Field Of The Invention
The present invention relates to stable Form N of Efavirenz, method for its preparation, pharmaceutical compositions comprising stable Form N of Efavirenz and its use in the treatment of HIV-1 infection.
Background Of The Invention
(4S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; commonly known as Efavirenz of Formula I is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor. Efavirenz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
(Formula Removed)
FORMULA I
Several processes have been reported for the preparation of Efavirenz for example, in U.S. Patent Nos. 5,519,021; 5,698,741; and 5, 663,467; International (PCT) Publication Nos. WO 94/03440; 95/20389; and 96/22955; and Tetrahedron Letters, 1995, 36, 937-940.
U S Patent Nos 6,639,071 and 5,965,729 disclose crystalline polymorphic forms of Efavirenz designated as Form I, II and III having specific X-Ray diffraction patterns.
U S. Patent No. 6,673,372 discloses polymorphic forms of Efavirenz designated as Form 2 and Form 5. Recently published application WO 06018853 discloses Form H1 of Efavirenz.
The present invf ntors have earlier prepared Efavirenz in novel polymorphic forms, designated as Form α, β, Γ, γ1. γ2, w. δ, N, 0 and P of Efavirenz, which are disclosed in WO 2006/040643. The novel polymorphic Forms N, O and P were found to be comparatively stable than the forms reported earlier and therefore can be employed industrially for developing into pharmaceutical dosage forms.
The present inventors have now developed a more stabilized form of Form N of Efavirenz.
Summary of The Invention
First aspect of the present invention relates to stable Form N of Efavirenz,
Second aspect of the present invention provides method for the preparation of stable Form N of Efavirenz comprising contacting Efavirenz Form N with an excipient.
Third aspect of the present invention provides a pharmaceutical composition comprising polymorphic stable Form N of Efavirenz.
Fourth aspect of the present invention provides a method of treating HIV-1 infections which comprises of administering to a mammal in need thereof a therapeutically effective amount of stable Form N of Efavirenz
Detailed Description Of The Invention
Form N of Efavirenz may be formed by the process comprising treating Form O of Efavirenz with water and isolating Form N of Efavirenz from the reaction mass thereof.
Form 0 of Efavirenz is stirred in water at low temperature for sufficient time to produce Form N. The resultant mixture is filtered and dried optionally under vacuum to get Form N of Efavirenz.
Form 0 in turn may be prepared by the process comprising dissolving Efavirenz in a water miscible organic solvent, removing the solvent from the solution and isolating Form 0 of Efavirenz from the
reaction mass thereof.
Efavirenz prepared by any method known in the art and present in any polymorphic form known to a person of ordinary skills in the art can be used as starting material.
Water miscible organic solvent is selected from a group comprising of methanol, ethanol, isopropanol, acetonitrile. acetone, tetrahydrofuran and 1,4-dioxane or mixtures thereof. The solvent can be removed from the resultant solution optionally under vacuum and the product obtained is then subjected to grinding between two surfaces, which can be further dried under vacuum to get Form 0 of Efavirenz. Examples of excipient include aerosil-200, aerosil R-972 and syloid. The mixture of Form N of Efavirenz and excipient may be stirred at the temperature of about 30 to about 50°C. The mixture may be stirred for about 4 to 8 hogrs under vacuum.
Form N of Efavirenz obtained by the present process may contain moisture content less than 1%. Stable Form N of Efavirenz of the present invention remains stable for about three months at 40°C with least contamination of other polymorphs such as Form I or Form 5 of Efavirenz. The stability data of Form N of Efavirenz obtained by the present process under different stability conditions is given in Table-1.
There is also provided a method of inhibition of HIV reverse transcriptase and its resistant varieties, the prevention and treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS) comprising administering stable Form N of Efavirenz.
The stable Form N of Efavirenz is usually administered as part of a pharmaceutical composition. Accordingly, there is provided a pharmaceutical composition that comprises stable Form N of Efavirenz and pharmaceutically acceptable carriers, diluents or excipient and optionally other therapeutic ingredients. The stable Form N of Efavirenz may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example peroral or parental.
It has been observed that ordinary packing of Form N of Efavirenz may lead to the contamination of other polymorphs such as Form I or Form 5, whereas the product remains stable in vacuum packing.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
EXAMPLE 1
PREPARATION OF FORM 0 OF EFAVIRENZ
Efavirenz (20 g) was dissolved in methanol (200 ml) at room temperature. Methanol was recovered completely from the resulting solution under vacuum at 38° C. The product obtained was further dried under vacuum at room temperature for 15 hours. The resulting material was ground further to obtain the title compound.
EXAMPLE 2
PREPARATION OF FORM N OF EFAVIRENZ
Form 0 of efavirenz (1.0 g) as prepared by example 1 was stirred in water (20 ml) at 10° C for 1.5 hours. The resultant mixture was filtered and dried at 40° C under vacuum for 15 hours to obtain the title compound
EXAMPLE 3
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and aerosil-200 (2.25g) was stirred under vacuum at 38°C for 6 hours. The product obtained was stable having moisture content of 0.32%.
EXAMPLE 4
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and aerosil-972 (2.25g) was stirred under vacuum at 38°C for 6 hours. The product obtained was stable having moisture content of 0.15%.
EXAMPLE 5
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and Syloid (2.25g) were stirred under vacuum at 38°C for 6 hours. The product obtained was stable having moisture content of 0.63%.
EXAMPLE 6
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (100g) was dried at 42°C under vacuum for 4.5 hours. The product obtained was stable having moisture content of 0.17%.
EXAMPLE 7
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and aerosil-200 (2.25g) was stirred under vacuum at 420C for 6 hours. The product obtained was stable having moisture content of 0.24%.
EXAMPLE 8
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and aerosil-972 (2.25g) was stirred under vacuum at 42°C for 6 hours. The product obtained was stable having moisture content of 0.11 %.
EXAMPLE 9
PREPARATION OF STABLE FORM N OF EFAVIRENZ
Form N of Efavirenz (15g) and Syloid (2.25g) were stirred under vacuum at 42°C for 6 hours. The product obtained was stable having moisture content of 0.49%.
All the samples were further exposed to stability conditions such as 40°C, 30°C and 25°C.
TABLE-1

(Table Removed)

WE CLAIM:
1. Stable Form N of Efavirenz.
2. Stable Form N of Efavirenz of claim 1, which remains stable for about three months

3 Stable Form N of Efavirenz of claim 1, having stability data as given in Table-1.
4 A process for the preparation of stable Form N of Efavirenz comprising contacting Efavirenz
Form N with an excipient.
5 The process according to claim 4, wherein Form N of Efavirenz is formed by the process
comprising of treating Form O of Efavirenz with water and isolating Form N of Efavirenz from the
reaction mass thereof.
6. The process according to claim 5, wherein Form 0 is prepared by the process comprising of dissolving Efavirenz in a water miscible organic solvent, removing the solvent from the solution and isolating Form 0 of Efavirenz from the reaction mass thereof.
7 The process according to claim 4, wherein excipient is selected from a group comprising of
aerosil-200, aerosil R-972 and syloid.
8 The profcess according to claim 4, wherein the mixture of Form N of Efavirenz and excipient is
stirred at the temperature of about 30 to about 50°C.
9. A pharmaceutical composition comprising polymorphic stable Form N of Efavirenz and pharmapeutically acceptable carriers, diluents or excipient and optionally other therapeutic ingredients.
10 A method of treating HIV-1 infections which comprises of administering to a mammal in need thereof a therapeutically effective amount of stable Form N of Efavirenz.