EP1888606A2 - Nouveau sel et procede associe - Google Patents

Nouveau sel et procede associe

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Publication number
EP1888606A2
EP1888606A2 EP06727135A EP06727135A EP1888606A2 EP 1888606 A2 EP1888606 A2 EP 1888606A2 EP 06727135 A EP06727135 A EP 06727135A EP 06727135 A EP06727135 A EP 06727135A EP 1888606 A2 EP1888606 A2 EP 1888606A2
Authority
EP
European Patent Office
Prior art keywords
acid
risedronate
ammonium
process according
phosphorous
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.)
Withdrawn
Application number
EP06727135A
Other languages
German (de)
English (en)
Inventor
Kreso Mihaljevic
Blazenko Bajic
Drazen Cavuzic
Ruzica Oreskovic
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.)
Pliva Hrvatska doo
Original Assignee
Pliva Hrvatska doo
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 GB0511000A external-priority patent/GB0511000D0/en
Priority claimed from GB0515775A external-priority patent/GB0515775D0/en
Application filed by Pliva Hrvatska doo filed Critical Pliva Hrvatska doo
Publication of EP1888606A2 publication Critical patent/EP1888606A2/fr
Withdrawn legal-status Critical Current

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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 System
    • 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 process of preparing risedronic acid, or a pharmaceutically acceptable salt thereof, novel ammonium risedronate salts and pharmaceutical compositions thereof, and the use of such novel salts and compositions in human therapy.
  • Risedronic acid is the international non-proprietary name of [l-hydroxy-2-(3- pyridinyl)ethylidene]bisphosphonic acid.
  • Risedronic acid has the following structural formula
  • a particularly preferred salt of risedronic acid is sodium risedronate.
  • Bisphosphonic acids such as risedronic acid, and pharmaceutically acceptable salts thereof, in particular sodium risedronate as referred to above, have been employed in the treatment of diseases of bone and calcium metabolism.
  • diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
  • Bisphosphonic acids tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.
  • all bisphosphonates do not exhibit the same degree of biological activity.
  • Some bisphosphonates have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or negative side effects in humans.
  • the salt and hydrate forms of bisphosphonates alter both their solubility and their bioavailability.
  • EP 1243592B describes a process of preparing risedronic acid by reacting 3- pyridylacetic acid with phosphorous acid and phosphorous trichloride in a solvent.
  • the solvent is chlorobenzene
  • the reaction is carried out at a temperature in the range of 85-100°C.
  • the solvent is fluorobenzene
  • the reaction is carried out at the reflux temperature of the reaction medium. Isolation of the risedronic acid involves separation thereof from the reaction mixture by treatment with alkali metal or ammonium hydroxide, bicarbonate or carbonate and subsequent treatment of the resulting alkali metal or ammonium risedronic acid salt with a strong mineral acid.
  • EP 04949844B also discloses a process of preparing bisphosphonic acids, but not risedronic acid.
  • Bisphosphonic acids, in particular alendronic acid, of the following general formula are prepared according to the process of EP 0494844B
  • n 2 to 8.
  • the process comprises melting a mixture of the corresponding aminocarboxylic acid and phosphorous acid obtained by heating at 90°C in the absence of an organic solvent, adding dropwise phosphorous trihalide under stirring and N 2 atmosphere, adding to the reaction mixture a hydrolyzing agent selected between water and a strong non-oxidizing acid and recovering the diphosphonic acid thus produced.
  • the process is described as being characterised in that the molar ratio between the aminocarboxylic acid, phosphorous acid and phosphorous trihalide in the reaction mixture is 1 :3:2 and 1 :20:6.
  • WO 01/57052 involves use of molten phosphorous acid, an amino carboxylic acid, phosphorous trihalide and a base in the bisphosphorylation step.
  • the base is employed to facilitate bisphosphorylation and can include organic and inorganic bases.
  • the more preferred bases are triethylamine, trimethylamine, potassium carbonate, pyridine and morpholine.
  • WO 05/063779 describes use of phosphorous oxychloride (POCl 3 ), instead of phosphorous trihalide. More specifically, WO 05/063779 describes reaction of a carboxylic acid with a mixture of phosphorous acid and phosphorous oxychloride, in the absence of solvents. Water, which is formed during bisphosphorylation, reacts with POCl 3 and consequently phosphoric acid (H 3 PO 4 ) is generated. The thus formed phosphoric acid can influence reaction conditions and can also form as an impurity in final product.
  • the scheme of the reaction is as follows
  • EP 1252170B describes a process for selectively producing sodium risedronate hemipentahydrate or monohydrate comprising the steps of (a) providing an aqueous solution of sodium risedronate, (b) heating the aqueous solution to a temperature from about 45 0 C to about 75 °C, (c) adding a solvent to the aqueous solution, characterised in that the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, amides and nitriles, and (d) optionally cooling the aqueous solution.
  • WO 03/086355 describes polymorph forms B, Bl, BB, C, D, E, F, G and H of sodium risedronate and processes of preparing these various polymorphs.
  • phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water.
  • This formation of phosphorous acid in situ preferably occurs as a first step in the process to allow subsequent reaction thereof with pyridylacetic acid, optionally present as a hydrohalide salt.
  • the presence of excess phosphorous trihalide in the reaction mixture also allows phosphorous acid to be formed during the reaction process and thus enables continued reaction of the phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt, to occur.
  • a process according to the present invention provides a reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide, whereby the phosphorous trihalide present in the reaction mixture allows continued in situ formation of phosphorous acid during the reaction process.
  • the present invention provides a process of preparing risedronic acid of formula (I)
  • reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide; reacting (i) and (ii) to yield risedronic acid and recovering the thus formed risedronic acid;
  • phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water.
  • phosphorous acid is formed in situ in the reaction mixture by initial reaction of the phosphorous trihalide and water. It is also preferred that the pyridylacetic acid is employed in the form of a hydrohalide salt.
  • a process according to the present invention can be represented by the following reaction scheme
  • X denotes halo, which can be bromo, chloro, fluoro or iodo, preferably chloro.
  • pyridylacetic acid is employed in the form of the hydrochloride salt.
  • the phosphorous trihalide employed is phosphorous trichloride.
  • the synthesis starts from preparation of phosphorous acid in situ, where phosphorous trihalide, preferably phosphorous trichloride, is added dropwise to water in step (1).
  • phosphorous trihalide preferably phosphorous trichloride
  • phosphorous acid is formed until all the water present is consumed (reacted).
  • a by product of this reaction is HX, which is degassed.
  • Phosphorous trihalide (excess), preferably phosphorous trichloride (excess) is then added continuously and a reaction mixture consisting of phosphorous acid and phosphorous trichloride is prepared according to step (2).
  • Pyridylacetic acid in the form of a hydrohalide salt preferably 3 -pyridylacetic acid hydrochloride
  • the reaction of phosphorous acid and pyridylacetic acid in the form of a hydrohalide salt, preferably 3 -pyridylacetic acid hydrochloride, in step (3) forms risedronic acid and water.
  • Water thus liberated from the reaction spontaneously reacts with the excess of phosphorous trihalide, preferably phosphorous trichloride, present in the reaction mixture so as to form phosphorous acid and HX.
  • This phosphorous acid then reacts further with pyridylacetic acid in the form of a hydrohalide salt, preferably 3- pyridylacetic acid hydrochloride, as described in step (3).
  • pyridylacetic acid optionally in the form of a hydrohalide salt substantially as hereinbefore described, is added to a reaction mixture comprising phosphorous acid at a temperature in the range of about 1O 0 C to 3O 0 C, preferably at a temperature in the range of about 2O 0 C to 25 0 C.
  • the resulting mixture is subsequently heated to a temperature in the range of about 6O 0 C to 100 0 C, preferably at a temperature on the range of about 6O 0 C to 9O 0 C.
  • the temperature does not exceed about 9O 0 C during the above reaction process, and in some embodiments it is preferred that the reaction temperature does not exceed about 7O 0 C.
  • a process of the present invention which is carried out in the absence of organic solvent and at a low temperature, provides advantages over the prior art processes for the preparation of bisphosphonic acids, which either require the presence of an organic solvent or an elevated process temperature.
  • a process according to the present invention further comprises a hydrolysis stage, which is advantageous in obviating the formation of undesirable polymers in the reaction mixture.
  • the process further comprises addition of a hydrolysing agent, such as water and / or a strong mineral acid, such as hydrochloric acid, followed by reflux for about 3 to 4 hours.
  • reaction mixture is preferably cooled to a temperature in the range of about 7O 0 C to 8O 0 C, followed by the addition of active carbon.
  • the resulting suspension is stirred, filtered and the carbon cake washed with water. The filtrate is then collected, evaporated under vacuum and water is added. Crystallization of risedronic acid occurs on cooling.
  • Risedronic free acid as prepared by the above described process can be further converted to a pharmaceutically acceptable salt, such as the sodium or ammonium salt.
  • a pharmaceutically acceptable salt such as the sodium or ammonium salt.
  • a process of preparing a pharmaceutically acceptable salt of risedronic acid comprises providing a reaction mixture comprising (i) pyridylacetic acid, optionally in the form of a hydrohalide salt, (ii) phosphorous acid and (iii) phosphorous trihalide; reacting (i) and (ii) to yield risedronic acid, converting the thus formed risedronic free acid to a pharmaceutically acceptable salt form, and recovering the pharmaceutically acceptable salt of risedronic acid, characterised in that said phosphorous acid is formed in situ in said reaction mixture.
  • the above process is further characterised in that the reaction of said pyridylacetic acid with phosphorous acid and phosphorous trihalide is carried out in the absence of an organic solvent.
  • Particularly preferred pharmaceutically acceptable salt forms prepared in accordance with the present invention are sodium risedronate and ammonium risedronate.
  • a suspension of risedronic free acid and water is heated to a temperature in the range of about 35 0 C to 95 0 C, preferably in the range of about 4O 0 C to 9O 0 C, followed by the addition of a base of the salt forming species, preferably a hydroxide of the salt forming species, for example sodium hydroxide or ammonium hydroxide to form a solution.
  • a base of the salt forming species preferably a hydroxide of the salt forming species, for example sodium hydroxide or ammonium hydroxide to form a solution.
  • the resulting solution is when required typically heated to reflux, typically at about 100 0 C, and again when required a C ⁇ alcohol, such as methanol or ethanol, is added. Subsequent cooling results in crystallization of the risedronate salt.
  • the solution in the case of the preparation of ammonium risedronate, following addition of the hydroxide the solution can be cooled prior to addition of the C 1-4 alcohol resulting in the formation of slurried crystals, which can be heated and subsequently cooled to yield crystals of the ammonium salt which are filtered, washed and dried.
  • sodium risedronate this may preferably be provided as the hemipentahydrate form in accordance with carrying out a process according to the present invention.
  • the hemipentahydrate is the thermodynamically preferred crystalline form of sodium risedronate under typical processing conditions, based on observations in the art that monohydrate crystals converted to the hemipentahydrate form.
  • Sodium risedronate hemipentahydrate is by weight of water from about 11.9% to about 13.9%, more preferably from about 12.5% to about 13.2% and most preferably about 12.9%.
  • Ammonium risedronate as provided by the present invention represents a novel salt of risedronic acid. According to the present invention, therefore, there is further provided ammonium risedronate.
  • ammonium risedronate preferably refers to the mono-ammonium salt of risedronic acid.
  • the di- and tri-ammonium salts are also included within this invention. It is also preferred that the ammonium salt is provided in anhydrous form, although hydrated or other solvated forms (such as the monohydrate, sesquihydrate or dihydrate) of the ammonium salt are also included in this invention.
  • Ammonium risedronate as provided by the present invention may exist in more than one polymorphic form, including the amorphous form.
  • Another important solid state property of a pharmaceutical compound that can depend on crystal structure is its rate of dissolution in aqueous media.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences because it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound can also affect its behavior on compaction and its storage stability. We have now found that the risedronate ammonium salt provided in accordance with the present invention has advantageous dissolution properties.
  • Thermodynamic properties can be used to distinguish between different salt forms and can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and differential thermal analysis (DTA).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • DTA differential thermal analysis
  • the melting point measurement varies from method to method.
  • Ammonium risedronate as provided by the present invention is characterised as having a melting point in the range of about 221 0 C to about 24O 0 C. It is recognised that the capillary method provides the most precise measurement.
  • the melting point of ammonium risedronate as provided by the present invention is in the range of about 233.5°C to about 235.0°C, and more preferably is in the range of about 234.O 0 C to about 234.5°C, when measured in a capillary method according to the standardised method within European Pharmacopoeia 2.2.14.
  • ammonium risedronate is characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
  • Ammonium risedronate according to the present invention is further characterised as having characteristic peaks (20): 11.94+0.02, 12.93+0.02, 17.03 ⁇ 0.02, 22.05 ⁇ 0.02 and 27.73 ⁇ 0.02.
  • Ammonium risedronate according to the present invention is still further characterised by the following other typical peaks (20): 14.37+0.02, 15.19+0.02, 21.47 ⁇ 0.02, 24.05 ⁇ 0.02 and 29.93+0.02°.
  • Ammonium risedronate according to the present invention is further characterised as having an FTIR transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2. More particularly, ammonium risedronate has characteristic IR absorbance at about 3084 ⁇ 4, 1552 ⁇ 4, 1469+4, 1185+4, 1155+4, 911+4, 892 ⁇ 4, 760 ⁇ 4, 605 ⁇ 4 and 540 ⁇ 4 cm “1 .
  • Ammonium risedronate according to the present invention is further characterised as having an FTNIR reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 3.
  • Ammonium risedronate can be still further characterised by a typical DSC thermograph as shown in Figure 4.
  • Ammonium risedronate has a DSC endotherm in the range of about 241 0 C to about 253°C.
  • Risedronic acid as prepared by the present invention has therapeutic utility in the treatment of diseases associated with bone resorption disorders and more specifically in the treatment of diseases of bone and calcium metabolism.
  • diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
  • the present invention further provides, therefore, a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
  • Excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • the term "therapeutically effective amount” means an amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, which is capable of preventing, ameliorating or eliminating a bone resorption disorder.
  • pharmaceutically acceptable it is meant that the carrier, diluent or excipient is compatible with risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, and is not deleterious to a recipient thereof.
  • risedronic acid or a pharmaceutically acceptable salt thereof is administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration.
  • risedronic acid or a pharmaceutically acceptable salt thereof can be used in creams, ointments or lotions.
  • the dose of risedronic acid or a pharmaceutically acceptable salt thereof can vary between about 0.01 and about 50 mg per kg of body weight per day.
  • Each unit dose can contain from about 0.1 to about 1000 mg, preferably about 1 to about 500 mg, of risedronic acid or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutical carrier.
  • This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of about 0.5 to about 5000 mg, preferably about 1 to about 2500 mg.
  • risedronic acid or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
  • the use of tablets is generally preferred for administration of risedronic acid or a pharmaceutically acceptable salt thereof, as provided by the present invention.
  • a preparation in the form of gelatin capsules can be obtained by mixing risedronic acid or a pharmaceutically acceptable salt thereof, with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain risedronic acid or a pharmaceutically acceptable salt thereof, typically in conjunction with a sweetener, which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
  • a sweetener which is preferably calorie-free, optionally antiseptics such as methylparaben and propylparaben, as well as a flavoring and an appropriate color.
  • Water-dispersible granules or powders can contain risedronic acid or a pharmaceutically acceptable salt thereof, mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example polyethylene glycols.
  • Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • Risedronic acid or a pharmaceutically acceptable salt thereof can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
  • risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in therapy.
  • the present invention further provides risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of bone resorption.
  • the present invention provides risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate, for use in the manufacture of a medicament for the treatment of diseases of bone and calcium metabolism, and even more specifically for the treatment of any one of the following: osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
  • the present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of bone resorption in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate.
  • the present invention provides a method of treating diseases of bone and calcium metabolism, such as osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions, in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, in particular ammonium risedronate.
  • diseases of bone and calcium metabolism such as osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions
  • which method comprises administering to the patient a therapeutically effective amount of
  • Figure 1 is an XRPD pattern of ammonium risedronate according to the present invention.
  • the XRPD pattern of ammonium risedronate was obtained by using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
  • Figure 2 is an FTIR transmission spectrum of ammonium risedronate according to the present invention recorded by KBr disc and resolution 4 cm '1 .
  • the FTIR pattern of ammonium risedronate was obtained by using Perkin Elmer Spectrum GX FT-IR Spectrometer (Detector: DTGS, Beam splitter: extended KBr, Spectral Range: 4000- 400cm '1 , Resolution: 4cm "1 , 4 scans, Samples prepared as KBr pellets).
  • Figure 3 is an FTNIR reflection spectrum of ammonium risedronate according to the present invention, recorded with solid probe accessories and resolution 8 cm “1 .
  • the FTNIR spectrum of ammonium risedronate was obtained by using Bruker NIR Multi Purpose Analyser (MPA).
  • MPA Bruker NIR Multi Purpose Analyser
  • the spectra were recorded in a diffuse reflectance mode using integrating sphere for collecting reflecting beams. The measurements were carried out over the range 4000 cm “1 - 12000 cm “1 , with a resolution of 8 cm “1 .
  • the spectra were averaged over 32 scans.
  • the system was governed via the software OPUS that includes routines for acquisition and processing of spectra).
  • Figure 4 is a DSC thermogram of ammonium risedronate according to the present invention, recorded at a heat rate of 10°C/min (endotherm temperature onset is at 241 0 C and egzotherm onset is at 253 0 C ).
  • the DSC pattern of ammonium risedronate was obtained by using a TA Instruments MDSC QlOOO, where the sample was scanned at 10°C/min in N 2 atmosphere in closed Al pan.
  • Example 1 42ml of water were charged to a 500ml four necked flask, to which was added dropwise 116ml of phosphorous trichloride over a period of 2.5 hours. During the dropwise addition of phosphorous trichloride, the reaction temperature was maintained in the range of 10-70 0 C depending on reaction kinetics. At 2O 0 C, 26.6g of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 7O 0 C over a period of one hour and maintained for half hour at this temperature. 34ml of water and 50ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (-112 0 C) and maintained at the reflux temperature for four hours.
  • Example 5 50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O 0 C and the pH was adjusted with ammonium hydroxide (25%) until a pH of about 4 was achieved. The solution was heated to the reflux ( ⁇ 100°C) and 60ml of methanol were slowly added under reflux. The solution was maintained at the reflux temperature ( ⁇ 77°C) for five minutes, and then allowed to cool. Crystallization of the salt started at about 74 0 C. The suspension was then slowly cooled to 0-5 0 C over a period of two hours and retained for one hour at this temperature. Risedronate ammonium salt, 12.9g, was obtained after filtration, washing with 20ml of a water / methanol cold solution (1 / 1) and drying.
  • Melting point was determined to be 234.0 - 234.5 0 C.
  • the melting point was determined on a capillary Buchi B-540 machine, according to EurPh. (2.2.14 Melting Point - Capillary method).

Abstract

L'invention concerne un procédé de préparation d'acide risédronique, ou d'un sel pharmaceutiquement acceptable de celui-ci, de nouveaux sels d'ammonium risédronate et de compositions pharmaceutiques de ceux-ci, ainsi que l'utilisation de tels nouveaux sels et nouvelles compositions en thérapie.
EP06727135A 2005-05-28 2006-05-18 Nouveau sel et procede associe Withdrawn EP1888606A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0511000A GB0511000D0 (en) 2005-05-28 2005-05-28 Novel salt
GB0515775A GB0515775D0 (en) 2005-07-30 2005-07-30 Process
PCT/GB2006/001830 WO2006129056A2 (fr) 2005-05-28 2006-05-18 Nouveau sel et procede associe

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EP1888606A2 true EP1888606A2 (fr) 2008-02-20

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Publication number Priority date Publication date Assignee Title
WO2007132478A2 (fr) 2006-05-11 2007-11-22 Ind-Swift Laboratories Limited Procédé de préparation de l'acide risédronique pur ou de ses sels
KR100775440B1 (ko) 2006-12-20 2007-11-12 동우신테크 주식회사 리세드로네이트 나트륨 헤미펜타히드레이트의 제조방법
EA201270328A1 (ru) * 2009-08-28 2012-09-28 Синтон Б. В. Способ получения 1-гидроксиалкилиден-1,1-дифосфоновых кислот

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HU204059B (en) * 1986-09-17 1991-11-28 Caola Kozmetikai Process for producing hydroxyphosphonic acids and their derivatives
US6562974B2 (en) * 2000-02-01 2003-05-13 The Procter & Gamble Company Process for making geminal bisphosphonates
US6638920B2 (en) * 2000-07-21 2003-10-28 Merck & Co., Inc. Compositions and methods of preventing or reducing the risk or incidence of skeletal injuries in horses
PL194770B1 (pl) * 2001-03-19 2007-07-31 Adamed Sp Z Oo Sposób wytwarzania kwasu rizedronowego
MXPA04010009A (es) * 2002-04-11 2005-07-01 Teva Pharma Polimorfos y pseudopolimorfos de sodio de risedronato novedosos.
ATE402942T1 (de) * 2003-01-17 2008-08-15 Teva Pharma Verfahren zur reduzierung des eisengehalts bei risedronat natrium
WO2005066190A1 (fr) * 2004-01-02 2005-07-21 Hexal A/S Nouveaux sels de risedronate

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