WO2005066190A1

WO2005066190A1 - New risedronate salts

Info

Publication number: WO2005066190A1
Application number: PCT/DK2004/000923
Authority: WO
Inventors: Herbert Fritz Preikschat; Erik Fischer; Michael Tranekjer; Lotte Basse Nielsen
Original assignee: Hexal AS
Current assignee: Sandoz AS
Priority date: 2004-01-02
Filing date: 2004-12-29
Publication date: 2005-07-21
Anticipated expiration: 2006-07-02

Abstract

New risedronate salts selected among disodium risedronate, monopotassium risedronate, dipotassium risedronate, monoammonium risedronate, diammonium risedronate, hemipiperazine risedronate, ethanolamine risedronate and morpholinoethanolamine risedronate and hydrates thereof are disclosed. The new salts have a very low tendency to incorporate additional water into their crystals, which make these salts stable during storage in ambient air. Further pharmaceutical compositions comprising the new risedronate salts and hydrates thereof are disclosed.

Description

NEW RISEDRONATE SALTS

•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.

BACKGROUND FOR THE INVENTION

Bisphosphonates have been proposed for use in the treatment of diseases of bone and calcium metabolism. In^' particular 3-pyridyl-l-hydroxyethylidene- 1, 1-bisphophonic acid, known as 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. In particular 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. Furthermore the use of the compounds^' for the 5 treatment of diseases characterised by abnormal calcium and phosphate metabolism was suggested. DE 42 44 422 Al discloses zinc and magnesium salts of risedronic acid and related bisphosphonic acids, and their use in pharmaceutical compositions. 10 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 . : Thermoanalytical characterization of the hydration states of risedronate;. Pp. 733-738 in Proceedings of the NATAS annual conference 25 on thermal analysis and applications (2002) found that at temperatures above 50 °C the monohydrate form was the most stable form. C. Barbey and M. Lecouvey disclose the crystal structure of a monohydrate of risedronic acid in Z. 30 Kristallogr. NCS 217 (2002) 137-138. In W.L. Gossmann et al . Acta Cryst. (2002) C59, m33-m36 the crystal structure of three hydrates of risedronate are disclosed. In the manufacture of monosodium risedronate the obtained product will usually be recovered as a

'mixture of the monohydrate and, the hemipentahydrate forms, and therefore it is often necessary to include a dehydrating step in order to convert the product to mainly monohydrate form, which is incorporated into pharmaceutical compositions. Due to the thermodynamic properties of monosodium risedronate monohydrate it will interact with surrounding moisture with the re- suit that the identity of the product will change due to absorption of water, unless suitable precautions are made . Thus there exist a need for stable compounds that are capable of providing the active compound risedronic acid, and do not interact with surrounding moisture by liberating or incorporating water..

SHORT DESCRIPTION OF THE INVENTION

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. Thus in one aspect 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. In one preferred aspect 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.

SHORT DESCRIPTION OF THE DRAWINGS 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 - θ 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.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly 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. Furthermore due to the low tendency of 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.

Surprisingly the 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. For example 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. In case that more than one hydrate is possible, 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. In one preferred embodiment the risedronate salt according to the invention is disodium risedro- nate anhydrate having the X-ray diffraction pattern shown in figure 1. In another preferred embodiment the risedronate salt according to the invention is disodium risedronate tetrahydrate having the X-ray diffraction pat- tern shown in -figure -2. ■ • In another preferred embodiment .the risedronate salt according to the invention is monopotassium risedronate dihydrate having the X-ray diffraction pattern shown in figure 3. In another preferred embodiment the risedronate salt according to the invention is dipotassium risedronate anhydrate having the X-ray diffraction pattern shown in figure 5. In an even further preferred embodiment 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.

In another aspect the invention relates to pharmaceutical compositions - comprising one or more risedronate salts or hydrates thereof according tothe invention. In one aspect of the 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. Furthermore, 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. Examples of 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-_. droxypropyl methylcellulose, ethylcellul^'ose, ^' hy- droxyethyl cellulose, methylcellulose, carboxymethyl cellulose, gelatin, acacia gum, tragacanth, polyvi- nylpyrrolidone, copolyvidone, and/or sodium alginate. 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,_. calcium stearate, zinc stearate, calcium behenate,. sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax and/or colloid silicon dioxide. Furthermore, if required, the composition may also include surfactants and other conventional components for solid, pharmaceutical compositions such as colouring agents, lakes, flavours and/or adsorbents . In some aspects of the invention 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

0.5 wt %, more preferably less than about 0.25 wt % of water. The compositions normally contain from about 0.5 to about 90% by weight, of the compounds of the salts according to the invention. The compositions

^"according 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 μm to 1000 μm, preferably in the range of 5 μm to 500 μm, such as in the range from about 10 μm to 300 μm. 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. For example, the pharmaceutical, composition .may according to the invention comprise up • to 1000. mg 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 skilled person will appreciate that dependent on the particular selected risedronate salt the equivalent amount of risedronic acid per mass unit of the salt depends on the counterion and the hydration state of the particular salt.- Thus, 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. In another embodiment, 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. In particular preferred embodiments 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, 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.

In another embodiment 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. The resulting agglomerate is dried in suitable dryers such as standard plate dryers, fluid bed dryers, vacuum and microwave dryers. To the dried agglomerates, glidants and/or lubricants and if required other conventional ingredients for solid pharmaceutical compositions are added. The resulting mixtμre is remixed and compressed into tablets- or filled into- capsules.- Optionally, agglomerates or tablets can be film- coated.

In still other embodiments of the invention 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. It is also clear to one skilled in the art that 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.

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%.

Modified release dosage forms:

In another aspect of the invention the composition is in the form of a modified release dosage form. The 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 .- Piref-. erabiy, 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.

In a further aspect 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. 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 parasitic infections forms another preferred embodiment of the invention. As examples of 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 -_. daily ^' dose of ;the ^• pharmaceutical composi-^" tions according to the invention is subject to the discretion of the attending physician, and will depend on several factors as it will be known within the area, such as the indication being treated the weight and age of the patient as well as the severe- ness of the condition. Other preferred examples of 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. A dosage taken with 28 days intervals of one or more risedronate salts or hydrates thereof equivalent to 129.92 mg risedronic acid for the treatment of osteoporosis. A dosage taken with 84 days intervals of one or more risedronate salts or hydrates thereof equivalent to 389.76 mg risedronic acid for the treatment of osteoporosis. A dosage taken with 168 days intervals of one or more risedronate salts or hydrates thereof equivalent to 779.52 mg risedronic acid for the treatment of osteoporosis. The invention is now further described by examples, which are provided for illustrative purposes and are not intended to be limiting for the invention in any way. EXAMPLES

Example 1. Preparation of disodium risedronate anhydrate

6 g risedronic acid was stirred in 12 ml water and heated to 60 "C. 20 ml 1 N NaOH was added whereby most of the risedronic acid was dissolved. The mix- ture was heated to reflux until all solids were dissolved and subsequently additionally 20 ml I N NaOH was added. The heating was turned off and the stirring continued over night. Next day the mixture was again heated to reflux and 30 ml ethanol was added under stirring. The heating was turned off and stirring continued for a few hours at ambient temperature, where the title compound precipitated. Finally the mixture was placed on ice under stirring for 3 hours. Subsequently the precipitated material was recovered by filtration and dried at 60 °C under vacuum. Yield 5 g (76%)

Microanalysis: C 25.76 %, H 2.63 %, N .2% Calculated for C₇H₉N0₇P₂Na₂ : C 25.71 %, H 2.63%, N 4.28%.

X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in Figure 1. Main X-ray diffraction peaks; 2-0 angles: 6.44, 19.56, 26.14, 31.32, 32.8, 34.24, 35.54, 36.64. Example 2. Preparation of disodium risedronate tetrahydrate

60 g Risedronic acid was stirred in 60 ml water and heated to 60°C. 200 ml 1 N NaOH was added whereby almost all solids were dissolved. The mixture was heated to reflux and further 200 ml IN NaOH was added . The mixture was stirred on an icebath for 2 hours, and 100 ml ethanol was added and stirring continued for further 2 hours. The formed disodium risedronate tetrahydrate was recovered by filtration as a crystalline solid. The product was dried in a drying cabin over night at room temperature.^' Yield: ^'65 g.

Microanalysis : C 20.93%, H 4.25%, N 3.48% Calculated for C₇H₁₇NNa₂0nP₂ : C 21.06%, H 4.29%, N 3.51%.

X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in Figure 2. Main X-ray diffraction peaks, 2-0 angles: 5.93, 6.21, 8.11, 10.15, 12.32, 15.8, 16.2, 17X42, 17.82.

Example 3. Preparation of monopotassium risedronate dihydrate

6 g risedronic acid was stirred in 12 ml water and heated to approximately 60 °C. 19.5 ml 1 N KOH was added and the mixture was -heated to reflux until a clear solution was obtained. The heating was turned - off and. the stirring continued over - night . Next day the^' mixture was placed on^' ice under^' stirring for 3 hours. Subsequently the precipitated material was recovered by filtration, washed with water/ethanol (1:1) and ethanol and dried at 60 °C under vacuum. Yield 6.1 g (91%)

Initially it was believed that this compound was a 1.75 hydrate, but closer inspection of the analytical results showed clearly that the compound was monopotassium risedronate dihydrate.

Microanalysis: C 23.92 %, H 3.80 %, N,3.88% Calculated for C₇H₁₄N0₉P₂K: C 23.54 %, H 3.95%, N 3.92%. X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in Figure 3.

Main X-ray diffraction peaks; 2-0 angles: 6.46, 13.34, 14.42, 21.82, 25.34, 26.02, 27.56, 28.48, 28.82, 29.78, 37.64.

The structure of monopotassium risedronate dihydrate was conclusively determined by utilising sin- gle crystal X-ray diffraction analysis. The structure is shown on figure 4. The experiment was repeated scaled up 500 fold with substantially same result. Example 4. Preparation of dipotassium risedronate anhydrate

6 g risedronic acid was stirred in 12 ml water and heated to approximately 60°C. 20 ml 1 N KOH was added and the mixture was heated to reflux where additional 19 ml IN NaOH was added. After a clear solution was obtained the heating was turned off and the stirring continued over night. Next day 30 ml ethanol was added, the mixture was placed on ice and stirred for one hour. Subsequently the precipitated material was recovered by filtration, washed with water/ethanol (1:1) and ethanol and dried at 60 °C under vacuum. Yield 6 g (79".6%)

X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in Figure 5.

Main X-ray diffraction peaks, 2-0 angles: 6.42, 13.3, 15.06, 16.62, 21.78, 23.78, 25.32, 26, 27.32, 28.44, 30.14, 31.68, 32.12, 37.62.

Example 5. Preparation of ammonium risedronate monohydrate

6 g risedronic acid was stirred with 12 ml wa- ter and an equivalent amount of ammonia in water (5.16 N) 3,87 ml) was added. The mixture was heated to reflux and 13 ml ethanol was added to the reaction mixture, which became turbid. Water was added until the mixture was clear. The heating was turned off and the_. mixture was..stirred over- night. The formed ^' crystals were recovered by filtra- tion, washed with water/ethanol (1:1) and dried at 60 °C under vacuum. Yield 5.4 g

Microanalysis: C 26.93%, H 4.25%, N 8.63% Calculated for C₇Hι_SN₂0₈P₂ : C 26.43%, H 5.07%, N 8.8%

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.

Microanalysis: C 25.19 %, H 5.40 %, N 8.29 % Calculated for C₇H₁₈N₂0₉P₂ : C 25.01 %, H 5.40 %, N 8.33 %. This analysis confirmed that the produce was monoammonium risedronate dihydrate. X-ray diffraction analysis on the prepared compound provided the X-ray diffraction pattern shown in ^"Figure ^' 6. Main X-ray diffraction peaks, 2-0 angles: 10.58, 14.39, 15.94, 16.59, 17.89, 19.47, 22.1, 22.48, 23.03, 23.48, 24.14, 27.43, 27.87, 30.6, 32.11, 35.82.

Example 7 Preparation of diammonium risedronate anhydrate

6g Risedronic acid was dispersed in 12 ml water under .stirring • and an_. equivalent amount of ammonia .(5.16 N) 7,74 ml was added.^'

All material was dissolved. The solution was heated to reflux and 25 ml ethylalcohol was added. Stirring without heating was continued over night. The obtained crystals were recovered by filtration, washed with ethanol/water (1:1) . Finally the crystals were dried at 50°C under vacuum. Yield 3.7g Microanalysis: C 26.68%, H 5.29%, N ^"13.09% Calculated for C₇H₁₇N₃0₇P₂ : C 26.51%, H 5.40%, N 13.25%.

X-ray diffraction analysis of the prepared com- pound provided the X-ray diffraction pattern shown in figure 7. Main X-ray diffraction -peaks, 2-0 angles: 6.13; 13.85; 14.05; 14.37; 16.15; 16.72; 18.35; 19.03; ^"' - 24.67.; 27.01.

5 Example 8. Preparation of hemipiperazine risedronate

To 3.01 g of risedronic acid dispersed in water 0.43 g of piperazine dissolved in 5 ml water was 10 added. The mixture was stirred over night and subsequently 0.3 g of crystalline solid was recovered by filtration. Ethanol was added in surplus and the mixture was cooled and stirred over night, whereafter 3 g of 15 crystalline ^• solid was recovered by filtration. The recovered solids were combined.

Microanalysis: C 32.08 %, H 4.65 %, N 8.61 % Calculated for

: C 33.14 %, H 4.94 %, 20 N 8.59 %.

Example 9. Preparation of ethanolamine risedronate anhydrate

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.

Microanalysis: C 31.30 %, H 5.11 %, N 7.72 % Calculated for C₉Hι₈N₂0₈P2 : C 31.41 %, H 5.27 %, N 8.14 %. Example 10. Preparation of morpholinoethanolamine risedronate

3.01 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. Upon repeated precipitation additional 0.7 g was recovered from the reaction mixture. Total yield 3.3 g (79.8 %) . Microanalysis : C 37 . 07 % , H 5 . 63 % , N 6 . 5 % Calculated, for^' C^'i₃H₂₄N₂0₉P₂ : C 37 . 69 ^' . %^', H 5 . 84 ;% , ^' N 6 . 76 ^'% .

Example 11. Stability study

In order to observe what amounts of water the Ris- edronate salts of the invention would incorporate upon storage the following stability experiments where performed.

Ammonium Risedronate dihydrate, disodium Risedronate tetrahydrate and potassium Risedronate dihydrate salts where stored for two months at either 25 °C/60 % relative humidity or 40 °C /75 % relative humidity. Samples were taken at the start of the experiment and after two months. The water content of the samples was by Karl Fischer titration using the protocol described below.

Karl Fischer titration

Dissolve sample corresponding to approximately 1 ml titrant in approximately 10 ml of Hydranal-Solvent (sulphur dioxide and imidazole in methanol) . Stir vigorously. Not all sample dissolves completely, but it is assumed that all water is dissolved by this procedure. The dissolved sample is titrated with Hy- dranal-Titrant 5 (solution of iodine, where 1 ml titrant corresponds to 5.00 mg water), resulting in the following reactions: CH₃OH + SO₂ + RN ^=^ [RNH]SO₃CH₃ H₂O + I₂ +. [RMΪ]S0₃CH_{3 ,} + 2 RN [RNH]SO₄CH₃ .+ 2 [KNH]I

The water content is calculated by the following equation : V • factor • c % water = • 100% m where V = Volume added titrant [ml] to equivalence strength = The factor of the titrant c = mg titrant per ml water, i.e., 5. m = Amount of sample [mg]

Results

The results from, the stability _.experiment are shown, in the table below. For all three salts investigated,-^• storage for 2 months at 25°C/60% RH or 40°C/75% RH resulted in no significant changes in water content as compared to the start analysis. All variations are within the expected analytical fluctuations.

Example 12. Pharmaceutical formulation

•^'The^' following , procedure, for ^• the .^' reparation of tab-^' lets containing risedronic acid serves as a non- limiting example of the pharmaceutical compositions according to the invention.

Procedure for manufacturing tablets containing a risedronate salt equivalent to 27.8 mg risedronic acid:

Ingredients Per tablet Per 10,000 tablets Potassium risedronate 35.2 mg 352.0 g dihydrate Lactose monohydrate . ^' 118.52 mg - - 1185.2 g Microcrystalline eel- 60.0 mg - -600.0 g lulose Crospovidone 2.4 mg 24.0 g Polyvinylpyrrolidone 4.8 mg 48.0 g Crospovidone 4.8 mg 48.0 g Microcrystalline eel- 12.0 mg 120.0 g lulose Colloidal silicon di- 0.48 mg 4.8 g oxide Magnesium stearate 1.8 mg 18.0 g

The active ingredient was mixed with lactose monohydrate, microcrystalline cellulose and crospovidone in high shear mixer for 3 minutes. Granulation liquid (purified water + polypovidone) was added to the blend with the mixer running for 3 minutes. 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 .. After milling, „ crospόvi-^' done, 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.

Similar procedures were used to prepare tablets containing Risedronate as the disodium Risedronate tetrahydrate salt or containing Risedronate as ammonium Risedronate dihydrate salt.

Example 13. Determination of particle sizes

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 μm.

Similar measurements were performed on ammonium Risedronate dihydrate salt. The mean particle size of am- monium Risedronate dihydrate was measured to approx. 40 μm.

Example 14. Stability of monopotassium risedro- nate dihydrate

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.

Further tablets containing all tablet exhibi- ents but no monopotassium risedronate ^' dihydrate were prepared for use as control using same method 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.

Samples of monopotassium risedronate dihydrate, granulate and tablets were stored for one month and two months at 25 °C, 60% relative humidity and at 40 °C, 75% relative humidity, and subsequently analysed as before. The results showed that the free monopotassium •-. risedronate- .dihydrate and; the .control without -rise--- dronate were perfectly stable during the given stor- age conditions and over the given time. The analysis further showed that there were overlaps between the signals from the control and the signals from the monopotassium risedronate dihydrate in the range of 2-0 of 20 to 40. Therefore the analysis of granulates and tablets was limited to the range 2-0 of 5 to 19.

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.

In this range no evidence of the formation of any other crystalline product or significant decay of the active sample was observed. Thus it was concluded that the investigated monopotassium risedronate dihydrate preparations in form of granulate and tablets are stable during the given storage conditions and the given time. The X-ray diffraction pattern for the granulates comprising monopotassium risedronate dihydrate is shown in figure 10.

The X-ray diffraction pattern for the tablets com- prising monopotassium risedronate dihydrate is shown in figure 11. Example 15. Stability of disodium risedronate tetrahydrate

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 result showed that the disodium risedronate 10 tetrahydrate and the prepared preparations in form of granulate and tablets were stable during the given storage conditions and the given time.

The X-ray diffraction patterns for the disodium rise- 1.5 dronate tetrahydrate are shown in figure 12.

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.

25 Example 16. Stability of ammonium risedronate dihydrate

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.

The X-ray diffraction patterns for the ammonium risedronate dihydrate are shown in figure 15.

The X-ray diffraction patterns for the granulates comprising ammonium risedronate dihydrate are shown in figure 16.

The X-ray diffraction patterns for the tablets com- prising ammonium risedronate dihydrate are shown in figure 17. ■ •

Claims

P A T E N T -C L A I M S 1. A risedronate salt selected among: disodium risedronate, monopotassium ^'risedronate,- . dipotassium risedronate, monoammonium risedronate, diammonium risedronate, hemipiperazine risedronate, ethanolamine risedronate and morpholinoethanolamine risedronate and hydrates thereof .

2. The salt according to claim 1, where the salt is selected among: disodium risedronate anhydrate, disodium risedronate tetrahydrate, monopotassium risedronate dihydrate, dipotassium risedronate anhydrate, monoammonium risedronate monohydrate, monoammonium risedronate dihydrate, diammonium rise- dronate anhydrate, hemipiperazine risedronate anhydrate, ethanolamine risedronate anhydrate and mor-^' pholinoethanolamine risedronate anhydrate.

3. The salt according to claim 2, where the salt is disodium risedronate anhydrate in crystalline form having the X-ray diffraction pattern shown in figure 1.

4. The .salt according to claim 2, where, the salt is disodium risedronate tetrahydrate in crystalline form having the X-ray diffraction pattern shown in figure 2.

5. The salt according to claim 2, where the salt is monopotassium risedronate dihydrate in crystalline form having the X-ray diffraction pattern shown in figure 3.

6. The salt according to claim 2, where the salt is dipotassium risedronate anhydrate in crystalline form having the ^'.X-ray -_. diffraction pattern shown in figure 5.

7. The salt according to claim 2, where the salt is monoammonium risedronate dihydrate in crystalline form having the X-ray diffraction pattern shown in figure 6.

8. The salt according to claim 2, where the salt is diammonium risedronate anhydrate in crystalline form having the X-ray diffraction pattern shown in figure 7.

9.- Pharmaceutical composition comprising a risedronate salt or a hydrate thereof according to any of the claims 1-8.

10. Pharmaceutical composition according to claim 9, further comprising one or more usual excipients .

11. Pharmaceutical composition according to claim 10, wherein one or more excipients are selected among: fillers, disintegrants, lubricants, carriers, colorants, flavourings.

12. Pharmaceutical composition according to any of claims 9-11, wherein the composition is in form of a tablet, a pill or a capsule.

13. Use of a risedronate salt or hydrate thereof according to any of the claims 1-8, for the manufacture of a pharmaceutical • composition for ^"the treatment of disorders in the bone ^"and/or calcium me- tabolism.

14. Use according to claim 13, wherein the disorder in the bone and/or calcium metabolism is selected among: osteoporosis, hyperparathyroidism, hy- percalcemia of malignancy, osteolytic bone metastases, myositis ossificans progressive, calcinosis uni- versalis, arthritis, neuritis, bursitis, tendiosis and other inflammatory conditions or Paget's disease. 15-. Use of a risedronate salt, or- a hydrate thereof according to any ^' of the claims 1-8, for the. manufacture of a pharmaceutical composition for the treatment of parasitic infections. 16. Use according to claim 15, where the parasitic infection is caused by Trypanosoma hrucei , Trypanosoma cruzi , Leishmania donovani , Leishmania in- fantum, Leishmania chagasi , Trypanosoma gondii and Plasmodium falciparum .