction mixture was cooled to 20 ^°C over 2 hours and the resulting crystal was filtered and then dried under vacuum at 50^°C to obtain risedronate sodium anhydrous (4.2 g, 96.4% of a theoretical value, LOD (by TGA) = 0.33%) X-ray powder diffractions and thermogravimetric analysis (TGA) of risedronate sodium hydrate prepared in this Example can be seen in FIGs. 1 to 4.

Industrial Applicability

The present invention provides a method for preparing risedronate sodium hydrates and anhydrous from risedronate sodium 2.5 hydrates as starting materials using a mixture of an organic solvent and water.

The present method has advantages of improved yield, low preparation cost and significantly reduced unnecessary by-products, compared to conventional methods. Accordingly, the method is environmentally friendly and thus advantageous in commercial mass-production.

Claims

1. A method for preparing risedronate sodium 1 hydrate, comprising: a) adding a mixture of a solvent and water in a mixing ratio of 6:4 to 9:1 to risedronate sodium 2.5 hydrate, wherein the solvent is selected from ethanol, methanol, isopropanol, acetonitrile and 1 ,4-dioxane, b) stirring the solution at a reflux temperature for 3 to 7 hours; and c) cooling the reaction mixture, followed by filtering and drying to prepare risedronate sodium 1 hydrate.

2. The method according to claim 1, wherein the solvent in step (a) is selected from ethanol and isopropanol.

3. The method according to claim 1, wherein the mixing ratio of the solvent and water in step (a) is 7:3.

4. The method according to claim 1, wherein the solution is stirred in step (b) for 5 hours.

5. A method for preparing risedronate sodium 1.5 hydrate, comprising: a) adding a mixture of a solvent and water in a ratio of 5:5 to 6:4 to risedronate sodium 2.5 hydrate, wherein the solvent is selected from methanol, ethanol and isopropanol; b) stirring the solution at an elevated temperature of 50⁰C to 70 °C for 6 to 8 hours; and c) cooling the reaction mixture, followed by filtering and air-drying to prepare risedronate sodium 1.5 hydrate.

6. The method according to claim 5, wherein the solvent in step (a) is isopropanol.

7. The method according to claim 5, wherein the mixing ratio of the solvent and water in step (a) is 6:4.

8. The method according to claim 5, wherein the solution is stirred in step (b) at a temperature of 60 °C for 7 hours

9. A method for preparing risedronate sodium anhydrous, comprising: a) adding methanol to risedronate sodium 2.5 hydrate; b) stirring the solution at a reflux temperature for 7 to 20 hours; and c) cooling the reaction mixture, followed by filtering and drying to prepare a risedronate sodium anhydrous.

10. The method according to claim 9, wherein the solution is stirred in step (b) for 12 hours.