WO2007125521A2 - Polymorphic form of zoledronic acid and processes for their preparation - Google Patents
Polymorphic form of zoledronic acid and processes for their preparation Download PDFInfo
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- WO2007125521A2 WO2007125521A2 PCT/IB2007/051644 IB2007051644W WO2007125521A2 WO 2007125521 A2 WO2007125521 A2 WO 2007125521A2 IB 2007051644 W IB2007051644 W IB 2007051644W WO 2007125521 A2 WO2007125521 A2 WO 2007125521A2
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- Prior art keywords
- zoledronic acid
- preparation
- aqueous solution
- crystalline form
- temperature
- Prior art date
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960004276 zoledronic acid Drugs 0.000 title claims abstract description 86
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000010409 thin film Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002441 X-ray diffraction Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000002411 thermogravimetry Methods 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001599 osteoclastic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- JKQKNOPRCFYWCF-UHFFFAOYSA-N (1-hydroxy-2-imidazol-1-yl-2-phosphonoethyl)phosphonic acid Chemical compound OP(=O)(O)C(O)C(P(O)(O)=O)N1C=CN=C1 JKQKNOPRCFYWCF-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- QAFBDRSXXHEXGB-UHFFFAOYSA-N imidazol-1-ylacetic acid Chemical compound OC(=O)CN1C=CN=C1 QAFBDRSXXHEXGB-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- the present invention provides a polymorphic form (Form A) of zoledronic acid and amorphous zoledronic acid.
- the present invention further provides processes for preparation of said Form A and amorphous zoledronic acid.
- the present invention provides pharmaceutical compositions comprising Form A or amorphous zoledronic acid.
- Zoledronic acid is chemically, (l-hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid of the Formula I,
- Bisphosphonates are a class of drugs developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification.
- Zoledronic acid belongs to the therapeutics class of geminal bisphosphonates.
- the principle pharmacologic action of zoledronic acid is inhibition of osteoclastic bone resorption of mineralized bone and cartilage through its binding to bone. It inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
- hypercalcemia high levels of blood calcium
- multiple myeloma tumors formed by the cells of the bone marrow
- certain types of bone metastases the spread of cancer
- U.S. Patent No 4,939,130 discloses a method for preparing zoledronic acid by reacting imidazol-1-yl-acetic acid with phosphoric acid and phosphorous trichloride and recrystallizing the product from water.
- PCT application No WO 2005/05447 discloses crystalline forms of zoledronic acid and zoledronate sodium and amorphous form of zoledronate sodium.
- the crystal form characterized by powder X-ray diffraction pattern having peaks at 2 ⁇ values (°) of 12.1, 12.8, 15.7 and 18.9 is designated as Form I.
- Amorphous form of the sodium salt of zoledronic acid is also reported which is obtained by treating zoledronic acid with sodium hydroxide in water followed by precipitating amorphous zoledronate sodium by concentration of the solution thereof under vacuum.
- the present inventors have developed a hitherto unknown polymorphic form of zoledronic acid, designated Form A, and the amorphous form of zoledronic acid.
- the present invention also provides processes for preparation of Form A of zoledronic acid, amorphous zoledronic acid and of Form I of zoledronic acid disclosed in the '447 Application.
- a first aspect of the present invention provides crystalline Form A of zoledronic acid having characteristic X-ray diffraction with the following characteristic peak values (2 ⁇ ): 9.2, 13.2, 14.6, 17.4, 18.4, and 25.4 ⁇ 0.2.
- the crystalline Form A exhibits characteristic Differential Scanning Calorimetric Thermogram as depicted in Figure 2 and Thermogravimetric Analysis profile as depicted in Figure 3.
- a second aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of, a) heating an aqueous solution zoledronic acid to about 6O 0 C to 100 0 C, b) cooling the solution of step a) to about 3O 0 C to -10 0 C, c) isolating crystalline Form A of zoledronic acid from the reaction mass.
- a third aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of, a) stirring a suspension of zoledronic acid in an organic solvent and optionally water, b) isolating crystalline Form A of zoledronic acid from the reaction mass thereof.
- Suitable organic solvent may contain water or water may be added additionally to the reaction mixture.
- Suitable organic solvent consists one or more of linear or branched chain carboxylic acid esters containing 3 to 8 carbon atoms, halogenated hydrocarbons, or aromatic hydrocarbons.
- the ester is preferably selected from among ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, or isobutyl acetate.
- the aromatic hydrocarbon is preferably selected from among benzene, toluene, o-, m-, p-xylene or mixtures thereof.
- the halogenated hydrocarbon is preferably selected from among dichloromethane, 1 ,2-dichloroethane, or chloroform.
- a fourth aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of about 5O 0 C to about 9O 0 C.
- a fifth aspect of the present invention provides amorphous zoledronic acid, having characteristic X-ray diffraction pattern as depicted in Figure 5 of the accompanying drawings.
- a sixth aspect of the present invention provides a process for the preparation of amorphous zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to spray drying.
- Zoledronic acid is dissolved in water and the solution is fed to a spray drier having inlet temperature of about 50 to about 100 0 C, outlet temperature of about 40 to about 95 0 C at a rate of about 1 mL/min to about 10 mL/min to obtain amorphous zoledronic acid by using two fluid pressure nozzles and rotary atomizer.
- a seventh aspect of the present invention provides a process for the preparation of Form I of zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of 9O 0 C to about 100 0 C.
- Zoledronic acid is dissolved in water and the solution is fed to agitated thin film drier at a rate of about 1 mL/min to about 10 mL/min under reduced pressure of about 5 to about 300 mmHg and temperature of about 9O 0 C to about 100 0 C to obtain crystalline Form I of zoledronic acid.
- An eighth aspect of the present invention provides a process for the preparation of Form I of zoledronic acid wherein the said process comprises of lyophilizing an aqueous solution of zoledronic acid.
- Zoledronic acid is dissolved in water, the solution is frozen from about -20 to about -6O 0 C and a pressure of about 10 to about 80 mTorr is applied.
- the temperature of the frozen mass is increased to about O 0 C in 1 to 10 hours and then maintained at about O 0 C for 1 to 24 hours.
- the temperarure is increased to about 1O 0 C in 1 to 12 hours and maintained at about 1O 0 C for 1 to 24 hours.
- the mass is heated to about 20 to about 5O 0 C and unloaded to obtain Form I of zoledronic acid.
- a ninth aspect of the present invention provides a pharmaceutical composition comprising crystalline Form A of zoledronic acid.
- a tenth aspect of the present invention provides a pharmaceutical composition comprising amorphous zoledronic acid.
- the crystalline Form A or amorphous zoledronic acid of the present invention can be used to prepare pharmaceutical compositions by methods known in the art, for example that disclosed in U.S. 4,939,130.
- Zoledronic acid can be prepared by methods known in the art, for example, using the process described in U.S. Patent No 4,939,130, which is incorporated by reference herein.
- Figure 1 depicts powder X-ray diffractogram of crystalline Form A of zoledronic acid.
- Figure 2 depicts Differential Scanning Calorimetric Thermogram of crystalline Form A of zoledronic acid.
- Figure 3 depicts and Thermogravimetric Analysis profile of crystalline Form A of zoledronic acid.
- Figure 4 depicts powder X-ray diffractogram of amorphous zoledronic acid. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
- Powder XRD of the samples were determined by using a Rigaku RU-H3R X-Ray Diffractometer X-Ray tube with Cu target anode, Power: 40 KV, scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
- DSC thermograms were recorded using a Mettler Toledo DSC821e Differential Scanning Calorimeter, sample weight: 3-5 mg, temperature range: 50-350° C, heating rate: 20° C/min, and Nitrogen flow set at 80.0 mL/min The percentage weight loss was recorded using a Perkin Elmer, Model Pyris 1 thermogravimetric analyzer (TGA), Temperature range: 20-350 0 C, Heating rate: 10° C/min, purged with Nitrogen.
- TGA thermogravimetric analyzer
- Zoledronic acid (5 g) was dissolved in water (250 mL). The solution was frozen at -4O 0 C and maintained at -4O 0 C for 2 hours and a pressure of 40-100 mtorr was applied. The temperature of the frozen mass was increased to O 0 C in 2 hours and the mass was maintained at O 0 C for 12 hours. The temperature of the mass was increased to 1O 0 C in 2 hours and the mass maintained at 1O 0 C for 12 hours. The mass was heated to 25 0 C and unloaded to obtain the title compound. Yield: 4.1 g
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention provides Form A and amorphous form of zoledronic acid. The present invention further provides processes for preparation of Form A, Form I and amorphous zoledronic acid. In addition the present invention provides pharmaceutical compositions comprising the polymorphic form and amorphous zoledronic acid.
Description
POLYMORPHIC FORM OF ZOLEDRONIC ACID AND PROCESSES FOR THEIR
PREPARATION
Field of the Invention
The present invention provides a polymorphic form (Form A) of zoledronic acid and amorphous zoledronic acid. The present invention further provides processes for preparation of said Form A and amorphous zoledronic acid. In addition, the present invention provides pharmaceutical compositions comprising Form A or amorphous zoledronic acid.
Background of the Invention
Zoledronic acid is chemically, (l-hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid of the Formula I,
Bisphosphonates are a class of drugs developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification. Zoledronic acid belongs to the therapeutics class of geminal bisphosphonates. The principle pharmacologic action of zoledronic acid is inhibition of osteoclastic bone resorption of mineralized bone and cartilage through its binding to bone. It inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. It is used in the treatment of hypercalcemia (high levels of blood calcium) that may occur in patients with some types of cancer and a type of cancer called multiple myeloma (tumors formed by the cells of the bone marrow) or certain types of bone metastases (the spread of cancer).
U.S. Patent No 4,939,130 discloses a method for preparing zoledronic acid by reacting imidazol-1-yl-acetic acid with phosphoric acid and phosphorous trichloride and recrystallizing the product from water. PCT application No WO 2005/05447 (herein after the '447 application) discloses crystalline forms of zoledronic acid and zoledronate sodium and amorphous form of zoledronate sodium. Of the crystal forms of zoledronic acid disclosed in the '447 application, the crystal
form characterized by powder X-ray diffraction pattern having peaks at 2Θ values (°) of 12.1, 12.8, 15.7 and 18.9 is designated as Form I. Amorphous form of the sodium salt of zoledronic acid is also reported which is obtained by treating zoledronic acid with sodium hydroxide in water followed by precipitating amorphous zoledronate sodium by concentration of the solution thereof under vacuum.
Summary of the Invention
The present inventors have developed a hitherto unknown polymorphic form of zoledronic acid, designated Form A, and the amorphous form of zoledronic acid. The present invention also provides processes for preparation of Form A of zoledronic acid, amorphous zoledronic acid and of Form I of zoledronic acid disclosed in the '447 Application.
Detailed Description of the Invention
A first aspect of the present invention provides crystalline Form A of zoledronic acid having characteristic X-ray diffraction with the following characteristic peak values (2Θ): 9.2, 13.2, 14.6, 17.4, 18.4, and 25.4 ± 0.2. The crystalline Form A exhibits characteristic Differential Scanning Calorimetric Thermogram as depicted in Figure 2 and Thermogravimetric Analysis profile as depicted in Figure 3.
A second aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of, a) heating an aqueous solution zoledronic acid to about 6O0C to 1000C, b) cooling the solution of step a) to about 3O0C to -100C, c) isolating crystalline Form A of zoledronic acid from the reaction mass.
A third aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of, a) stirring a suspension of zoledronic acid in an organic solvent and optionally water, b) isolating crystalline Form A of zoledronic acid from the reaction mass thereof.
Suitable organic solvent may contain water or water may be added additionally to the reaction mixture. Suitable organic solvent consists one or more of linear or branched chain carboxylic acid esters containing 3 to 8 carbon atoms, halogenated hydrocarbons, or aromatic hydrocarbons. The ester is preferably selected from among ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, or isobutyl acetate. The aromatic hydrocarbon is preferably selected from
among benzene, toluene, o-, m-, p-xylene or mixtures thereof. The halogenated hydrocarbon is preferably selected from among dichloromethane, 1 ,2-dichloroethane, or chloroform.
A fourth aspect of the present invention provides a process for the preparation of crystalline Form A of zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of about 5O0C to about 9O0C.
Zoledronic acid is dissolved in water and the solution is fed to agitated thin film drier at a rate of 1 to 10 ml/minute under reduced pressure of 5 to 300 mm Hg and temperature of about 50 to about 9O0C to obtain crystalline Form A of zoledronic acid. A fifth aspect of the present invention provides amorphous zoledronic acid, having characteristic X-ray diffraction pattern as depicted in Figure 5 of the accompanying drawings.
A sixth aspect of the present invention provides a process for the preparation of amorphous zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to spray drying. Zoledronic acid is dissolved in water and the solution is fed to a spray drier having inlet temperature of about 50 to about 1000C, outlet temperature of about 40 to about 950C at a rate of about 1 mL/min to about 10 mL/min to obtain amorphous zoledronic acid by using two fluid pressure nozzles and rotary atomizer.
A seventh aspect of the present invention provides a process for the preparation of Form I of zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of 9O0C to about 1000C.
Zoledronic acid is dissolved in water and the solution is fed to agitated thin film drier at a rate of about 1 mL/min to about 10 mL/min under reduced pressure of about 5 to about 300 mmHg and temperature of about 9O0C to about 1000C to obtain crystalline Form I of zoledronic acid.
An eighth aspect of the present invention provides a process for the preparation of Form I of zoledronic acid wherein the said process comprises of lyophilizing an aqueous solution of zoledronic acid.
Zoledronic acid is dissolved in water, the solution is frozen from about -20 to about -6O0C and a pressure of about 10 to about 80 mTorr is applied. The temperature of the frozen mass is increased to about O0C in 1 to 10 hours and then maintained at about O0C for 1 to 24
hours. Then the temperarure is increased to about 1O0C in 1 to 12 hours and maintained at about 1O0C for 1 to 24 hours. The mass is heated to about 20 to about 5O0C and unloaded to obtain Form I of zoledronic acid.
A ninth aspect of the present invention provides a pharmaceutical composition comprising crystalline Form A of zoledronic acid.
A tenth aspect of the present invention provides a pharmaceutical composition comprising amorphous zoledronic acid.
The crystalline Form A or amorphous zoledronic acid of the present invention can be used to prepare pharmaceutical compositions by methods known in the art, for example that disclosed in U.S. 4,939,130.
Zoledronic acid can be prepared by methods known in the art, for example, using the process described in U.S. Patent No 4,939,130, which is incorporated by reference herein.
Brief Description of Figures Figure 1 depicts powder X-ray diffractogram of crystalline Form A of zoledronic acid. Figure 2 depicts Differential Scanning Calorimetric Thermogram of crystalline Form A of zoledronic acid.
Figure 3 depicts and Thermogravimetric Analysis profile of crystalline Form A of zoledronic acid.
Figure 4 depicts powder X-ray diffractogram of amorphous zoledronic acid. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Powder XRD of the samples were determined by using a Rigaku RU-H3R X-Ray Diffractometer X-Ray tube with Cu target anode, Power: 40 KV, scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
DSC thermograms were recorded using a Mettler Toledo DSC821e Differential Scanning Calorimeter, sample weight: 3-5 mg, temperature range: 50-350° C, heating rate: 20° C/min, and Nitrogen flow set at 80.0 mL/min
The percentage weight loss was recorded using a Perkin Elmer, Model Pyris 1 thermogravimetric analyzer (TGA), Temperature range: 20-3500C, Heating rate: 10° C/min, purged with Nitrogen.
EXAMPLE 1 Preparation of crystalline Form A of zoledronic acid
Zoledronic acid (175 g) was dissolved in deionized water (3.8 L) at 80 to 850C. The solution was filtered through hyflo bed and cooled to 250C in about 4 hours. The cooled solution was stirred at 25 to 150C for 20 hours. The product obtained was dried at 40 to 450C under vacuum for 4-5 hours to afford the title compound. Yield: 63 g
XRD matches Figure 1.
EXAMPLE 2
Preparation of crystalline Form A of zoledronic acid
A suspension of zoledronic acid (5 g) in ethyl acetate (47.5 mL) and water (2.5 mL) was stirred at 15 to 2O0C for about 36 hours. The product obtained was dried at 40 to 450C for 4 hours to afford the title compound.
Yield: 3.3 g
XRD matches Figure 1.
EXAMPLE 3 Preparation of crystalline Form A of zoledronic acid
Zoledronic acid (5 g) was dissolved in water (100 mL) at 95 to 970C. The solution was filtered through hyflo bed and cooled to 5 to 1O0C in 10 to 15 minutes. The cooled solution was stirred for 1 hour and filtered and the product obtained was dried to afford the title compound. Yield: 4.5 g XRD matches Figure 1.
EXAMPLE 4 Preparation of crystalline Form A of zoledronic acid
Zoledronic acid (5 g) was dissolved in water (250 mL) at 6O0C. The solution was maintained at 6O0C and fed to agitated thin film drier at the rate of 5 ml/min under reduced pressure of 10 mm Hg. The temperature was kept at 750C and the title compound was obtained. Yield: 4.0 g XRD matches Figure 1.
EXAMPLE 5 Preparation of amorphous zoledronic acid
Zoledronic acid (5 g) was dissolved water (250 rnL) at 6O0C. The solution was maintained at 6O0C and fed to spray drier at a rate of 5 ml/min (inlet temperature: 750C, outlet temperature 550C) to afford the title compound. Yield: 3.5 g XRD matches Figure 4.
EXAMPLE 6
Preparation of amorphous zoledronic acid Zoledronic acid (5 g) was dissolved in water (250 mL at 6O0C. The solution was maintained at
6O0C and fed to spray drier at a rate of 5 ml/min (inlet temperature: 750C, outlet temperature at
550C) to afford the title compound.
Yield: 3.3 g
XRD matches Figure 4. EXAMPLE 7
Preparation of crystalline Form I of zoledronic acid
Zoledronic acid (5 g) was dissolved in water (125 mL) at 9O0C. The solution was maintained at 9O0C and fed to agitated thin film drier at the rate of 5 ml/min under reduced pressure of 10 mm Hg. The temperature was kept at 950C and the title compound was obtained. Yield: 3.9 g
EXAMPLE 8
Preparation of crystalline Form I of zoledronic acid
Zoledronic acid (5 g) was dissolved in water (250 mL). The solution was frozen at -4O0C and maintained at -4O0C for 2 hours and a pressure of 40-100 mtorr was applied. The temperature of the frozen mass was increased to O0C in 2 hours and the mass was maintained at O0C for 12 hours. The temperature of the mass was increased to 1O0C in 2 hours and the mass maintained at 1O0C for 12 hours. The mass was heated to 250C and unloaded to obtain the title compound. Yield: 4.1 g
Claims
We Claim: 1.Crystalline Form A of zoledronic acid having an X-ray diffraction pattern wherein characteristic 2Θ values are obtained at the following characteristic peak values (2Θ): 9.2, 13.2, 14.6, 17.4, 18.4, and 25.4 ± 0.2 2. The crystalline form of claim 1, further characterized by a Differential Scanning Calorimetric Thermogram as depicted in Figure 2. 3. The crystalline form of claim 1, further characterized by a Thermo gravimetric Analysis profile as depicted in Figure 3. 4. A process for the preparation of a crystalline form of zoledronic acid which has characteristic peak values (2Θ): 9.2, 13.2, 14.6, 17.4, 18.4, and 25.4 ± 0.2, wherein said process comprises the use of an aqueous solution medium for dissolving or dispersing zoledronic acid. 5. The process for claim 4 which further comprises of a) heating an aqueous solution zoledronic acid to about 6O0C to 1000C, and b) cooling the solution of step a) to about 3O0C to -100C. 6. The process for claim 4 which further comprises of stirring a suspension of zoledronic acid in a mixture of water and an organic solvent 7. The process according to claim 6 wherein the organic solvent at least one of comprising of C3_8 esters, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof. 8. The process according to claim 7 wherein the organic solvent comprises one or more of a linear or branched chain carboxylic acid ester containing 3 to 8 carbon atoms, a halogenated hydrocarbon, or an aromatic hydrocarbon. 9. The process according to claim 7 wherein the organic solvent is ethyl acetate. 10. A process of claim 4 wherein said process further comprises subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of about 5O0C to about 9O0C. 11. The process according to claim 10 wherein the temperature is about 600C. 12. Amorphous zoledronic acid. 13. A process for the preparation of amorphous zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to spray drying. 14. A process for the preparation of Form I of zoledronic acid wherein the said process comprises of subjecting an aqueous solution of zoledronic acid to agitated thin film drying at a temperature of about 9O0C to about 1000C . 15. The process according to claim 14 wherein the temperature is about 900C. 16. A process for the preparation of Form I of zoledronic acid wherein said process comprises of lyophilizing an aqueous solution of zoledronic acid.
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| WO2008064849A1 (en) * | 2006-11-27 | 2008-06-05 | Novartis Ag | Crystalline forms of zoledronic acid |
| US8399023B2 (en) | 2009-07-31 | 2013-03-19 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
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| DE10199052I1 (en) * | 1986-11-21 | 2002-01-10 | Novartis Ag | New substituted alkane diphosphonic acids |
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| CA2517387A1 (en) * | 2003-02-27 | 2004-09-10 | Teva Pharmaceutical Industries Ltd | Process for purification of zoledronic acid |
| EP1567533B1 (en) * | 2003-07-03 | 2009-03-11 | Teva Pharmaceutical Industries Ltd. | Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation |
| ES2337063T3 (en) * | 2003-08-21 | 2010-04-20 | Sun Pharmaceuticals Industries Ltd. | PROCESS FOR THE PREPARATION OF BISPHOSPHONIC ACID. |
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| EP1716161B1 (en) * | 2003-12-23 | 2011-05-04 | Alchymars S.p.A. | Ibandronic acid monosodium salt in the amorphous form |
| WO2005063717A1 (en) * | 2003-12-26 | 2005-07-14 | Natco Pharma Limited | An improved process for the preparation of zoledronic acid |
| CN1693308A (en) * | 2005-04-15 | 2005-11-09 | 扬子江药业集团有限公司 | Process for preparing dazoline phospho acid |
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| AR054673A1 (en) * | 2005-07-28 | 2007-07-11 | Gador Sa | A CRYSTAL FORM OF THE ZOLEDRONIC ACID, A PROCESS FOR THEIR OBTAINING AND THE PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT |
| JP2009507831A (en) * | 2005-09-12 | 2009-02-26 | ドクター レディズ ラボラトリーズ リミテッド | Crystalline trihydrate of zoledronic acid |
| WO2007069049A2 (en) * | 2005-12-16 | 2007-06-21 | Wockhardt Ltd | Processes for the preparation of pure zoledronic acid |
| WO2007096896A1 (en) * | 2006-02-20 | 2007-08-30 | Alembic Limited | An improved process for the preparation of biphosphonic derivatives |
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| WO2008064849A1 (en) * | 2006-11-27 | 2008-06-05 | Novartis Ag | Crystalline forms of zoledronic acid |
| JP2010510970A (en) * | 2006-11-27 | 2010-04-08 | ノバルティス アーゲー | Crystalline form of zoledronic acid |
| US8399023B2 (en) | 2009-07-31 | 2013-03-19 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
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