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WO2005066190A1 - Nouveaux sels de risedronate - Google Patents

Nouveaux sels de risedronate Download PDF

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Publication number
WO2005066190A1
WO2005066190A1 PCT/DK2004/000923 DK2004000923W WO2005066190A1 WO 2005066190 A1 WO2005066190 A1 WO 2005066190A1 DK 2004000923 W DK2004000923 W DK 2004000923W WO 2005066190 A1 WO2005066190 A1 WO 2005066190A1
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Prior art keywords
risedronate
salt
anhydrate
ray diffraction
dihydrate
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PCT/DK2004/000923
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English (en)
Inventor
Herbert Fritz Preikschat
Erik Fischer
Michael Tranekjer
Lotte Basse Nielsen
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Hexal A/S
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Publication of WO2005066190A1 publication Critical patent/WO2005066190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present ' invention relates to new risedronate salts having improved stability compared with the previously known monosodium risedronate salt . Further the invention relates to pharmaceutical compositions comprising said new risedronate salts.
  • 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 has been proposed or used for the treatment of disorders in the bone and calcium metabolism, such as osteoporosis, hyperparathyroidism, hypercalcemia of malig- nancy, 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 hrucei , Trypanosoma cruzi , Leishmania dono- vani , Leishmania infantum, Leishmania chagasi , Trypanosoma gondii and Plasmodium falciparum .
  • the bisphosphonates were initially disclosed in EP 186 405, describing the bisphosphonate compounds ⁇ and pharmaceutical compositions comprising said " compounds.
  • DE 42 44 422 Al discloses zinc and magnesium salts of risedronic acid and related bisphosphonic acids, and their use in pharmaceutical compositions.
  • WO 01/56983 A2 discloses a process for selective crystallisation of monosodium risedronate mono- hydrate or monosodium risedronate hemipentahydrate .
  • WO 01/57052 Al discloses a process for the manufacture of geminal bisphosphonates, including 15. risedronate, • and EP .1 243 592 ,A2 disclose an alternative method for producing risedronic acid. It is known that monosodium risedronate exists in three crystalline hydration states, anhydrate, mono and hemipentahydrate. The hemipentahydrate is 20 the thermodynamically preferred crystalline form under typical processing conditions. However, Nancy Redman-Furey et al .
  • the present invention provides new salts of risedronic acid, which form crystals that are stable and do not liberate water or incorporate water from the surroundings.
  • the present invention relates to new risedronic salts and hydrates thereof that are stable in the ambient air, and do not or in a low degree incorporate or lose water during the storage, preparation of pharmaceutical compositions and storage of said pharmaceutical compositions.
  • the invention relates to risedronic acid salts selected from disodium risedronate, monopotassium risedronate, dipotassium risedronate, monoammonium risedronate,- diammonium risedronate, piperazine risedronate, ethanolamine rise- dronate and morpholinoethanolamine risedronate, and hydrates thereof .
  • the risedronate salts according to the invention form well defined crystals such as disodium risedronate anhydrate, disodium risedronate tetrahy- drate, monopotassium risedronate dihydrate, dipotassium risedronate anhydrate, monoammonium risedronate monohydrate, monoammonium risedronate dihydrate, diammonium risedronate anhydrate, hemipiperazin risedronate anhydrate, ethanolamine risedronate anhydrate and .morpholinoethanolamine risedronate anhydrate.
  • Figure 1 shows the X-ray diffraction pattern of disodium risedronate anhydrate prepared according to Example 1.
  • Figure 2 shows the X-ray diffraction pattern of disodium risedronate tetrahydrate, prepared in accor- dance with Example 2.
  • Figure 3 shows the X-ray diffraction pattern of monopotassium risedronate dihydrate prepared according to Example 3.
  • Figure 4 shows the structure of monopotassium risedronate dihydrate.
  • Figure 5 shows the X-ray diffraction pattern of dipotassium risedronate anhydrate prepared according to Example 4.
  • Figure 6 shows the X-ray diffraction pattern of monoammonium risedronate • dihydrate', • prepared ' according to Example 6.
  • Figure 7 shows the X-ray diffraction pattern of diammonium risedronate anhydrate, prepared according to Example 7.
  • Figure 8 shows the X-ray diffraction pattern of monopotassium risedronate dihydrate, before and after storage confer example 14. 2-0 range of 3-40.
  • Figure 9 shows the X-ray diffraction pattern of monopotassium risedronate dihydrate, before and after storage confer example 14. 2 - ⁇ range of 5-19.
  • Figure 10 shows the X-ray diffraction patterns of granulate comprising . monopotassium risedronate dihydrate before .and after storage confer example 14.
  • - Figure 11 shows the X-ray diffraction patterns of tablets comprising monopotassium risedronate dihydrate before and after storage confer example 14.
  • Figure 12 shows the X-ray diffraction pattern of disodium risedronate tetrahydrate, before and after storage confer example 15.
  • Figure 13 shows the X-ray diffraction patterns of granulate comprising disodium risedronate tetrahy- drate before and after storage confer example 15.
  • Figure 14 shows the X-ray diffraction patterns of tablets comprising disodium risedronate tetrahydrate before and after storage confer example 15.
  • Figure 15 shows the X-ray diffraction pattern of monoammonium risedronate dihydrate, before and after storage confer example 16.
  • Figure 16 shows the X-ray diffraction patterns of granulate comprising monoammonium risedronate di- hydrate before and after storage confer example 16.
  • Figure 17 shows the X-ray diffraction patterns of tablets comprising, .-.monoammonium ' risedronate di- . hydrate before and ' after storage confer example 16.
  • the salts according to the invention contain well defined amounts of water, and they do not tend to interact with the moisture of the air by incorporating additional water in the crystal structure.
  • This high stability in ambient air facilitates the handling of the compounds during the production and the ' use of the compounds for the manufacture- of pharmaceutical compositions, since no precautions in order to protect the compounds from ambient air is necessary.
  • the compounds according to the invention to incorporate water the compounds are very stable, and their composition remain well defined and unchanged for a very long period of time.
  • This high stability is particularly useful when the risedronate salts according to the invention are incorporated into solid pharmaceutical compositions, because these pharmaceutical compositions will also be stable for a long period in ambient air without particular precautions such as moisture protective coatings or storage in containers having particular means for absorbing water such as silica capsules.
  • the low tendency of the risedronate salts according to the invention to incorporate additional water in the crystals can be shown in several ways, as the skilled person will appreciate. One way is toanalyse -.the salts, stored ' for . various periods- of . time at controlled conditions e.g. 25 °C and 60% relative humidity or 40 °C and 75% relative humidity. By analysing water content by Karl Fischer titration the low tendency of the risedronate salts to incorporate water can be shown.
  • This method is the preferred method for demon- strating the stability of the risedronate salts according to the invention since it can be adapted to reflect realistic storage conditions for storage of medical compounds and preparations. Furthermore it has the benefit that it can be applied to the rise- dronate- salts as such, mixtures- comprising the risedronate salts as well as prepared pharmaceutical com-, positions. In particular the method may be applied to risedronate salts as such, granulates or tablets comprising one or more risedronate salts.
  • risedronate salts according to the invention do not incorporate additional water or do only incorporate water in a very low extend.
  • the risedronate salts according to the invention may in principle be prepared using conventional methods for producing basic addition salts.
  • the risedronate salts according to the invention may be produced starting from rise- dronic acid provided in aqueous solution by adding an aqueous solution of the corresponding base with the subsequent precipitation of the desired risedronate salt with ethanol and collecting the precipitate.
  • the risedronate salts may be recovered in one of -these forms depending, on the particular conditions- during preparation and/or precipitation thereof. It is within the skills of the trained practitioner to select suitable conditions for the preparation of a particular desired product.
  • the risedronate salt according to the invention is disodium risedro- nate anhydrate having the X-ray diffraction pattern shown in figure 1.
  • the risedronate salt according to the invention is disodium risedronate tetrahydrate having the X-ray diffraction pat- tern shown in -figure -2. ⁇ •
  • the risedronate salt according to the invention is monopotassium risedronate dihydrate having the X-ray diffraction pattern shown in figure 3.
  • the risedronate salt according to the invention is dipotassium risedronate anhydrate having the X-ray diffraction pattern shown in figure 5.
  • the risedronate salt according to the invention is monoammonium risedronate dihydrate having the X-ray diffraction pattern shown in figure 6. In an even further preferred embodiment the risedronate salt according to the invention is diam- monium risedronate anhydrate having the X-ray diffraction pattern shown in figure 7.
  • the invention relates to pharmaceutical compositions - comprising one or more risedronate salts or hydrates thereof according tothe invention.
  • the salts ac- cording to the invention can be administered systemi- cally or locally as a composition in form of pills, tablets, pellets, granules, hard and soft capsules, powders, or in any other pharmaceutical form known by the person skilled in the art.
  • the com- positions are in some aspects of the invention formulated as modified release compositions.
  • the compositions according to the present invention are produced in a manner known per se, wherein the salts according to the invention are mixed • with pharmaceutically inert inorganic and/ororganic excipients ' or additives, and prepared into a suitable dosage form.
  • Suitable excipients and additives include for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatiz- ers, thickening agents, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts . for changing the osmotic pressure, coating agents and/or antioxidants.
  • suitable fillers include, but are not restricted to agents such as microcrystalline cellulose, lactose, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dex- trin, dextran and maltodextrin, calcium carbonate, calcium phosphate and/or hydrogen phosphate, sulphate .
  • Suitable binders include, for example, lactose, starches, modified starch, dextrin, dextran and mal- todextrin, microcrystalline cellulose, sugars, poly- ethylene glycols, ' hydroxypropyl cellulose, - "hy- .
  • Suitable disintegrating agents comprise cross- carmellose sodium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches, sodium starch glycolate microcrystalline cellulose, magnesium aluminium silicate and/or polyacrylin potassium.
  • Suitable lubricants according to the invention comprises agents such as magnesium stearate, .
  • suitable com- positions comprise, a defined amount of water ranging from about 0.01 to 10 wt %, such as from about 0.5 to 7.5 wt %, preferably from about 1 to 4 wt % of water. In other aspects of the invention suitable compositions comprises only small amounts of water, such as less than about 1 wt %, preferably less than about
  • compositions normally contain from about 0.5 to about 90% by weight, of the compounds of the salts according to the invention.
  • “accord to the invention may- for ..example ' comprise two or ' more compound ' s of the salts according ' to the invention.
  • the mean particle size of the active salts according to the invention are within the range from 1 ⁇ m to 1000 ⁇ m, preferably in the range of 5 ⁇ m to 500 ⁇ m, such as in the range from about 10 ⁇ m to 300 ⁇ m.
  • the amount of the risedronate salts according to the invention comprised in one pharmaceutical composition may be selected based on the intended indication, intended frequency of administration and the intended recipient of the pharmaceutical composition.
  • the pharmaceutical, composition .may according to the invention comprise up • to 1000.
  • risedronate salts or hydrates thereof preferably in the range of 0.1 mg to 1000 mg, more preferred in the range of 0.5 mg to 100 mg, and most preferred in the range of 1 mg to 50 mg.
  • the equivalent amount of risedronic acid per mass unit of the salt depends on the counterion and the hydration state of the particular salt.-
  • another measure for the amount of a risedronate salt would be the indication of the equivalent amount of risedronic acid. This measurement has the advantage that the amount of two different risedronate salts or hydrates thereof can immediately be compared.
  • the pharmaceutical composition may according to the invention comprise an amount of a risedronate salt according to the inven- tion equivalent to up to ,500 mg risedronic acid, preferably equivalent to the range of 0.1 mg to 500 ⁇ mg risedronic acid-, more preferred -equivalent ⁇ to. the range of 0.5 mg to 100 mg risedronic acid, and most preferred equivalent to the range of 1 mg to 50 mg risedronic acid.
  • the pharmaceutical compositions according to the invention comprises an amount of one or more risedronate salts equivalent to 4.64 mg, 27.84 mg or 32.48 mg risedronic acid.
  • the solid pharmaceutical compositions according to the present invention may in one embodiment be prepared as described below: The .mixture of the active substance, filler .
  • binder binder, buffering • agent, disintegrating agent and if required a surfactant and other conventional ingredients for solid pharmaceutical compositions is mixed employing suitable mix- ers .
  • Glidants and/or lubricants are added and the mixture is re-homogenised.
  • the resulting mixture is compressed into tablets or filled into capsules. If needed, tablets can be film- coated.
  • the solid pharmaceutical composition according to the invention is prepared as described below:
  • the mixture of the active substance, filler, binder, buffering agent, disintegrating agent and if required a surfactant and other conventional ingredients for solid pharmaceutical compositions is mixed employing suitable mix- ers, agglomerated with a suitable solvent such as water, ethanol, methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate, isopropyl acetate, methyl acetate, di- chloromethane and methanol , and mixtures of these solvents such as ethanol and acetone, methanol and acetone, dichloromethane and methanol, and the mixtures thereof.
  • suitable solvent such as water, ethanol, methanol, isopropyl alcohol, n-butyl alcohol, acetone, diethyl ether, ethyl acetate, isopropyl acetate, methyl acetate, di-
  • agglomerate is dried in suitable dryers such as standard plate dryers, fluid bed dryers, vacuum and microwave dryers.
  • suitable dryers such as standard plate dryers, fluid bed dryers, vacuum and microwave dryers.
  • glidants and/or lubricants and if required other conventional ingredients for solid pharmaceutical compositions are added.
  • the resulting mixt ⁇ re is remixed and compressed into tablets- or filled into- capsules.
  • agglomerates or tablets can be film- coated.
  • the solid composition is in the form of pellets, which can be prepared by a variety of processes.
  • the commonly utilized processes include balling, spheronization, extrusion, spray congealing, spray drying, melt ex- trusion and/or crystallization.
  • appropriate additives can also be introduced to the composition or during the processes to facilitate the preparation of the solid carrier or the dosage forms, depending on the need of the individual process.
  • Coated dosage forms In suitable aspects .of ' th invention the . .solid compo- . sition is in the form of coated dosage form.
  • the coating may be prepared from at least one film-former such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, at least from one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
  • film-former such as hydroxypropyl methylcellulose, hydroxypropyl cellulose
  • plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.
  • a coating may then be applied, for example by spray- coating with an organic or water-based film coating composition.
  • Coating ingredient combinations are commercially available and known by the person skilled in the art.
  • the coating may comprise, for example, 0.5 to 10% by weight of a tablet composition, particularly 1 to 6%, and preferably 2 to 3%.
  • composition in the form of a modified release dosage form.
  • modified release dosage form may for example be in the form of a matrix, osmotic or coated composition
  • a modified release dosage form as used herein means a dosage form designed to effect delivery over an ex- tended period of time.
  • Various extended release dosage forms can be readily designed by one skilled in the art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of- coating- materials ⁇ and/or coating thickness .
  • the extended release dosage forms are " in the form of a solid composition coated with a pH- independent agent, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose.
  • the invention relates to the use of one or more risedronate salts and hydrates according to the invention for the manufacture of pharmaceutical compositions for the treatment of os- teoporosis, hyperparathyroidism, hypercalcemia of malignancy, osteolytic bone metastases, myositis ossi- ficans progressive, calcinosis universalis, arthritis, neuritis, bursitis, tendiosis and other inflammatory conditions .
  • the use of one or more risedronate salts and hydrates according to the invention for the manufacture of a pharmaceutical composition for the treatment of Paget's disease forms another preferred embodiment of the invention.
  • risedronate salts and hydrates according to the invention for the manufacture of a pharmaceutical composition for the treatment of parasitic infections forms another preferred embodiment of the invention.
  • parasitic infections that can be treated with pharmaceutical compositions according to the invention can be men ⁇ tioned infections with Trypanosoma brucei , Trypanosoma cruzi , Leishmania donovani , Leishmania infantum, Leishmania chagasi , Trypanosoma gondii and Plasmodium falciparum. ' . : The - .
  • dosages according to the invention is a daily dosage of one or more risedronate salts or hydrates thereof equivalent to 4.64 mg risedronic acid for the treatment of osteoro- porosis, a daily dosage of one or more risedronate ' salts or hydrates thereof equivalent to 27.84 mg- risedronic acid for the ' treatment of P ' aget' s ⁇ disease or an weekly dosage of one or more risedronate salts or hydrates thereof equivalent to 32.48 mg risedronic acid for the treatment of osteoporosis.
  • X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in Figure 2.
  • Example 6 Preparation of monoammonium risedronate dihydrate .
  • 602.26 g risedronic acid was stirred in 1200 ml. water and 600 ml 5.16 M ' ammonia in water was added in one portion. The mixture was heated until reflux whereby all material dissolved. 1000 ml ethanol and 750 ml water were added to the mixture, which subsequently was stirred at ambient temperature over night . The product was recovered by filtration, rinsed with a water/ethanol mixture (1:1) and dried at 60 °C under vacuum. Yield 629 g.
  • risedronic acid 25 6 g risedronic acid was dispersed in 12 ml water under stirring and 1.22 g (1.2 ml) ethanolamine was added. The mixture was heated to reflux until all material was dissolved. Stirring without heating was 30 continued over night. Some material was precipitated in form of a gum. A surplus of ethanol was added and the stirring was continued for another day. The formed crystalline ethanolamine risedronate was recovered by filtration,' , washed . with ' ethanol. and dried at 60 °C under vacuum. Yield 3 g.
  • risedronic acid was dispersed in 10 ml water and 1.31 g (1.35 g, 97%) 4- (2 -hydroxyethyl) - ' morpholine was added. The suspension was heated to ' reflux until all material was dissolved. The stirring was continued over night without heating. A sample of the mixture was collected and etha- nol was added until crystals were formed, which were used as seed crystals. Ethanol was added to the reaction mixture, seed crystals were added and the mixture was stirred on ice for one hour. The obtained ' crystals were recovered by filtration, washed with ethanol/water (1:1) and ethanol. Finally the crystals were dried at 60 °C under vacuum. Yield 2.6 g.
  • m Amount of sample [mg]
  • the active ingredient was mixed with lactose monohydrate, microcrystalline cellulose and crospovidone in high shear mixer for 3 minutes.
  • Granulation liquid purified water + polypovidone
  • the wetted mass was dried in a drying cabinet at an inlet temperature of 40 °C, until -the desired moisture content was reached.
  • the dried granules were then milled to achieve fine ' ' ranules ..
  • microcrystalline cellulose and colloidal silicon dioxide was added to the granule mixture and mixed for 10 minutes in a Turbula mixer. Magnesium stearate was added and mixed for additional 1 minute.
  • the granules were compressed into tablets containing 27.84 mg risedronic acid.
  • Particle size distribution was measured using an instrument of the type Malvern Mastersizer S Longbed, which measures the size of particles by laser diffraction. The particles are measured by dispersing the active ingredient in coconut oil followed by ul-trasonification. The dispersion • is slowly added to a defined ' amount of coconut oil, until an obscuration of 10-15% is reached.
  • the mean particle size of potassium Risedronate dihydrate was measured to approx. 200 ⁇ m.
  • Monopotassium risedronate dihydrate was prepared as described in example 3.
  • a granulate comprising monopotassium risedro- nate dihydrate was prepared as described in example 11, and tablets comprising monopotassium risedronate dihydrate was prepared as described in example 12.
  • Monopotassium risedronate dihydrate, granulate and tablets were initially analyzed using a Philips PW1820/3711 powder diffractometer, operated in reflection (Bragg-Bretano) mode.
  • the samples were mounted in a 14 by 14 by 0.4 mm sample holder for data collection.
  • the data were- collected in the range 3° -40°- in steps of 0.02" in 2-0. Data were accumulated for 2 hours.
  • the X-ray diffraction pattern of the monopotassium risedronate dihydrate samples is shown in figure 8 for the complete range of 2-0, and in figure 9 for - the range of 2-0 of 5-19.
  • Disodium risedronate tetrahydrate was prepared 5 as described in example 2.
  • the stability of the free salt, granulate or tablets comprising the compound was analysed as described in example 13.
  • the X-ray diffraction patterns for the granulates comprising disodium risedronate tetrahydrate are shown in figure 13. 20 The X-ray diffraction patterns for the tablets comprising disodium risedronate tetrahydrate are shown in figure 14.
  • Ammonium risedronate dihydrate was prepared as 30 described in example 6.
  • the stability of the free salt, granulate or tablets comprising the compound was analysed as described in example 13. The result showed that the Ammonium risedronate •dihydrate and the.. . prepared preparations .in form, of granulate and tablets were stable during the given storage conditions and the given time.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux sels de risédronate choisis parmi le risédronate de disodium, le risédronate de monopotassium, le risédronate de dipotassium, le risédronate de monoammonium, le risénodrate de diammonium, le risédronate d'hémipipérazine, le risédronate d'éthanolamine et le risédronate de morpholinoéthanolamine et des hydrates de ceux-ci. Ces nouveaux sels ont une très faible tendance à absorber de l'eau supplémentaire dans leurs cristaux, ce qui les rend stables au stockage à l'air ambiant. D'autres compositions pharmaceutiques comprenant les nouveaux sels de risédronate et leurs hydrates sont décrits.
PCT/DK2004/000923 2004-01-02 2004-12-29 Nouveaux sels de risedronate WO2005066190A1 (fr)

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DKPA200400002 2004-01-02
DKPA200400002 2004-01-02
DKPA200401176 2004-08-02
DKPA200401176 2004-08-02

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WO2005066190A1 true WO2005066190A1 (fr) 2005-07-21

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WO2006129056A3 (fr) * 2005-05-28 2007-03-29 Pliva Hrvatska D O O Nouveau sel et procede associe
WO2007039635A3 (fr) * 2005-10-06 2007-06-21 Innate Pharma Sa Sels phosphoantigenes de bases organiques et procedes de cristallisation correspondants
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
WO2007083243A3 (fr) * 2006-01-20 2007-11-29 Aurobindo Pharma Ltd Procede ameliore de preparation d’hemipentahydrate de risedronate de sodium
WO2009003001A3 (fr) * 2007-06-27 2009-04-02 Reddys Lab Ltd Dr Préparation d'hémi-pentahydrate de risédronate de sodium
US8076483B2 (en) 2006-05-11 2011-12-13 M/S. Ind Swift Laboratories Limited Process for the preparation of pure risedronic acid or salts
WO2014092604A1 (fr) * 2012-12-11 2014-06-19 Petrov Sergei Yurievich Procédé de fabrication de sels de monoéthanolamine d'acides phosphoniques

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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
WO2004037252A1 (fr) * 2002-10-25 2004-05-06 Zentiva, A.S. Nouvelle forme cristalline de sel de sodium d'acide 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonique
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GOSSMAN W L ET AL: "THREE HYDRATES OF THE BISPHOSPHONATE RISEDRONATE, CONSISTING OF ONE MOLECULAR AND TWO IONIC STRUCTURES", ACTA CRYSTALLOGRAPHICA SECTION C. CRYSTAL STRUCTURE COMMUNICATIONS, MUNKSGAARD, COPENHAGEN, DK, vol. 50, no. 2, 11 January 2003 (2003-01-11), pages M33 - M36, XP009024776, ISSN: 0108-2701 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006129056A3 (fr) * 2005-05-28 2007-03-29 Pliva Hrvatska D O O Nouveau sel et procede associe
WO2007039635A3 (fr) * 2005-10-06 2007-06-21 Innate Pharma Sa Sels phosphoantigenes de bases organiques et procedes de cristallisation correspondants
WO2007083243A3 (fr) * 2006-01-20 2007-11-29 Aurobindo Pharma Ltd Procede ameliore de preparation d’hemipentahydrate de risedronate de sodium
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
WO2009003001A3 (fr) * 2007-06-27 2009-04-02 Reddys Lab Ltd Dr Préparation d'hémi-pentahydrate de risédronate de sodium
WO2014092604A1 (fr) * 2012-12-11 2014-06-19 Petrov Sergei Yurievich Procédé de fabrication de sels de monoéthanolamine d'acides phosphoniques
RU2529194C2 (ru) * 2012-12-11 2014-09-27 Сергей Юрьевич Петров Способ получения моноэтаноламиновых солей фосфоновых кислот

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