DESC:F O R M 2

THE PATENTS ACT, 1970

(39 of 1970)

COMPLETE SPECIFICATION

(Section 10, rule 13)

“Process for the preparation of Efavirenz monohydrate”

Mylan Laboratories Ltd,

Plot No 564/A/22,

Road No 92, Jubilee Hills,

Hyderabad – 500033

India

The following specification specifically describes the nature of this invention and the manner in which it is to be performed.

FIELD OF INVENTION:

The present invention relates to a process for the preparation of crystalline efavirenz monohydrate.

BACKGROUND OF THE INVENTION:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as a part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded post exposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission.

Efavirenz (Formula-I) has chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.

U.S patent No. 5,519,021 discloses efavirenz and related compounds along with the synthesis of efavirenz. However, in this patent efavirenz polymorphic forms are not mentioned.

US 6,939,964 and US 6,639,071 claims crystalline efavirenz polymorphic form-I, II and III. In US 6,673,372 efavirenz polymorphic form-1, 2, 3, 4 & 5 are mentioned. WO 2006018853 claims efavirenz crystalline Form H1, amorphous form and preparation thereof.

WO 2006/040643 application claims crystalline forms a, ß, ?, ?1, ? 2, ?, d, O, N, P and amorphous form efavirenz.

Molecular Crystals and Liquid Crystals 2009; 515; 190–198 journal discloses crystalline efavirenz monohydrate. The present invention provides a process for the preparation of crystalline efavirenz monohydrate.

OBJECT AND SUMMARY OF THE INVENTION:

Main object of the present invention is to provide a process for the preparation of crystalline efavirenz monohydrate.

One aspect of the present invention is to provide a process for the preparation of crystalline efavirenz monohydrate comprising the steps of:

a) dissolving efavirenz in formic acid,

b) adding the dissolved efavirenz solution to water, and

c) isolating crystalline efavirenz monohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :

Figure 1: illustrates the powder X-ray diffraction pattern of crystalline efavirenz monohydrate.

Figure 2: illustrates the DSC thermograph of crystalline efavirenz monohydrate.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a process for the preparation of crystalline efavirenz monohydrate.
Instrumentation

Powder X-ray Diffraction (PXRD)

The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on BRUKER D-8 Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 20.0 °C/min over a temperature range of 30°C-330°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with pin holes were used.

The main aspect of the present invention is to provide a process for the preparation of crystalline efavirenz monohydrate comprising the steps of:

a) dissolving efavirenz in formic acid,

b) adding the dissolved efavirenz solution to water, and

c) isolating crystalline efavirenz monohydrate.

As per the present invention, efavirenz is dissolved in formic acid and filtered. The filterate is added to the water at 0 to -5 ?C and stirred for 1-5 hours preferably 2-3 hours, wherein water is taken 30 to 50 volumes (w/v) with respect to efavirenz. The precipitated product is filterered, washed and dried to give crystalline efavirenz monohydrate.

All patents, patent applications, and non-patent publications cited herein by reference should be considered in their entirety. The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Examples

Example-1 Process for the preparation crystalline efavirenz monohydrate.

Efavirenz (100 g) was dissolved in formic acid (450 ml) at 40-45°C and the solution was filtered through hy-flo. The bed was washed with formic acid. The filtrate was added to pre-cooled water (4.0L) at 1 to -6°C for 30-60 min and stirred the reaction mass at -4 to -6°C for 2-3h. The precipitated product was filtered, washed with 1.0L of chilled water and dried the wet material in tray dryer at 30±2°C till moisture content reaches to 5-15% to get crystalline efavirenz monohydrate (93 g).
,CLAIMS:We claim:

1. A process for the preparation of crystalline efavirenz monohydrate comprising the steps of:

a) dissolving efavirenz in formic acid,

b) adding the dissolved efavirenz solution to water, and

c) isolating crystalline efavirenz monohydrate.

2. The process according to claim 1, wherein efavirenz solution is added to water at a temperature of 0 to -5°C.