CA2649489A1 - Pharmaceutically acceptable salts and polymorphic forms - Google Patents
Pharmaceutically acceptable salts and polymorphic forms Download PDFInfo
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- CA2649489A1 CA2649489A1 CA002649489A CA2649489A CA2649489A1 CA 2649489 A1 CA2649489 A1 CA 2649489A1 CA 002649489 A CA002649489 A CA 002649489A CA 2649489 A CA2649489 A CA 2649489A CA 2649489 A1 CA2649489 A1 CA 2649489A1
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- Prior art keywords
- tetra
- sodium
- sodium risedronate
- alkali metal
- risedronic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Abstract
The present invention is concerned with new risedronate salts and new polymorphic forms thereof, specifically a pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid and new polymorphic forms thereof, processes of preparing the same, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
Description
PHARMACEUTICALLY ACCEPTABLE SALTS AND POLYMORPHIC FORMS
The present invention is concerned with new risedronate salts and new polymorphic forms thereof, processes of preparing the same, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
Risedronic acid is the international non-proprietary name of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid. Risedronic acid has the following structural formula N O \ POH
HO 'OH
OH
0 \OH
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 botli 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
HO-II I II_OH
I I I
OH ( i H2)r, OH
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.
The present invention is concerned with new risedronate salts and new polymorphic forms thereof, processes of preparing the same, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.
Risedronic acid is the international non-proprietary name of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid. Risedronic acid has the following structural formula N O \ POH
HO 'OH
OH
0 \OH
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 botli 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
HO-II I II_OH
I I I
OH ( i H2)r, OH
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 (POC13), 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 POC13 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 POC13 + 3H20 -* 3HC1 + 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 45 C to about 75 C, (c) adding a solvent to the aqueous solution, characterised in that the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, amides and nitriles, and (d) optionally cooling the aqueous solution.
Various forins of sodium salts of risedronic acid are also known. For example, WO
04/037252 discloses crystalline hydrated forms of sodium risedronate, which contain from 6.4 up to 22 weight % of sodium based on the anhydrous substance, and in the case where the sodium content is lower than 7.5 weight %, then 15 to 23 weiglit % of crystalline water is present, or in the case where the sodium content is higher than 7.5 weight %, then 4.5 to 18 weight % of crystalline water is present.
Specifically, there is disclosed (i) the pentahydrate of the monosodium salt, which contains from 5.5 to 7.5 weight % of sodium and 20 to 23 weight % of crystalline water, (ii) the trihydrate of the trisodium salt, which contains from 19 to 21 weight % of sodium and 12 to 14 weight % of crystalline water and (iii) the monohydrate of the disodium salt, which contains from 13 to 15 weight % of sodium and 4.5 to 6.5 weight % of crystalline water.
WO 03/086355 describes polymorph forms B, B1, BB, C, D, E, F, G and H of sodium risedronate and processes of preparing these various polymorphs.
According to the present invention, there is now provided, however, a pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid.
Pharmaceutically acceptable alkali metal salts include sodium and potassium salts.
Specifically, there is provided by the present invention tetra-sodium risedronate.
The present invention also provides tetra-sodium risedronate as tetra-sodium risedronate Form I, tetra-sodium risedronate Form II and tetra-sodium risedronate Form III.
Tetra-sodium risedronate Form I as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
Tetra-sodium risedronate Form I according to the present invention is further characterised as having characteristic peaks (20): 6.33, 9.76, 11.05, 12.15, 12.65, 15.13, 16.77, 17.0, 18.99, 22.23, 22.61 and 30.53 .
Tetra-sodium risedronate Form I 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.
Tetra-sodium risedronate Form I 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.
WO 05/063779 describes use of phosphorous oxychloride (POC13), 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 POC13 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 POC13 + 3H20 -* 3HC1 + 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 45 C to about 75 C, (c) adding a solvent to the aqueous solution, characterised in that the solvent is selected from the group consisting of alcohols, esters, ethers, ketones, amides and nitriles, and (d) optionally cooling the aqueous solution.
Various forins of sodium salts of risedronic acid are also known. For example, WO
04/037252 discloses crystalline hydrated forms of sodium risedronate, which contain from 6.4 up to 22 weight % of sodium based on the anhydrous substance, and in the case where the sodium content is lower than 7.5 weight %, then 15 to 23 weiglit % of crystalline water is present, or in the case where the sodium content is higher than 7.5 weight %, then 4.5 to 18 weight % of crystalline water is present.
Specifically, there is disclosed (i) the pentahydrate of the monosodium salt, which contains from 5.5 to 7.5 weight % of sodium and 20 to 23 weight % of crystalline water, (ii) the trihydrate of the trisodium salt, which contains from 19 to 21 weight % of sodium and 12 to 14 weight % of crystalline water and (iii) the monohydrate of the disodium salt, which contains from 13 to 15 weight % of sodium and 4.5 to 6.5 weight % of crystalline water.
WO 03/086355 describes polymorph forms B, B1, BB, C, D, E, F, G and H of sodium risedronate and processes of preparing these various polymorphs.
According to the present invention, there is now provided, however, a pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid.
Pharmaceutically acceptable alkali metal salts include sodium and potassium salts.
Specifically, there is provided by the present invention tetra-sodium risedronate.
The present invention also provides tetra-sodium risedronate as tetra-sodium risedronate Form I, tetra-sodium risedronate Form II and tetra-sodium risedronate Form III.
Tetra-sodium risedronate Form I as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
Tetra-sodium risedronate Form I according to the present invention is further characterised as having characteristic peaks (20): 6.33, 9.76, 11.05, 12.15, 12.65, 15.13, 16.77, 17.0, 18.99, 22.23, 22.61 and 30.53 .
Tetra-sodium risedronate Form I 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.
Tetra-sodium risedronate Form I 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.
Tetra-sodium risedronate Form I can be still further characterised by a typical DSC
thermograph as shown in Figure 4. Tetra-sodium risedronate Form I has a DSC
endotherm temperature onset of about 175 C.
Tetra-sodium risedronate Form II as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.
Tetra-sodium risedronate Form II according to the present invention is further characterised as having characteristic peaks (20): 4.33, 5.03, 5.48, 6.94, 9.94, 11.06, 11.89, 12.94, 13.16, 14.14, 16.63, 21.38 and 22.20 .
Tetra-sodium risedronate Form II 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 6.
Tetra-sodium risedronate Form II according to the present invention is furtlzer characterised as having an FTNIR reflection spectru.m, or substantially the same FTNIR reflection spectrum, as shown in Figure 7.
Tetra-sodium risedronate Form II can be still fu.rther characterised by a typical DSC
tllermograph as shown in Figure 8. Tetra-sodium risedronate Form II has a DSC
endotherm temperature onset of about 120 C. , Tetra-sodium risedronate Form III as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.
Tetra-sodium risedronate Form III according to the present invention is further characterised as having characteristic peaks (20): 5.17, 5.57 and 7.06 .
Tetra-sodium risedronate Form III 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 10.
Tetra-sodium risedronate Form III 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 11.
Tetra-sodium risedronate Form III can be still further characterised by a typical DSC
thermograph as shown in Figure 12. Tetra-sodium risedronate Form III has a DSC
endotherm temperature onset of about 80 C.
The present invention also provides a process of preparing a tetra-(alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described, which comprises contacting risedronic free acid with a source of a pharmaceutically acceptable alkali metal and thus converting the free acid to a tetra-(alkali metal) salt of risedronic acid. More particularly, a process according to the present invention comprises contacting a suspension of risedronic free acid with a source of a pharmaceutically acceptable alkali metal, adjusting the pH to about 13 to 14, preferably about 13.4, and thereby converting the risedronic free acid to a tetra-(alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described.
Preferably the source of the pharmaceutically acceptable alkali metal is the corresponding alkali metal hydroxide, preferably sodium hydroxide, whereby addition of the hydroxide achieves adjustment to the above referred to pH range of 13 to 14.
Suitably the reaction scheme can be illustrated as follows.
N \ ~OH N 0 ONa POH P-ONa HO + NaOH -~ I HO +H20 /OH ~ONa /P -OH /P -ONa O O
In a preferred embodiment of the present invention, a process as described herein prepares tetra-sodium risedronate as any one of Forms I, II or III as described herein.
Preferably, for preparation of tetra-sodium risedronate Form I, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4.
Preferably a C1_4alcohol, such as methanol or ethanol, is added at a temperature of up to about 30 C, followed by crystallization of tetra-sodium risedronate Form I
according to the present invention.
Preferably, for preparation of tetra-sodium risedronate Form II, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4. The solution is heated to reflux and preferably a Cl-4alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling and filtration to obtain tetra-sodium risedronate Form II
according to the present invention.
Preferably, for preparation of tetra-sodium risedronate Form III, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4. The solution is heated to reflux and preferably a Cl-4alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling, further addition of a C1_4alcohol and filtration to obtain tetra-sodium risedronate Form III according to the present invention.
Suitably risedronic acid as employed in the above reactions is prepared by the reaction of phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt. Suitably the reaction is also carried out in the presence of phosphorous trihalide and phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water. This can be represented by the following reaction scheme.
(1) PX3 (excess) + H20 (2) PX3 (excess) + H3PO3 + HX
N
CO2H=HX
(3) PX3 (excess) + H3P03 + CO2H.HX
N~ O'' Ps OH
OH
HO + (H20 + PX3 (excess)) 30 H3PO3 + HX
,OH
-OH
Preferably pyridylacetic acid is employed in the form of the hydrochloride salt and the phosphorous trihalide employed is phosphorous trichloride.
A tetra-(alkali metal) salt of risedronic acid as provided by the present invention has therapeutic utility in the treatment of diseases associated with bone resorption disorders and more specifically in the treatment of diseases of bone and calcium metabolism. 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 conlposition comprising a therapeutically effective dose of a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid as prepared by the present invention, 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 a tetra-(alkali metal) salt of risedronic acid as prepared by the present invention 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, a tetra-(alkali metal) salt of risedronic acid 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, a tetra-(alkali metal) salt of risedronic acid can be used in creams, ointments or lotions.
To achieve the desired prophylactic or therapeutic effect, the dose of a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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, a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid as provided by the present invention.
A preparation in the form of gelatin capsules can be obtained by mixing a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid 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.
A tetra-(alkali metal) salt of risedronic acid can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
There is also provided by the present invention a tetra-(alkali metal) salt of risedronic acid, for use in therapy.
The present invention further provides a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid. 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 a tetra-(alkali metal) salt of risedronic acid.
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.
Figure 1 is an XRPD pattern of tetra-sodium risedronate Form I according to the present invention.
Figure 2 is an FTIR transmission spectrum of tetra-sodium risedronate Form I
according to the present invention recorded by KBr disc and resolution 4 cm 1.
Figure 3 is an FTNIR reflection spectrum of tetra-sodium risedronate Fonn I
according to the present invention, recorded with solid probe accessories and resolution 8 cm l.
Figure 4 is a DSC thermogram of tetra-sodium risedronate Form I according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 175 C ).
Figure 5 is an XRPD pattern of tetra-sodium risedronate Form II according to the present invention.
Figure 6 is an FTIR transmission spectrum of tetra-sodium risedronate Form II
according to the present invention recorded by KBr disc and resolution 4 cm 1.
Figure 7 is an FTNIR reflection spectrum of tetra-sodium risedronate Form II
according to the present invention, recorded with solid probe accessories and resolution 8 cm l.
Figure 8 is a DSC thermogram of tetra-sodium risedronate Form II according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 120 C ).
Figure 9 is an XRPD pattern of tetra-sodium risedronate Form III according to the present invention.
Figure 10 is an FTIR transmission spectrum of tetra-sodium risedronate Form III
according to the present invention recorded by KBr disc and resolution 4 cm"1.
Figure 11 is an FTNIR reflection spectrum of tetra-sodium risedronate Form III
according to the present invention, recorded with solid probe accessories and resolution 8 cm 1.
Figure 12 is a DSC thermogram of tetra-sodiuin risedronate Form III according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 80 C ).
The above referenced XRPD analysis was carried out for each of polymorphs I, II and III with following experimental conditions:
Samples after being powdered in a mortar and pestle are applied directly into a Phillips' original circular sample holder (16 mm Sample holder preparation diameter) PW1811/16, manually pressed with the Phillips' original sample preparation kit PW1770/10, and closed with the Phillips' original bottom plate PW1 811/00 Instrument Philips X'Pert PRO
Goniometer PW3050/60 Generator PW3040; 45 kV, 40 mA
X-Ray tube PW3373/00; Cu anode LFF
Focus Linear Sample stage PW3072/60 or PW3064 Scan angle ran e(20 4- 40 Scan mode Continuous absolute scan Step size 20) 0.016 Time per step 100 seconds X-ray radiation CuKa Primary soller slit 0.04 rad Primary mask 10 mm PDS Fixed, 1/2 Secondary soller slit 0.04 rad Filter Ni Detector X'Celerator (2.022 20) Control program X'Pert Data Collector The above referenced FTIR transmission spectra for each of polymorphs I, II
and III
were 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).
The above referenced FTNIR reflection spectra for each of polymorphs I, II and III
were 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).
The above referenced DSC thermograms for each of polymorphs I, II and III were obtained by using a TA Instruments MDSC Q1000, where the sample was scanned at C/min in N2 atmosphere in closed Al pan.
Example 1 100m1 of water and 15g of risedronic acid were charged to a 1000m1 three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
800m1 of methanol were slowly added under room temperature (up to 30 C).
Crystallization of the salt started at about 30 C, when 320m1 of methanol were added. When all 400m1 of methanol were added, the suspension was maintained at the room temperature (-24 C) for three hours. Risedronate tetra-sodium salt, 21.17 g, was obtained after filtration, washed with 100ml of a water / methanol solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form I.
Example 2 200m1 of water and 15g of risedronic acid were charged to a 2000ml three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
The solution was heated to reflux (-100 C) and 800m1 of methanol were slowly added under reflux. Crystallization of the salt started at about 78 C, when 320m1 of methanol were added. When all 800m1 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 0-5 C over the period of two hours and retained for one hour at this temperature. Risedronate tetra-sodium salt, 19.58 g, was obtained after filtration, washed with 100ml of a water / methanol cold solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form II.
Example 3 100m1 of water and 15g of risedronic acid were charged to a 500m1 three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
The solution was heated to reflux (-100 C) and 300m1 of methanol were slowly added under reflux. Crystallization of the salt started at about 78 C, when 130m1 of methanol were added. When al1300m1 of methanol were added, the suspension was maintained at the reflux temperature (-77 C) for five minutes, and then allowed to cool to 60 C, followed by addition of 100m1 of methanol. The suspension was then slowly cooled to 0-5 C over the period of two hours and retained for one hour at this temperature. Risedronate tetra-sodium salt, 20.98 g, was obtained after filtration, washed with 50ml of a water / methanol cold solution (1 / 4) and dried.
Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form III.
thermograph as shown in Figure 4. Tetra-sodium risedronate Form I has a DSC
endotherm temperature onset of about 175 C.
Tetra-sodium risedronate Form II as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.
Tetra-sodium risedronate Form II according to the present invention is further characterised as having characteristic peaks (20): 4.33, 5.03, 5.48, 6.94, 9.94, 11.06, 11.89, 12.94, 13.16, 14.14, 16.63, 21.38 and 22.20 .
Tetra-sodium risedronate Form II 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 6.
Tetra-sodium risedronate Form II according to the present invention is furtlzer characterised as having an FTNIR reflection spectru.m, or substantially the same FTNIR reflection spectrum, as shown in Figure 7.
Tetra-sodium risedronate Form II can be still fu.rther characterised by a typical DSC
tllermograph as shown in Figure 8. Tetra-sodium risedronate Form II has a DSC
endotherm temperature onset of about 120 C. , Tetra-sodium risedronate Form III as provided by the present invention can be characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.
Tetra-sodium risedronate Form III according to the present invention is further characterised as having characteristic peaks (20): 5.17, 5.57 and 7.06 .
Tetra-sodium risedronate Form III 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 10.
Tetra-sodium risedronate Form III 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 11.
Tetra-sodium risedronate Form III can be still further characterised by a typical DSC
thermograph as shown in Figure 12. Tetra-sodium risedronate Form III has a DSC
endotherm temperature onset of about 80 C.
The present invention also provides a process of preparing a tetra-(alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described, which comprises contacting risedronic free acid with a source of a pharmaceutically acceptable alkali metal and thus converting the free acid to a tetra-(alkali metal) salt of risedronic acid. More particularly, a process according to the present invention comprises contacting a suspension of risedronic free acid with a source of a pharmaceutically acceptable alkali metal, adjusting the pH to about 13 to 14, preferably about 13.4, and thereby converting the risedronic free acid to a tetra-(alkali metal) salt of risedronic acid according to the present invention substantially as hereinbefore described.
Preferably the source of the pharmaceutically acceptable alkali metal is the corresponding alkali metal hydroxide, preferably sodium hydroxide, whereby addition of the hydroxide achieves adjustment to the above referred to pH range of 13 to 14.
Suitably the reaction scheme can be illustrated as follows.
N \ ~OH N 0 ONa POH P-ONa HO + NaOH -~ I HO +H20 /OH ~ONa /P -OH /P -ONa O O
In a preferred embodiment of the present invention, a process as described herein prepares tetra-sodium risedronate as any one of Forms I, II or III as described herein.
Preferably, for preparation of tetra-sodium risedronate Form I, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4.
Preferably a C1_4alcohol, such as methanol or ethanol, is added at a temperature of up to about 30 C, followed by crystallization of tetra-sodium risedronate Form I
according to the present invention.
Preferably, for preparation of tetra-sodium risedronate Form II, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4. The solution is heated to reflux and preferably a Cl-4alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling and filtration to obtain tetra-sodium risedronate Form II
according to the present invention.
Preferably, for preparation of tetra-sodium risedronate Form III, a suspension of risedronic free acid and water is maintained at about 20 C, followed by the addition of sodium hydroxide to form a solution. Suitably the pH is adjusted to about 13.4. The solution is heated to reflux and preferably a Cl-4alcohol, such as methanol or ethanol, is added under reflux. Crystallization of tetra-sodium risedronate starts under reflux followed by cooling, further addition of a C1_4alcohol and filtration to obtain tetra-sodium risedronate Form III according to the present invention.
Suitably risedronic acid as employed in the above reactions is prepared by the reaction of phosphorous acid with pyridylacetic acid, optionally present as a hydrohalide salt. Suitably the reaction is also carried out in the presence of phosphorous trihalide and phosphorous acid is formed in situ in the reaction mixture by the reaction of phosphorous trihalide and water. This can be represented by the following reaction scheme.
(1) PX3 (excess) + H20 (2) PX3 (excess) + H3PO3 + HX
N
CO2H=HX
(3) PX3 (excess) + H3P03 + CO2H.HX
N~ O'' Ps OH
OH
HO + (H20 + PX3 (excess)) 30 H3PO3 + HX
,OH
-OH
Preferably pyridylacetic acid is employed in the form of the hydrochloride salt and the phosphorous trihalide employed is phosphorous trichloride.
A tetra-(alkali metal) salt of risedronic acid as provided by the present invention has therapeutic utility in the treatment of diseases associated with bone resorption disorders and more specifically in the treatment of diseases of bone and calcium metabolism. 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 conlposition comprising a therapeutically effective dose of a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid as prepared by the present invention, 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 a tetra-(alkali metal) salt of risedronic acid as prepared by the present invention 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, a tetra-(alkali metal) salt of risedronic acid 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, a tetra-(alkali metal) salt of risedronic acid can be used in creams, ointments or lotions.
To achieve the desired prophylactic or therapeutic effect, the dose of a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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, a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid as provided by the present invention.
A preparation in the form of gelatin capsules can be obtained by mixing a tetra-(alkali metal) salt of risedronic acid 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 a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid 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.
A tetra-(alkali metal) salt of risedronic acid can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
There is also provided by the present invention a tetra-(alkali metal) salt of risedronic acid, for use in therapy.
The present invention further provides a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid, 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 a tetra-(alkali metal) salt of risedronic acid. 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 a tetra-(alkali metal) salt of risedronic acid.
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.
Figure 1 is an XRPD pattern of tetra-sodium risedronate Form I according to the present invention.
Figure 2 is an FTIR transmission spectrum of tetra-sodium risedronate Form I
according to the present invention recorded by KBr disc and resolution 4 cm 1.
Figure 3 is an FTNIR reflection spectrum of tetra-sodium risedronate Fonn I
according to the present invention, recorded with solid probe accessories and resolution 8 cm l.
Figure 4 is a DSC thermogram of tetra-sodium risedronate Form I according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 175 C ).
Figure 5 is an XRPD pattern of tetra-sodium risedronate Form II according to the present invention.
Figure 6 is an FTIR transmission spectrum of tetra-sodium risedronate Form II
according to the present invention recorded by KBr disc and resolution 4 cm 1.
Figure 7 is an FTNIR reflection spectrum of tetra-sodium risedronate Form II
according to the present invention, recorded with solid probe accessories and resolution 8 cm l.
Figure 8 is a DSC thermogram of tetra-sodium risedronate Form II according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 120 C ).
Figure 9 is an XRPD pattern of tetra-sodium risedronate Form III according to the present invention.
Figure 10 is an FTIR transmission spectrum of tetra-sodium risedronate Form III
according to the present invention recorded by KBr disc and resolution 4 cm"1.
Figure 11 is an FTNIR reflection spectrum of tetra-sodium risedronate Form III
according to the present invention, recorded with solid probe accessories and resolution 8 cm 1.
Figure 12 is a DSC thermogram of tetra-sodiuin risedronate Form III according to the present invention, recorded at a heat rate of 10 C/min (endotherm temperature onset is at 80 C ).
The above referenced XRPD analysis was carried out for each of polymorphs I, II and III with following experimental conditions:
Samples after being powdered in a mortar and pestle are applied directly into a Phillips' original circular sample holder (16 mm Sample holder preparation diameter) PW1811/16, manually pressed with the Phillips' original sample preparation kit PW1770/10, and closed with the Phillips' original bottom plate PW1 811/00 Instrument Philips X'Pert PRO
Goniometer PW3050/60 Generator PW3040; 45 kV, 40 mA
X-Ray tube PW3373/00; Cu anode LFF
Focus Linear Sample stage PW3072/60 or PW3064 Scan angle ran e(20 4- 40 Scan mode Continuous absolute scan Step size 20) 0.016 Time per step 100 seconds X-ray radiation CuKa Primary soller slit 0.04 rad Primary mask 10 mm PDS Fixed, 1/2 Secondary soller slit 0.04 rad Filter Ni Detector X'Celerator (2.022 20) Control program X'Pert Data Collector The above referenced FTIR transmission spectra for each of polymorphs I, II
and III
were 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).
The above referenced FTNIR reflection spectra for each of polymorphs I, II and III
were 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).
The above referenced DSC thermograms for each of polymorphs I, II and III were obtained by using a TA Instruments MDSC Q1000, where the sample was scanned at C/min in N2 atmosphere in closed Al pan.
Example 1 100m1 of water and 15g of risedronic acid were charged to a 1000m1 three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
800m1 of methanol were slowly added under room temperature (up to 30 C).
Crystallization of the salt started at about 30 C, when 320m1 of methanol were added. When all 400m1 of methanol were added, the suspension was maintained at the room temperature (-24 C) for three hours. Risedronate tetra-sodium salt, 21.17 g, was obtained after filtration, washed with 100ml of a water / methanol solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form I.
Example 2 200m1 of water and 15g of risedronic acid were charged to a 2000ml three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
The solution was heated to reflux (-100 C) and 800m1 of methanol were slowly added under reflux. Crystallization of the salt started at about 78 C, when 320m1 of methanol were added. When all 800m1 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 0-5 C over the period of two hours and retained for one hour at this temperature. Risedronate tetra-sodium salt, 19.58 g, was obtained after filtration, washed with 100ml of a water / methanol cold solution (1 / 4) and dried. Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form II.
Example 3 100m1 of water and 15g of risedronic acid were charged to a 500m1 three necked flask. The suspension was maintained at room temperature (-20 C) and the pH
was adjusted with sodium hydroxide (40%) until a pH of about 13.4 was achieved.
The solution was heated to reflux (-100 C) and 300m1 of methanol were slowly added under reflux. Crystallization of the salt started at about 78 C, when 130m1 of methanol were added. When al1300m1 of methanol were added, the suspension was maintained at the reflux temperature (-77 C) for five minutes, and then allowed to cool to 60 C, followed by addition of 100m1 of methanol. The suspension was then slowly cooled to 0-5 C over the period of two hours and retained for one hour at this temperature. Risedronate tetra-sodium salt, 20.98 g, was obtained after filtration, washed with 50ml of a water / methanol cold solution (1 / 4) and dried.
Analysis carried out confirmed the risedronate tetra-sodium salt thus prepared to be tetra-sodium risedronate form III.
Claims (42)
1. A pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid.
2. A pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid according to claim 1, wherein the alkali metal is sodium or potassium.
3. Tetra-sodium risedronate.
4. Tetra-sodium risedronate Form I characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 1.
5. Tetra-sodium risedronate Form I characterised as having characteristic peaks (20): 6.33, 9.76, 11.05, 12.15, 12.65, 15.13, 16.77, 17.0, 18.99, 22.23, 22.61 and 30.53°.
6. Tetra-sodium risedronate Form I characterised as having an FTIR
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2.
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 2.
7. Tetra-sodium risedronate Form I characterised as having an FTNIR reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 3.
8. Tetra-sodium risedronate Form I characterised by a DSC thermograph as shown in Figure 4.
9. Tetra-sodium risedronate Form I according to claim 8, having a DSC
endotherm temperature onset of about 175°C.
endotherm temperature onset of about 175°C.
10. Tetra-sodium risedronate Form II characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 5.
11. Tetra-sodium risedronate Form II characterised as having characteristic peaks (20): 4.33, 5.03, 5.48, 6.94, 9.94, 11.06, 11.89, 12.94, 13.16, 14.14, 16.63, 21.38 and 22.200.
12. Tetra-sodium risedronate Form II characterised as having an FTIR
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 6.
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 6.
13. Tetra-sodium risedronate Form II characterised as having an FTNIR
reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 7.
reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 7.
14. Tetra-sodium risedronate Form II characterised by a DSC thermograph as shown in Figure 8.
15. Tetra-sodium risedronate Form II according to claim 14, having a DSC
endotherm temperature onset of about 120°C.
endotherm temperature onset of about 120°C.
16. Tetra-sodium risedronate Form III characterised as having an X-ray powder diffraction pattern, or substantially the same X-ray powder diffraction pattern, as shown in Figure 9.
17. Tetra-sodium risedronate Form III characterised as having characteristic peaks (20): 5.17, 5.57 and 7.06°.
18. Tetra-sodium risedronate Form III characterised as having an FTIR
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 10.
transmission spectrum, or substantially the same FTIR transmission spectrum, as shown in Figure 10.
19. Tetra-sodium risedronate Form III characterised as having an FTNIR
reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 11.
reflection spectrum, or substantially the same FTNIR reflection spectrum, as shown in Figure 11.
20. Tetra-sodium risedronate Form III characterised by a DSC thermograph as shown in Figure 12.
21. Tetra-sodium risedronate Form III according to claim 20, having a DSC
endotherm temperature onset of about 80°C.
endotherm temperature onset of about 80°C.
22. A process of preparing a tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21, which comprises contacting risedronic free acid with a source of a pharmaceutically acceptable alkali metal and thus converting the free acid to a tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21.
23. A process according to claim 22, which comprises contacting a suspension of risedronic free acid with a source of a pharmaceutically acceptable alkali metal, adjusting the pH to about 13 to 14 and thereby converting the risedronic free acid to a tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21.
24. A process according to claim 23, which comprises adjusting the pH to about 13.4.
25. A process according to any of claims 22 to 24, wherein the source of the pharmaceutically acceptable alkali metal is the corresponding alkali metal hydroxide.
26. A process according to claim 25, wherein the corresponding alkali metal hydroxide is sodium hydroxide.
27. A process according to any of claims 22 to 26, which prepares tetra-sodium risedronate Form I according to any of claims 4 to 9.
28. A process according to claim 27, which comprises maintaining a suspension of risedronic free acid and water at about 20°C, adding sodium hydroxide to form a solution, adjusting the pH to about 13.4, adding a C1-4alcohol at a temperature of up to about 30°C, and crystallizing tetra-sodium risedronate Form I according to any of claims 4 to 9.
29. A process according to any of claims 22 to 26, which prepares tetra-sodium risedronate Form II according to any of claims 10 to 15.
30. A process according to claim 29, which comprises maintaining a suspension of risedronic free acid and water at about 20°C, adding sodium hydroxide to form a solution, adjusting the pH to about 13.4, heating the solution to reflux and adding a C1-4alcohol under reflux, crystallizing tetra-sodium risedronate under reflux, cooling, filtering and crystallizing tetra-sodium risedronate Form II according to any of claims to 15.
31. A process according to any of claims 22 to 26, which prepares tetra-sodium risedronate Form III according to any of claims 16 to 21.
32. A process according to claim 31, which comprises maintaining a suspension of risedronic free acid and water at about 20°C, adding sodium hydroxide to form a solution, adjusting the pH to about 13.4, heating the solution to reflux, adding a C1-4alcohol under reflux, crystallizing tetra-sodium risedronate under reflux, cooling, further adding a C1-4alcohol, filtering and crystallizing to obtain tetra-sodium risedronate Form III according to any of claims 16 to 21.
33. A pharmaceutical composition comprising a therapeutically effective dose of a pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
34. A pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21, for use in therapy.
35. A pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21, 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.
36. Use according to claim 35, in the manufacture of a medicament for the treatment of diseases of bone and calcium metabolism.
37. Use according to claim 36, 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.
38. Use according to claim 37, in the manufacture of a medicament for the treatment of osteoporosis.
39. 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 a pharmaceutically acceptable tetra-(alkali metal) salt of risedronic acid according to any of claims 1 to 21.
40. A method according to claim 39, for treating diseases of bone and calcium metabolism.
41. A method according to claim 39 or 40, for the treatment of any one of osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions.
42. A method according to claim 41, for the treatment of osteoporosis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0609465.0A GB0609465D0 (en) | 2006-05-12 | 2006-05-12 | Pharmaceutically acceptable salts and polymorphic forms |
| GB0609465.0 | 2006-05-12 | ||
| PCT/GB2007/000792 WO2007132138A1 (en) | 2006-05-12 | 2007-03-06 | Pharmaceutically acceptable salts and polymorphic forms |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2649489A1 true CA2649489A1 (en) | 2007-11-22 |
Family
ID=36637404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002649489A Abandoned CA2649489A1 (en) | 2006-05-12 | 2007-03-06 | Pharmaceutically acceptable salts and polymorphic forms |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2018392A1 (en) |
| CA (1) | CA2649489A1 (en) |
| EA (1) | EA200870525A1 (en) |
| GB (1) | GB0609465D0 (en) |
| WO (1) | WO2007132138A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2016084A2 (en) | 2006-05-11 | 2009-01-21 | Ind-Swift Laboratories Limited | Process for the preparation of pure risedronic acid or salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ293349B6 (en) * | 2002-10-25 | 2004-04-14 | Léčiva, A.S. | Novel crystalline form of 3-pyridyl-1-hydroxyethylidene-1,1-bisphopshonoc acid sodium salt |
-
2006
- 2006-05-12 GB GBGB0609465.0A patent/GB0609465D0/en active Pending
-
2007
- 2007-03-06 WO PCT/GB2007/000792 patent/WO2007132138A1/en active Application Filing
- 2007-03-06 EP EP07712850A patent/EP2018392A1/en not_active Withdrawn
- 2007-03-06 CA CA002649489A patent/CA2649489A1/en not_active Abandoned
- 2007-03-06 EA EA200870525A patent/EA200870525A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2018392A1 (en) | 2009-01-28 |
| EA200870525A1 (en) | 2009-04-28 |
| WO2007132138A1 (en) | 2007-11-22 |
| GB0609465D0 (en) | 2006-06-21 |
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