WO2009008009A1 - Novel crystalline form b of carvedilol dihydrogen phosphate - Google Patents
Novel crystalline form b of carvedilol dihydrogen phosphate Download PDFInfo
- Publication number
- WO2009008009A1 WO2009008009A1 PCT/IN2008/000441 IN2008000441W WO2009008009A1 WO 2009008009 A1 WO2009008009 A1 WO 2009008009A1 IN 2008000441 W IN2008000441 W IN 2008000441W WO 2009008009 A1 WO2009008009 A1 WO 2009008009A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dihydrogen phosphate
- carvedilol
- crystalline form
- carvedilol dihydrogen
- novel crystalline
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a novel crystalline form B of carvedilol dihydrogen phosphate and to the process for its preparation.
- Carvedilol has structure as shown in formula 1.
- Carvedilol is disclosed in US patent No. 4,503,067 (assigned to Boehringer Mannheim, GmbH, Germany) and it is chemically known as ( ⁇ )-l -(9H-carbazol-4-yloxy)-3-[[2(2- methoxyphenoxy)ethyl]amino]-2-propanol
- Carvedilol is a racemic mixture of R(+) and S(-) enantiomers. Both enantiomers are nonselective ⁇ -adrenergic blocking agent with Ot 1 blocking activity while S(-) enantiomer also has non-selective ⁇ -adrenoreceptor blocking activity. Carvedilol is used for treatment of hypertension, congestive heart failure and angina.
- Patent US 6515010 covers carvedilol methane sulfonate.
- Another patent US 7,056,942 assigned to Teva discloses crystalline carvedilol hydrochloride hydrate.
- the synthetic exploration of novel crystalline forms and/or solvates thereof of a pharmaceutically active compound provides a possibility to obtain a new form or solavte that has improved characteristics such as bulk density, particle size, stability, solubility in aqueous solution and ease of processing in the formulation for preparing suitable pharmaceutical dosages.
- the present invention provides a novel crystalline form of carvedilol dihydrogen phosphate refered to as Form B.
- the present invention further provides a process for preparation of carvedilol dihydrogen phosphate refered as Form B that comprises of:
- Figure 1 is an X-ray powder diffractogram (XRPD) for Form B of carvedilol dihydrogen phosphate.
- Figure 2 is an FT-IR spectrum for Form B of carvedilol dihydrogen phosphate.
- Figure 3 is Differential Scanning Calorimetry (DSC) for Form B of carvedilol dihydrogen phosphate.
- the present invention provides novel crystalline form of carvedilol dihydrogen phosphate referred to as Form B which is identified by XRPD pattern as shown in figure 1.
- Form B novel crystalline form of carvedilol dihydrogen phosphate referred to as Form B which is identified by XRPD pattern as shown in figure 1.
- the characteristic peaks of carvedilol dihydrogen phosphate referred to as Form B are as shown in the table 1. Table 1:
- the crystalline Form B of carvedilol dihydrogen phosphate described herein is further identified by FT-IR spectrum as shown in figure 2.
- the FT-IR spectrum of crystalline Form B of carvedilol dihydrogen phosphate described herein has characteristic bands at 3406, 3330, 3062, 2397, 1942, 1902, 1625, 1603, 1587, 1505, 1471, 1454, 1441, 13961346, 1332, 1252,1218, 1180, 1125, 1098 cm- 1 .
- the Form B of carvedilol dihydrogen phosphate of the present invention is further characterized by differential scanning calorimetry which is shown in figure 3.
- the present invention provides process to obtain crystalline carvedilol dihydrogen phosphate referred as Form B hereinabove that comprises of: (i) dissolving carvedilol base in aprotic polar solvent (ii) addition of phosphoric acid, (iii) heating the solution, (iv) adding water to hot solution, (v) cooling, and
- step (i) the carvedilol base is dissolved in polar aprotic solvent that is selected from amides such as formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures thereof.
- polar aprotic solvent that is selected from amides such as formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures thereof.
- the preferred aprotic polar solvent is N,N-dimethyl formamide.
- the slurry of carvedilol base in aprotic polar solvent is stirred at 25-3O 0 C to get a clear solution.
- the ortho phosphoric acid is added to the clear solution of carvedilol base in aprotic solvent at 25-3O 0 C.
- the ortho-phosphoric acid may be anhydrous or in the form of aqueoues solution.
- the mixture of carvedilol base and phosphoric acid in aprotic solvent is heated to the temperature in the range of 40-100 0 C, preferably at 50-70 0 C and most preferably at 55-60 °C.
- the addition of water to the reaction mixture is performed at temperature in the range of 40-
- the crystalline solid that is separated is isolated by filtration and then dried.
- the effective amount of crystalline carvedilol dihydrogen phosphate form B can be used to prepare suitable formulation along with non toxic pharmaceutically acceptable carriers and/or other active ingredients for the treatment of hypertension, congestive heart failure and angina.
- the powder X-ray diffraction spectrum is measured using Philips (PAN alytical X'pert pro) difractogram (copper anti cathode) and expressed in terms of inter planar distance d, Bragg' s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense peak).
- the FTIR spectra were obtained using a Perkin-Elmer, Spectrum- 100 instrument.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A novel crystalline form B of carvedilol dihydrogen phosphate having X-ray diffraction pattern as shown in figure 1. A process for the preparation of crystalline form B of carvedilol dihydrogen phosphate according to claim 1 that comprises dissolving carvedilol base in aprotic polar solvent, addition of phosphoric acid, heating the solution, adding water to hot solution, cooling, and isolation of solid.
Description
NOVEL CRYSTALLINE FORM B OF CARVEDILOL DIHYDROGEN PHOSPHATE
FIELD OF THE INVENTION
The present invention relates to a novel crystalline form B of carvedilol dihydrogen phosphate and to the process for its preparation.
BACKGROUND OF THE INVENTION
Carvedilol has structure as shown in formula 1. Carvedilol is disclosed in US patent No. 4,503,067 (assigned to Boehringer Mannheim, GmbH, Germany) and it is chemically known as (±)-l -(9H-carbazol-4-yloxy)-3-[[2(2- methoxyphenoxy)ethyl]amino]-2-propanol
Carvedilol is a racemic mixture of R(+) and S(-) enantiomers. Both enantiomers are nonselective β-adrenergic blocking agent with Ot1 blocking activity while S(-) enantiomer also has non-selective β-adrenoreceptor blocking activity. Carvedilol is used for treatment of hypertension, congestive heart failure and angina.
There are several patents and patent applications that are directed to crystalline salts, amorphous salts, solvates thereof and to their preparation.
The product patent US 4,503,067 (Boehringer Mannheim) describes salts of carvedilol with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
Patent US 6515010 covers carvedilol methane sulfonate.
Another patent US 7,056,942 assigned to Teva discloses crystalline carvedilol hydrochloride hydrate.
The patent application US 2005/240,027 (SmithKline Beecham) disclose crystalline carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dihydrate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate methanol solvate and carvedilol hydrogen phosphate.
In the patent application US 2005/277,689 (Glaxo SmithKline) crystalline salt, anhydrous forms or solvate of carvedilol selected from the group consisting of carvedilol mandelate, lactate, maleate, sulfate, glutarate, mesylate, phosphate, citrate, hydrogen bromide, oxalate, hydrochloride, benzoate and corresponding anhydrous forms or solvates thereof are described.
The patent application US 2005/261,355 (SB Pharmco) covers carvedilol hydrobromide monohydrate and anhydrous carvedilol hydrobromide.
The patent application US 2005/148,779 (GlaxoSmithKline) claims crystalline carvedilol monocitrate monohydrate
To the organic chemist, the synthetic exploration of novel crystalline forms and/or solvates thereof of a pharmaceutically active compound provides a possibility to obtain a new form or solavte that has improved characteristics such as bulk density, particle size, stability, solubility in aqueous solution and ease of processing in the formulation for preparing suitable pharmaceutical dosages.
Thus, there exist a need exists to develop different carvedilol forms which have improved characteristics. The present invention is directed to the same.
SUMMARY OF THE INVENTION
The present invention provides a novel crystalline form of carvedilol dihydrogen phosphate refered to as Form B.
The present invention further provides a process for preparation of carvedilol dihydrogen phosphate refered as Form B that comprises of:
(i) dissolving carvedilol base in aprotic polar solvent, (ii) addition of phosphoric acid, (iii) heating the solution, (iv) adding water to hot solution,
(v) cooling, and (vi) isolation.
DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffractogram (XRPD) for Form B of carvedilol dihydrogen phosphate.
Figure 2 is an FT-IR spectrum for Form B of carvedilol dihydrogen phosphate. Figure 3 is Differential Scanning Calorimetry (DSC) for Form B of carvedilol dihydrogen phosphate.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides novel crystalline form of carvedilol dihydrogen phosphate referred to as Form B which is identified by XRPD pattern as shown in figure 1. The characteristic peaks of carvedilol dihydrogen phosphate referred to as Form B are as shown in the table 1.
Table 1:
The crystalline Form B of carvedilol dihydrogen phosphate described herein is further identified by FT-IR spectrum as shown in figure 2. The FT-IR spectrum of crystalline Form B of carvedilol dihydrogen phosphate described herein has characteristic bands at 3406, 3330, 3062, 2397, 1942, 1902, 1625, 1603, 1587, 1505, 1471, 1454, 1441, 13961346, 1332, 1252,1218, 1180, 1125, 1098 cm-1.
The Form B of carvedilol dihydrogen phosphate of the present invention is further characterized by differential scanning calorimetry which is shown in figure 3.
In an another aspect, the present invention provides process to obtain crystalline carvedilol dihydrogen phosphate referred as Form B hereinabove that comprises of: (i) dissolving carvedilol base in aprotic polar solvent (ii) addition of phosphoric acid, (iii) heating the solution, (iv) adding water to hot solution, (v) cooling, and
(vi) isolation.
In step (i), the carvedilol base is dissolved in polar aprotic solvent that is selected from amides such as formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures thereof. The preferred aprotic polar solvent is N,N-dimethyl formamide. The slurry of carvedilol base in aprotic polar solvent is stirred at 25-3O0C to get a clear solution.
The ortho phosphoric acid is added to the clear solution of carvedilol base in aprotic solvent at 25-3O0C. The ortho-phosphoric acid may be anhydrous or in the form of aqueoues solution.
After the addition of orthophosphoric acid, the mixture of carvedilol base and phosphoric acid in aprotic solvent is heated to the temperature in the range of 40-100 0C, preferably at 50-70 0C and most preferably at 55-60 °C.
The addition of water to the reaction mixture is performed at temperature in the range of 40-
100 0C, preferably at 50-70 0C and most preferably at 55-60 0C. The water addition is carried out slowly over a period of 10 - 120 minutes.
After water addition the reaction mixture is slowly cooled to -5 to 3O0C, preferably to 0- 1O0C.
The crystalline solid that is separated is isolated by filtration and then dried.
The effective amount of crystalline carvedilol dihydrogen phosphate form B can be used to prepare suitable formulation along with non toxic pharmaceutically acceptable carriers and/or other active ingredients for the treatment of hypertension, congestive heart failure and angina.
The following example is provided to illustrate the present invention and is not limit to the scope of the invention.
EXAMPLES The powder X-ray diffraction spectrum is measured using Philips (PAN alytical X'pert pro) difractogram (copper anti cathode) and expressed in terms of inter planar distance d, Bragg' s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense peak). The scanning parameters included: measurment range: 3-40 degrees two theta; continuous scan. The FTIR spectra were obtained using a Perkin-Elmer, Spectrum- 100 instrument.
Example: Preparation of crystalline form B of carvedilol dihydrogen phosphate
100 g of carvedilol base was added to 200 ml of N,N-dimethyl formamide and stirred to get clear solution. The ortho-phosphoric acid was added in 5-10 minutes and slowly heated to 55-6O0C followed by addition of water at 55-6O0C. Mixture was stirred for 5-10 minutes and then slowly cooled to 0-50C. The solid was filtered, washed with water and dried. The yield was 100 g. The crystalline solid melted at 156.10C and had water 5.49% by KF.
Claims
1. A novel crystalline form B of carvedilol dihydrogen phosphate having X-ray diffraction pattern as shown in figure 1.
2. The crystalline form B of carvedilol dihydrogen phosphate according to claim 1 having X-ray diffraction pattern with characteristics peaks as shown in the table 1.
3. A novel crystalline form B of carvedilol dihydrogen phosphate according to claim 1 having FT-IR spectrum as shown in figure 2.
4. A novel crystalline form B of carvedilol dihydrogen phosphate according to claim 1 having DSC as shown in figure 3.
5. A process for the preparation of crystalline form B of carvedilol dihydrogen phosphate according to claim 1 that comprises of:
(i) dissolving carvedilol base in aprotic polar solvent,
(ii) addition of phosphoric acid,
(iii) heating the solution, (iv) adding water to hot solution,
(v) cooling, and
(vi) isolation of solid.
6. A process according to claim 5 wherein the aprotic solvent is selected from formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures thereof, preferably N,N-dimethyl formamide.
7. A process according to claim 5 wherein heating is carried out at temperature in the range of 40-100 °C, preferably at 50-70 0C and most preferably at 55-60 0C.
8. A process according to claim 5 wherein water is added at temperature in the range of 40-100 0C, preferably at 50-70 °C and most preferably at 55-60 °C.
9. A process according to claim 5 wherein cooling is carried out at temperature in the range of -5 to 3O0C, preferably to 0-100C.
10. A process according to claim 5 wherein the solid is isolated by filtration.
Dated this 9th day of July 2008
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN980/KOL/2007 | 2007-07-11 | ||
| IN980KO2007 | 2007-07-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2009008009A1 true WO2009008009A1 (en) | 2009-01-15 |
| WO2009008009A4 WO2009008009A4 (en) | 2009-03-05 |
Family
ID=39827949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2008/000441 WO2009008009A1 (en) | 2007-07-11 | 2008-07-09 | Novel crystalline form b of carvedilol dihydrogen phosphate |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2009008009A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892858A (en) * | 2015-12-21 | 2017-06-27 | 上海科胜药物研发有限公司 | A kind of carvidilol dihydric phosphate novel crystal forms |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050240027A1 (en) * | 2002-06-27 | 2005-10-27 | Brook Christopher S | Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment |
| WO2008002683A2 (en) * | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
-
2008
- 2008-07-09 WO PCT/IN2008/000441 patent/WO2009008009A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050240027A1 (en) * | 2002-06-27 | 2005-10-27 | Brook Christopher S | Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment |
| WO2008002683A2 (en) * | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106892858A (en) * | 2015-12-21 | 2017-06-27 | 上海科胜药物研发有限公司 | A kind of carvidilol dihydric phosphate novel crystal forms |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009008009A4 (en) | 2009-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7902378B2 (en) | Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment | |
| US20090163721A1 (en) | Crystalline solids of carvedilol and processes for their preparation | |
| US10059715B2 (en) | Acid addition salt of ibrutinib | |
| US8278461B2 (en) | Stable amorphous form of carvedilol dihydrogen phosphate with stabilizer | |
| WO2017008773A1 (en) | Crystalline forms of obeticholic acid | |
| US20080167477A1 (en) | Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same | |
| JP2009513569A (en) | A new chemical method for the synthesis of quinoline compounds. | |
| JP2007532548A (en) | Crystalline polymorph of bazedoxifene acetate | |
| US7981897B2 (en) | Crystal form of (3-cyano-1H-Indo1-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl]methanone, hydrochloride | |
| US8344159B2 (en) | Carvedilol phosphate sesquihydrate | |
| US20200131211A1 (en) | Salts of Antiviral Phosphonate Analogues and Process for Preparation Thereof | |
| US20090012296A1 (en) | Processes for the preparation of crystalline form beta of imatinib mesylate | |
| WO2009008009A1 (en) | Novel crystalline form b of carvedilol dihydrogen phosphate | |
| JP2002526498A (en) | Method for producing naphthyridine carboxylic acid derivative (methanesulfonate sesquihydrate) | |
| EP1051398B1 (en) | Thermodynamically stable form of (r)-3- (4-fluorophenyl) sulphonyl]amino] -1,2,3,4- tetrahydro -9h-carbazole -9-propanoic acid (ramatroban) | |
| US20080249317A1 (en) | Novel amorphous form of carvedilol phosphate and processes for the preparation thereof | |
| WO2008093350A1 (en) | Novel anhydrous crystalline form of carvedilol dihydrogen phosphate | |
| KR20160078359A (en) | A STABLE POLYMORPH OF THE SALT OF (2R)-4-OXO-4-[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-α]PYRAZIN-7(8H)-YL]-1-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE WITH L-TARTARIC ACID | |
| US20060030711A1 (en) | Crystalline polymorph of pipindoxifene hydrochloride monohydrate | |
| US20060030591A1 (en) | Crystalline polymorph of pipindoxifene hydrochloride monohydrate | |
| MXPA00005858A (en) | Thermodynamically stable form of (r)-3-[ [(4-fluorophenyl) sulphonyl]amino]-1,2,3,4- tetrahydro -9h-carbazole -9-propanoic acid (ramatroban) | |
| CZ20002325A3 (en) | Thermodynamically stable modification of I ramatroban, process of its preparation and use | |
| CN106892858A (en) | A kind of carvidilol dihydric phosphate novel crystal forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08789915 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 08789915 Country of ref document: EP Kind code of ref document: A1 |