Methods for the preparation of polymorphs of doxazosin mesylate

Details Methods for the preparation of polymorphs of doxazosin mesylate Methods for the preparation of polymorphs of doxazosin mesylate

2000-07-13

2002-06-04

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06399775

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods for preparing crystalline polymorphic forms of doxazosin mesylate.
BACKGROUND OF THE INVENTION
The compound 1-(4-amino-6, 7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxan-2-yl)carbonyl]piperazine mono methane sulfonate is known by the common name “doxazosin mesylate”. Doxazosin mesylate is a pharmaceutically acceptable salt known to be useful in the treatment of hypertension and benign prostatic hyperplasia.
Doxazosin mesylate exists in a number of crystalline polymorphic forms. The Chinese Journal of Medicinal Chemistry (1995, 5:266-270) describes three crystal forms, Form A, Form B and Form C. The article discloses that Form A is obtained by recrystallization of doxazosin mesylate from ethanol; and Forms B and C are produced from recrystallization of doxazosin mesylate from chloroform and water, respectively. Gr{haeck over (c)}man, et al (Farmacevtski vestnik, 1977, 48:292-293) describe Forms A, B, C, D and E of doxazosin mesylate. Grafe and Mörsdorf (CA 02224884, CA 02224916, CA 02225022) disclose methods for the preparation of doxazosin mesylate forms which do not correspond to the polymorphic forms of the present application.
Methods of preparing doxazosin mesylate typically involve dissolving doxazosin base in solvents such as chloroform and dimethylformamide. Difficulties in removing all the solvent from the precipitate may result in a final formulation that contains pharmacologically impermissible levels of the solvent that are toxic and that may adversely effect the activity of the doxazosin mesylate.
Therefore, methods of preparing Forms A and D doxazosin mesylate using solvents that are readily removed from the doxazosin mesylate residue and do not impose problems of pharmacological toxicity are highly desirable.
SUMMARY OF THE INVENTION
In accordance with the present invention, a process for the preparation of Form D doxazosin mesylate is provided, which comprises:
(a) dissolving doxazosin base and methanesulfonic acid in an alcohol having from 1 to 8 carbon atoms;
(b) precipitating the Form D from the resulting solution; and
(c) separating the Form D doxazosin mesylate product.
In a preferred embodiment, the solvent is methanol.
In another aspect, the present invention provides a process for the preparation of Form A of doxazosin mesylate, which comprises:
(a) dissolving doxazosin base and methanesulfonic acid in an alcohol having from 1 to 8 carbon atoms, a halohydrocarbon selected from the group consisting of dichloromethane, chloroform and trichloroethane, or mixtures thereof;
(b) precipitating the Form A from the resulting solution; and
(c) separating the Form A doxazosin mesylate product.
In a preferred embodiment, the solvent is methanol.
In accordance with a further aspect of the invention, a process is provided for converting Form D doxazosin mesylate to Form A, which comprises:
(a) dissolving Form D and a solvent mixture of a lower alcohol having from 1 to 8 carbon atoms and a halohydrocarbon selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane and trichloroethane;
(b) precipitating the Form A from the resulting solution; and
(c) separating the Form A doxazosin mesylate product.

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