Crystalline sodium phenytoin monohydrate

Details Crystalline sodium phenytoin monohydrate Crystalline sodium phenytoin monohydrate

1999-05-03

2001-06-12

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S398000

Reexamination Certificate

active

06245917

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a crystalline form of sodium phenytoin monohydrate, to pharmaceutical formulations containing the same, and to methods for preparing and using the substance.
BACKGROUND OF THE INVENTION
Phenytoin is the generic name for 5,5-diphenyl-2,4-imidazolidinedione. It also is known as diphenylhydantoin. It is used extensively to treat convulsive disorders such as epilepsy. Because phenytoin is poorly soluble in aqueous mixtures, it cannot be effectively used in injectable solutions, or even in solid preparations for oral use. The compound generally is utilized as a sodium salt, which is readily soluble in water. However, even sodium phenytoin anhydrate rapidly dissociates into phenytoin, which then precipitates from aqueous solutions, thereby making uniform dosing difficult. Moreover, commercial production of sodium phenytoin anhydrate results in complex mixtures of polymorphic forms of the product, and the individual polymorphs exhibit different aqueous solubilities and dissolution rates, thereby further exacerbating dosing irregularities. To date, there has been no single crystal form of any phenytoin sodium capable of analysis by x-ray diffraction.
An object of this invention is to provide a new chemical substance that is a crystalline form of a monohydrate of sodium phenytoin. The new compound can be crystallized into a single crystal form which can readily be analyzed by x-ray diffraction. The sodium phenytoin monohydrate crystal form of this invention is stable for prolonged periods of time, and it exhibits excellent aqueous solubility characteristics, thereby allowing for improved uniformity of dosing. The new chemical compound is readily formulated for both oral and parenteral administration to humans for treatment of epilepsy and other convulsive disorders.
SUMMARY OF THE INVENTION
This invention provides a new chemical substance which is a crystalline form of sodium phenytoin monohydrate. The crystal form has a characteristic and unique x-ray diffraction pattern. The invention also provides a pharmaceutical composition comprising the crystalline sodium phenytoin monohydrate admixed with a carrier, diluent, or excipient therefor. The invention additionally provides a method for preparing the crystal form, as well as a method for treating convulsant disorders comprising administering an anticonvulsive effective amount of the crystal form. The crystal form can also be used to stabilize polymorphic mixtures of sodium phenytoin.
In a preferred embodiment, the sodium phenytoin monohydrate crystal form has the following distinctive x-ray pattern (2-theta values measured using CuK
&agr;
radiation:
2-Theta
d (Å)
Relative Intensities (I)
12.1
7.3
100
27.2
3.3
80
22.7
3.9
73
15.5
5.7
71
18.4
4.8
67
20.3
4.4
60
21.2
4.2
54
6.2
14.2
49
In a more preferred embodiment, the crystal form of this invention is identified by the following 2-theta values measured using CuK
&agr;
radiation: 12.1, 18.4, and 21.2.
In the most preferred embodiment, the crystal form is identified by the following unique 2-theta value measured using CuK
&agr;
radiation: 12.1.


REFERENCES:
patent: 2242775 (1941-05-01), Bywater
patent: 2409754 (1946-10-01), Henze
patent: 2409755 (1946-10-01), Henze
patent: 2409756 (1946-10-01), Henze
patent: 2684371 (1954-07-01), Levy
patent: 4304782 (1981-12-01), Dumont et al.
patent: 4642316 (1987-02-01), Fawzi et al.
patent: 4696814 (1987-09-01), Kao et al.
The Merck Index, Twelfth Edition, p. 1260, No. 7475, 1996.

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