Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
  • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• • 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 an improved form of Form I celiprolol hydrochloride and a process for the production thereof.
• Chemically celiprolol is N'-[3-Acetyl-4-[(1 ,1 -dimethylethyl)amino]-2- hydroxypropoxy]phenyl]-N,N-diethyl urea and belongs to the ⁇ -blocker class of antihypertensive agents.
• celiprolol hydrochloride exists in several polymorphic modifications and that these can be distinguished by their infrared spectral characteristics and x-ray diffraction patterns (Burger et al Acta. Pharm. Technol., 34(3), 147-151 (1988); Sugiyama et al., lyakuhin Kenkyu, 21 (1 ), 27-39, (1990).
• Celiprolol hydrochloride has been prepared by treating celiprolol base in acetone with aqueous hydrochloric acid rArzneim. Forsch., 33(1), 2-4 (1983)]. However, this method generally gave mixtures of Form I and Form II celiprolol hydrochloride, or Form II celiprolol hydrochloride exclusively.
• this method suffers from difficulties in work-up such as difficulties in stirring and slow filtration.
• An object of this invention is to produce an improved form of Form I celiprolol hydrochloride which has highly desirable handling properties such as filtration, drying characteristics and flowability.
• Form I celiprolol hydrochloride having improved filtration and drying characteristics is provided.
• the process comprises dissolving celiprolol base or Form II celiprolol hydrochloride in a water-miscible organic solvent or a homogeneous mixture of the aforesaid solvents and water, adding hydrochloric acid and subsequently recovering improved form of Form I celiprolol hydrochloride from the solution thereof.
• the water-miscible organic solvent or solvents has the characteristic that it solubilizes celiprolol base and hydrochloric acid and precipitates the desired form of Form I celiprolol hydrochloride, slowly and uniformly.
• the process is carried out at a temperature ranging from about ambient to the reflux temperature of the solvent used. More preferably, it is carried out at ambient temperature.
• Suitable water-miscible organic solvents include the group consisting of ketones, e.g., acetone; alcohols, e.g., ethanol, isopropyl alcohol, n-propanol or n-butanol; acetonitrile; tetrahydrofuran; dioxan; and mixtures thereof.
• the solution containing celiprolol base may be seeded with crystals of Form I celiprolol hydrochloride prior to the addition of hydrochloric acid or the slurry may be cooled prior to filtration.
• the product can be recovered by any standard method known in the art such as by filtration, filtration under vacuum, centrifugation or decantation and drying.
• a new process for consistently producing an improved form of Form I celiprolol hydrochloride is provided.
• celiprolol base having melting point 110- 117 Q C for the preparation of celiprolol hydrochloride does not give Form I consistently.
• celiprolol base which has been dried at a temperature below 70 Q C, more preferably below 55 9 C with a moisture content of less than 5% w/w and having melting point 80-100 e C, leads to consistency in achieving Form I celiprolol hydrochloride.
• Such a base is characterized by its distinct infared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 1 10 Q C.
• the moisture content in the celiprolol base may vary from 2-5% w/w but it generally remains as a monohydrate (4.5% w/w water content).
• the present invention also provides a process for the conversion of celiprolol hyrochloride Form II to Form I celiprolol hydrochloride using similar conditions for crystallization as those described above which give Form I celiprolol hydrochloride.
• Form I celiprolol hydrochloride prepared by the process of the present invention is characterized by its infrared spectral data which matches with the infrared spectrum given in the Analytical profiles of Drug substances. DETAILED DESCRIPTION OF THE INVENTION
• Celiprolol free base 25gm, moisture content 4.71 % w/w was dissolved in a mixture of acetone (395ml) and water (8ml) at 25-30-C.
• Activated carbon 2.5gm was added to the clear solution and stirred for 15 minutes. Filtered it through hyflo bed, cooled the filtrate to about 20 Q C and seeded the clear filtrate with celiprolol hydrochloride Form 1 crystals. Added cone. Hydrochloric acid (5.4 ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with acetone and dried under reduced pressure to give 22.15gm of celiprolol hydrochloride
• Celiprolol free base (12.5 gm, moisture content 4.71 % w/w) was dissolved in aqueous tetrahydrofuran (205ml) at 25-30 9 C. Added activated carbon and stirred for 30 minutes. Carbon was removed by filtration through hyflo-bed, seeded the clear filtrate with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid (2.7ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with aqueous tetrahydrofuran and dried under reduced pressure to give
• Celiprolol free base (12.5gm, moisture content 4.71 % w/w) was dissolved in acetone (196ml) at 25-30 Q C.
• Activated carbon (1.25gm) was added to the clear solution and stirred for 15 minutes. Filtered off the carbon through hyflo-bed, cooled the filtrate to about 20 9 C and seaded the clear solution with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid slowly till the pH was about 6. The resulting suspension was stirred for about 10 minutes at about 20 9 C, filtered the solid, washed with acetone and dried under vacuum to give 12.4 gm of dry Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
• Form I celiprolol hydrochloride (10gm) was suspended in absolute ethanol (50ml) at 55-60 9 C overnight and the resulting suspension was refluxed to get a clear solution. Seeded the clear solution with Form I celiprolol hydrochloride crystals. Cooled it to about 10 9 C and stirred at this temperature for about 30 minutes. The separated solid was filtered and dried under vacuum to afford 9.5gm of Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.

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• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
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• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2000
  • 2000-07-24 PL PL00353243A patent/PL353243A1/xx not_active Application Discontinuation
  • 2000-07-24 EP EP00944158A patent/EP1204408A2/en not_active Withdrawn
  • 2000-07-24 WO PCT/IB2000/001023 patent/WO2001008633A2/en not_active Ceased
  • 2000-07-24 AU AU58390/00A patent/AU5839000A/en not_active Abandoned
  • 2000-07-24 BR BR0012864-3A patent/BR0012864A/pt not_active Application Discontinuation
  • 2000-07-24 JP JP2001513366A patent/JP2003505485A/ja active Pending
• 2002
  • 2002-01-25 ZA ZA200200693A patent/ZA200200693B/xx unknown

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