WO2005063717A1 - An improved process for the preparation of zoledronic acid - Google Patents

An improved process for the preparation of zoledronic acid Download PDF

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Publication number
WO2005063717A1
WO2005063717A1 PCT/IN2004/000392 IN2004000392W WO2005063717A1 WO 2005063717 A1 WO2005063717 A1 WO 2005063717A1 IN 2004000392 W IN2004000392 W IN 2004000392W WO 2005063717 A1 WO2005063717 A1 WO 2005063717A1
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Prior art keywords
reaction mass
zoledronic acid
acid
temperature
improved process
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PCT/IN2004/000392
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French (fr)
Inventor
Muddasani Pulla Reddy
Vattikuti Usha Rani
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Priority to IN1053CH2003 priority Critical
Priority to IN1053/CHE/2003 priority patent/IN2003CH01053A/en
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Publication of WO2005063717A1 publication Critical patent/WO2005063717A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503Five-membered rings
    • C07F9/6506Five-membered rings having the nitrogen atoms in positions 1 and 3

Abstract

The invention disclosed in this application relates to an improved process for the preparation of zoledronic acid of formula (I) given below which comprises heating at a temperature in the range of 50-80 °C a solution of imidazol-1-ylacetic acid hydrochloride with ortho-phosphoric acid in a solvent medium where boiling point of the solvent used in lesser or close to that of phosphorous trichloride, adding phosphorous trichloride to the reaction mass slowly over a period of 2-3hr at a temperature in the range of 50-80 °C, keeping the resulting reaction mass at a temperature in the range of 50-80 °C for a period of 1-6hr, adding hydrochloric acid to the reaction mass and keeping the reaction mass at a temperature in the range of 60-120 °C, separating the organic solvent from the reaction mass while it is still hot, and diluting the aqueous layer containing zoledronic acid with water miscible solvent. Zoledronic acid is widely used as a bone resorption inhibitor.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF ZOLEDRONIC ACID FIELD OF INVENTION

The present invention relates to an improved process for the preparation of zoledronic acid. Zoledronic acid, which is l-hydroxy-:2-imidazol-l-yl-phosphonoefhyl- bisphosphonic acid, has the formula-I given below.

Figure imgf000002_0001

Zoledronic acid is shown to have direct effects on osteoclast maturation. It is widely used as a bone resorption inhibitor.

BACKGROUND OF INVENTION

Zoledronic acid of the formula-I was reported in US pat. No. 4,939,130 by Ciba-Geigy (Switzerland). According to the process disclosed in this patent imidazol-1-ylacetic acid hydrochloride is reacted with phosphorous trichloride and phosphoric acid in the presence of chlorobenzene at 100°C. Boiling of the reaction mass with cone, hydrochloric acid and dilution with acetone gave zoledronic acid in 41% yield. The reaction was done on a 6.0g output scale.

The above process has some disadvantages like no control on exothermic nature of reaction, no control on loss of phosphorus trichloride due to vigorous evolution of hydrogen chloride gas and poor yield. Loss of phosphorous trichloride will lead to shortage of required moles of this reagent in the reaction. Shortage of phosphorous trichloride will lead to formation of gummy impurities and poor yield. Also, the boiling point (131-132 °C) of chlorobenzene used in the process is higher than the boiling point (76 °C) of phosphorous trichloride. Controlling the reaction temperature (100 °C) is not possible using chlorobenzene as a solvent. Another disadvantage in the prior art is the reaction mass becomes very thick within no time and mixing of reagents is practically impossible using standard stirrers.

Zolidronic acid, has become a well-known bone resorption inhibition drug that has now been on the market and has shown great promise as a valuable bone resorption inhibitor with few side effects. Keeping in view of the difficulties in commercialization of above- mentioned process for the preparation of zoledronic acid we aimed to develop a simple and economical process for commercial production of zoledronic acid.

We observed that a promising approach for such a process is to (a) control the rate of reaction by controlling the addition of one or more reagents (b) do the reaction at lowest possible temperature so that the loss of reagents such as phosphorous trichloride can be avoided and (c) improve the mixing capacity of reagents to the maximum possible time of reaction so that the yield can be consistent at any scale of reaction.

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of zoledronic acid.

Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid at much higher yield (ca. 80%) than the yield (41%) obtained in the prior art process.

Yet another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is free from the problems experienced hitherto in the scaling up of the process for commercial purposes.

Still another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the yield of zoledronic acid produced is consistent.

Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid which is commercially applicable. Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the exothermic nature of the reaction mass is avoided by controlling the addition of phosphorous trichloride, thereby making the process safe.

Another objective of the present invention is to provide an improved process for the preparation of zoledronic acid wherein the reaction is conducted at lowest possible temperature such as 50-80 °C for better control over stirring problem.

Another objective of the present invention is to provide an improved process for the preparation of zoledronic which is simple and economical.

The present invention has been developed based on our finding that by controlling the rate of addition of phosphorus trichloride to the reaction mass exothermic nature of the reaction can be controlled. Further, the reaction takes place at temperatures as low as 50 °C. Therefore, heating of reaction mass to 100 °C as mentioned in the prior art is not essential to get optimum yield of zoledronic acid. Also, stirring of reaction mass by using standard stirrers became easy without any difficulty.

Accordingly, the present invention provides an improved process for the preparation of zoledronic acid of the formula I

Figure imgf000004_0001

which comprises: (i) heating at a temperature in the range of 50-80 °C a solution of imidazol-1- ylacetic acid hydrochloride with ortho-phosphoric acid in a solvent medium where boiling point of the solvent used is lesser or close to that of phosphorous trichloride (ii) adding phosphorous trichloride to the reaction mass slowly over a period of 2- 3hr at a temperature in the range of 50-80 °C (iii) keeping the resulting reaction mass at a temperature in the range of 50-80 °C for a period of l-6hr (iv) adding hydrochloric acid to the reaction mass and keeping the reaction mass at a temperature in the range of 60-120 °C (v) separating the organic solvent from the reaction mass while it is still hot (vi) diluting the aqueous layer containing zoledronic acid with water miscible solvents (vii) filtering the crude zoledronic acid and (viii) recrystallising zoledronic acid from water or aqueous alcohols

In a preferred embodiment of the present invention temperature of the reaction mass during phosphorous trichloride addition in the step (i) may be preferably 60-70 °C. Initial maintenance of reaction mass for first two hours should be in the range of 50-60 °C. Solvent used for the reaction should be hydrocarbon solvents such as heptane, cyclohexane, benzene, fluorobenzene, halogenated solvent such as chloroform, ethylene dichloride, carbon tetrachloride, preferably cyclohexane or ethylene dichloride. Solvents like toluene, xylene or chlorobenzene can also be used if one controls the rate of phosphorous trichloride addition and maintains the reaction temperature between 50- 80°C. After implementing these process parameters yield of zoledronic acid was found to be more than 75%.

Preferred reaction time in step (iii) is between 4-6hr. Temperature of reaction mass during the hydrolysis in step (iv) is preferably the boiling point of reaction mass containing water and the organic solvent used, preferably 80-100 °C. This simplification has led to the synthesis of zoledronic acid in a very simple and easy to adopt manner suitable for any commercial scale. Also, without any repeated recrystallization techniques, zoledronic acid could be prepared in very high purity (>99.8%).

The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example. Example 1

Preparation of zoledronic acid (i) Preparation of Imidazol-1-ylacetic acid

Into a 1-L, three-necked RB flask is charged lOOg of imidazole, 40ml of DMF, 400ml of toluene, 180g of potassium carbonate and lOg of potassium iodide. After stirring for lOmin, 240g of methyl chloroacetate was added slowly over a period of 1.5-2.0hr at 25- 30°C. The reaction mass was kept under stirring at 25-30 °C for lhr and slowly heated to 60-65°C. After maintaining at the same temperature for 2-3h reaction was found to be over by TLC. The reaction mass was cooled to 25-30°C and added 200ml of ethyl acetate. The reaction mass was stirred for 20-3 Omin and decanted the top organic layer. The residue was once again extracted with ethyl acetate (200ml). Finally water (200ml) was added to the reaction mass and stirred for 3 Omin. Inorganic salts were removed by filtration and the filtrate extracted with ethyl acetate (2 x 200ml). All ethyl acetate extractions were combined and distilled off under vaccum to get 220g of crude mass.

The crude mass was suspended in 500ml of water and refluxed for 4-5h. Reaction mass became a clear liquid. The reaction mass was treated with charcoal and distilled off water under vaccum keeping the temperature below 80°C. The residue was cooled to 25-30°C and added 250ml of methanol. The suspension was stirred for lh and filtered the mass. The wet cake was washed with 50ml of methanol and dried at 50-60°C to get 150g of white crystalline solid of imidazol-1-ylacetic acid. Melting point is 268-269 °C. Purity by HPLC is 99.2%. (ii) Preparation of imidazol-lylacetic acid hydrochloride

Into a 500-ml, three-necked RB flask is added 200ml of isopropanol and 60g of imidizol- 1-ylacetic acid prepared by the process described in step (i). The contents were heated to 70°C and maintained for 20min. A solution of IPA-HC1 (150g, 14% solution) was added to the reaction mass at 60-70°C over a period of 60-90min. After maintaining a 60-70°C for 30min, reaction mass was cooled to 25-30°C and kept for 2h before filtration. The wet cake was washed with 50ml of IPA and dried at 60-70°C to get 70g of white crystalline imidazol-lylacetic acid hydrochloride.

(iii) Preparation of zoledronic acid

Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (ii), 105g of o-phosphoric acid and 250ml of ethylene dichloride. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5h keeping the temperature below 80°C. After maintaining at 70-80°C for 4h the reaction was quenched by adding 30ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6h. The reaction mass was cooled to 25-30°C, separated ethylene- dichloride layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3 ti reaction mass was filtered and the wet cake washed with 100ml of acetone. The Zoledronic acid so produced was dried at 50-60°C to get 85g of white crystalline solid. Purity by HPLC is 98.5%.

A small sample was dissolved in 20 times refluxing water and cooled to 25-30°C. Pure zoledronic acid was isolated by filtration. Purity by HPLC is 99.4%.

Example 2 Preparation of zoledronic acid

Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1, 105g of o- phosphoric acid and 250ml of cyclohexane. The reaction mass was heated to 50-55°C and added 152g of phosphorous trichloride over a period of 2.0-2.5h keeping the temperature below 80°C. After maintaining at 80°C for 6h, the reaction was quenched by adding 100 ml of water and 165g of concentrated HC1. The reaction mass Was heated to reflux temperature and maintained for 5-6h. The reaction mass was cooled to 25-30°C, separated cyclohexane layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10°C. After maintaining for 2-3h reaction mass was filtered and the wet cake washed with 100ml of acetone. Crude zoledronic acid was dried at 50-60°C to get 80g as white crystalline solid. Purity by HPLC is 98.0%.

The above crude zoledronic acid was taken into a 2L glass flask and added 1600ml of DM water. The reaction mass was heated to 90-95°C and maintained for 2-3h to dissolve the solid. Carbon (lOg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30°C and maintained for 3-4h before filtration. Wet cake was washed with water and dried at 50-60°C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 70g. Purity by HPLC is 99.3%.

Example 3 Preparation of zoledronic acid

Into a 200L glass flask containing 10.5kg of o-phosphoric acid and 25L of chlorobenzene was added 6.0 kg of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1. The reaction mass was heated to 50-55 °C and added 15.2 kg of phosphorous trichloride over a period of 2.0-2.5hr keeping the temperature below 80 °C. After maintaining at 60-80 °C for 5hr the reaction was quenched by adding 3.0 L of water and 16.5 kg of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30 °C, separated chlorobenzene layer, and treated the aqueous layer with carbon. Acetone (70.0 L) was added to the reaction mass and cooled to 5-10 °C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 10.0 L of acetone. Crude zoledronic acid was dried at 50-60 °C to get 8.0 kg as white crystalline solid. Purity by HPLC is 99.0%. The above crude zoledronic acid was taken into a 250-L, glass lined reactor and added 160 L of DM water. The reaction mass was heated to 90-95 °C and maintained for 2-3hr to dissolve the solid. Carbon (1.0 kg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30 °C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50-60 °C till the moisture content reached 6- 10%. Yield of pure zoledronic acid, as monohydrate was 7.0 Kg. Purity by HPLC is 99.8%.

Advantages of present invention:

1. Zoledronic acid is produced at much higher yield (ca. 80%) than the yield (41%) as per the prior art process.

2. • The process is free from the problems experienced hitherto in the scaling up of the process for commercial purposes. Hence the process is useful for commercial application.

3. The yield of zoledronic acid produced is consistent and in a purity of more than 99.8%.

4. There is no exothermic reaction in the process and therefore the process is simple and safe.

Claims

We Claim:
1. An improved process for the preparation of zoledronic acid of formula-I,
Figure imgf000010_0001
which comprises, (i) heating at a temperature in the range of 50-80 °C a solution of imidazol-lylacetic acid hydrochloride with ortho-phosphoric acid in a solvent medium where boiling point of the solvent used is lesser or close to that of phosphorous trichloride, (ii) adding phosphorous trichloride to the reaction mass slowly over a period of 2- 3hr at a temperature in the range of 50-80 °C. (iii) keeping the resulting reaction mass at a temperature in the range of 50-80 °C for a period of l-6hr. (iv) adding hydrochloric acid to the reaction mass and keeping the reaction mass at a temperature in the range of 60-120 °C. (v) separating the organic solvent from the reaction mass. (vi) diluting the aqueous layer containing zoledronic acid with water miscible solvents . (vii) filtering the crude zoledronic acid and (viii) recrystallising zoledronic acid from water or aqueous alcohols.
2. An improved process as claimed in claim 1 wherein the solvent employed in the reaction in step (i) is selected from hydrocarbon solvents such as cyclohexane, hexane, heptane, benzene, fluorobenzene, halogenated solvents such as chloroform, ethylene dichloride, carbon tatrachloride, preferably, cyclohexane, ethylene dichloride, or heptane.
3. An improved process as claimed in claims 1 and 2 wherein the hydrochloric acid used in step (v) is 2-4 times the weight of imidazol-1-ylacetic acid hydrochloride used in the process.
4. An improved process as claimed in claims 1-3 wherein the amount of miscible solvent used in step (vii) is 10-20 times, preferably 10-15 times the weight of imidazol-1-ylacetic acid hydrochloride used in the process.
5. An improved process as claimed in claims 1-4 wherein the miscible solvent used in step (vii) is selected from acetone, methanol, isopropanol, acetonitrile, THF, preferably methanol or acetone.
6. An improved process as claimed in claims 1-5 wherein the amount of water used in recrystallization of crude zoledronic acid is 20-30 times the weight of imidazol-1-ylacetic acid hydrochloride used in the process.
7. An improved process for the preparation of zoledronic acid of the formula-I substantially as herein described with reference to Examples.
PCT/IN2004/000392 2003-12-26 2004-12-20 An improved process for the preparation of zoledronic acid WO2005063717A1 (en)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007069049A2 (en) * 2005-12-16 2007-06-21 Wockhardt Ltd Processes for the preparation of pure zoledronic acid
WO2007125521A2 (en) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Polymorphic form of zoledronic acid and processes for their preparation
EP1931326A1 (en) * 2005-09-12 2008-06-18 Dr. Reddy's Laboratories Ltd. Crystalline trihydrate of zoledronic acid
EP2192126A1 (en) 2008-11-26 2010-06-02 Synthon B.V. Process for making zoledronic acid
WO2010060619A1 (en) * 2008-11-26 2010-06-03 Synthon B.V. Process for making zoledronic acid
US20100197931A1 (en) * 2005-07-28 2010-08-05 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
WO2011023280A1 (en) * 2009-08-28 2011-03-03 Synthon B.V. Process for making 1-hydroxyalkylidene-1,1-biphosphonic acids
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
CN102372741A (en) * 2011-11-15 2012-03-14 海南锦瑞制药股份有限公司 Zoledronic acid crystal and lyophilized powder injection thereof
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8524912B2 (en) 2008-10-31 2013-09-03 Zaklady Farmaceutyczne Polpharma Sa Process for the preparation of [1-hydroxy-2-(1H-imidazol-1-yl)- ethylidene]bisphosphonic acid
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
US20100197931A1 (en) * 2005-07-28 2010-08-05 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
US8952172B2 (en) * 2005-07-28 2015-02-10 Gador S.A. Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it
JP2009507831A (en) * 2005-09-12 2009-02-26 ドクター レディズ ラボラトリーズ リミテッド Crystalline trihydrate of zoledronic acid
EP1931326A4 (en) * 2005-09-12 2009-12-16 Reddys Lab Ltd Dr Crystalline trihydrate of zoledronic acid
EP1931326A1 (en) * 2005-09-12 2008-06-18 Dr. Reddy's Laboratories Ltd. Crystalline trihydrate of zoledronic acid
WO2007069049A3 (en) * 2005-12-16 2009-04-16 Wockhardt Ltd Processes for the preparation of pure zoledronic acid
WO2007069049A2 (en) * 2005-12-16 2007-06-21 Wockhardt Ltd Processes for the preparation of pure zoledronic acid
WO2007125521A3 (en) * 2006-05-02 2008-01-10 Ranbaxy Lab Ltd Polymorphic form of zoledronic acid and processes for their preparation
WO2007125521A2 (en) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Polymorphic form of zoledronic acid and processes for their preparation
US8524912B2 (en) 2008-10-31 2013-09-03 Zaklady Farmaceutyczne Polpharma Sa Process for the preparation of [1-hydroxy-2-(1H-imidazol-1-yl)- ethylidene]bisphosphonic acid
EP2192126A1 (en) 2008-11-26 2010-06-02 Synthon B.V. Process for making zoledronic acid
WO2010060619A1 (en) * 2008-11-26 2010-06-03 Synthon B.V. Process for making zoledronic acid
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9334296B2 (en) 2009-07-31 2016-05-10 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8933057B2 (en) 2009-07-31 2015-01-13 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US10323052B2 (en) 2009-07-31 2019-06-18 Grunenthal Gmbh Crystallization method and bioavailability
WO2011023280A1 (en) * 2009-08-28 2011-03-03 Synthon B.V. Process for making 1-hydroxyalkylidene-1,1-biphosphonic acids
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
CN102372741B (en) 2011-11-15 2013-10-16 海南锦瑞制药股份有限公司 Zoledronic acid crystal and lyophilized powder injection thereof
CN102372741A (en) * 2011-11-15 2012-03-14 海南锦瑞制药股份有限公司 Zoledronic acid crystal and lyophilized powder injection thereof
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability

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