Field of the Invention

The field of the invention relates to processes for the preparation of polymorphic forms of efavirenz. More particularly, it relates to the preparation of Form I and Form II of efavirenz. The invention also relates to pharmaceutical compositions that include the Form I of efavirenz and use of said compositions for treatment of HTV-I infections in combination with other antiretro viral agents.

Background of the Invention

Efavirenz of Formula I is an HIV-I specific, non-nucleoside, reverse transcriptase inhibitor. Chemically, efavirenz is (4iS)-6-chloro-4-(cyclopropylethynyl)-4- (trifluoromethyl)-l,4-dihydro-2H-3,l-benzoxazin-2-one. It is indicated for the treatment of ΗIV-1 infection in combination with other antiretro viral agents.

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. 6,639,071 discloses that efavirenz was previously crystallized from a heptane-tetrahydrofuran (TFfF) solvent system by the crystallization procedure which required the use of high temperatures (about 9O0C) to dissolve the final product. Crystals were formed by nucleation during the cooling process. This crystallization provides minimal purification. The final product slurry was extremely difficult to mix and handle due to its high viscosity and heterogeneous nature. The problem was solved by the addition of an anti-solvent to initiate the crystallization.

The inventors have found that the prior art process for the preparation of Form II of efavirenz is not suitable from a commercial point of view because the process requires milling of the slurry obtained after addition of water to reduce the crystal size. The present inventors have found that this process is very tedious and is not commercially scalable.

U.S. Patent No. 6,673,372 discloses polymorphic forms of efavirenz designated as Form 2 and Form 5.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Dscription of the Drawings Figure 1 is an X-ray powder diffraction pattern of Form II of efavirenz. Figure 2 is an X-ray powder diffraction pattern of Form I of efavirenz.

Summary of the Invention

The form II of efavirenz when made by the process of the present invention is easy to isolate and handle, thus making the process amenable for commercial scale use.

In one general aspect there is provided a process for the preparation of Form II of efavirenz. The process includes obtaining a solution of efavirenz in one or more organic solvents; adding an anti-solvent to the solution; and isolating the Form II of efavirenz by the removal of the solvents.

Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation and centrifugation. The process may include further forming of the product so obtained into a finished dosage form.

The process may include further drying of the product obtained.

In another general aspect there is provided a process for the preparation of Form I of efavirenz. The process includes drying Form II of efavirenz under vacuum at a temperature from about 5O0C or more for about 6 hours or more. In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the Form I of efavirenz; and one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect there is provided a method for treating HTV-I infections in a warm-blooded animal. The method includes providing a pharmaceutical composition to the warm-blooded animal, the pharmaceutical composition comprising Form I of efavirenz.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

The inventors have developed a process for the preparation of polymorphic forms of efavirenz. More particularly, the inventors have developed a process for the preparation of Form II and conversion of Form II to Form I of efavirenz.

The term "Form II" of efavirenz refers to a polymorph of efavirenz having, for example, an X-Ray Powder Diffraction (XRPD) pattern substantially as depicted in Figure 1. The term "Form I" of efavirenz refers to a polymorph of efavirenz having, for example, an X-Ray Powder Diffraction (XRPD) pattern substantially as depicted in Figure 2.

In one aspect, a process for the preparation of Form II of efavirenz is provided, wherein the process includes the steps of:

a) obtaining a solution of efavirenz in one or more organic solvents;

b) adding an anti-solvent to the solution; and

c) isolating the Form II of efavirenz by the removal of the solvents.

In general, the solution of efavirenz may be obtained by dissolving efavirenz in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction in which efavirenz is formed. If a suspension is obtained in a solvent, the suspension containing efavirenz may be heated to obtain a solution. It may be heated from about 300C to about 1500C, for example from about 500C to about 1000C. It may be heated from about 10 minutes to about 24 hours. More particularly, it may be heated for about 2-3 hours.

The efavirenz can be prepared by any of the methods known in the art including those described in U.S. Patent Nos. 5,519,021; 5,698,741; 5,663,467; and WO 94/03440; 95/20389; and 96/22955.

The term "efavirenz" includes all polymorphic forms, amorphous form, solvates, hydrates, and mixtures thereof.

The term "suitable solvents" includes any solvent or solvent mixture in which efavirenz can be solubilized, including, for example, aromatic hydrocarbons; lower alkanols; chlorinated hydrocarbons; polar aprotic solvents, or mixtures thereof.

The aromatic hydrocarbon may include one or more of benzene, toluene, and xylene. Examples of alkanol include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable lower alkanol solvents include methanol, ethanol, n-propanol, isopropanol and butanol. Examples of chlorinated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. A suitable polar aprotic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. Mixtures of all of these solvents are also contemplated.

A suitable anti-solvent that may be added to precipitate out Form II of efavirenz includes C6-8 straight or branched chain alkanes, petroleum ether, C5-7 cycloalkanes, C4-12 ethers, and mixtures thereof. The reaction mass can be stirred for some time for example, from about 10 minutes to about 6 hours to get Form II of efavirenz. The solvent may be removed from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation and centrifugation. The product may be washed and dried by conventional methods.

In one aspect, the solution may be cooled before filtration to obtain better yields of the Form II of efavirenz. It may be cooled from about 1000C to about O0C, for example from about 5O0C to about 1O0C.

In a further aspect, a process for the preparation of Form I of efavirenz is provided, wherein the process includes the steps of: a) obtaining a solution of efavirenz in one or more organic solvents;

b) adding an anti-solvent to the solution;

c) isolating Form II of efavirenz by the removal of the solvents; and

d) drying the isolated Form II under vacuum at a temperature from about

5O0C or more, and obtaining the Form I of efavirenz.

In yet another aspect, a process for the preparation of Form I of efavirenz is provided, wherein the process includes the step of:

a) drying Form II under vacuum at a temperature from about 5O0C or more, and obtaining the Form I of efavirenz.

Form II of efavirenz can be converted into Form I of efavirenz by drying under vacuum at a temperature from about 5O0C or more for example, at a temperature from about 6O0C to about 1000C.

The resulting Form I of efavirenz may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. hi these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.

The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

The Form I of efavirenz can be administered for the treatment of HIV-I infections in combination with other antiretroviral agents, in a warm-blooded animal.

For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds. 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.

Example 1: Preparation of Form II of efavirenz

Efavirenz (5 gm) was dissolved in toluene (5 ml) by heating to 700C. Hexane (75 ml) was added to this solution and the resultant mass was cooled to ambient temperature and further stirred for 30 minutes. The product obtained was filtered, washed with a mixture of toluene and hexane (1:15) and finally dried at 35-4O0C under vacuum.

Yield: 4.15 gm

Example 2: Preparation of Form I of efavirenz

Form II of efavirenz (4.15 g) prepared by example 1 was dried under vacuum at 50-600C for 12 hours. The solid obtained was subsequently dried at 75-800C for about 6- 12 hours to obtain the title compound.

Yield: 4.15 g

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. For example, it is understood that the various polymorphic forms of efavirenz can be incorporated in dosage forms for treating conditions for which efavirenz is useful.