WO2007074475A2 - Novel polymorphic forms of ibandronate - Google Patents
Novel polymorphic forms of ibandronate Download PDFInfo
- Publication number
- WO2007074475A2 WO2007074475A2 PCT/IN2006/000501 IN2006000501W WO2007074475A2 WO 2007074475 A2 WO2007074475 A2 WO 2007074475A2 IN 2006000501 W IN2006000501 W IN 2006000501W WO 2007074475 A2 WO2007074475 A2 WO 2007074475A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ibandronate
- monosodium monohydrate
- novel
- monohydrate
- water
- Prior art date
Links
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 title claims description 26
- 229940015872 ibandronate Drugs 0.000 title claims description 21
- VBDRTGFACFYFCT-UHFFFAOYSA-M sodium;hydroxy-[(1r)-1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate;hydrate Chemical compound O.[Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O VBDRTGFACFYFCT-UHFFFAOYSA-M 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000013078 crystal Substances 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 3
- 238000007865 diluting Methods 0.000 claims 1
- -1 ibandronate monohydrate Chemical class 0.000 claims 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000013505 freshwater Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 229960005236 ibandronic acid Drugs 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000004682 monohydrates Chemical group 0.000 description 3
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YDWXRULMHQZBEX-UHFFFAOYSA-N 3-[methyl(pentyl)amino]propanoic acid;hydrochloride Chemical compound Cl.CCCCCN(C)CCC(O)=O YDWXRULMHQZBEX-UHFFFAOYSA-N 0.000 description 1
- 0 CCCCCN(C)CCC(*)(**(C)(C)C)O Chemical compound CCCCCN(C)CCC(*)(**(C)(C)C)O 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940028101 boniva Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical class [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
Definitions
- Present invention relates to novel polymorphic forms of ibandronate, particularly ibandronate monosodium monohydrate, process for their preparation and pharmaceutical compositions containing them.
- Patent DE3623397 (corresponding US Pat 4,927,814) describes preparation of diphosphonate derivatives, pharmaceutical compositions and methods of use. Notable among them is [l-Hydroxy-3-(memylpentylamino)propylidene]bisphosphonic acid monosodium monohydrate of formula-I,
- Monosodium monohydrate salt of ibandronic acid known as boniva is available in the market as bone resorption inhibitor.
- the drug substance can exist in amorphous form. Different polymorphs, pseudo polymorphs, or the amorphous form differ in their physical properties such as melting point, solubility, etc. These physical properties can appreciably influence the pharmaceutical properties such as dissolution rate and bioavailability. It is desirable that the drug substance is stable for extended periods of time without any need for specialized storage conditions. It is therefore important to evaluate a polymorphism of drug substance. Also, the identification of polymorphic form of a drug substance enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.
- ibandronate monosodium in its hydrate form exhibits polymorphism and two novel crystalline forms and one amorphous form of ibandronate monosodium can be synthesized by changing the crystallization conditions such as solvent, temperature, etc. These novel forms are found to be stable, reproducible, and suitable for pharmaceutical preparations. Water content in these forms is 4-6% w/w, preferably close to 5.0% w/w indicating for monohydrate form.
- the main objective of the present invention is to provide stable, novel crystalline forms of ibandronate monosodium designated as Form I and Form II, process for preparation of the said novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
- Water content in these forms is 4- 6% w/w, preferably 4.8-5.2% w/w indicating for monohydrate form.
- Another objective of the present invention is to provide stable, novel amorphous ibandronate monosodium designated as Form III, process for the said amorphous form and pharmaceutical compositions containing the said form. Water content in this form is 4.8-5.2% as monohydrate.
- Form I a novel crystalline form of ibandronate monosodium monohydrate, designated as Form I, characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ (intensity in %) 2.99
- ibandronate monosodium monoliydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in a suitable aqueous solvent at elevated temperature. The resultant solution is cooled to ambient temperature and filtered to get Form I crystals of ibandronate monosodium monohydrate.
- the suitable solvent is selected from a group consisting of water miscible solvents such as acetone, methanol, acetonitrile, and tetrahydrofuran.
- a novel crystalline form of ibandronate monosodium monohydrate designated as Form II, characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ (intensity in %) at about 4.94 (100.0), 11.05 (0.7), 14.11 (0.9), 17.17 (1.8), 18.60 (1.4), 19.95 (1.7), 25.90 (1.3), and 36.39 (0.9) degrees.
- ibandronate monosodium monohydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in aqueous isopropanol at elevated temperature. The resultant solution is cooled to ambient temperature and the crystals of Form II ibandronate monosodium monohydrate are isolated by filtration.
- a novel amorphous form designated as Form III of ibandronate monosodium monohydrate is provided.
- the amorphous ibandronate monosodium monohydrate according to the present invention is characterized by powder X-ray diffraction and microscopic examination.
- the XRD diffractogram is characterized by the absence of well-defined peaks, which are an essential feature of a crystalline compound.
- a process for the preparation of ibandronate monosodium monohydrate can be made by conventional techniques such as lyophilisation or evaporation (under vacuum) of a solution, preferably aqueous solution.
- Preferred method for amorphous form is to use spray-drying technique. This is a well- known and very efficient process suitable for commercial scale operation.
- the invention further includes pharmaceutical compositions comprising the polymorphic form of ibandronate monosodium monohydrate disclosed herein and a pharmaceutically acceptable carrier.
- These compositions may be in any suitable form such as tablets or capsules.
- Figure 1 is an X-ray powder diffraction pattern of Form I crystals of ibandronate monosodium monohydrate.
- Figure 2 is an X-ray powder diffraction pattern of Form II crystals of ibandronate monosodium monohydrate.
- Figure 3 is an X-ray powder diffraction pattern of Form III amorphous ibandronate monosodium monohydrate.
- Figure 4 is an X-ray powder diffraction pattern of 150mg tablet prepared from Form I crystals of ibandronate monosodium monohydrate.
- X-ray powder diffraction spectrum was recorded on a Siemens D5000 X-ray powder diffractometer having a copper-K ⁇ radiation.
- Example 1 The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
- Example 1 The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
- Reaction mass was diluted with 560ml of methanol and kept under stirring for 2hr. Crystallization of ibandronate began after 30min. Reaction mass was filtered and the wet cake washed with 50ml of 1:4 aqueous methanol. The wet solid was dried in the oven at 6O 0 C to get 145g of ibandronate as white solid.
- ibandronate 25g was taken into a 250ml three-necked RB flask and dissolved in 200ml of water. Water was distilled of from the reaction mass and added 100ml of fresh water. The reaction mass was treated with 2g of carbon and filtered. The filtrate was taken into a RB flask and added 200ml of acetone at 50-60 0 C. Crystallization of ibandronate began immediately. The reaction mass was cooled to 25 0 C and maintained for lhr before filtration. The wet solid was washed with 50ml of acetone and dried at 6O 0 C to get 2Og of Form I crystals of ibandronate monosodium monohydrate.
- Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 5ml of ethanol at 7O 0 C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 5ml of aqueous ethanol (4:1) and dried at 60°C to get 4.1g of Form I crystals of ibandronate monosodium monohydrate.
- Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 1 OmI of THF at 6O 0 C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 60 0 C to get 4.Og of Form I crystals of ibandronate monosodium monohydrate.
- Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 5O 0 C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 60 0 C to get 3.8g of Form I crystals of ibandronate monosodium monohydrate.
- Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 10ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 6O 0 C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 5ml of aqueous acetonitrile (1:1) and dried at 60°C to get 4.Og of Form II crystals of ibandronate monosodium monohydrate.
- Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 50ml of fresh water. The reaction mass was heated to 6O 0 C and treated with Ig of carbon. The reaction mass was filtered while hot. The filtrate was taken into a RB flask and freeze dried to get amorphous Form III ibandronate monosodium monohydrate.
- Form I crystals of ibandronate monosodium monohydrate prepared according to the process given in Example 1 is employed in an amount equivalent to 150mg of ibandronic acid per single dosage unit.
- Composition of one tablet is as given below.
- Present invention discloses novel polymorphic forms of ibandronate monosodium monohydrate designated as Form I, Form II, and Form III.
- Present invention discloses a commercially viable process for the reparation of novel polymorphic forms of ibandronate monosodium monohydrate.
- novel polymorphic forms of ibandronate monosodium monohydrate are suitable for pharmaceutical formulations such as tablets or capsules.
Landscapes
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to novel and stable polymorphic forms of ibandronate monosodium monohydrate of formula I and processes for their preparation. Ibandronate monosodium monohydrate is useful, as bone resorption inhibitor. The novel crystalline forms are designated as Form I, Form II and the amorphous ibandronate monosodium monohydrate as Form III.
Description
NOVEL POLYMORPHIC FORMS OF IBANDRONATE INTRODUCTION:
Present invention relates to novel polymorphic forms of ibandronate, particularly ibandronate monosodium monohydrate, process for their preparation and pharmaceutical compositions containing them.
Patent DE3623397 (corresponding US Pat 4,927,814) describes preparation of diphosphonate derivatives, pharmaceutical compositions and methods of use. Notable among them is [l-Hydroxy-3-(memylpentylamino)propylidene]bisphosphonic acid monosodium monohydrate of formula-I,
I
Monosodium monohydrate salt of ibandronic acid known as boniva is available in the market as bone resorption inhibitor.
The aforesaid US patent describes the preparation of ibandronic acid from the corresponding β-aminopropionic acid by reductive bisphosphonylation. However, no process for the preparation of pharmaceutically acceptable monosodium monohydrate salt of ibandronic acid is disclosed. There is a need to produce ibandronate monosodium monohydrate in a reproducible, pure and crystalline form to enable formulations to meet exact pharmaceutical requirements and specifications. It is known that pharmaceutical substances can exhibit polymorphism. Polymorphism is commonly defined as the ability of any substance to have two or more different crystal structures. Pharmaceutical substances may also encapsulate water or solvent molecules when crystallized. These solvates or hydrates are referred to as pseudo polymorphs. It is also possible that the drug substance can exist in amorphous form. Different polymorphs, pseudo polymorphs, or the amorphous form differ in their physical properties such as melting point, solubility, etc.
These physical properties can appreciably influence the pharmaceutical properties such as dissolution rate and bioavailability. It is desirable that the drug substance is stable for extended periods of time without any need for specialized storage conditions. It is therefore important to evaluate a polymorphism of drug substance. Also, the identification of polymorphic form of a drug substance enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.
We have found that ibandronate monosodium in its hydrate form exhibits polymorphism and two novel crystalline forms and one amorphous form of ibandronate monosodium can be synthesized by changing the crystallization conditions such as solvent, temperature, etc. These novel forms are found to be stable, reproducible, and suitable for pharmaceutical preparations. Water content in these forms is 4-6% w/w, preferably close to 5.0% w/w indicating for monohydrate form.
Accordingly the main objective of the present invention is to provide stable, novel crystalline forms of ibandronate monosodium designated as Form I and Form II, process for preparation of the said novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms. Water content in these forms is 4- 6% w/w, preferably 4.8-5.2% w/w indicating for monohydrate form.
Another objective of the present invention is to provide stable, novel amorphous ibandronate monosodium designated as Form III, process for the said amorphous form and pharmaceutical compositions containing the said form. Water content in this form is 4.8-5.2% as monohydrate.
DESCRIPTION OF THE INVENTION:
According to one aspect of the present invention there is provided a novel crystalline form of ibandronate monosodium monohydrate, designated as Form I, characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ (intensity in %) 2.99
(1.2), 6.02 (100), 9.79 (1.6), 12.29 (2.2), 14.28 (1.4), 14.99 (1.1), 16.78 (2.7), 17.17 (4.9),
18.03 (1.9), 18.42 (1.4), 19.59 (3.3), 20.12 (2.9), 20.54 (2.0), 21.42 (3.7), 23.67 (Ll)5 24.21 (1.3), 24.73 (2.5), 25.18 (3.5), 25.96 (1.0), 26.73 (1.9), 28.58 (2.0), 28.95 (1.9), 30.49 (3.1), 31.12 (1.0), 34.26 (1.3), 35.72 (1.6), 36.49 (1. 9), and 43.81 (1.1) degrees.
According to another aspect of the present invention there is provided a process for preparation of Form I of ibandronate monosodium monoliydrate. Thus, ibandronate monosodium monohydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in a suitable aqueous solvent at elevated temperature. The resultant solution is cooled to ambient temperature and filtered to get Form I crystals of ibandronate monosodium monohydrate. The suitable solvent is selected from a group consisting of water miscible solvents such as acetone, methanol, acetonitrile, and tetrahydrofuran.
According to one aspect of the present invention there is provided a novel crystalline form of ibandronate monosodium monohydrate, designated as Form II, characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ (intensity in %) at about 4.94 (100.0), 11.05 (0.7), 14.11 (0.9), 17.17 (1.8), 18.60 (1.4), 19.95 (1.7), 25.90 (1.3), and 36.39 (0.9) degrees.
According to another aspect of the present invention there is provided a process for the preparation of Form II of ibandronate monosodium monohydrate. Thus, ibandronate monosodium monohydrate prepared according to the process disclosed in our pending Indian patent application 996/CHE/05 is dissolved in aqueous isopropanol at elevated temperature. The resultant solution is cooled to ambient temperature and the crystals of Form II ibandronate monosodium monohydrate are isolated by filtration.
According to one aspect there is provided a novel amorphous form designated as Form III of ibandronate monosodium monohydrate. The amorphous ibandronate monosodium monohydrate according to the present invention is characterized by powder X-ray diffraction and microscopic examination. The XRD diffractogram is characterized by the absence of well-defined peaks, which are an essential feature of a crystalline compound.
According to another aspect of the present invention there is provided a process for the preparation of ibandronate monosodium monohydrate. The amorphous form of ibandronate monosodium monohydrate can be made by conventional techniques such as lyophilisation or evaporation (under vacuum) of a solution, preferably aqueous solution. Preferred method for amorphous form is to use spray-drying technique. This is a well- known and very efficient process suitable for commercial scale operation.
The invention further includes pharmaceutical compositions comprising the polymorphic form of ibandronate monosodium monohydrate disclosed herein and a pharmaceutically acceptable carrier. These compositions may be in any suitable form such as tablets or capsules.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffraction pattern of Form I crystals of ibandronate monosodium monohydrate.
Figure 2 is an X-ray powder diffraction pattern of Form II crystals of ibandronate monosodium monohydrate.
Figure 3 is an X-ray powder diffraction pattern of Form III amorphous ibandronate monosodium monohydrate. Figure 4 is an X-ray powder diffraction pattern of 150mg tablet prepared from Form I crystals of ibandronate monosodium monohydrate.
X-ray powder diffraction spectrum was recorded on a Siemens D5000 X-ray powder diffractometer having a copper-Kα radiation.
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1
(i) Preparation of ibandronate
Into a IL four-necked RB flask equipped with mechanical stirrer and reflux condenser was charged lOOg of 3-(N-Methyl-N-pentylamino)propionic acid hydrochloride and 49g of crystalline phosphorous acid. The reaction mass was heated to 750C and started the addition of phosphorous trichloride slowly over a period of 2hr. Reaction mass was maintained at reflux for 4hr without stirring. Reaction mass was cooled to 3O0C and added 80ml of water. Reaction mass was heated to reflux temperature and maintained at reflux for 7hr. Water (150ml was added to the reaction mass and adjusted the pH to 4.3- 4.4 using aqueous sodium hydroxide. Reaction mass was diluted with 560ml of methanol and kept under stirring for 2hr. Crystallization of ibandronate began after 30min. Reaction mass was filtered and the wet cake washed with 50ml of 1:4 aqueous methanol. The wet solid was dried in the oven at 6O0C to get 145g of ibandronate as white solid.
(ii) Preparation of Form I crystals of ibandronate monosodium monohydrate:
Above prepared ibandronate (25g) was taken into a 250ml three-necked RB flask and dissolved in 200ml of water. Water was distilled of from the reaction mass and added 100ml of fresh water. The reaction mass was treated with 2g of carbon and filtered. The filtrate was taken into a RB flask and added 200ml of acetone at 50-600C. Crystallization of ibandronate began immediately. The reaction mass was cooled to 250C and maintained for lhr before filtration. The wet solid was washed with 50ml of acetone and dried at 6O0C to get 2Og of Form I crystals of ibandronate monosodium monohydrate.
Example 2 Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 5ml of ethanol at 7O0C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with
5ml of aqueous ethanol (4:1) and dried at 60°C to get 4.1g of Form I crystals of ibandronate monosodium monohydrate.
Example 3 Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 1 OmI of THF at 6O0C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 600C to get 4.Og of Form I crystals of ibandronate monosodium monohydrate.
Example 4 Preparation of Form I crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 20ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 5O0C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed with 50ml of aqueous THF (4:1) and dried at 600C to get 3.8g of Form I crystals of ibandronate monosodium monohydrate.
Example 5 Preparation of Form II crystals of ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 10ml of fresh water. The reaction mass was treated with O.lg of carbon and filtered. The filtrate was taken into a RB flask and added 10ml of acetonitrile at 6O0C. The reaction mass was cooled to 25°C and filtered. The wet solid was washed
with 5ml of aqueous acetonitrile (1:1) and dried at 60°C to get 4.Og of Form II crystals of ibandronate monosodium monohydrate.
Example 6
Preparation of Amorphous Form III ibandronate monosodium monohydrate:
Ibandronate (5g) prepared as per the process described in step (i) of example 1 above was taken into a RB flask and dissolved in 40ml of water. Water was distilled of from the reaction mass and added 50ml of fresh water. The reaction mass was heated to 6O0C and treated with Ig of carbon. The reaction mass was filtered while hot. The filtrate was taken into a RB flask and freeze dried to get amorphous Form III ibandronate monosodium monohydrate.
Example 7
Form I crystals of ibandronate monosodium monohydrate prepared according to the process given in Example 1 is employed in an amount equivalent to 150mg of ibandronic acid per single dosage unit. Composition of one tablet is as given below.
* Equivalent to 150mg of ibandronic acid
Above prepared tablet was taken and powdered using a mortar and pestle. The resultant powder was subjected for powder XRD.
Advantages of Present Invention: 1. Present invention discloses novel polymorphic forms of ibandronate monosodium monohydrate designated as Form I, Form II, and Form III.
2. Present invention discloses a commercially viable process for the reparation of novel polymorphic forms of ibandronate monosodium monohydrate.
3. The novel polymorphic forms of ibandronate monosodium monohydrate are suitable for pharmaceutical formulations such as tablets or capsules.
Claims
1. Novel and stable crystalline Form I of ibandronate monosodium monohydrate of the formula I,
2. Novel and stable crystalline Form II of ibandronate monosodium monohydrate of the formula I given in claim 1 characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ (intensity in %) 4.94 (100.0), 11.05 (0.7), 14.11 (0.9), 17.17 (1.8), 18.60 (1.4), 19.95 (1.7), 25.90 (1.3), and 36.39 (0.9) degrees as shown in Figure 2 of the drawings accompanying this specification.
3. Novel and stable amorphous Form III ibandronate monosodium monohydrate of the formula I given in claim 1 characterized by an X-ray powder diffraction pattern as shown in figure 3 of drawings.
4. A process for preparation of novel, stable & crystalline Form I of ibandronate monosodium monohydrate having the formula I and characteristics given in Fig 1 which comprises dissolving ibandorate in water and diluting the mass with an organic solvent and filtering the resultant crystals to get the Form I ibandronate monosodium monohydrate.
5. A process as claimed in claim 4 wherein the organic solvent used is selected from acetone, methanol, ethanol, acetonitrile and tetrahydrofuran.
6. A process according to claims 4 and 5 wherein the ratio between water and organic solvent is 1 :0.5 to 1:105 preferably 1 : 2.
7. A process for the preparation of novel Form II of ibandronate monosodium monohydrate of the formula I having the characteristics given above which comprises crystallizing ibandronate from an aqueous isopropanol.
8. A process according to claim 7 wherein the ratio between water and isopropanol is 1:0.5 to 1:10, preferably 1: 2.
9. A process for the preparation of novel amorphous Form III ibandronate monosodium monohydrate of formula I having the characteristics as shown in figure 3 which comprises dissolving ibandronate in water and freeze drying or spray drying to get amorphous ibandronate monosodium monohydrate.
10. A pharmaceutical composition comprising the crystalline Form I of ibandronate monohydrate as defined in claim 1 and a pharmaceutically acceptable carrier having powder X-ray diffraction pattern as shown in figure 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1936CH2005 | 2005-12-27 | ||
| IN1936/CHE/2005 | 2005-12-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2007074475A2 true WO2007074475A2 (en) | 2007-07-05 |
| WO2007074475A3 WO2007074475A3 (en) | 2007-09-07 |
Family
ID=37890132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2006/000501 WO2007074475A2 (en) | 2005-12-27 | 2006-12-21 | Novel polymorphic forms of ibandronate |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007074475A2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009042179A1 (en) * | 2007-09-24 | 2009-04-02 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronic acid and processeses for the preparation thereof |
| EP2046342A2 (en) * | 2006-07-28 | 2009-04-15 | Dr. Reddy's Laboratories Ltd. | Crystalline form a of ibandronic acid and process for the preparation |
| WO2009053445A2 (en) * | 2007-10-26 | 2009-04-30 | Chemo Ibérica, S.A. | Polymorphic forms of ibandronate sodium and processes for preparation thereof |
| US7563918B2 (en) | 2004-08-23 | 2009-07-21 | Teva Pharmaceutical Industries Ltd. | Solid and crystalline ibandronate sodium and processes for preparation thereof |
| EP2128166A1 (en) | 2008-05-20 | 2009-12-02 | Chemo Ibérica, S.A. | Polymorphic forms of Ibandronate sodium and processes for preparation thereof |
| EP2316840A1 (en) | 2007-04-19 | 2011-05-04 | Dr. Reddy's Laboratories Limited | Ibandronate Sodium Polymorphs |
| WO2012093975A1 (en) * | 2011-01-06 | 2012-07-12 | Mahmut Bilgic | Water soluble formulations comprising ibandronate sodium with a water content less than 11 % by weight |
| WO2013109198A1 (en) * | 2012-01-18 | 2013-07-25 | Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇ | Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b |
| WO2013179305A1 (en) * | 2012-06-01 | 2013-12-05 | Hetero Research Foundation | Ibandronate sodium solid dispersion |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4927814A (en) * | 1986-07-11 | 1990-05-22 | Boehringer Mannheim Gmbh | Diphosphonate derivatives, pharmaceutical compositions and methods of use |
| WO2001052859A1 (en) * | 2000-01-20 | 2001-07-26 | F. Hoffmann-La Roche Ag | Pharmaceutical parenteral composition containing a biphosphonate |
| WO2006002348A2 (en) * | 2004-06-23 | 2006-01-05 | Teva Pharmaceutical Industies Ltd. | Solid and crystalline ibandronic acid |
| WO2006024024A2 (en) * | 2004-08-23 | 2006-03-02 | Teva Pharmaceutical Industries Ltd. | Solid and crystalline ibandronate sodium and processes for preparation thereof |
| WO2006045578A2 (en) * | 2004-10-29 | 2006-05-04 | F. Hoffmann-La Roche Ag | Process for the preparation of ibandronate |
| WO2006081963A1 (en) * | 2005-02-01 | 2006-08-10 | F.Hoffmann-La Roche Ag | Ibandronate polymorph a |
| WO2006081962A1 (en) * | 2005-02-01 | 2006-08-10 | F.Hoffmann-La Roche Ag | Ibandronate polymorph b |
| WO2007013097A1 (en) * | 2005-07-25 | 2007-02-01 | Natco Pharma Limited | Improved process for the preparation of ibandronate sodium |
-
2006
- 2006-12-21 WO PCT/IN2006/000501 patent/WO2007074475A2/en active Application Filing
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4927814A (en) * | 1986-07-11 | 1990-05-22 | Boehringer Mannheim Gmbh | Diphosphonate derivatives, pharmaceutical compositions and methods of use |
| WO2001052859A1 (en) * | 2000-01-20 | 2001-07-26 | F. Hoffmann-La Roche Ag | Pharmaceutical parenteral composition containing a biphosphonate |
| WO2006002348A2 (en) * | 2004-06-23 | 2006-01-05 | Teva Pharmaceutical Industies Ltd. | Solid and crystalline ibandronic acid |
| WO2006024024A2 (en) * | 2004-08-23 | 2006-03-02 | Teva Pharmaceutical Industries Ltd. | Solid and crystalline ibandronate sodium and processes for preparation thereof |
| WO2006045578A2 (en) * | 2004-10-29 | 2006-05-04 | F. Hoffmann-La Roche Ag | Process for the preparation of ibandronate |
| WO2006081963A1 (en) * | 2005-02-01 | 2006-08-10 | F.Hoffmann-La Roche Ag | Ibandronate polymorph a |
| WO2006081962A1 (en) * | 2005-02-01 | 2006-08-10 | F.Hoffmann-La Roche Ag | Ibandronate polymorph b |
| WO2007013097A1 (en) * | 2005-07-25 | 2007-02-01 | Natco Pharma Limited | Improved process for the preparation of ibandronate sodium |
Non-Patent Citations (2)
| Title |
|---|
| DUU-GONG WU: "BONIVA (ibandronate sodium) Tablets 2.5 mg" CHEMISTRY REVIEW, [Online] 2 July 2003 (2003-07-02), XP002427781 Retrieved from the Internet: URL:http://www.fda.gov/cder/foi/nda/2003/2 1-455_Boniva_chemr.pdf> [retrieved on 2007-04-03] & CENTER FOR DRUG EVALUATION AND RESEARCH, [Online] 2 July 2003 (2003-07-02), XP002427783 Retrieved from the Internet: URL:http://www.fda.gov/cder/foi/nda/2003/2 1-455_Boniva.htm> [retrieved on 2007-04-03] * |
| ROCHE: "BONIVA(R) F. C. Tablets (150 mg)" MATERIAL SAFETY DATA SHEET, [Online] 7 April 2005 (2005-04-07), XP002427782 Retrieved from the Internet: URL:http://www.msds-gsk.com/13025801.pdf> [retrieved on 2007-04-03] * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7563918B2 (en) | 2004-08-23 | 2009-07-21 | Teva Pharmaceutical Industries Ltd. | Solid and crystalline ibandronate sodium and processes for preparation thereof |
| EP2046342A2 (en) * | 2006-07-28 | 2009-04-15 | Dr. Reddy's Laboratories Ltd. | Crystalline form a of ibandronic acid and process for the preparation |
| EP2046342A4 (en) * | 2006-07-28 | 2011-05-04 | Reddys Lab Ltd Dr | Crystalline form a of ibandronic acid and process for the preparation |
| EP2316840A1 (en) | 2007-04-19 | 2011-05-04 | Dr. Reddy's Laboratories Limited | Ibandronate Sodium Polymorphs |
| EP2316841A1 (en) | 2007-04-19 | 2011-05-04 | Dr. Reddy's Laboratories Limited | Ibandronate sodium polymorphs |
| WO2009042179A1 (en) * | 2007-09-24 | 2009-04-02 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of ibandronic acid and processeses for the preparation thereof |
| WO2009053445A2 (en) * | 2007-10-26 | 2009-04-30 | Chemo Ibérica, S.A. | Polymorphic forms of ibandronate sodium and processes for preparation thereof |
| WO2009053445A3 (en) * | 2007-10-26 | 2009-10-15 | Chemo Ibérica, S.A. | Polymorphic forms of ibandronate sodium and processes for preparation thereof |
| EP2128166A1 (en) | 2008-05-20 | 2009-12-02 | Chemo Ibérica, S.A. | Polymorphic forms of Ibandronate sodium and processes for preparation thereof |
| WO2012093975A1 (en) * | 2011-01-06 | 2012-07-12 | Mahmut Bilgic | Water soluble formulations comprising ibandronate sodium with a water content less than 11 % by weight |
| WO2013109198A1 (en) * | 2012-01-18 | 2013-07-25 | Koçak Farma İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇ | Processes for the preparation of sodium ibandronate monohydrate polymorphs a, b and mixture of polymorphs a with b |
| WO2013179305A1 (en) * | 2012-06-01 | 2013-12-05 | Hetero Research Foundation | Ibandronate sodium solid dispersion |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007074475A3 (en) | 2007-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2007074475A2 (en) | Novel polymorphic forms of ibandronate | |
| EP1930011B1 (en) | Crystalline form of ibandronate sodium | |
| US7511174B2 (en) | Solid and crystalline ibandronic acid | |
| US20080132707A1 (en) | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates | |
| CA2795157C (en) | Raltegravir salts and crystalline forms thereof | |
| CA2530193A1 (en) | Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation | |
| EP1931326A1 (en) | Crystalline trihydrate of zoledronic acid | |
| EP3820851A1 (en) | Solid state forms of omecamtiv mecarbil & omecamtiv mecarbil dihcl | |
| CA2479668A1 (en) | Crystalline forms of quetiapine hemifumarate | |
| EP2220031A1 (en) | Polymorphic forms of aliskiren hemifumarate and process for preparation thereof | |
| WO2007109799A2 (en) | Polymorphs of eszopiclone malate | |
| CA2818984C (en) | Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size | |
| CA2603129A1 (en) | Crystalline forms of pregabalin | |
| EP2078025B1 (en) | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof | |
| US20100125149A1 (en) | Ibandronate sodium polymorphs | |
| WO2007026379A2 (en) | Novel crystalline forms of risedronate monosodium | |
| EP1795530A1 (en) | Process for preparing known pantoprazole sodium sesquihydrate | |
| CA3167087A1 (en) | Solid state forms of avasopasem manganese and process for preparation thereof | |
| US8765976B2 (en) | Polymorphic forms of Warfarin potassium and preparations thereof | |
| EP2315742A2 (en) | Gabapentin enacarbil salts and processes for their preparation | |
| WO2009003001A2 (en) | Preparation of risedronate sodium hemi-pentahydrate | |
| EP2109613A2 (en) | Polymorphs of eszopiclone malate | |
| CZ298328B6 (en) | Semicrystalline form of risedronate monosodium, process for its preparation and medicamentous form containing thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 06842775 Country of ref document: EP Kind code of ref document: A2 |