[go: up one dir, main page]

WO2007042048A2 - Methode amelioree de preparation de risedronate sodique cristallin - Google Patents

Methode amelioree de preparation de risedronate sodique cristallin Download PDF

Info

Publication number
WO2007042048A2
WO2007042048A2 PCT/DK2006/050054 DK2006050054W WO2007042048A2 WO 2007042048 A2 WO2007042048 A2 WO 2007042048A2 DK 2006050054 W DK2006050054 W DK 2006050054W WO 2007042048 A2 WO2007042048 A2 WO 2007042048A2
Authority
WO
WIPO (PCT)
Prior art keywords
sodium
risedronate
aqueous solvent
procedure according
crystalline
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DK2006/050054
Other languages
English (en)
Other versions
WO2007042048A3 (fr
Inventor
Herbert Fritz Preikschat
Erik Fischer
Frederick Beck
Jacob Bennekou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AS
Original Assignee
Sandoz AS
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
Priority claimed from EP05388086A external-priority patent/EP1775302A1/fr
Application filed by Sandoz AS filed Critical Sandoz AS
Publication of WO2007042048A2 publication Critical patent/WO2007042048A2/fr
Publication of WO2007042048A3 publication Critical patent/WO2007042048A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Definitions

  • the present invention relates to a new method for preparing crystalline monosodium risedronate having an uniform and highly reproducible water content.
  • the invention relates to new crystalline monosodium risedronate forms prepared by the new procedure.
  • the invention relates to pharmaceutical compositions comprising said new sodium risedronate forms.
  • Bisphosphonates have been proposed for use in the treatment of diseases of bone and calcium metabolism.
  • 3-pyridyl-l-hydroxyethylidene- 1, 1-bisphophonic acid known as risedronic acid
  • risedronic acid 3-pyridyl-l-hydroxyethylidene- 1, 1-bisphophonic acid, known as risedronic acid
  • risedronic acid has been proposed or used for the treatment of disorders in the bone and calcium metabolism, such as osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, osteolytic bone metastases, myositis ossifi- cans progressive, calcinosis universalis, arthritis, neuritis, bursitis, tendiosis and other inflammatory conditions .
  • risedronate salts have further been used for the treatment of Paget' s disease.
  • Bisphosphonates have also been proposed for the use in the treatment of parasitic infections.
  • risedronic acid have been proposed for the treatment of infections such as infections with Try- panosoma brucei, Trypanosoma cruzi, Leishmania dono- vani , Leishmania infantum, Leishmania chagasi , Trypanosoma gondii and Plasmodium falciparum.
  • WO 01/56983 A2 discloses a process for selec- tive crystallisation of monosodium risedronate mono- hydrate or monosodium risedronate hemipentahydrate .
  • WO 01/57052 Al discloses a process for the manufacture of geminal bisphosphonates, including risedronate, and EP 1 243 592 A2 disclose an alterna- tive method for producing risedronic acid.
  • C. Barbey and M. Lecouvey disclose the crystal structure of a monohydrate of risedronic acid in Z. Kristallogr. NCS 217 (2002) 137-138.
  • WO 2004/037252 discloses a new hydrated crys- talline form of sodium risedronate.
  • WO 2005/012314 discloses a process for controlling the crystal structure of sodium risedronate.
  • the process provides preferentially the hemipentahydrate form of mono sodium risedronate.
  • sodium risedronate has until now been found to exist in many different hydration and crystalline forms prepared by slightly different methods, where the particular temperature, solvent etc., may be decisive for the particular obtained polymorph.
  • sodium risedronate has often been provided as a mixture of two or more polymorphs . There exists therefore a need for a reliable method for providing sodium risedronate in a uniform and well defined form.
  • the present invention relates to a procedure for preparing crystalline sodium risedronate comprising following steps: a) one equivalent risedronic acid monohydrate is suspended in a first non-aqueous solvent, b) a solution of approximately one equivalent base and one equivalent sodium ions in a sec- ond non-aqueous solvent is added; c) optionally, the mixture is cooled; and d) the precipitated sodium risedronate is recovered.
  • the procedure according to the invention provides crystalline mono sodium risedronate in a highly- uniform well defined crystalline hydration form. Further, the procedure is very reliable and not in a high degree affected by minor changes in the condi- tions during the crystallization, such as changes of temperature, time, concentration etc.
  • the invention relates to new crystalline mono sodium risedronate forms produced by the inventive procedure.
  • the invention re- lates to crystalline mono sodium risedronate hemi- hydrate, preferably having the X-ray diffraction pattern shown in figure 1.
  • the invention relates to crystalline mono sodium risedronate anhy- drate having the X-ray diffraction pattern shown in figure 2.
  • the invention relates to crystalline mono sodium risedro- nate having the X-ray diffraction pattern shown in figure 3.
  • compositions comprising said new crystalline mono sodium risedronate forms prepared by the inventive procedure form further aspects of the present invention.
  • the invention is based on the realization that one method of controlling the hydration form would be controlling the amount of available water during the crystallisation.
  • One way of controlling the amount of available water during the crystallization is to secure that substantially all the water in the crystallization mixture is provided together with the rise- dronic acid, which is known and commercially avail- able as the monohydrate .
  • step a) of the procedure according to the invention one equivalent risedronic acid is suspended in a first non-aqueous solvent. This is usually done under agitation or stirring of the mixture.
  • the suspension may in principle take place under any suitable temperature between the melting point and the boiling point of the solvent; however, usually it is preferred to suspend the risedronic acid in the solvent under heating.
  • step a) it may even be possible to perform the procedure according to the invention with only partly dissolution of the risedronic acid in step a) since the dissolution rate of solid risedronic acid will be in- creased when the base is added in step b) .
  • non-aqueous solvent is intended to mean any solvent capable of completely or partially dissolving the risedronic acid monohydrate, which solvent does not contain water.
  • non-aqueous solvents can be mentioned alcohols, acetone, ethers, such as dihydrofu- ran, hexane and toluene.
  • the non-aqueous solvent is an alcohol having 1-5 C-atoms such as methanol ethanol, pro- panol, isopropanol, butanol, pentanol, ethylenglycol and propylenglycol .
  • the non-aqueous solvent may even be a mixture of two or more non-aqueous solvents .
  • a solution of approximately one equivalent base and one equivalent sodium ions in a second nonaqueous solvent is added to the suspension of risedronic acid in a first non-aqueous solvent.
  • the base may in principle be any base having a sufficient base strength to release one H-atom from the risedronic acid. It is preferred to use a base that does not produce water by the reaction with ris- edronic acid. It is further preferred to use a base that does not provide positive ions to the solution except sodium ions .
  • Examples of preferred bases include: ammonia, methylamine and sodium alcoholate such as sodium methanolate, sodium ethanolate and sodium ethylene- glycolate .
  • any compound capable of releasing the required sodium ions may in principle provide the sodium ions .
  • the base and the sodium ions provided by a sodium salt or a sodium alcoholate such as sodium methanolate, sodium ethanolate and sodium ethyleneglycolate .
  • the second non-aqueous solvent may be the same as the first non-aqueous solvent or the second nonaqueous solvent may be a different solvent selected from same definition.
  • Sodium alcoholates are for the most cases commercially available.
  • a method for providing the solution of approximately one equivalent base and one equivalent sodium ions in a second non-aqueous solvent is the dissolution of approximately one equivalent sodium in an alcohol, preferably an alcohol hav- ing 1-5 C-atoms .
  • an alcohol preferably an alcohol hav- ing 1-5 C-atoms .
  • This dissolution one equivalent of a sodium alcoholate will be formed providing both the base and the sodium ions required according to the invention. This method is preferred for sodium alcoholates that are not commercially available.
  • dissolution of sodium in an alcohol strictly spoken is not a simple dissolution process but a chemical reaction between sodium and alcohol forming sodium cations, alcoholate anions and hydrogen. However for simplicity this reaction is in this description and claims called dissolution.
  • the sodium is dissolved in an alco- hoi selected among methanol, ethanol, propanol, iso- propanol, butanol and ethyleneglycol .
  • stirring is continued in e.g. 10-60 minutes after mixing to allow mixing and reaction to take place.
  • the solution of risedronic acid in the first non-aqueous solvent still contains solid risedronic acid when the solution containing the base and the sodium ions is added, it is preferred to stir the mixture for a certain period e.g. 10-60 minutes before proceeding to step c) in order to secure that all risedronic acid has been converted into a sodium risedronate salt.
  • step c) the mixture is cooled.
  • the mixture is cooled under stirring.
  • the sodium risedronate may precipitate immediately after the addi- tion of sodium ions and base in step b) or it may first precipitate during the cooling. Thus, it may be possible to dispense with the step c) . Even if the sodium risedronate precipitates immediately after the addition in step b) it is usually preferred to cool the mixture in step c) in order to obtain a higher yield, however, it may be desired under particular selected conditions to avoid the cooling step c) and continue directly with the separation step d) di- rectly after step b) .
  • crystallization may be initiated using usual procedures for initiating crystallisation, such as scratching on the side of the container, adding seed crystals etc.
  • concentration in the mixture from step b) is sufficiently high. This will usually be the case as a result of the selection of a sufficiently high concentration of risedronic acid in step a) and a corresponding high concentration of the solution in step b) .
  • concentration of the mixture from step b) is not sufficiently high the concentration may be increased by removing part of the solvent before cooling and precipitation e.g. by evaporation of solvent.
  • step d) the precipitated crystalline sodium risedronate is recovered using procedures well known within the area.
  • step d) is performed by way of a fil- tration process.
  • the filtrate may be concentrated by evaporation of part of the solvent and further sodium risedronate crystallized from the concentrated filtrate and thereby increasing the yield.
  • the obtained crystalline sodium risedronate is usually rinsed with cold solvent and dried before using the product.
  • the amount of water available during the crystallization is strictly limited. Therefore, the reagents used in the procedure should be substantially free of water.
  • the risedronic acid monohydrate should be provided in a form where substantially all water present is the water bound in stoichiometric amounts in the crystal structure.
  • the solvents used in the procedure according to the invention should have a water content of less than 0.5%, preferably less than 0.1%, more preferred less than 0.05 %, even more preferred less than 0.01%, and in a particular preferred embodiment less than 0.005%.
  • the base and the sodium ions should be provided without adding water to the system, such as by providing the base and the sodium ions as anhydrous reagents .
  • the solvents selected as the first and the second non-aqueous sol- vents determines the particular form in which the sodium risedronate is obtained.
  • the first and the second non-aqueous solvents are both methanol.
  • the sodium risedronate is recovered as mono- sodium risedronate hemihydrate .
  • this form is called form A.
  • the monosodium risedronate hemihydrate (Form A) has been analyzed using powder X-ray diffraction analysis and it was found that it had the X-ray diffraction pattern shown in figure 1.
  • the invention relates to crystalline sodium risedronate hemihydrate, pref- erably having the x-ray diffraction pattern shown in figure 1.
  • Form A can easily be converted into monosodium risedronate hemipentahydrate by contacting with excess water.
  • Form A may be converted into sodium risedronate hemipentahydrate by stirring a dispersion thereof in water.
  • stirring the mono sodium risedronate hemihydrate (Form A) with water at a temperature between 0 and 50 0 C, preferably at ambient temperature, and for a period between 2 and 48 hours, preferably 24 hours, provides a satisfactory conversion.
  • the procedure according to the invention is the first nonaqueous solvent propylene glycol and the second non- aqueous solvent methanol.
  • the sodium risedronate is recovered as monosodium risedronate anhydrate .
  • this form is called form B.
  • the sodium risedronate has been analyzed using powder X-ray diffraction analysis and it was found that it had the X-ray diffraction pattern shown in figure 2.
  • the invention relates to crystalline monosodium risedronate anhydrate, preferably having the x-ray diffraction pattern shown in figure 2.
  • the first non- aqueous solvent n-propanol and the second non-aqueous solvent methanol are the first non- aqueous solvent n-propanol and the second non-aqueous solvent methanol.
  • this form is called form C.
  • the sodium risedronate has been analyzed using powder X-ray diffraction analysis and it was found that it had the X-ray diffraction pattern shown in figure 3.
  • the invention relates to crystalline monosodium risedronate having the x- ray diffraction pattern shown in figure 3.
  • the first and the second non-aqueous solvents are both ethanol .
  • the sodium risedronate is recovered in form C .
  • compositions comprising crystal- line sodium risedronate prepared according to the invention form another aspect of the invention.
  • the pharmaceutical composition may according to the invention comprise one or more mono sodium risedronate forms according to the invention and further excipients well known within the pharmaceutical area.
  • the pharmaceutical compositions may be prepared using well known techniques for formulating such compositions .
  • risedronic acid monohydrate (the acid is commercially available) was suspended in 300 ml anhydrous methanol under reflux with stirring.
  • risedronic acid monohydrate (the acid is commercially available) was suspended in 600 ml anhydrous methanol under reflux with stirring.
  • 4.6 g Sodium was dissolved in 400 ml anhydrous methanol and slowly added dropwise over a period of 105 minutes to the suspension of risedronic acid maintaining the heating and refluxing of the reaction mixture and subsequently the reaction mixture was stirred under reflux for additionally 45 minutes.
  • the container was placed on ice and stirring was continued for 45 minutes and subsequently the crystalline material was recovered by filtration.
  • Example 3 Powder X-ray diffraction analysis sodium risedronate hemihydrate .
  • Form A as prepared according to example 1 was analysed by powder X-ray diffraction analysis.
  • the X-ray diffraction pattern is shown in figure 1.
  • the disclosed pat- tern is different from previously known X-day diffraction patterns, confirming that the monosodium risedronate hemihydrate as prepared in example 1 differs from previous known sodium risedronate forms.
  • risedronic acid monohydrate (the acid is commercially available) was suspended in 200 ml anhydrous propylene glycol and heated to a temperature of 60°C with stirring.
  • the obtained product was analysed by microanalysis. Based on the micro analysis it was found that the product was an anhydrous form.
  • the x-ray powder diffraction pattern of the obtained product was recorded and is shown in figure 2.
  • risedronic acid monohydrate (the acid is commercially available) was suspended in 200 ml anhydrous n-propanol and heated to a temperature of 95°C with stirring.
  • the crystalline material was washed with 200 ml cold n-propanol and remaining liquid was removed from the crystalline material by suction and the crystals were dried at 45-50 0 C. 30.7 grams of crystals was obtained.
  • risedronic acid monohydrate (the acid is commercially available) was suspended in 200 ml anhydrous ethanol and refluxed a temperature of 80 0 C with stirring.
  • the crystalline material was washed with 50 ml cold ethanol and remaining liquid was removed from the crystalline material by suction and the crystals were dried at 45-50 0 C. 30 grams of crystals was obtained.
  • the x-ray powder diffraction pattern of the ob- tained product was recorded and is shown in figure 4. Based on the recorded X-ray diffraction pattern it was determined that the product was identical to form C.
  • Example 7 Conversion of sodium risedronate hemihydrate to sodium risedronate hemipentahydrate .
  • the solid material was recovered by filtration and dried at 50°C for 5 hours.

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une nouvelle méthode de préparation de risédronate sodique cristallin, mise en oeuvre dans des conditions telles que la disponibilité d'eau est strictement limitée. L'invention concerne également de nouvelles formes du risédronate sodique préparées selon la nouvelle méthode de l'invention. Ces nouvelles formes du risédronate sodique sont utiles pour la préparation de compositions pharmaceutiques destinées au traitement de maladies osseuses et du métabolisme calcique.
PCT/DK2006/050054 2005-10-11 2006-10-05 Methode amelioree de preparation de risedronate sodique cristallin Ceased WO2007042048A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US72556605P 2005-10-11 2005-10-11
EP05388086A EP1775302A1 (fr) 2005-10-11 2005-10-11 Méthode pour la préparation de risedronate de sodium cristallin
EP05388086.0 2005-10-11
US60/725,566 2005-10-11

Publications (2)

Publication Number Publication Date
WO2007042048A2 true WO2007042048A2 (fr) 2007-04-19
WO2007042048A3 WO2007042048A3 (fr) 2007-06-07

Family

ID=37575193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2006/050054 Ceased WO2007042048A2 (fr) 2005-10-11 2006-10-05 Methode amelioree de preparation de risedronate sodique cristallin

Country Status (1)

Country Link
WO (1) WO2007042048A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007291033A (ja) * 2006-04-26 2007-11-08 Permachem Asia Ltd ３―ピリジル―１―ヒドロキシエチリデン−１、１―ビスホスホン酸ナトリウム塩ａ型結晶の製造方法
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20011061A1 (es) * 2000-02-01 2001-11-20 Procter & Gamble Cristalizacion selectiva del acido 3-piridil-1-hidroxi-etiliden-1,1-bisfosfonico sodio como el hemipentahidrato o el monohidrato
WO2003086355A1 (fr) * 2002-04-11 2003-10-23 Teva Pharmaceutical Indudstries, Ltd. Nouveaux polymorphes et pseudopolymorphes de risedronate de sodium
CZ20023574A3 (en) * 2002-10-25 2004-04-14 Léčiva, A.S. New crystalline form of the sodium salt of 3-pyridyl-1-hydroxyehtylidene-1,1-bisphosphonic acid
CZ298639B6 (cs) * 2004-02-05 2007-12-05 Zentiva, A. S. Krystalická forma risedronátu monosodného

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007291033A (ja) * 2006-04-26 2007-11-08 Permachem Asia Ltd ３―ピリジル―１―ヒドロキシエチリデン−１、１―ビスホスホン酸ナトリウム塩ａ型結晶の製造方法
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts

Also Published As

Publication number Publication date
WO2007042048A3 (fr) 2007-06-07

Similar Documents

Publication Publication Date Title
US8193355B2 (en) Process for preparing sodium risedronate hemipentahydrate
CN102807530B (zh) 制备不含杂质的无定型罗苏伐他汀钙的方法
CA2585027C (fr) Methode de preparation de bisphosphonates
US7872144B2 (en) Process for producing biphosphonic acids and forms thereof
US7276604B2 (en) Crystalline form of the sodium salt of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid
EP1924587B1 (fr) Forme cristalline de l'acide zoledronique, son procede d'obtention et composition pharmaceutique la renfermant
EP1775302A1 (fr) Méthode pour la préparation de risedronate de sodium cristallin
EP1390373B9 (fr) Procede de preparation d'acide 4-amino-1-hydroxybutylidene-1, 1-biphosphonique
WO2007032808A1 (fr) Trihydrate cristallin de l'acide zolédronique
EP1651656B1 (fr) Procede pour controller la structure cristalline du risedronate
TWI804079B (zh) 經標記之咪唑并[1,2-a]嘧啶之合成
WO2007042048A2 (fr) Methode amelioree de preparation de risedronate sodique cristallin
US20080194525A1 (en) Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof
WO2014091386A2 (fr) Procédé perfectionné pour la préparation d'acide minodronique
JP2010508376A (ja) ビホスホン酸、及びその塩の製造方法
WO2007074475A2 (fr) Nouvelles formes polymorphes de l'ibandronate
EP1923394A1 (fr) Réactif et son utilisation dans la préparation de bisphosphonates
KR20090005206A (ko) 순수한 리세드론산 또는 염의 제조 방법
UA67832C2 (uk) СПОСІБ ОТРИМАННЯ [S-(R<sup>*</sup>,S<sup>*</sup>)]-<font face="Symbol">b</font>-[[[1-[1-ОКСО-3-(4-ПІПЕРИДИНІЛ)ПРОПІЛ]-3-ПІПЕРИДИНІЛ]КАРБОНІЛ]АМІНО]-3-ПІРИДИНПРОПАНОВОЇ КИСЛОТИ ТА ЇЇ ПОХІДНИХ
EP1798236A1 (fr) Procédé de préparation d' acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique et leurs formes hydratées
CA3096316A1 (fr) Polymorphe de neridronate de sodium et son procede de preparation
CA2623533A1 (fr) Sels et hydrates pharmaceutiquement acceptables de l'acide risedronique
EP1888606A2 (fr) Nouveau sel et procede associe
KR100878034B1 (ko) 결정상 리세드로네이트 모노소듐 모노하이드레이트 및 이의제조방법
WO2007026379A2 (fr) Formes cristallines de risedronate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06791491

Country of ref document: EP

Kind code of ref document: A2