US20050261355A1 - Carvedilol hydobromide - Google Patents

Carvedilol hydobromide Download PDF

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US20050261355A1
US20050261355A1 US10/518,206 US51820604A US2005261355A1 US 20050261355 A1 US20050261355 A1 US 20050261355A1 US 51820604 A US51820604 A US 51820604A US 2005261355 A1 US2005261355 A1 US 2005261355A1
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carvedilol
compound according
theta
degrees
carvedilol hydrobromide
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Inventor
Pingyun Chen
Qunying Dai
Philip Cell'Orco
Claire Hisler
David Igo
Lee Katrincic
Clifford Labaw
Li-Jen Ping
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SB Pharmco Puerto Rico Inc
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SB Pharmco Puerto Rico Inc
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Priority to US10/518,206 priority Critical patent/US20050261355A1/en
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Priority to US11/548,368 priority patent/US7649010B2/en
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    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 salt of carvedilol, corresponding compositions containing such a carvedilol salt or corresponding solvates thereof, and/or methods of using the aforementioned compound(s) in the treatment of certain disease states in mammals, in particular man.
  • the present invention further relates to a novel crystalline form of carvedilol hydrobromide, which is the hydrobromide salt of 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, and/or other carvedilol hydrobromide solvates thereof, compositions containing such salts and/or solvates of carvedilol hydrobromide, and methods of using the aforementioned salt(s) and/or solvate(s) to treat hypertension, congestive heart failure, and angina, etc.
  • Carvedilol 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]-amino]-2-propanol is known as Carvedilol.
  • Carvedilol is depicted by the following chemical structure:
  • Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al. (i.e., assigned to Boehringer Mannheim, GmbH, Mannheim-Waldhof, Fed. Rep. of Germany), which was issued on Mar. 5, 1985.
  • Carvedilol is synthesized as free base for incorporation in medication that is available commercially.
  • the aforementioned free base form of Carvedilol is a racemic mixture of R(+) and S( ⁇ ) enantiomers, where nonselective ⁇ -adrenoreceptor blocking activity is exhibited by the S( ⁇ ) enantiomer and ⁇ -adrenergic blocking activity is exhibited by both R(+) and S( ⁇ ) enantiomers.
  • Those unique features or characteristics associated with such a racemic Carvedilol mixture contributes to two complementary pharmacologic actions: i.e., mixed venous and arterial vasodilation and non-cardioselective, beta-adrenergic blockade.
  • Carvedilol is used-for treatment of hypertension, congestive heart failure and angina.
  • the currently commercially available carvedilol product is a conventional, tablet prescribed as a twice-a-day medication in the United States.
  • solubility of carvedilol is limited by the solubility of its protonated form or its corresponding salt formed in-situ.
  • the hydrochloride salt of carvedilol generated in-situ in an acidic medium, such as in a simulated gastric fluid, is less soluble in such medium than the protonated form of carvedilol.
  • a salt, and/or novel crystalline form of carvedilol i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate, and/or other solvates thereof
  • carvedilol i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate, and/or other solvates thereof
  • Such benefits would include products with the ability to achieve desired or prolonged drug levels in a systemic system by sustaining absorption along the gastro-intestinal tract of mammals (i.e., such as humans), particularly in regions of neutral pH, where a drug, such as carvedilol, has minimal solubility.
  • a novel crystalline form of carvedilol hydrobromide salt can be isolated as a pure, crystalline solid, which exhibits much higher aqueous solubility than the corresponding free base or other prepared crystalline salts of carvedilol, such as the hydrochloride salt.
  • This novel crystalline form also has potential to improve the stability of carvedilol in formulations due to the fact that the secondary amine functional group attached to the carvedilol core structure, a moiety pivotal to degradation processes, is protonated as a salt.
  • the present invention is directed to overcoming these and other problems encountered in the art.
  • the present invention relates to a salt of carvedilol, corresponding compositions containing such a carvedilol salt or corresponding solvates thereof, and/or methods of using the aforementioned compound(s) in the treatment of certain disease states in mammals, in particular man.
  • the present invention provides a salt, and/or novel crystalline form of carvedilol hydrobromide (i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate), and/or other solvates thereof.
  • carvedilol hydrobromide i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate
  • other solvates thereof i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate
  • the present invention further relates to pharmaceutical compositions, which contain the aforementioned salt and/or novel crystalline forms and/or solvates of carvedilol hydrobromide.
  • the present invention relates to a method of treating hypertension, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of a salt and/or novel crystalline form of carvedilol (i.e., as defined by the aforementioned salts and/or solvates) or a corresponding pharmaceutical composition, which contains such aforementioned salt, and/or novel crystalline forms of carvedilol., etc.
  • a salt and/or novel crystalline form of carvedilol i.e., as defined by the aforementioned salts and/or solvates
  • a corresponding pharmaceutical composition which contains such aforementioned salt, and/or novel crystalline forms of carvedilol., etc.
  • FIG. 1 is an x-ray powder diffractogram for carvedilol hydrobromide monohydrate.
  • FIG. 2 is a differential scanning calorimetry thermogram for carvedilol hydrobromide monohydrate.
  • FIG. 3 is an FT-Raman spectrum for carvedilol hydrobromide monohydrate.
  • FIG. 4 is an FT-Raman spectrum for carvedilol hydrobromide monohydrate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 5 is an FT-Raman spectrum for carvedilol hydrobromide monohydrate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 6 is an FT-IR spectrum for carvedilol hydrobromide monohydrate.
  • FIG. 7 is an FT-IR spectrum for carvedilol hydrobromide monohydrate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 8 is an FT-IR spectrum for carvedilol hydrobromide monohydrate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 9 is a view of a single molecule of carvedilol hydrobromide monohydrate. The hydroxyl group and the water molecule are disordered.
  • FIG. 10 are views of molecules of carvedilol hydrobromide monohydrate showing the N—H . . . Br . . . H—N interactions.
  • the top view focuses on Br1 and the bottom view focuses on Br2.
  • the interaction between the carvedilol cation and the bromine anion is unusual.
  • Each carvedilol molecule makes two chemically different contacts to the bromine anions.
  • Each bromine anion sits on a crystallographic special position (that is, on a crystallographic two-fold axis) which means that there are two half bromine anions interacting with each carvedilol cation.
  • FIG. 11 is a differential scanning calorimetry thermogram for carvedilol hydrobromide dioxane solvate.
  • FIG. 12 is an FT-Raman spectrum for carvedilol hydrobromide dioxane solvate.
  • FIG. 13 is an FT-Raman spectrum for carvedilol hydrobromide dioxane solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 14 is an FT-Raman spectrum for carvedilol hydrobromide dioxane solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 15 is an FT-IR spectrum for carvedilol hydrobromide dioxane solvate.
  • FIG. 16 is an FT-IR spectrum for carvedilol hydrobromide dioxane solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 17 is an FT-IR spectrum for carvedilol hydrobromide dioxane solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 18 is a differential scanning calorimetry thermogram for carvedilol hydrobromide 1-pentanol solvate.
  • FIG. 19 is an FT-Raman spectrum for carvedilol hydrobromide 1-pentanol solvate.
  • FIG. 20 is an FT-Raman spectrum for carvedilol hydrobromide 1-pentanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 21 is an FT-Raman spectrum for carvedilol hydrobromide 1-pentanol solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 22 is an FT-IR spectrum for carvedilol hydrobromide 1-pentanol solvate.
  • FIG. 23 is an FT-IR spectrum for carvedilol hydrobromide 1-pentanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 24 is an FT-IR spectrum for carvedilol hydrobromide 1-pentanol solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 25 is a differential scanning calorimetry thermogram for carvedilol hydrobromide 2-methyl-1-propanol solvate.
  • FIG. 26 is an FT-Raman spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate.
  • FIG. 27 is an FT-Raman spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 28 is an FT-Raman spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 29 is an FT-IR spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate.
  • FIG. 30 is an FT-IR spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 31 is an FT-IR spectrum for carvedilol hydrobromide 2-methyl-1-propanol solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 32 is a differential scanning calorimetry thermogram for carvedilol hydrobromide trifluoroethanol solvate.
  • FIG. 33 is an FT-Raman spectrum for carvedilol hydrobromide trifluoroethanol solvate.
  • FIG. 34 is an FT-Raman spectrum for carvedilol hydrobromide trifluoroethanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 35 is an FT-Raman spectrum for carvedilol hydrobromide trifluoroethanol solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 36 is an FT-IR spectrum for carvedilol hydrobromide trifluoroethanol solvate.
  • FIG. 37 is an FT-IR spectrum for carvedilol hydrobromide trifluoroethanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 38 is an FT-IR spectrum for carvedilol hydrobromide trifluoroethanol solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 39 is a differential scanning calorimetry thermogram for carvedilol hydrobromide 2-propanol solvate.
  • FIG. 40 is an FT-Raman spectrum for carvedilol hydrobromide 2-propanol solvate.
  • FIG. 41 is an FT-Raman spectrum for carvedilol hydrobromide 2-propanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 42 is an FT-Raman spectrum for carvedilol hydrobromide 2-propanol solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 43 is an FT-IR spectrum for carvedilol hydrobromide 2-propanol solvate.
  • FIG. 44 is an FT-IR spectrum for carvedilol hydrobromide 2-propanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 45 is an FT-IR spectrum for carvedilol hydrobromide 2-propanol solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 46 is an x-ray powder diffractogram for carvedilol hydrobromide n-propanol solvate #1.
  • FIG. 47 shows the thermal analysis results for carvedilol hydrobromide n-propanol solvate #1.
  • FIG. 48 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #1.
  • FIG. 49 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #1 in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 50 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #1 in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 51 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #1.
  • FIG. 52 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #1 in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 53 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #1 in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 54 is an x-ray powder diffractogram for carvedilol hydrobromide n-propanol solvate #2.
  • FIG. 55 shows the thermal analysis results for carvedilol hydrobromide n-propanol solvate #2.
  • FIG. 56 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #2.
  • FIG. 57 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #2 in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 58 is an FT-Raman spectrum for carvedilol hydrobromide n-propanol solvate #2 in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 59 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #2.
  • FIG. 60 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #2 in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 61 is an FT-IR spectrum for carvedilol hydrobromide n-propanol solvate #2 in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 62 is an x-ray powder diffractogram for carvedilol hydrobromide anhydrous.
  • FIG. 63 shows the thermal analysis results for carvedilol hydrobromide anhydrous.
  • FIG. 64 is an FT-Raman spectrum for carvedilol hydrobromide anhydrous.
  • FIG. 65 is an FT-Raman spectrum for carvedilol hydrobromide anhydrous in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 66 is an FT-Raman spectrum for carvedilol hydrobromide anhydrous in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 67 is an FT-IR spectrum for carvedilol hydrobromide anhydrous.
  • FIG. 68 is an FT-IR spectrum for carvedilol hydrobromide anhydrous in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 69 is an FT-IR spectrum for carvedilol hydrobromide anhydrous in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 70 is an x-ray powder diffractogram for carvedilol hydrobromide ethanol solvate.
  • FIG. 71 shows the thermal analysis results for carvedilol hydrobromide ethanol solvate.
  • FIG. 72 is an FT-Raman spectrum for carvedilol hydrobromide ethanol solvate.
  • FIG. 73 is an FT-Raman spectrum for carvedilol hydrobromide ethanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 74 is an FT-Raman spectrum for carvedilol hydrobromide ethanol solvate in the 2000-400 cm ⁇ 1 region of the spectrum.
  • FIG. 75 is an FT-IR spectrum for carvedilol hydrobromide ethanol solvate.
  • FIG. 76 is an FT-IR spectrum for carvedilol hydrobromide ethanol solvate in the 4000-2000 cm ⁇ 1 region of the spectrum.
  • FIG. 77 is an FT-IR spectrum for carvedilol hydrobromide ethanol solvate in the 2000-500 cm ⁇ 1 region of the spectrum.
  • FIG. 78 is an x-ray powder diffractogram for carvedilol hydrobromide dioxane solvate.
  • FIG. 79 is an x-ray powder diffractogram for carvedilol hydrobromide 1-pentanol solvate.
  • FIG. 80 is an x-ray powder diffractogram for carvedilol hydrobromide 2-methyl-1-propanol solvate.
  • FIG. 81 is an x-ray powder diffractogram for carvedilol hydrobromide trifluoroethanol solvate.
  • FIG. 82 is an x-ray powder diffractogram for carvedilol hydrobromide 2-propanol solvate.
  • the present invention provides a salt and/or novel crystalline form of carvedilol, i.e., such as carvedilol hydrobromide monohydrate, carvedilol hydrobromide anhydrate, and/or other solvates thereof.
  • the present invention relates to a pharmaceutical composition, which comprises the aforementioned salts and/or solvates of carvedilol and a pharmaceutically acceptable carrier.
  • the present invention relates to a method of treating hypertension, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of a salt and/or novel crystalline form of carvedilol (i.e., as defined by the aforementioned salts and/or solvates) or a corresponding pharmaceutical composition, which contains such aforementioned salt, and/or novel crystalline forms of carvedilol.
  • a salt and/or novel crystalline form of carvedilol i.e., as defined by the aforementioned salts and/or solvates
  • a corresponding pharmaceutical composition which contains such aforementioned salt, and/or novel crystalline forms of carvedilol.
  • the present invention relates to a compound, which is a salt of carvedilol hydrobromide (such as crystalline carvedilol hydrobromide mono hydrate), and/or a carvedilol solvate thereof.
  • carvedilol hydrobromide can be isolated readily as a novel crystalline form, which displays much higher solubility when compared to the free base of carvedilol.
  • crystalline carvedilol hydrobromide monohydrate of the present invention can be prepared by crystallization from an acetone-water solvent system containing carvedilol and hydrobromic acid.
  • suitable solvates of the instant invention may be prepared by preparing a slurry of the carvedilol hydrobromide salt in a solvent, such as dioxane, 1-pentanol, 2-methyl-1-propanol, trifluoroethanol, 2-propanol and n-propanol.
  • a solvent such as dioxane, 1-pentanol, 2-methyl-1-propanol, trifluoroethanol, 2-propanol and n-propanol.
  • Suitable solvates of carvedilol as defined in the present invention include, but are not limited to carvedilol hydrobromide 1-pentanol solvate, carvedilol hydrobromide 2-methyl-1-pentanol solvate, carvedilol hydrobromide trifluoroethanol solvate, carvedilol hydrobromide 2-propanol solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol hydrobromide n-propanol solvate #2, carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide anhydrate, etc.
  • carvedilol hydrobromide anhydrate can be prepared by dissolving carvedilol in a solvent, such as dichloromethane, acetonitrile or isopropyl acetate, followed by the addition of anhydrous HBr (HBr in acetic acid or gaseous HBr).
  • a solvent such as dichloromethane, acetonitrile or isopropyl acetate
  • the compounds of the present invention may exist in forms as stereoisomers, regioisomers, or diastereiomers, etc. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms.
  • carvedilol may exist as as racemic mixture of R(+) and S( ⁇ ) enantiomers, or in separate respectively optically forms, i.e., existing separately as either the R(+) enantiomer form or in the S(+) enantiomer form. All of these individual compounds, isomers, and mixtures thereof are included within the scope of the present invention.
  • the various forms of carvedilol hydrobromide and/or corresponding solvates are distinguished from each other using different spectroscopic identification techniques, such as Infrared (IR), Raman, Differential Scanning Calorimetry (DSC) and X-ray powder diffraction, etc.
  • IR Infrared
  • Raman Raman
  • DSC Differential Scanning Calorimetry
  • X-ray powder diffraction etc.
  • a salt or novel crystalline form of carvedilol which includes carvedilol hydrobromide monohydrate, anhydrate, and/or other solvates thereof, are characterized by spectroscopic data as described below and depicted in FIGS. 1-82 .
  • crystalline carvedilol hydrobromide monohydrate (see, Example 1: Form 1) is identified by an x-ray diffraction pattern as shown substantially in FIG. 1 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 6.5 ⁇ 0.2 (2 ⁇ ), 10.3 ⁇ 0.2 (2 ⁇ ), 15.7 ⁇ 0.2 (2 ⁇ ), 16.3 ⁇ 0.2 (2 ⁇ ), 19.8 ⁇ 0.2 (2 ⁇ ), 20.1 ⁇ 0.2 (2 ⁇ ), 21.9 ⁇ 0.2 (2 ⁇ ), 25.2 ⁇ 0.2 (2 ⁇ ), and 30.6 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide dioxane solvate (see, Example 2: Form 2) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 78 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 7.7 ⁇ 0.2 (2 ⁇ ), 8.4 ⁇ 0.2 (2 ⁇ ), 15.6 ⁇ 0.2 (2 ⁇ ), 17.0 ⁇ 0.2 (2 ⁇ ), 18.7 ⁇ 0.2 (2 ⁇ ), 19.5 ⁇ 0.2 (2 ⁇ ), 21.4 ⁇ 0.2 (2 ⁇ ), 23.7 ⁇ 0.2 (2 ⁇ ), and 27.9 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide 1-pentanol solvate (see, Example 3: Form 3) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 79 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 77.5 ⁇ 0.2 (2 ⁇ ), 7.8 ⁇ 0.2 (2 ⁇ ), 15.2 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 22.1 ⁇ 0.2 (2 ⁇ ), and 31.4 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide 2-methyl-1-propanol solvate (see, Example 4: Form 4) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 80 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 7.8 ⁇ 0.2 (2 ⁇ ), 8.1 ⁇ 0.2 (2 ⁇ ), 16.3 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 21.8 ⁇ 0.2 (2 ⁇ ), and 28.5 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide trifluoroethanol solvate (see, Example 5: Form 5) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 81 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e.,. 7.7 ⁇ 0.2 (2 ⁇ ), 8.4 ⁇ 0.2 (2 ⁇ ), 15.6 ⁇ 0.2 (2 ⁇ ), 16.9 ⁇ 0.2 (2 ⁇ ), 18.9 ⁇ 0.2 (2 ⁇ ), 21.8 ⁇ 0.2 (2 ⁇ ), 23.8 ⁇ 0.2 (2 ⁇ ), 23.7 ⁇ 0.2 (2 ⁇ ), and 32.7 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide 2-propanol solvate (see, Example 6: Form 6) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 82 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 7.9 ⁇ 0.2 (2 ⁇ ), 8.3 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 21.7 ⁇ 0.2 (2 ⁇ ), 23.2 ⁇ 0.2 (2 ⁇ ), 23.6 ⁇ 0.2 (2 ⁇ ), and 32.1 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide n-propanol solvate #1 (see, Example 7: Form 7) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 46 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 7.9 ⁇ 0.2 (2 ⁇ ), 8.5 ⁇ 0.2 (2 ⁇ ), 17.0 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 21.6 ⁇ 0.2 (2 ⁇ ), 23.1 ⁇ 0.2 (2 ⁇ ), 23.6 ⁇ 0.2 (2 ⁇ ), and 21.2 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide n-propanol solvate #2 (see, Example 8: Form 8) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 54 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 8.0 ⁇ 0.2 (2 ⁇ ), 18.8 ⁇ 0.2 (2 ⁇ ), 21.6 ⁇ 0.2 (2 ⁇ ), 23.1 ⁇ 0.2 (2 ⁇ ), 25.9 ⁇ 0.2 (2 ⁇ ), 27.2 ⁇ 0.2 (2 ⁇ ), 30.6 ⁇ 0.2 (2 ⁇ ), and 32.2 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide anhydrous (see, Example 9: Form 9) also is identified by an x-ray diffraction pattern as shown substantially in Figure 62 , which depicts characteristic peaks in degrees two-theta (2e): i.e.,. 6.6 ⁇ 0.2 (2 ⁇ ), 16.1 ⁇ 0.2 (2 ⁇ ), 17.3 ⁇ 0.2 (2 ⁇ ), 21.2 ⁇ 0.2 (2 ⁇ ), 22.1 ⁇ 0.2 (2 ⁇ ), 24.1 ⁇ 0.2 (2 ⁇ ), and 27.9 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide ethanol solvate (see, Example 10: Form 10) also is identified by an x-ray diffraction pattern as shown substantially in FIG. 70 , which depicts characteristic peaks in degrees two-theta (2 ⁇ ): i.e., 8.1 ⁇ 0.2 (2 ⁇ ), 8.6 ⁇ 0.2 (2 ⁇ ), 13.2 ⁇ 0.2 (2 ⁇ ), 17.4 ⁇ 0.2 (2 ⁇ ), 18.6 ⁇ 0.2 (2 ⁇ ), 21.8 ⁇ 0.2 (2 ⁇ ), 23.2 ⁇ 0.2 (2 ⁇ ), 23.7 ⁇ 0.2 (2 ⁇ ), and 27.4 ⁇ 0.2 (2 ⁇ ).
  • Crystalline carvedilol hydrobromide monohydrate further is identified by an infrared spectrum as shown substantially in FIG. 6 .
  • Carvedilol hydrobromide anhydrate also an infrared spectrum which comprises characteristic absorption bands expressed in wave numbers as shown substantially in FIG. 67 .
  • Crystalline carvedilol hydrobromide monohydrate is identified also by a Raman spectrum as shown substantially in FIG. 3 .
  • Carvedilol hydrobromide anhydrate also a Raman spectrum which comprises characteristic peaks as shown substantially in FIG. 64 .
  • compositions which contain the aforementioned salt and/or novel crystalline forms and/or solvates of carvedilol hydrobromide.
  • carvedilol forms described herein which include salt and/or novel crystalline forms of carvedilol, indicate that those forms may be particularly suitable for inclusion in medicinal agents, pharmaceutical compositions, etc.
  • solubility of various carvedilol salts, anhydrates, and/or solvates as those described herein may facilitate provision or development of a dosage form from which the drug substance becomes available for bioabsorption throughout the gastrointestinal tract (i.e., in particular the lower small intestine and colon).
  • a dosage form from which the drug substance becomes available for bioabsorption throughout the gastrointestinal tract (i.e., in particular the lower small intestine and colon).
  • Compounds or compositions within the scope of this invention include all compounds or compositions, wherein the compound of the present invention is contained in an amount effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • the quantity of the compound or composition of the present invention administered will vary depending on the patient and the mode of administration and can be any effective amount.
  • Treatment regimen for the administration of the compounds and/or compositions of the present invention can also be determined readily by those with ordinary skill in art.
  • the quantity of the compound and/or composition of the present invention administered may vary over a wide range to provide in a unit dosage an effective amount based upon the body weight of the patient per day to achieve the desired effect.
  • composition of the present invention is presented as a unit dose and taken preferably from 1 to 2 times daily, most preferably once daily to achieve the desired effect.
  • the compounds, and/or or compositions of the present invention can be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
  • the composition is adapted for oral administration.
  • compositions of the present invention are prepared using conventional materials and techniques, such as mixing, blending and the like.
  • compounds and/or pharmaceutical composition can also include, but are not limited to, suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
  • the composition will contain a compound of the present invention, such as a salt of carvedilol or active compound(s), together with the adjuvants, carriers and/or excipients.
  • a pharmaceutical composition of the present invention comprises an effective amount of a salt of carvedilol (i.e., such as carvedilol hydrobromide monohydrate), corresponding solvates (i.e., as identified herein) and/or anhydrates (i.e., carvedilol anhydrate) thereof, with any, of the characteristics noted herein, in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients.
  • carvedilol i.e., such as carvedilol hydrobromide monohydrate
  • corresponding solvates i.e., as identified herein
  • anhydrates i.e., carvedilol anhydrate
  • solid unit dosage forms can be conventional types known in the art.
  • the solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
  • the tablets, capsules, and the like can also contain a binder, such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin.
  • a liquid carrier such as a fatty oil.
  • tablets can be coated with shellac, sugar, or both.
  • a syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
  • these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like.
  • the percentage of the compound in compositions can, of course, be varied as the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the oral maintenance dose is between about 25 mg and about 50 mg, preferably given once daily.
  • the preferred unit dosage forms include tablets or capsules.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipients.
  • a pharmaceutical adjuvant, carrier or excipients include, but are not limited to sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable carrier, including adjuvants, excipients or stabilizers.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • active compounds may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds and/or compositions prepared according to the present invention can be used to treat warm blooded animals, such as mammals, which include humans.
  • the present invention relates to a method for treatment of hypertension, congestive heart failure and angina in a mammal in need thereof, which method comprises administering to said mammal an effective amount of carvedilol hydrobromide monohydrate, or solvates thereof, with any of the characteristics noted herein.
  • a suitable reactor is charged with acetone.
  • the acetone solution is sequentially charged with carvedilol, water and 48% aqueous HBr. On addition of the water, the acetone slurry becomes a solution.
  • the reaction mixture is stirred at room temperature. A solid precipitates during the course of the stir. The precipitate is filtered and the collected cake is washed with acetone. The cake is dried under vacuum to a constant weight. The cake is weighed and stored in a polyethylene container.
  • Form 1 is slurried in dioxane between 0 and 40° C. for 2 days. The product is filtered and mildly dried.
  • Form 1 is slurried in 1-pentanol between 0° C. and 40° C. for 2 days. The product is filtered and mildly dried.
  • Form 1 is slurried in 2-Methyl-1-Propanol between 0° C. and 40° C. for 2 days. The product is filtered and mildly dried.
  • Form 1 is slurried in trifluoroethanol between 0° C. and 40° C. for 2 days. The product is filtered and mildly dried.
  • Form 1 is slurried in 2-propanol between 0° C. and 40° C. for 2 days. The product is filtered and mildly dried.
  • Carvedilol free base is dissolved in n-propanoI/water (95:5), and stoichiometric hydrobromic acid is added. The solution is cooled, and crystallization ensues. The product is filtered, washed with process solvent, and dried.
  • Carvedilol HBr monohydrate (Form 1) is dissolved in n-propanol at ambient temperature. The n-propanol is slowly evaporated off, giving a white solid.
  • Carvedilol free base is dissolved in a solvent (dichloromethane, isopropyl acetate, and acetonitrile have been used) and anhydrous HBr is added (HBr in acetic acid or gaseous HBr). The solution is cooled, and crystallization ensues. The product is filtered, washed with process solvent, and dried.
  • Carvedilol free base is dissolved in ethanol, and anhydrous HBr is added (HBr in acetic acid). The solution is cooled, and crystallization ensues. The product is filtered, washed with process solvent, and dried.

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AU2003251627A1 (en) 2004-01-19
AU2003251627A8 (en) 2004-01-19
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