Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-28
2003-08-26
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S457000
Reexamination Certificate
active
06610862
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparation of warfarin sodium. More specifically, the present invention relates to a process for preparing warfarin sodium from warfarin sodium 2-propanol clathrate by solvent expulsion.
2. Background
Warfarin sodium, known by the chemical name 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one sodium salt, is a well established, widely used oral anticoagulant and rodenticide. (See, for example, U.S. Pat. No. 4,113,744 issued Sep. 12, 1978.)
According to U.S. Pat. No. 3,192,232, warfarin sodium prepared by existing methods often has as undesirable slight yellow color. (See also, U.S. Pat. No. 3,077,481).
U.S. Pat. No. 3,246,013 also emphasizes the difficulties encountered with the preparation of a high purity warfarin sodium. This patent discloses that the removal of the 2-propanol solvent from warfarin sodium 2-propanol clathrate cannot be achieved even with heating at 100° C. over P
2
O
5
for 3-5 hours in a high vacuum (0.1 mm Hg). U.S. Pat. No. 3,077,481 further discloses that heating the clathrate at higher temperatures (145° C.) in air at a high vacuum (1.0 mm Hg) for prolonged time periods (24 hours) results in undesirable decomposition. Also, heating at still higher temperatures (230° C.), while successfully removing 2-propanol from the clathrate, results in rapid decomposition.
The present process is contrary to these teachings and provides a flexible and cost effective method of preparing warfarin sodium from warfarin sodium 2-propanol clathrate, using a single vessel, in one step, and yielding directly a pure, dry, pharmacopoeia grade substance.
The present process avoids complications and difficulties encountered in the prior art procedures, for example, the use of alkaline aqueous media and decomposition of warfarin sodium previously encountered in the prior art.
This invention succeeds where previous efforts have failed and presents a simple synthesis of warfarin sodium from warfarin sodium 2-propanol clathrate.
SUMMARY OF THE INVENTION
In summary, the present invention is a method by which warfarin sodium may be easily prepared in a commercially feasible manner. Its purity makes it very useful in the pharmaceutical industry.
The present invention provides a process which is simple, cost effective and viable for manufacturing warfarin sodium from its parent 2-propanol clathrate.
The present invention is a method for producing pure warfarin sodium from warfarin sodium 2-propanol clathrate by thermal, nondestructive solvent expulsion. The solvent expulsion according to the present invention is achieved by heating warfarin sodium 2-propanol clathrate at a temperature from about 100° C. to about 170° C., preferably at a temperature of from about 130° C. to about 160° C. and more preferably at a temperature of from about 145° C. to about 155° C. under controlled heat transfer conditions.
The solvent expulsion may be accomplished by heating the clathrate in air or, preferably in an inert atmosphere. Preferred gases for the inert atmosphere are nitrogen and argon. The solvent expulsion may be conducted at partial pressures ranging from that of a relative vacuum to 760 mm Hg. Atmospheric pressure or a reduced pressure of from about 50 mm Hg to about 100 mm Hg are preferred. The solvent expulsion may take from about 2 to about 30 hours; in preferred embodiments, the solvent expulsion takes from about 6 hours to about 20 hours.
Controlled heat transfer conditions may be provided by heating in a suitable oven including, for example, a turbo oven, a vacuum tray oven, a paddle rotary oven, a fluid bed oven, other dynamic ovens, ovens that can move the sample in the oven, and others. A special turbo oven that includes the possibility of using an inert gas (nitrogen, argon, helium) blanket in the oven by incorporating an inlet-outlet valve purge system is preferred.
In another aspect, the invention relates to pure warfarin sodium produced by the method of the invention. The pure warfarin sodium contains less then about 0.5%, preferably less than 0.4% and more preferably less than about 0.2%, 2-propanol. The pure warfarin sodium contains less than about 1% non-solvent impurities. The invention also relates to a pharmaceutical composition comprising pure warfarin sodium produced by the method of the invention.
Further objectives and advantages will become apparent from a consideration of the description and non-limiting examples.
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Bercovici Sorin
Chernyak Shimon
Ulanenko Konstantin
Covington Raymond
Gollin Michael A.
Haddaway Keith G.
Rotman Alan L.
Taro Pharmaceutical Industries Ltd.
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