WO2008093350A1 - Nouvelle forme cristalline anhydre de dihydrogène phosphate de carvédilol - Google Patents

Nouvelle forme cristalline anhydre de dihydrogène phosphate de carvédilol Download PDF

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Publication number
WO2008093350A1
WO2008093350A1 PCT/IN2007/000057 IN2007000057W WO2008093350A1 WO 2008093350 A1 WO2008093350 A1 WO 2008093350A1 IN 2007000057 W IN2007000057 W IN 2007000057W WO 2008093350 A1 WO2008093350 A1 WO 2008093350A1
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WO
WIPO (PCT)
Prior art keywords
dihydrogen phosphate
carvedilol
water
carvedilol dihydrogen
anhydrous crystalline
Prior art date
Application number
PCT/IN2007/000057
Other languages
English (en)
Inventor
Rajesh Kumar Thaper
Manoj Devilalji Prabhvat
A. V. Mouneshwarachar
Yogesh Dadaji Pawar
Pankaj P. Daramwar
Pritesh R. Upadhyay
Original Assignee
Lupin Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lupin Limited filed Critical Lupin Limited
Publication of WO2008093350A1 publication Critical patent/WO2008093350A1/fr

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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 anhydrous crystalline form of carvedilol dihydrogen phosphate, referred to as Form A.
  • Carvedilol is chemically known as ( ⁇ )-1-(9H-carbazol-4-yloxy)-3-[[2(2- methoxyphenoxy)ethyl]amino]-2-propanol having following structure (formula 1).
  • Carvedilol is disclosed in US patent No. 4 503 067.
  • Carvedilol is a nonselective ⁇ - adrenergic blocking agent with ⁇ i blocking activity. It is used for treatment of hypertension, congestive heart failure and angina.
  • carvedilol is synthesized as free base for incorporation in medication that is available commercially.
  • WO 2004/002419 discloses carvedilol phosphate salts such as carvedilol dihydrogen phosphate and its hemihydrate and dihydrate which are characterized by PXRD, FT-IR and FT-Raman spectroscopic methods.
  • WO 2005/051383 discloses various crystalline forms of carvedilol salts such as mandelate, lactate, maleate, sulfate, glutarate and benzoate.
  • One of the most important physical properties of a pharmaceutical compound is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient.
  • Other important properties relate to the ease of processing the form into pharmaceutical dosages, such as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
  • the present invention provides a novel anhydrous crystalline form of carvedilol dihydrogen phosphate referred to as Form A having water content below 1.3%.
  • step (b) adding a solution of step (a) to aqueous H 3 PO 4 ,
  • step (c) adding mixture of step (b) to water and
  • Figure 1 is an X-ray powder diffractogram for Form A of carvedilol dihydrogen phosphate
  • Figure 2 is an FT-IR spectrum for Form A of carvedilol dihydrogen phosphate
  • Figure 3 shows the thermogravimetric analysis (TGA) results for Form A of carvedilol dihydrogen phosphate
  • carvedilol dihydrogen phosphate can be readily isolated as a novel anhydrous crystalline form referred to as Form A.
  • the present invention provides a novel anhydrous crystalline carvedilol dihydrogen phosphate referred to as Form A is characterized by PXRD pattern with characteristic peaks at about 6.50, 7.06, 9.65, 12.99, 13.66, 14.97, 15.84, 17.69, 18.15, 18.44, 18.92, 19.58, 20.22, 20.94, 22.10, 23.10, 23.58, 24.53, 25.10, 27.51 , 28.32 degrees two theta (figure 1).
  • the FT-IR spectrum of anhydrous carvedilol dihydrogen phosphate (Form A) of the present invention (figure 2) has characteristic bands at about 3224, 3071, 2841, 1625, 1604, 1587, 1505, 1454, 1442, 1346, 1332, 1252, 1218 cr ⁇ 1 (figure 2).
  • the novel form of anhydrous of carvedilol dihydrogen phosphate designated as Form A is further characterized by weight loss in the range of about 0.4 % to 1.3 %, typically in the range of 0.7-1.0 % as measured by thermogravimetric analysis over the temperature range between about 25 °C and about 200 °C (figure 3).
  • the crystalline carvedilol dihydrogen phosphate (Form A) of the present invention can be obtained by process comprising:
  • step (a) preparing a solution of carvedilol base in water miscible solvent, (b) adding a solution of step (a) to aqueous H 3 PO 4 ,
  • step (c) adding mixture of step (b) to water and
  • step (a) the solvent is selected from dimethylformamide (DMF) 1 tetrahydrofuran (THF), acetonitrile, diethylene glycol, dimethylacetamide, sulfplane or mixture thereof.
  • the step (b) and step (c) can be performed at a temperature of 0-70 °C.
  • the step (c) can be performed in reverse manner i.e water is added to mixture of step (b).
  • the ratio of substrate to solvent in step (a) is from 1:0.1 to 1:10, preferably it is 1:1 to 1:3.
  • the effective amount of Form A of carvedilol dihydrogen phosphate can be used to prepare pharmaceutical composition in association with one or more non toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically for the treatment of hypertension, congestive heart failure and angina in a mammal in need thereof.
  • 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).
  • 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).
  • thermogravimetric analysis was done using Perkin Elmer Pyris 1 TGA instrument.
  • Example 1 A solution of carvedilol base (20 g) in DMF (40 mL) was prepared and to that one molar aqueous H 3 PO 4 (3.4 mL) was added. This solution was then added to the cold water (120 mL). The reaction mixture was stirred for 5 to 10 minutes at 0-5 0 C. The solid was filtered, washed with water and dried. Yield: 19 g. M.P.: 145-147 °C.
  • Example 2 A solution of carvedilol base (20 g) in DMF (40 mL) was prepared and to that one molar aqueous H 3 PO 4 (3.4 mL) was added. This solution was then added to the cold water (120 mL). The reaction mixture was stirred for 5 to 10 minutes at 0-5 0 C. The solid was filtered, washed with water and dried. Yield: 19 g. M.P.: 145-147 °C.
  • Example 2 A solution of carvedilol base (20 g

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  • 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

L'invention concerne une nouvelle forme cristalline anhydre de dihydrogène phosphate de carvédilol, désignée forme A, ayant une teneur en eau inférieure à 1,3%. L'invention porte également sur un procédé de préparation de cette forme A, ainsi que sur les données PXRD, FT-IR et TGA.
PCT/IN2007/000057 2007-01-31 2007-02-12 Nouvelle forme cristalline anhydre de dihydrogène phosphate de carvédilol WO2008093350A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN119KO2007 2007-01-31
IN119/KOL/2007 2007-01-31

Publications (1)

Publication Number Publication Date
WO2008093350A1 true WO2008093350A1 (fr) 2008-08-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124644B2 (en) * 2006-06-28 2012-02-28 Teva Pharmaceutical Industries Ltd. Carvedilol phosphate
US8278461B2 (en) 2007-08-21 2012-10-02 Lupin Limited Stable amorphous form of carvedilol dihydrogen phosphate with stabilizer
CN106892858A (zh) * 2015-12-21 2017-06-27 上海科胜药物研发有限公司 一种卡维地洛磷酸二氢盐新晶型

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051383A1 (fr) * 2003-11-25 2005-06-09 Sb Pharmco Puerto Rico Inc. Sels de carvedilol, compositions correspondantes, procedes d'administration et/ou de traitement

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005051383A1 (fr) * 2003-11-25 2005-06-09 Sb Pharmco Puerto Rico Inc. Sels de carvedilol, compositions correspondantes, procedes d'administration et/ou de traitement

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124644B2 (en) * 2006-06-28 2012-02-28 Teva Pharmaceutical Industries Ltd. Carvedilol phosphate
US8278461B2 (en) 2007-08-21 2012-10-02 Lupin Limited Stable amorphous form of carvedilol dihydrogen phosphate with stabilizer
CN106892858A (zh) * 2015-12-21 2017-06-27 上海科胜药物研发有限公司 一种卡维地洛磷酸二氢盐新晶型

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