WO2006129056A2

WO2006129056A2 - Process and novel salt

Info

Publication number: WO2006129056A2
Application number: PCT/GB2006/001830
Authority: WO
Inventors: Kreso Mihaljevic; Blazenko Bajic; Drazen Cavuzic; Ruzica Oreskovic
Original assignee: Pliva Hrvatska doo
Current assignee: Pliva Hrvatska doo
Priority date: 2005-05-28
Filing date: 2006-05-18
Publication date: 2006-12-07
Anticipated expiration: 2007-11-28
Also published as: EP1888606A2; WO2006129056A3

Abstract

The present invention relates to a process of preparing risedronic acid, or a pharmaceutically acceptable salt thereof, novel risedronate ammonium salts and pharmaceutical compositions thereof, and the use of such novels salts and compositions in human therapy.

Description

PROCESS AND NOVEL SALT

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 novels 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. Such 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, and pharmaceutically acceptable salts thereof, tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in biological activity, 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.

Processes of preparing risedronic acid, and salts thereof, are known in the art, and some examples thereof are as follows.

EP 1243592B describes a process of preparing risedronic acid by reacting 3- pyridylacetic acid with phosphorous acid and phosphorous trichloride in a solvent. In the case where the solvent is chlorobenzene, the reaction is carried out at a temperature in the range of 85-100°C. In the case where 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

where n is 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 N₂ 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 (POCl₃), 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 POCl₃ and consequently phosphoric acid (H₃PO₄) 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

POCl₃ + 3H₂O → 3HCl + H₃PO₄

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 45⁰C 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.

We have now developed a process for preparing risedronic acid, which employs advantageous operating conditions compared to the known processes in the art for the preparation of bisphosphonic acids. In particular, the present invention avoids the use of high temperatures and organic solvents which have hitherto been used in the preparation of risedronic acid. There is now provided by the present invention, therefore, a process of preparing risedronic acid of formula (I)

(I)

which process comprises forming phosphorous acid in situ in a reaction mixture, reacting the thus formed phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt, and recovering the thus formed risedronic acid.

In a particularly preferred embodiment of the present invention 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. Additionally, 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. Preferably, therefore, 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.

Preferably, therefore, the present invention provides a process of preparing risedronic acid of formula (I)

(I)

which 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 and recovering the thus formed risedronic acid;

characterised in that phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water.

It is this in situ formation of phosphorous acid in the reaction mixture which differentiates the process of the present invention from the prior art and which enables the present process of the invention to be carried out at low temperatures and in the absence of organic solvents. It will be appreciated that the avoidance of both high temperatures and the use of organic solvents in accordance with the present invention provides considerable benefit over the prior art process techniques, where solid phosphorous acid was added to the prior art reaction mixtures, thus requiring the use of high temperatures and suitable organic solvent systems.

According to the present invention there is also provided a process of preparing risedronic acid of formula (I)

(D

which process comprises reacting pyridylacetic acid, optionally in the form of a hydrohalide salt, with phosphorous acid, in the presence of phosphorous trihalide, to yield risedronic acid and recovering the thus formed risedronic acid, characterised in that the reaction of said pyridylacetic acid with phosphorous acid is carried out in the absence of an organic solvent.

Substantially as hereinbefore described it is preferred in accordance with the present invention that 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. In this preferred embodiment, a process according to the present invention can be represented by the following reaction scheme

(1) PX₃ (excess) + H₂O

(2) PX₃ (excess) + H₃PO₃ + HX

(3) PX₃ (excess) + H₃PO₃ +

(H₂O + PX₃ (excess)) H₃PO₃ + HX

where X denotes halo, which can be bromo, chloro, fluoro or iodo, preferably chloro. Preferably, therefore, pyridylacetic acid is employed in the form of the hydrochloride salt. Furthermore, it is preferred that the phosphorous trihalide employed is phosphorous trichloride.

More specifically, it can be seen from the above reaction scheme that the synthesis starts from preparation of phosphorous acid in situ, where phosphorous trihalide, preferably phosphorous trichloride, is added dropwise to water in step (1). During the reaction, 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, is then charged to the reaction mixture. 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).

Preferably according to the present invention 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 1O⁰C to 3O⁰C, preferably at a temperature in the range of about 2O⁰C to 25⁰C. Preferably the resulting mixture is subsequently heated to a temperature in the range of about 6O⁰C to 100⁰C, preferably at a temperature on the range of about 6O⁰C to 9O⁰C. Preferably, therefore, the temperature does not exceed about 9O⁰C during the above reaction process, and in some embodiments it is preferred that the reaction temperature does not exceed about 7O⁰C. As hereinbefore described, therefore, 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.

The term "about" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, at about can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, desirably up to 10%, more desirably up to 5%, and even more desirably up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.

Suitably, 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. Preferably, therefore, 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.

Following the above described reflux stage, the reaction mixture is preferably cooled to a temperature in the range of about 7O⁰C to 8O⁰C, 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. In this embodiment of the invention it is not essential that the free acid is recovered from the reaction mixture prior to conversion into a selected pharmaceutically acceptable salt form. According to the present invention, therefore, there is further provided a process of preparing a pharmaceutically acceptable salt of risedronic acid, which process 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.

Suitably in the preparation of a pharmaceutically acceptable salt according to the present invention a suspension of risedronic free acid and water is heated to a temperature in the range of about 35⁰C to 95⁰C, preferably in the range of about 4O⁰C to 9O⁰C, 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. The resulting solution is when required typically heated to reflux, typically at about 100⁰C, and again when required a C^alcohol, such as methanol or ethanol, is added. Subsequent cooling results in crystallization of the risedronate salt. Alternatively, 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_1-4alcohol 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.

For 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.

As used herein, ammonium risedronate preferably refers to the mono-ammonium salt of risedronic acid. However, 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).

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 221⁰C to about 24O⁰C. 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.O⁰C to about 234.5°C, when measured in a capillary method according to the standardised method within European Pharmacopoeia 2.2.14.

In a preferred embodiment of the present invention, 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 241⁰C to about 253°C.

Risedronic acid as prepared by the present invention, or a pharmaceutically acceptable salt of risedronic acid as described herein, 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. Such 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 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.

As used herein, 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.

By "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.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, 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. For topical application, risedronic acid or a pharmaceutically acceptable salt thereof, can be used in creams, ointments or lotions.

To achieve the desired prophylactic or therapeutic effect, 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.

When a solid composition in the form of tablets is prepared, 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. 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.

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.

There is also provided by the present invention 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. More specifically, 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. More specifically, 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.

The present invention is now further illustrated by the following Examples and Figures, which are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention. Unless otherwise required by the context, as used herein reference to risedronate salts do not denote the material in any particular physical state and include amorphous material as well as material in any crystalline form.

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). (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 241⁰C and egzotherm onset is at 253⁰C ). 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 N₂ 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 10-70⁰C depending on reaction kinetics. At 2O⁰C, 26.6g of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 7O⁰C 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 (-112⁰C) and maintained at the reflux temperature for four hours. The solution was cooled to 7O⁰C and 0.8g of active carbon was added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 14ml of water. The filtrate was collected and vacuum evaporated. 50ml of water were then added and slowly cooled. Crystallization of risedronic acid started at about 56⁰C. The suspension was then slowly cooled to 0-5⁰C and retained for three hours at this temperature. Risedronic acid, 31.5g, was obtained after filtration, washing with 14 ml of cold water and drying.

Example 2

210ml of water were charged to a 2000ml four necked flask, to which was added dropwise 580ml 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 10-70⁰C depending on reaction kinetics. At 2O⁰C, lOOg of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 9O⁰C over a period of 1.5 hours. 170ml of water and 250ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (~112⁰C) and maintained at the reflux temperature for four hours. The solution was cooled to 8O⁰C and 3g of active carbon were added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 70ml of water. The filtrate was collected and vacuum evaporated. 250ml of water were added and slowly cooled. Crystallization of risedronic acid started at about 6O⁰C. The suspension was then slowly cooled to 0-5⁰C and retained for two hours at this temperature. Risedronic acid, 115.8g, was obtained after filtration, washing with 100ml of cold water and drying. Example 3

210ml of water were charged to a 2000ml four necked flask, to which was added dropwise 580ml 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 10-70⁰C depending on reaction kinetics. At 22⁰C₅ lOOg of pyridylacetic acid hydrochloride were charged. The reaction was performed by slow heating to 64⁰C over a period of 1.5 hours. 200ml of water and 250ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (~112°C) and maintained at the reflux temperature for four hours. The solution was cooled to 8O⁰C and 3g of active carbon were added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 70ml of water. The filtrate was collected and vacuum evaporated. 250ml of water were added and slowly cooled. Crystallization of risedronic acid started at about 58⁰C. The suspension was than slowly cooled to 0-5⁰C and retained for 1.5 hours at this temperature. Risedronic acid, 134.7g, was obtained after filtration, washing with 100ml of cold water and drying.

Example 4

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C and the pH was adjusted with sodium hydroxide (20%) until a pH of about 4 was achieved. The solution was heated to reflux (~100°C) and 60ml of methanol were slowly added under reflux. Crystallization of the salt started at about 9O⁰C, when 20ml of methanol was added. When all 60ml of methanol were added, the suspension was maintained at the reflux temperature (~77°C) for five minutes, and then allowed to cool. The suspension was then slowly cooled to 0-5⁰C in the period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 15.8 g, was obtained after filtration, washed with 20ml of a water / methanol cold solution (1 / 1) and dried.

Example 5 50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C 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 74⁰C. The suspension was then slowly cooled to 0-5⁰C 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.

Example 6

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C and the pH was adjusted with ammonium hydroxide (25%) until a pH of about 4 was achieved. The solution was heated to 8O⁰C and allowed to cool by adding dropwise 60ml of methanol. Crystallization of the salt started at about 53⁰C when about 40ml of methanol were added. The suspension was then slowly cooled to 0-5⁰C over a period of 1.5 hours and retained for one hour at this temperature. Risedronate ammonium salt, 12.7 g, was obtained after filtration, washing with 20ml of a water / methanol cold solution (1 / 1) and drying.

Example 7

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C and the pH was adjusted with ammonium hydroxide (25%) until a pH of about 4 was achieved. The solution was cooled to 22⁰C, and 60ml of methanol were slowly added. On adding methanol, the temperature slightly increased to -28⁰C. Crystallization of the formed salt started at about 27⁰C when about 50ml of methanol were added. When all 60ml of methanol were added to the suspension, this was then slowly cooled to 2O⁰C, and slurry crystals were obtained. The suspension was heated to 7O⁰C, the slurry crystals dissolved, and then slowly cooled to 0-5⁰C over a period of two hours, and retained for one hour at this temperature. Crystallization of the formed salts started at about 53⁰C. Risedronate ammonium salt, 12.5g, was obtained, filtrated and washed with 20ml of a water / methanol cold solution (1 / 1) and dried.

Melting point was determined to be 234.0 - 234.5 ⁰C. The melting point was determined on a capillary Buchi B-540 machine, according to EurPh. (2.2.14 Melting Point - Capillary method).

Example 8

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 9O⁰C and the pH was adjusted with sodium hydroxide (20%) until a pH of about 4 was achieved. The solution was heated to reflux (~100°C) and 60ml of methanol were slowly added under reflux. Crystallization of the salt started at about 9O⁰C, when 20ml of methanol was added. When all 60ml of methanol were added, the suspension was maintained at the reflux temperature (~77°C) for five minutes, and then allowed to cool. The suspension was then slowly cooled to 0-5⁰C in the period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 14.2g, was obtained after filtration, washed with 20ml of a water / methanol cold solution (1 / 1) and dried.

Example 9

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C and the pH was adjusted with sodium hydroxide (20%) until a pH of about 4 was achieved. The solution was heated to reflux (~100°C) and 60ml of ethanol were slowly added under reflux. Crystallization of the salt started at about 9O⁰C, when 20ml of ethanol was added. When all 60ml of ethanol were added, the suspension was maintained at the reflux temperature (-82⁰C) for five minutes, and then allowed to cool. The suspension was then slowly cooled to 0-5⁰C in the period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 14.3g, was obtained after filtration, washed with 20ml of a water / ethanol cold solution (1 / 1) and dried. Example 10

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 9O⁰C and the pH was adjusted with sodium hydroxide (20%) until a pH of about 4 was achieved. The solution was allowed to cool and crystallization of the salt started at about 67⁰C. The suspension was then slowly cooled to 0-5⁰C over a period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 13.2g, was obtained after filtration and dried.

Example 11

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 6O⁰C and the pH was adjusted with sodium hydroxide (20%) until a pH of about 4 was achieved. The solution allowed cooling and crystallization of the salt started at about 4O⁰C. The suspension was then slowly cooled to 0-5⁰C over a period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 13.6g, was obtained after filtration and dried.

Example 12

50ml of water and 15g of risedronic acid were charged to a 250ml three necked flask. The suspension was heated to 4O⁰C and the sodium hydroxide (20%) was added until risedronic acid was dissolved. After the risedronic acid was dissolved the crystallization of the salt started immediately at about 4O⁰C. The suspension was then slowly cooled to 0-5⁰C over a period of two hours and retained for one hour at this temperature. Risedronate sodium salt, 12.2g, was obtained after filtration and dried.

Claims

1. A process of preparing risedronic acid of formula (I)

(I)

2. A process according to claim 1, characterised in that the reaction of said pyridylacetic acid with phosphorous acid is carried out in the absence of an organic solvent.

3. A process of preparing risedronic acid of formula (I)

(I) which process comprises reacting pyridylacetic acid, optionally in the form of a hydrohalide salt, with phosphorous acid, in the presence of phosphorous trihalide, to yield risedronic acid and recovering the thus formed risedronic acid, characterised in that the reaction of said pyridylacetic acid with phosphorous acid is carried out in the absence of an organic solvent.

4. A process according to any of claims 1 to 3, wherein phosphorous acid is formed in situ by the reaction of phosphorous trihalide and water.

5. A process according to any of claims 1 to 4, which 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.

6. A process of preparing risedronic acid of formula (I)

(D

7. A process according to any of claims 1 to 6, wherein the pyridylacetic acid is employed in the form of a hydrohalide salt.

8. A process according to any of claims 1 to 7, represented by the following reaction scheme

(1) PX₃ (excess) + H₂O

(2) PX₃ (excess) + H₃PO₃ + HX

(3) PX₃ (excess) + H₃PO₃ +

+ (H₂O + PX₃ (excess)) H₃PO₃ + HX

where X denotes halo, which can be bromo, chloro, fluoro or iodo.

9. A process according to claim 8, wherein halo is chloro.

10. A process according to any of claims 1 to 9, wherein said pyridylacetic acid, optionally in the form of a hydrohalide salt, is added to a reaction mixture comprising phosphorous acid at a temperature in the range of about 1O⁰C to 3O⁰C.

11. A process according to claim 10, wherein said pyridylacetic acid, optionally in the form of a hydrohalide salt, is added to said reaction mixture at a temperature in the range of about 2O⁰C to 25⁰C.

12. A process according to claim 10 or 11, wherein a resulting mixture of pyridylacetic acid and phosphorous acid is heated to a temperature in the range of about 6O⁰C to 100⁰C.

13. A process according to claim 12, wherein the resulting mixture is heated to a temperature in the range of about 6O⁰C to 9O⁰C.

14. A process according to any of claims 1 to 13, wherein the temperature of a reaction mixture of pyridylacetic acid and phosphorous acid does not exceed about 90°C.

15. A process according to claim 14, wherein the temperature of said reaction mixture does not exceed about 70°C.

16. A process according to any of claims 1 to 15, which further comprises addition of a hydrolysing agent.

17. A process according to claim 16, wherein the hydrolysing agent is water and / or a strong mineral acid.

18. A process according to claim 17, wherein the mineral acid is hydrochloric acid.

19. A process of preparing a pharmaceutically acceptable salt of risedronic acid, which process comprises carrying out a process according to any of claims 1 to 18 and converting the thus prepared risedronic acid to a pharmaceutically acceptable salt thereof, and recovering the pharmaceutically acceptable salt of risedronic acid.

20. A process of preparing a pharmaceutically acceptable salt of risedronic acid, which comprises forming phosphorous acid in situ in a reaction mixture, reacting the thus formed phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt, and converting the thus formed risedronic free acid to a pharmaceutically acceptable salt form, and recovering the pharmaceutically acceptable salt of risedronic acid.

21. A process according to claim 19 or 20, wherein the salt is a sodium salt.

22. A process according to claim 21, wherein sodium risedronate hemipentahydrate is prepared.

23. A process according to claim 19 or 20, wherein the salt is an ammonium salt.

24. A process according to any of claims 19 to 23, wherein a suspension of risedronic free acid and water is heated to a temperature in the range of about 35⁰C to 95⁰C, followed by the addition of a hydroxide of the salt forming species to form a solution.

25. A process according to claim 24, wherein said suspension of risedronic free acid and water is heated to a temperature in the range of about 4O⁰C to 9O⁰C.

26. A process according to claim 24 or 25, wherein said hydroxide is sodium hydroxide or ammonium hydroxide.

27. A process according to any of claims 24 to 26, wherein said solution is heated to reflux followed by the addition of a C_1-4alcohol, followed by subsequent cooling to yield crystals of a pharmaceutically acceptable risedronate salt.

28. A process according to any of claims 24 to 26, dependent on claim 23, wherein the solution is cooled prior to addition of a C_1-4alcohol resulting in the formation of slurried crystals, which crystals are heated and subsequently cooled to yield crystals of ammonium risedronate.

29. Ammonium risedronate.

30. Mono-ammonium risedronate.

31. Ammonium risedronate according to claim 29 or 30, characterised as having a melting point in the range of about 221⁰C to about 24O⁰C.

32. Ammonium risedronate according to claim 31, characterised as having a melting point in the range of about 233.5°C to about 235.0°C.

33. Ammonium risedronate according to claim 31 or 32, characterised as having a melting point in the range of about 234.0°C to about 234.5°C.

34. Ammonium risedronate characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.

35. Ammonium risedronate 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.

36. Ammonium risedronate according to claim 35, 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°.

37. Ammonium risedronate characterised as having an FTIR transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2.

38. Ammonium risedronate characterised as having 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.

39. Ammonium risedronate characterised as having an FTNIR reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 3.

40. Ammonium risedronate characterised by a DSC thermograph as shown in Figure 4.

41. Ammonium risedronate characterised by a DSC endotherm in the range of about 241⁰C to about 253°C.

42. A pharmaceutical composition comprising a therapeutically effective dose of ammonium risedronate according to any of claims 29 to 41, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

43. Ammonium risedronate according to any of claims 29 to 41, for use in therapy.

44. Ammonium risedronate according to any of claims 29 to 41, 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.

45. Use according to claim 44, in the manufacture of a medicament for the treatment of diseases of bone and calcium metabolism.

46. Use according to claim 45, in the manufacture of a medicament 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.

47. Use according to claim 46, in the manufacture of a medicament for the treatment of osteoporosis.

48. 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 ammonium risedronate according to any of claims 29 to 41.

49. A method according to claim 48, for treating diseases of bone and calcium metabolism.

50. A method according to claim 48 or 49, for the treatment of osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.

51. A method according to claim 50, for the treatment of osteoporosis.