WO2013109198A1 - Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b - Google Patents

Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b Download PDF

Info

Publication number
WO2013109198A1
WO2013109198A1 PCT/TR2012/000214 TR2012000214W WO2013109198A1 WO 2013109198 A1 WO2013109198 A1 WO 2013109198A1 TR 2012000214 W TR2012000214 W TR 2012000214W WO 2013109198 A1 WO2013109198 A1 WO 2013109198A1
Authority
WO
WIPO (PCT)
Prior art keywords
ibandronate
polymorph
mixture
ray diffraction
polymorphs
Prior art date
Application number
PCT/TR2012/000214
Other languages
French (fr)
Inventor
Tuncer Aslan
Ender KOÇAK
Original Assignee
Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇ filed Critical Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇
Publication of WO2013109198A1 publication Critical patent/WO2013109198A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]

Definitions

  • the present invention relates to processes for the preparation of [l-Hydroxy-3- (methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate (Ibandronate) polymorphs or mixture of polymorphs.
  • Ibandronate As most of the pharmaceutical substances Ibandronate also shows polymorphsm. Among the other polymorphs, form A and form B or their mixtures A+B are well known for Ibandronate. Too many factors play important role on polymorphism such as temperature, cooling rate, solvent used, reaction time and seeding. Polymorphism can affect solid state properties of a drug substances as a result the drug products. Different polymorphs of the substances can have different properties such as solubility which is a very important parameter for dissolution.
  • the sodium salt of Ibandronic acid inhibits farnesyl pyrophosphate synthase, resulting in a reduction in geranylgeranyl GTPase signaling proteins and apoptosis of osteoclasts.
  • Sodium Ibandronate Monohydrate increases bone mineral density, decreases bone remodeling, inhibits osteoclast-mediated bone resorption, and reduces metastases-related and corticosteroid-related bone.
  • US Patent No. 4927814 teaches preparation of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate.
  • alkali salt of bisphosphanate can be isolated by precipitating from water /methanol or from water /acetone and in this way they can be purified.
  • procedure given in this basic patent is followed for the preparation of Ibandronate, a mixture of A+B form of the Ibandronate are obtained but the process has not been reported in detail instead referenced to a general example.
  • US patent No7582789 B2 describes a process for the preparation of Ibandronate polymorph B.
  • Ibandronate polymorph B is crystallized out from a mixture of water/acetone or water/tetrahydrofuran at a temperature around 35 °C.
  • Eiermann et.al. tells a process in the patent application No W02006/081963A1 how to obtain Ibandronate polymorph A.
  • Ibandronate is dissolved in water, a part of the water is evaporated at high temperatures and then cooled to 60 °C, followed addition of a preheated acetone.
  • solvent used in crystallization process is most important parameter to get desired polymorph of Ibandronate.
  • ethanol favors formation of Ibandronate polymorph B.
  • Even dry Ibandronate polymorph A is added to a suspension of Ibandronate polymorph B in ethanol, after a couple hours polymorph A is completely converted to the polymorph B (X-ray analysis).
  • Use of water as a solvent provides formation of Ibandronate polymorph A. For example, first dissolving any form of Sodium Ibandronate Monohydrate in water and then evaporating the solvent under reduced pressure resulted in Ibandronate polymorph A.
  • a Rigaku Ultima 4 X-ray diffracto meter is used for the measurements of X-ray diffractograms.
  • the scanning range was 2-40 degrees two-theta.
  • Figure 1 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph A as obtained in example 2
  • Figure 2 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph B as obtained in example 3
  • Figure 3 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph A+ B as obtained in example 4
  • Obtaining polymorph A of Ibandronate by the process according to this invention is characterized in that dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate in water and evaporating the solvent to dryness under reduced pressure at a temperature from 40 °C to 95 °C.
  • polymorph B of Ibandronate by the process according to this invention is characterized in that dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate at a temperature from 5 °C to 75 °C In water and adding a Ci-C 4 alcohol especially ethanol to initialize crystallization which is completed within 5 to 90 minutes.
  • Obtaining a A + B polymorphs mixture of Ibandronate by the process according to this invention consists of the steps: a) dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l- phosphonic acid monosodium monohydrate in water b) evaporating the solvent under reduced pressure at a temperature from 40 °C to 95 °C; c) cooling reaction medium to a temperature range from 5 °C to 70 °C d) adding a Ci-C 4 alcohol and stirring the suspension 5 to 30 minutes; and e) isolating mixture of A+B form of Ibandronate via filtration.
  • a 2 L flask was equipped with magnetic stirrer, thermometer, condenser and pressure equalized addition funnel. The system was connected to a caustic scrubber. The flask was charged with 100 g (0.58 mol) 3-(N-methyl-N- pentyl)amino propionic acid hydrochloride, 47.3 g (0.58 mol) phosphorous acid and 450 g of sunflower oil at room temperature. The reaction mixture was heated to 73-75 °C and stirred until all the components were completely dissolved (25-30 minutes). To this mixture was added 119.6 g (0.87 mol) of phosphorous trichloride in about 5-10 minutes. The mixture is stirred at this temperature about 3-4 hours.
  • the desired product 3-(N- Methyl-N-pentyl)amino-l-hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate was precipitated by adding 790 g of methanol and isolated after drying 128.2 g in 62% yield. For further purification, the product was taken into 1185 g of methanol, refluxed for 40-50 minutes, cooled to 20-25 °C and filtered. After drying, 123 g of final product was obtained as a white solid. The product was a polymorphic mixture A and B of -(N-Methyl-N-pentyl)amino-l-hydroxypropen- 1,1-diphosphonic acid monosodium salt monohydrate.
  • a 500 mL flask was charged with 20 gr of-(N-Methyl-N-pentyl)amino-l- hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate (obtained according to reference example 1) and 100 g of water.
  • the mixture was heated to about 60-80 °C and stirred until a clear solution was obtained.
  • the solution is concentrated under reduced pressure in rotary evaporator to of its initial volume (around 25-35 ml) at a temperature about 60 °C to 75 °C.
  • the flask was transferred to magnetic stirrer equipped with contact thermometer, oil bath (about 60 °C) and condenser.
  • a 500 mL flask was charged with 20 gr of-(N-Methyl-N-pentyl)amino-l- hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate (obtained according to reference example 1) and 100 g of water.
  • the mixture was heated to 70-80 °C and stirred until a clear solution was obtained.
  • the solution is concentrated under reduced pressure in rotary evaporator to dryness at a temperature from 60 °C to 95 °C.
  • the flask was transferred to magnetic stirrer and cooled to 20-25 °C. At this temperature 100 ml of ethanol was added to reaction mixture, and was stirred at this temperature for 5-15 minutes and filtered.
  • the crystalline product was dried in a vacuum oven for 6-10 hours at 55-60 °C and obtained 18.2 g.
  • the X-ray powder diffraction analysis showed that the product was a mixture of Ibandronate polymorph A and B.
  • the ratio of the polymorphs can relatively be adjusted by optimizing reaction conditions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

The present invention relates to processes for the preparation of [1-Hydroxy-3-(methylpentylamino) propylidene] bis-1,1-phosphonic acid monosodium monohydrate (Ibandronate) polymorphs or mixture of polymorphs.

Description

DESCRIPTION
PROCESSES FOR THE PREPARATION OF SODIUM IBANDRONATE MONOHYDRATE POLYMORPHS A, B AND MIXTURE OF POLYMORPHS A WITH B
The present invention relates to processes for the preparation of [l-Hydroxy-3- (methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate (Ibandronate) polymorphs or mixture of polymorphs.
As most of the pharmaceutical substances Ibandronate also shows polymorphsm. Among the other polymorphs, form A and form B or their mixtures A+B are well known for Ibandronate. Too many factors play important role on polymorphism such as temperature, cooling rate, solvent used, reaction time and seeding. Polymorphism can affect solid state properties of a drug substances as a result the drug products. Different polymorphs of the substances can have different properties such as solubility which is a very important parameter for dissolution.
The sodium salt of Ibandronic acid inhibits farnesyl pyrophosphate synthase, resulting in a reduction in geranylgeranyl GTPase signaling proteins and apoptosis of osteoclasts. Sodium Ibandronate Monohydrate increases bone mineral density, decreases bone remodeling, inhibits osteoclast-mediated bone resorption, and reduces metastases-related and corticosteroid-related bone.
-Sodium Ibandronate Monohydrate is used for the treatment of diseases such as osteoporosis, Paget's disease and hypercalcemia of malignanch.
US Patent No. 4927814 teaches preparation of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate. In this patent it states that alkali salt of bisphosphanate can be isolated by precipitating from water /methanol or from water /acetone and in this way they can be purified. When procedure given in this basic patent is followed for the preparation of Ibandronate, a mixture of A+B form of the Ibandronate are obtained but the process has not been reported in detail instead referenced to a general example.
US patent No7582789 B2 describes a process for the preparation of Ibandronate polymorph B. In this patent form B is crystallized out from a mixture of water/acetone or water/tetrahydrofuran at a temperature around 35 °C. Eiermann et.al. tells a process in the patent application No W02006/081963A1 how to obtain Ibandronate polymorph A. In the process Ibandronate is dissolved in water, a part of the water is evaporated at high temperatures and then cooled to 60 °C, followed addition of a preheated acetone.
In the above mentioned patent and patent application seems that temperature is most important factor to get desired polymorph. For example in the US patent IMo7582789 B2 to obtain Ibandronate polymorph B a temperature range from 10 °C to 45 °C especially 35 °C is given. Again in the patent application No W02006/081963A1 to get form A crystallization temperature should be around 60 °C even to keep this temperature apolar solvent acetone is preheated to 50-55 °C.
In present invention it is found that among others solvent used in crystallization process is most important parameter to get desired polymorph of Ibandronate. For example use of Ci-C4 alcohols, preferably ethanol favors formation of Ibandronate polymorph B. Even dry Ibandronate polymorph A is added to a suspension of Ibandronate polymorph B in ethanol, after a couple hours polymorph A is completely converted to the polymorph B (X-ray analysis). Use of water as a solvent provides formation of Ibandronate polymorph A. For example, first dissolving any form of Sodium Ibandronate Monohydrate in water and then evaporating the solvent under reduced pressure resulted in Ibandronate polymorph A. Although it looks amorphous at the beginning, when the flask opened it became crystalline on the surface of flask and X-ray diffraction analysis shows that it is Ibandronate polymorph A. Considering formation of polymorph A and B and by optimizing reaction conditions a polymorphic mixture of A+B can be obtained very easily following a simple procedure. Thus, first any form of the Sodium Ibandronate Monohydrate is dissolved in water; second the solvent is evaporated under reduced pressure and then mixture is cooled to room temperature, an Ci-C4 alcohols is added after stirring 5-90 minutes at this temperature the product is isolated via filtration. X-ray analysis shows it is a mixture of polymorphs. Even the ratio of the polymorphs can relatively be adjusted by controlling reaction condition.
A Rigaku Ultima 4 X-ray diffracto meter is used for the measurements of X-ray diffractograms. The scanning range was 2-40 degrees two-theta.
It is an aspect of the invention to develop a process for the preparation of Ibandronate polymorph A which is characterized by X-ray diffraction peaks (reflections) at about 6.0, 10.3, 11.5, 15.5, 17.2, 18.3, 19.2, 23.8, 26.3, 26.7, 31.5 and 32.3 ± 2 degrees two theta by using water as a solvent and controlling reaction conditions.
It is another aspect of the invention to develop a process for the preparation of Ibandronate polymorph A having X-ray powder diffraction pattern as shown in Figure 1.
It is an aspect of the invention to develop a process for the preparation of Ibandronate polymorph B which is characterized by X-ray diffraction peaks (reflections) at about 6.2, 9.8, 12.2, 14.2, 14.9, 17.0, 17.8, 18.2, 19.3, 20.2, 20.3, 21.4, 25.1, 26.7, 28.2, 30.2, 32.0, and 35,4 + 2 degrees two theta by using a Ci- C4 alcohol/water mixture and controlling reaction conditions.
It is another aspect of the invention to develop a process for the preparation of Ibandronate polymorph B having X-ray powder diffraction pattern as shown in Figure 2.
It is an aspect of the invention to develop a process for the preparation of Ibandronate polymorph A and polymorph B mixture which is characterized by X-ray diffraction peaks (reflections) at about 6.2, 9.8, 10.1, 11.5, 12.2, 14.3, 15.0, 15.7, 17.2, 18.5, 19.3, 23.7, 24.8, 26.2and 31.1 ± 2 degrees two theta by using a water/Ci-C4 alcohol mixture and controlling reaction conditions.
It is another aspect of the invention to develop a process for the preparation of polymorph A and polymorph B having X-ray powder diffraction pattern as shown in Figure 3. Especially, X-ray diffraction peaks at about ten and twelve are important to determine it is a polymorphic mixture of A and B.
DESCRIPTION OF FIGURES
Figure 1 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph A as obtained in example 2
Figure 2 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph B as obtained in example 3
Figure 3 shows an X-ray diffraction pattern of crystalline Sodium Ibandronate Monohydrate polymoph A+ B as obtained in example 4 Obtaining polymorph A of Ibandronate by the process according to this invention is characterized in that dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate in water and evaporating the solvent to dryness under reduced pressure at a temperature from 40 °C to 95 °C.
Obtaining polymorph B of Ibandronate by the process according to this invention is characterized in that dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate at a temperature from 5 °C to 75 °C In water and adding a Ci-C4 alcohol especially ethanol to initialize crystallization which is completed within 5 to 90 minutes.
Obtaining a A + B polymorphs mixture of Ibandronate by the process according to this invention consists of the steps: a) dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l- phosphonic acid monosodium monohydrate in water b) evaporating the solvent under reduced pressure at a temperature from 40 °C to 95 °C; c) cooling reaction medium to a temperature range from 5 °C to 70 °C d) adding a Ci-C4 alcohol and stirring the suspension 5 to 30 minutes; and e) isolating mixture of A+B form of Ibandronate via filtration.
EXAMPLE 1
Preparation of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l- phosphonic acid monosodium salt monohydrate
A 2 L flask was equipped with magnetic stirrer, thermometer, condenser and pressure equalized addition funnel. The system was connected to a caustic scrubber. The flask was charged with 100 g (0.58 mol) 3-(N-methyl-N- pentyl)amino propionic acid hydrochloride, 47.3 g (0.58 mol) phosphorous acid and 450 g of sunflower oil at room temperature. The reaction mixture was heated to 73-75 °C and stirred until all the components were completely dissolved (25-30 minutes). To this mixture was added 119.6 g (0.87 mol) of phosphorous trichloride in about 5-10 minutes. The mixture is stirred at this temperature about 3-4 hours. Water (500 g) was added carefully to quench reaction mixture. Ethyl acetate (237 g) was added and the layers were separated. The organic phase was washed with 500 g of water ones more to take all phosphorous intermediates into aqueous phase. The aqueous phases were combined and refluxed at 106 °C for 3-4 hours. The mixture was cooled to 20-25 °C, the pH of the mixture was adjusted to 4-4.5 by adding 50% NaOH solution (390 g) and filtered. The desired product 3-(N- Methyl-N-pentyl)amino-l-hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate was precipitated by adding 790 g of methanol and isolated after drying 128.2 g in 62% yield. For further purification, the product was taken into 1185 g of methanol, refluxed for 40-50 minutes, cooled to 20-25 °C and filtered. After drying, 123 g of final product was obtained as a white solid. The product was a polymorphic mixture A and B of -(N-Methyl-N-pentyl)amino-l-hydroxypropen- 1,1-diphosphonic acid monosodium salt monohydrate.
EXAMPLE 2
Preparation of Ibandronate polymorph A
A 500 mL flask was charged with 20 gr of-(N-Methyl-N-pentyl)amino-l- hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate (obtained according to reference example 1) and 100 g of water. The mixture was heated to 70-80 °C and stirred until a clear solution was obtained. The solution is concentrated under reduced pressure in rotary evaporator to dryness at a temperature from 60 °C to 95 °C. After evaporation of the solvent, the product was dried at this temperature range for 1-3 hours. The crystalline product was taken and further dried in a vacuum oven for 6-10 hours at 55-60 °C and obtained 18.7g. The X-ray powder diffraction analysis showed that the product was Ibandronate polymorph A
EXAMPLE 3
Preparation of Ibandronate polymorph B
A 500 mL flask was charged with 20 gr of-(N-Methyl-N-pentyl)amino-l- hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate (obtained according to reference example 1) and 100 g of water. The mixture was heated to about 60-80 °C and stirred until a clear solution was obtained. The solution is concentrated under reduced pressure in rotary evaporator to of its initial volume (around 25-35 ml) at a temperature about 60 °C to 75 °C. The flask was transferred to magnetic stirrer equipped with contact thermometer, oil bath (about 60 °C) and condenser. At this temperature 100 ml of ethanol was added to reaction mixture, immediately crystallization started. The mixture was stirred at this temperature for 50-70 minutes. Cooled to 20-25 °C and filtered. The crystalline product was dried in a vacuum oven for 6-10 hours at 55-60 °C and obtained 16.8 g. The X-ray powder diffraction analysis showed that the product was Ibandronate polymorph B. To get Ibandronate form B crystallization can be done in any temperature from 0 to 75 °C, here temperature is not important but use of a C1-C4 alcohol especially ethanol is important for the formation of polymorph B.
EXAMPLE 4
Preparation of Ibandronate polymorph A+B mixture
A 500 mL flask was charged with 20 gr of-(N-Methyl-N-pentyl)amino-l- hydroxypropen-l,l-diphosphonic acid monosodium salt monohydrate (obtained according to reference example 1) and 100 g of water. The mixture was heated to 70-80 °C and stirred until a clear solution was obtained. The solution is concentrated under reduced pressure in rotary evaporator to dryness at a temperature from 60 °C to 95 °C. The flask was transferred to magnetic stirrer and cooled to 20-25 °C. At this temperature 100 ml of ethanol was added to reaction mixture, and was stirred at this temperature for 5-15 minutes and filtered. The crystalline product was dried in a vacuum oven for 6-10 hours at 55-60 °C and obtained 18.2 g. The X-ray powder diffraction analysis showed that the product was a mixture of Ibandronate polymorph A and B. The ratio of the polymorphs can relatively be adjusted by optimizing reaction conditions.

Claims

1. The present invention relates to processes for the preparation of [1-Hydroxy- 3-(methylpentylamino)propylidene]bis-l,l-phosphonic acid monosodium monohydrate (Ibandronate) polymorph A, polymorph B and their mixture.
2. The said process of claim 1 for obtaining polymorph A of Ibandronate is characterized in that dissolving any form of [l-Hydroxy-3- (methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate in water and evaporating the solvent to dryness under reduced pressure at a temperature from 40 °C to 95 °C.
3. The said process of claim 1 for obtaining polymorph B of Ibandronate is characterized in that dissolving any form of [l-Hydroxy-3- (methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate at a temperature from 5 °C to 75 °C in wafer, concentrating the mixture under reduced pressure about 1/4 of it original volume and adding a Ci-C4 alcohol especially ethanol to initialize crystallization which is completed within 5 to 90 minutes.
4. The said process of claim 1 for obtaining a polymorphic mixture of A + B of Ibandronate consists of the steps: a. dissolving any form of [l-Hydroxy-3-(methylpentylamino) propylidene]bis-l,l-phosphonic acid monosodium monohydrate in water b. evaporating the solvent under reduced pressure at a temperature from 40 °C to 95°C; c. cooling reaction medium to a temperature range from 5 °C to 70 °C d. adding a C1-C4 alcohol and stirring the suspension 5 to 30 minutes; and e. isolating mixture of A+B form of Ibandronate via filtration.
5. Ibandronate polymorph B obtained according to said process of claims 1 and
2 is characterized by X-ray diffraction peaks (reflections) at about at 6.0, 10.3, 11.5, 15.5, 17.2, 18.3, 19.2, 23.8, 26.3, 26.7, 31.5 and 32.3 ± 2 degrees two theta.
6. Ibandronate Polymorph A of claims 1, 2 and 5 is characterized by the X-ray diffraction pattern substantially as shown in Figure 1.
7. Ibandronate polymorph B obtained according to said process of claims 1 and
3 is characterized by X-ray diffraction peaks (reflections) at about at 6.2, 9.8, 12.2, 14.2, 14.9, 17.0, 17.8, 18.2, 19.3, 20.2, 20.3, 21.4, 25.1, 26.7, 28.2, 30.2, 32.0, and 35,4 ± 2 degrees two theta.
8. Ibandronate Polymorph B of claims 1, 2 and 6 is characterized by the X-ray diffraction pattern substantially as shown in Figure 2.
9. Ibandronate polymorphic mixture of A and B obtained according to said process of claims 1 and 4 is characterized by X-ray diffraction peaks (reflections) at about at 6.0, 10.3, 11.5, 15.5, 17.2, 18.3, 19.2, 23.8, 26.3, 26.7, 31.5 and 32.3 ± 2 degrees two theta.
10. Ibandronate polymorphic mixture of A and B of claims 1, 2 and 9 is characterized by the X-ray diffraction pattern substantially as shown in Figure 3.
PCT/TR2012/000214 2012-01-18 2012-12-14 Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b WO2013109198A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2012/00588 2012-01-18
TR2012/00588A TR201200588A2 (en) 2012-01-18 2012-01-18 Processes for preparing sodium ibandronate monohydrate polymorphs and mixtures with polymorphs.

Publications (1)

Publication Number Publication Date
WO2013109198A1 true WO2013109198A1 (en) 2013-07-25

Family

ID=47004341

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2012/000214 WO2013109198A1 (en) 2012-01-18 2012-12-14 Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b

Country Status (2)

Country Link
TR (1) TR201200588A2 (en)
WO (1) WO2013109198A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109608492A (en) * 2018-12-19 2019-04-12 深圳市第二人民医院 A kind of bisphosphonate compound and preparation method thereof for osteoporosis

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927814A (en) 1986-07-11 1990-05-22 Boehringer Mannheim Gmbh Diphosphonate derivatives, pharmaceutical compositions and methods of use
WO2006081963A1 (en) 2005-02-01 2006-08-10 F.Hoffmann-La Roche Ag Ibandronate polymorph a
WO2006081962A1 (en) * 2005-02-01 2006-08-10 F.Hoffmann-La Roche Ag Ibandronate polymorph b
WO2007074475A2 (en) * 2005-12-27 2007-07-05 Natco Pharma Limited Novel polymorphic forms of ibandronate
WO2008014510A2 (en) * 2006-07-28 2008-01-31 Dr. Reddy's Laboratories Limited Crystalline form a of ibandronic acid and process for the preparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927814A (en) 1986-07-11 1990-05-22 Boehringer Mannheim Gmbh Diphosphonate derivatives, pharmaceutical compositions and methods of use
WO2006081963A1 (en) 2005-02-01 2006-08-10 F.Hoffmann-La Roche Ag Ibandronate polymorph a
WO2006081962A1 (en) * 2005-02-01 2006-08-10 F.Hoffmann-La Roche Ag Ibandronate polymorph b
US7582789B2 (en) 2005-02-01 2009-09-01 Hoffmann-La Roche Inc. Ibandronate polymorph
WO2007074475A2 (en) * 2005-12-27 2007-07-05 Natco Pharma Limited Novel polymorphic forms of ibandronate
WO2008014510A2 (en) * 2006-07-28 2008-01-31 Dr. Reddy's Laboratories Limited Crystalline form a of ibandronic acid and process for the preparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109608492A (en) * 2018-12-19 2019-04-12 深圳市第二人民医院 A kind of bisphosphonate compound and preparation method thereof for osteoporosis
CN109608492B (en) * 2018-12-19 2021-02-09 深圳市第二人民医院 Diphosphonic acid compound for osteoporosis and preparation method thereof

Also Published As

Publication number Publication date
TR201200588A2 (en) 2012-07-23

Similar Documents

Publication Publication Date Title
EP1504012B9 (en) Preparation of biphosphonic acids and salts thereof
EP1891081B1 (en) Process for producing bisphosphonic acids and forms thereof
JP2008517964A (en) Ibandronate manufacturing method
KR20080031475A (en) Crystalline form of zoledronic acid, process to obtain the same and pharmaceutical composition comprising the same
JP2008525432A (en) [1-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid and method for producing hemi-5-hydrate monosodium salt
WO2014091386A2 (en) An improved process for preparation of minodronic acid
WO2013109198A1 (en) Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b
JP2010508376A (en) Method for producing biphosphonic acid and salt thereof
EP1981896B1 (en) An improved process for the preparation of risedronate sodium hemi-pentahydrate
US8076483B2 (en) Process for the preparation of pure risedronic acid or salts
AU2020289084B2 (en) Process for the preparation of the polymorph f of sodium neridronate
WO2008152518A2 (en) Process for the preparation of risedronic acid or risedronate sodium
EP2609101B1 (en) Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof
WO2008065542A2 (en) An improved process for the preparation of risedronate sodium
WO2008035131A1 (en) An improved process for the preparation of bisphosphonic acid
WO2009034580A1 (en) Improved process for the preparation of risedronate sodium hemipentahydrate
WO2011016738A1 (en) A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate
KR100798855B1 (en) Method for preparing sodium risedronate hemipentahydrate
EP2180003A1 (en) Preparation of ibandronate trisodium
CZ298383B6 (en) Monosodium risedronate amorphous form
CZ298328B6 (en) Semicrystalline form of risedronate monosodium, process for its preparation and medicamentous form containing thereof
CZ20041249A3 (en) Trisodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12823273

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12823273

Country of ref document: EP

Kind code of ref document: A1