HRP990182A2 - Crystalline efavirenz - Google Patents

Description

The field of technology

Efavirenz, a potent reverse transcriptase inhibitor, is obtained in crystalline form. Crystalline Efavirenz exists in several physical forms, termed Form 1, 2, 3, 4, and 5, and distinguished by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods useful in the treatment of human immunodeficiency virus (HIV).

State of the art

Reverse transcriptase is a common form of retrovirus replication. Viral replication dictates that virally encoded reverse transcriptase produce DNA copies of viral sequences by reverse transcribing the viral RNA genome. Therefore, reverse transcriptase is a clinically relevant target for chemotherapy of retroviral infections, since inhibition of virally encoded reverse transcriptase terminates viral replication.

Efavirenz is a compound effective in the treatment of human immunodeficiency virus (HIV), a retrovirus that causes progressive destruction of the human immune system, resulting in AIDS. Effective treatment by inhibiting HIV reverse transcriptase is achieved with nucleoside-based inhibitors, such as azidothymidine, as well as non-nucleoside inhibitors. Benzoxazinones such as Efavirenz have proven to be useful non-nucleoside inhibitors of HIV reverse transcriptase. Efavirenz, by its chemical name, is (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and is represented by the formula (I):

[image]

Efavirenz is not only a highly effective reverse transcriptase inhibitor, but is also effective in reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a reverse transcriptase inhibitor, crystal forms that exhibit chemical and physical advantages are necessary in the preparation, purification and formulation of preparations.

Treatment or prevention of the aforementioned disorders is achieved by applying a therapeutically effective amount of Efavirenz to a human or animal in need of such treatment or prevention. Treatment with Efavirenz can be carried out by its individual use, use as an ingredient of a pharmaceutical preparation or in combination with other antiviral agents, immunomodulators, antibiotics and vaccines. The compound can be administered enterally or parenterally, in solid or liquid dosage forms.

Efavirenz was previously not known to exist in stable crystalline polymorphic forms. Therefore, there is a need for stable crystalline forms of the drug, as well as for reliable and reproducible procedures for their preparation.

Presentation of the essence of the invention

In one aspect, the present invention relates to crystalline Efavirenz. A related aspect relates to the crystalline forms of Efavirenz, named Form 1, Form 2, Form 3, Form 4 and Form 5. These forms are distinguished from each other by differential scanning calorimetry (DSC) and x-ray powder diffraction analysis.

Further aspects of the invention include pharmaceutical compositions of crystalline Efavirenz and its five forms. The crystalline products of this invention may be formulated into conventional solid pharmaceutical dosage forms or used to prepare liquid dosage forms by combining a therapeutically effective amount of the crystalline drug with a pharmaceutically acceptable carrier. Crystalline products can be used in pharmaceutical preparations that can be combined with other antiviral agents, immunomodulators, antibiotics or vaccines.

In a further aspect, the present invention includes a method of inhibiting reverse transcriptase comprising administering an amount of Efavirenz sufficient to contact the reverse transcriptase with an effective inhibitory amount of the active ingredient of the drug.

In certain aspects, the invention includes methods for treating infections caused by retroviruses, such as human immunodeficiency virus, and disorders involving viral replication, comprising the administration of a therapeutically effective amount of a pharmaceutical composition comprising the novel crystalline forms of Efavirenz of the present invention.

Another object of the present invention is to describe a novel method for treating HIV infection, comprising administering to a host in need thereof therapeutically effective combinations of Forms 1, 2, 3, 4 and 5 of Efavirenz with one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

Brief description of the drawing

The invention is illustrated according to the attached drawings described below.

Figure 1 shows an x-ray powder diffraction pattern of Form 1 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 2 shows an x-ray powder diffraction pattern of Form 2 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 3 shows an x-ray powder diffraction pattern of Form 3 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 4 shows an x-ray powder diffraction pattern of Form 4 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 5 shows a differential calorimetric thermogram of Form 1 crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 6 shows a differential calorimetric thermogram of Form 2 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 7 shows a differential calorimetric thermogram of Form 3 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 8 shows a differential calorimetric thermogram of Form 4 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 9 shows an x-ray powder diffraction pattern of Form 5 of the crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 10 shows a differential calorimetric thermogram of Form 5 crystalline form of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Detailed description of the invention

In a first embodiment, the present invention describes Form 1 of crystalline Efavirenz.

In its recommended form, Form 1 crystalline Efavirenz is in a substantially pure form.

In the following preferred embodiment, Form 1 of crystalline Efavirenz is described by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2 , 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 ± 0.2 and 24.8 ± 0.2.

In the following recommended form, Form 1 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 1.

In the following recommended form, Form 1 of crystalline Efavirenz is described by a differential scanning calorimetry thermogram peaking at about 138°C to 140°C.

In the following recommended form, Form 1 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram substantially consistent with that shown in Figure 5.

In a more preferred embodiment, Form 1 of crystalline Efavirenz is characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2 , 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 ± 0.2 and 24.8 ± 0.2, and a differential scanning calorimetric thermogram peaking at about 138°C to about 140°C.

In the following preferred form, Form 1 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 1, and a differential scanning calorimetric thermogram peaking at about 138°C to about 140°C.

In another embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 1 crystalline Efavirenz and a pharmaceutically acceptable carrier.

In the recommended form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 1 crystalline Efavirenz.

In a more preferred form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 50 mg to about 200 mg of Form 1 crystalline Efavirenz.

In another more preferred embodiment, the pharmaceutical composition contained in a capsule or compressed tablet as a dosage form contains more than about 10% by weight of the disintegrating agent relative to the total dry weight of the dosage form.

In the next recommended form, the pharmaceutical preparation is in liquid form.

In a more preferred form, the liquid form contains about 0.1 to about 15% by weight of crystalline Efavirenz Form 1 and a liquid carrier that contains about 50 to about 99% by weight of the medium chain fatty acid polyolester.

In an even more recommended form, the preparation is contained in a soft gelatin capsule, wherein polyol esters of medium chain fatty acids consist mainly of triglycerides of C8 to C10 fatty acids.

In another more preferred form, the liquid form contains about 0.1 to about 15% by weight of crystalline Efavirenz Form 1 and a liquid carrier that contains about 50 to about 99% by weight of medium chain fatty acid polyolester, and contains a sweetener in the range of about 0.1 to about 50% by weight.

In the next more preferred form, the pharmaceutical composition which is in liquid form consists of about 0.1 to about 10 wt% Form 1 crystalline Efavirenz and a liquid carrier of about 50 to about 99 wt% vegetable oil.

In an even more preferred form, the pharmaceutical composition is contained in a soft gelatin capsule, wherein the vegetable oil is soybean oil or peanut oil.

In the next more preferred form, the pharmaceutical preparation which is in liquid form consists of about 0.1 to about 10 wt% Form 1 crystalline Efavirenz and a liquid carrier of about 50 to about 99 wt% vegetable oil, and contains a sweetener in the range of about 1.0 to about 50 wt%.

In a third form, a capsule or compressed tablet as a pharmaceutical dosage form consists of:

a) therapeutically effective amounts of Form 1 crystalline Efavirenz;

b) surfactant;

c) disintegrator,

d) binding agents, i

e) lubricant.

In the recommended form, the therapeutically effective amount is about 50 mg to about 200 mg of Form 1 crystalline Efavirenz, the surfactant is sodium lauryl sulfate, the disintegrant is sodium starch glycolate, the binding agent is lactose, and the lubricant is magnesium stearate.

In a fourth embodiment, the present invention describes a method for inhibiting viral replication by a virally encoded reverse transcriptase, comprising administering Form 1 crystalline Efavirenz, in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active drug substance.

In a preferred embodiment, the compound is administered to a human or animal for the purpose of inhibiting HIV reverse transcriptase in vivo.

In a fifth embodiment, the present invention describes a method for treating an infection caused by a human immunodeficiency virus, comprising administering to a host in need of such treatment a therapeutically effective amount of Form 1 crystalline Efavirenz.

In the recommended form, Form 1 crystalline Efavirenz is administered in doses of about 1 to about 1000 mg per dose.

In a more preferred form, Form 1 crystalline Efavirenz is administered in doses of about 50 to about 200 mg per dose.

In a sixth form, Form 1 of crystalline Efavirenz is prepared by recrystallization of Efavirenz from a hydrocarbon solvent.

In the seventh form, Form 1 crystalline Efavirenz is prepared by a process comprising:

1) recrystallization of Efavirenz from a suitable solvent;

2) crystal isolation, i

3) drying the crystals at a suitable temperature, which gives Form 1 of crystalline Efavirenz in mostly pure form.

In the more recommended form, a suitable solvent is heptane or a mixture of tetrahydrofuran and heptane, the crystals are isolated by filtration, a suitable temperature is about 70 to about 95°C, and mostly pure means purer than 90 percent.

In an eighth embodiment, Form 1 of crystalline Efavirenz is prepared by heating Form 2, Form 3, Form 4 or Form 5 of Efavirenz or mixtures thereof.

In a ninth embodiment, crystalline Efavirenz Form 1 is prepared by mixing a thick solution of Efavirenz Form 2, Efavirenz Form 3, or mixtures thereof in a hydrocarbon solvent.

In a tenth embodiment, the present invention describes Form 2 of crystalline Efavirenz.

In its recommended form, Form 2 crystalline Efavirenz is in a substantially pure form.

In the following preferred form, Form 2 of crystalline Efavirenz is described by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2 , 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2.

In the following preferred form, Form 2 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 2.

In the following preferred form, Form 2 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram peaking at about 116°C to about 119°C.

In the following recommended form, Form 2 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram substantially consistent with that shown in Figure 6.

In a more preferred embodiment, Form 2 of crystalline Efavirenz is characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2 , 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2, and a differential scanning calorimetric thermogram peaking at about 116°C to about 119°C.

In the following preferred form, Form 2 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 2, and a differential scanning calorimetric thermogram peaking at about 116°C to about 119°C.

In an eleventh embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 2 crystalline Efavirenz and a pharmaceutically acceptable carrier.

In the recommended form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 2 crystalline Efavirenz.

In the following preferred form, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is about 0.1 percent to about 15 percent of Form 2 crystalline Efavirenz.

In a twelfth embodiment, the present invention describes a method for inhibiting viral replication by a virally encoded reverse transcriptase, comprising administering Form 2 of crystalline Efavirenz, in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active drug substance.

In a thirteenth embodiment, the present invention describes a method for the treatment of viral disorders, such as human immunodeficiency virus infection, and other indications, comprising administering to a host in need of such treatment a therapeutically effective amount of Form 2 crystalline Efavirenz.

In the recommended form, Form 2 crystalline Efavirenz is administered in doses of about 1 to about 1000 mg per dose.

In the fourteenth form, Form 2 of crystalline Efavirenz is prepared by a rapid crystallization process from a saturated alkane solution of Efavirenz.

In the recommended form, rapid crystallization includes:

1) dissolving Efavirenz in a suitable solvent at a suitable temperature, thereby obtaining a saturated solution;

2) filtering the saturated solution; and

3) rapid cooling of the saturated solution, thereby producing Form 2 of crystalline Efavirenz.

In a more preferred form, a suitable solvent is heptane, a suitable temperature is about 70 to 80°C, and rapid cooling of the saturated solution consists of bringing the saturated solution into contact with a cold surface.

In a fifteenth embodiment, the present invention describes Form 3 of crystalline Efavirenz in substantially pure form.

In the following preferred embodiment, Form 3 of crystalline Efavirenz is described by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2 , 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2.

In the following preferred form, Form 3 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 3.

In the following preferred form, Form 3 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram peaking at about 108°C to about 110°C.

In the following recommended form, Form 3 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram substantially consistent with that shown in Figure 7.

In a more preferred embodiment, Form 3 crystalline Efavirenz is characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2 , 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2, and a differential scanning calorimetric thermogram peaking at about 108°C to about 110°C.

In the following more preferred form, Form 3 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 3, and a differential scanning calorimetric thermogram peaking at about 108°C to about 110°C.

In a sixteenth embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 3 crystalline Efavirenz and a pharmaceutically acceptable carrier.

In the recommended form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 3 crystalline Efavirenz.

In the following preferred form, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is about 0.1 percent to about 15 percent of Form 3 crystalline Efavirenz.

In a seventeenth embodiment, the present invention describes a method for inhibiting viral replication by a virally encoded reverse transcriptase, comprising administering Form 3 of crystalline Efavirenz, in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the drug's active ingredient.

In an eighteenth embodiment, the present invention describes a method for treating a viral infection caused by human immunodeficiency virus, comprising administering to a host in need of such treatment a therapeutically effective amount of Form 3 crystalline Efavirenz.

In the recommended form, Form 3 crystalline Efavirenz is administered in doses of about 1 to about 1000 mg per dose.

In a nineteenth form, Form 3 crystalline Efavirenz is prepared by mixing a thick solution of Form 1 Efavirenz, Form 2 Efavirenz, or a mixture thereof, in a hydrocarbon solvent, and isolating the crystals.

In the recommended form, the hydrocarbon is heptane, and the crystals are isolated by filtration.

In a twentieth embodiment, the present invention describes Form 4 of crystalline Efavirenz.

In the recommended form, Form 4 crystalline Efavirenz is in a substantially pure form.

In the following preferred embodiment, Form 4 of crystalline Efavirenz is described by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2 , 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2 and 24.3 ± 0.2.

In the following preferred form, Form 4 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 4.

In the following preferred form, Form 4 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram peaking at about 95°C to about 100°C.

In the following recommended form, Form 4 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram substantially consistent with that shown in Figure 8.

In a more preferred embodiment, Form 4 of crystalline Efavirenz is characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2 , 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2 and 24.3 ± 0.2, and a differential scanning calorimetric thermogram peaking at about 95°C to about 100°C.

In the following more preferred form, Form 4 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 4, and a differential scanning calorimetric thermogram peaking at about 95°C to about 100°C.

In a twenty-first embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of crystalline Efavirenz Form 4 and a pharmaceutically acceptable carrier.

In the recommended form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 4 crystalline Efavirenz.

In the following preferred form, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is about 0.1 percent to about 15 percent of Form 4 crystalline Efavirenz.

In a twenty-second embodiment, the present invention describes a method for inhibiting viral replication by a virally encoded reverse transcriptase, comprising administering Form 4 of crystalline Efavirenz, in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active drug substance.

In a twenty-third embodiment, the present invention describes a method for treating an infection caused by a human immunodeficiency virus, comprising administering to a host in need of such treatment a therapeutically effective amount of Form 4 crystalline Efavirenz.

In the recommended form, Form 4 crystalline Efavirenz is administered in doses of from about 1 to about 1000 mg per dose.

In the twenty-fourth form, Form 4 of crystalline Efavirenz is prepared by recrystallization from a mixed solvent system.

In the twenty-fifth form, Form 4 of crystalline Efavirenz is prepared by a process comprising:

1) adding a suitable solvent to the Efavirenz solution to obtain the final solution;

2) distilling the final solution into a complex solution from which Efavirenz crystallizes as Form 4 crystals; and

3) crystal isolation.

In the recommended form, a suitable solvent is heptane, the solution contains tetrahydrofuran and Efavirenz, the complex solvent has about 1 to about 10 percent tetrahydrofuran in heptane, and isolation is accomplished by filtration.

In a twenty-sixth embodiment, the present invention describes Form 5 of crystalline Efavirenz.

In its recommended form, Form 5 crystalline Efavirenz is in a substantially pure form.

In the following preferred embodiment, Form 5 of crystalline Efavirenz is described by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2 , 20.6 ± 0.2, 21.3 ± 0.2, 22.8 ± 0.2, 24.8 ± 0.2, 27.4 ± 0.2, 28.2 ± 0.2 and 31.6 ± 0.2.

In the following preferred form, Form 5 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 9.

In the following preferred form, Form 5 of crystalline Efavirenz is described by a differential scanning calorimetry thermogram peaking at about 108°C to about 110°C.

In the following recommended form, Form 5 of crystalline Efavirenz is described by a differential scanning calorimetric thermogram substantially consistent with that shown in Figure 10.

In a more preferred embodiment, Form 5 of crystalline Efavirenz is characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2 .

In the next more preferred form, Form 5 of crystalline Efavirenz is described by an x-ray powder diffraction pattern substantially consistent with that shown in Figure 9, and a differential calorimetric thermogram peaking at about 108°C to about 110°C.

In a twenty-seventh embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of crystalline Efavirenz Form 5 and a pharmaceutically acceptable carrier.

In the recommended form, the pharmaceutical composition is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 5 crystalline Efavirenz.

In the following recommended form, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is about 0.1 percent to about 15 percent of Form 5 crystalline Efavirenz.

In a twenty-eighth embodiment, the present invention describes a method for inhibiting viral replication by a virally encoded reverse transcriptase, comprising administering Form 5 of crystalline Efavirenz, in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active drug substance.

In a twenty-ninth embodiment, the present invention describes a method for treating an infection caused by a human immunodeficiency virus, comprising administering to a host in need of such treatment a therapeutically effective amount of Form 5 crystalline Efavirenz.

In the recommended form, Form 5 crystalline Efavirenz is administered in doses of from about 1 to about 1000 mg per dose.

In the thirtieth form, Form 5 of crystalline Efavirenz is prepared by recrystallization from a mixed solvent system.

In a thirty-first embodiment, the present invention describes a method of treating HIV infection comprising administering, in combination, to a host in need thereof, a therapeutically effective amount of:

a) Forms 1, 2, 3, 4 or 5 of crystalline Efavirenz; and

b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In a thirty-second embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of Form 1, Form 2, Form 3, Form 4, Form 5, or mixtures thereof, and a pharmaceutically acceptable carrier.

Efavirenz is known by its chemical name, (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and is represented by the formula (I):

[image]

The synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one is possible using 4-chloroaniline which is available on the market. After reaction with pivaloyl chloride in the presence of hydroxide to obtain the corresponding amide, treatment with alkyl lithium and ethyl trifluoroacetate follows, and then acidification with a mineral acid, resulting in a trifluoroketone salt (Scheme 1).

Scheme 1

[image]

The free base consequently reacts with benzyl alcohol in the presence of acid to give benzylamine, which is alkylated in the presence of a chiral inducer with cyclopropylethynyl lithium to give the chiral alcohol (Scheme 2).

Scheme 2

[image]

Carbinol is oxidized to benzyl imine, which undergoes an intramolecular cyclization. The benzyl group is removed and the free amine is cyclized, yielding the active drug ingredient represented by formula (I) (Scheme 3).

Scheme 3

[image]

Procedures for the synthetic preparation of Efavirenz are further described in the oft-cited US patent application no. 60/032980, which is incorporated herein by reference.

Five forms are distinguished, designated as Form 1, Form 2, Form 3, Form 4, and Form 5. Each individual form is distinguishable from the others by x-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). Each form can be isolated in substantially pure form under the conditions described. Furthermore, mutual conversion of forms from one to another is possible, according to the procedures presented here.

Form 1 is thermodynamically the most stable. Its melting point is around 138 to 140°C, which is the highest temperature compared to the other 4 forms. Due to its increased stability, it is often used to prepare medicine. All other forms can be converted to Form 1 during drying at about 60°C to about 110°C. It is advisable to carry out the translation and drying in a drying oven at about 70 to about 110°C, under reduced pressure. A range of about 75 to about 85°C is more recommended. Form 5 is converted to Form 1 by heating to 95°C under reduced pressure. Forms 2 and 3 can also be converted to Form 1 using a hydrocarbon solution, at about 65°C to about 75°C. Heptane is the most recommended hydrocarbon for this translation. Form 4, on the contrary, cannot be converted to Form 1 under these conditions, as it is soluble at about 70°C. Form 1 can be directly crystallized from heptane when the saturated solution is heated to about 60 to about 75°C and held at that temperature until Form 1 begins to crystallize.

Form 2 can be obtained by rapid crystallization. Rapid crystallization can be achieved by filtering a saturated heptane solution of Efavirenz at about 70 to about 80°C, and crystallization preferably occurs when the solution is brought into contact with a cooling surface. Form 2 has a melting point of about 116 to about 119°C, according to differential scanning calorimetry, and therefore has exceptional stability. The needles are usually larger than in other forms. Form 2 repels various impurities common in the process of obtaining Efavirenz. Form 2 is therefore an important tool for the commercialization of Efavirenz, which involves purification of the second yield and reprocessing of those batches that do not meet drug specifications. Furthermore, larger crystals provide numerous advantages in the extraction process, including reduced filtration and drying times, as well as better fluidity of thick solutions. Form 2 can be converted to Form 1 by heating in a dryer at about 95 to 100°C for approximately 15 minutes. Alternatively, Form 1 can be prepared from Form 2 by dissolving Form 2 in heptane heated to about 70°C and holding under these conditions for approximately 2 hours. The recommended concentration of this thick solution is about 12 mL of solvent per gram of Form 2 Efavirenz. Form 2 can also be converted to Form 3 by dissolving in heptane at room temperature over a period of about 8 hours to about 24 hours. Form 2 can be converted to Form 4 by dissolving Form 2 in heptane to achieve a concentration of about 10 mL of solvent per gram of Efavirenz, and adding THF to a concentration of about 4 to about 6 mL of THF in about 100 mL of a heptane/THF solution.

Form 3 can be obtained by mixing a hydrocarbon thick solution of Form 1 or Form 2 at about 25°C. Heptane is the most recommended solvent. In general, Form 2 is converted to Form 3 faster than Form 1. This conversion takes from about 8 h to about 24 h. The conversion of Form 1 to Form 3 takes at least about 48 hours. Form 3 has a melting point of about 108 to about 110°C, according to differential scanning calorimetry, and is the most stable form in concentrated solutions of Efavirenz at room temperature. Form 3 can be converted to Form 1 by drying at about 85 to about 90°C for about 12 to about 24 hours. Conversion of Form 3 to Form 1 can also be accomplished by heating a heptane thick solution, having a concentration of about 10 mL to about 14 mL of solvent per gram of Form 3 Efavirenz, to about 65 to about 75°C and maintaining it at this temperature for about 2 hours.

Form 4 has a melting point of about 95 to about 100°C, according to differential scanning calorimetry. Form 4 has the most suitable morphology after drying, which allows advantages in the preparation process related to the handling of the crystalline substance. Furthermore, Form 4 has a recommended crystalline form, and is therefore particularly suitable for shaping preparations. Crystals can be obtained from a Form 1 or Form 2 hydrocarbon solution, when a cyclic ether such as tetrahydrofuran (THF) is added, resulting in a solvent composition of about 4 to about 6 percent THF relative to the hydrocarbon (vol/vol). Heptane is the most recommended hydrocarbon. Direct crystallization from approximately 5% THF in heptane solution is possible. The solubility of Efavirenz in THF/heptane mixtures is generally high, so in order to increase the yield, it is recommended to follow a certain protocol of procedures. After crystallization of Form 4, the concentration of THF is approximately reduced to less than 1%, which is achieved by exchanging the solvent with heptane. Form 4 can also be obtained by crystallization from a saturated solution in methylcyclohexane. Recrystallization from unbranched heptane generally gives Forms 4, 1, and 2, as well as mixtures thereof. As Form 4 is the form that is most often formed during the crystallization of Efavirenz from a hydrocarbon/THF mixture, it is precisely this form that is isolated as a wet cake in the production of the drug for the market. Form 4 can be converted to Form 1 by drying the crystals at about 80 to about 100°C for about 12 to about 24 hours, preferably in a vacuum dryer. To prepare larger quantities of Form 1 than Form 4, it is recommended that the preparation involves heating the wet cake of Form 4 to about 30 to about 50°C, thereby removing most of the solvent, after which the temperature can be raised to about 80°C to about 100 °C, which completes the translation.

Form 5 has a melting point of about 108 to 110°C, according to differential scanning calorimetry. Form 5 represents the most thermodynamically stable crystalline form below 40°C. Form 5 is highly crystalline, and its additional advantage is the exclusion of impurities, which is useful in the preparation process. Crystals can be obtained by recrystallization from a dilute THF/heptane solution. Crystals can be obtained from solutions from which either Form 1 or Form 4 were previously isolated.

Possible conversions between certain forms of this invention will be understood from Scheme 4.

Scheme 4

[image]

DEFINITIONS

The following abbreviations are used: "THF" means tetrahydrofuran, "GC" means gas chromatography, "DMSO" means dimethylsulfoxide, "TMEDA" means N,N,N',N'-tetramethylethylenediamine.

The term "hydrocarbon", as used herein, refers to alkane solvents. Examples include, but are not limited to, solvents such as pentane, hexane, heptane, octane, nonane, decane, and the like. Recommended mixed solvent systems in this invention are systems consisting of tetrahydrofuran and hydrocarbons.

The term "thick solution", as used herein, means a saturated solution of Efavirenz and an additional amount of Efavirenz to provide a heterogeneous solution of Efavirenz and solvent.

This invention describes Efavirenz Form 1, Efavirenz Form 2, Efavirenz Form 3, Efavirenz Form 4 and Efavirenz Form 5, in substantially pure form. As used herein, "substantially pure" means a compound that is greater than 90 percent pure, including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 percent.

When dissolved, Efavirenz loses its crystalline structure, so it is referred to as Efavirenz solution. All forms of this invention can be used to prepare liquid compositions in which the drug is dissolved or suspended. In addition, crystalline Efavirenz can be incorporated into solid formulations.

A therapeutically effective amount of crystalline Efavirenz is combined with a pharmaceutically suitable carrier to provide the pharmaceutical compositions of this invention. By "therapeutically effective amount" is meant an amount that, when administered alone or with an additional therapeutic agent, is effective in preventing, controlling, or alleviating a disease or condition or the progression of a disease or condition. The combination of the compounds described here is preferably a synergistic combination. Synergy, as described by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds administered in combination is greater than the additive effect of the compounds administered individually. In general, the synergistic effect is most clearly observed at suboptimal concentrations of the compounds. Synergy can be manifested as lower cytotoxicity, increased antiviral effect or some other desirable effect of the combination compared to the individual ingredients.

The compounds of this invention are useful for inhibiting HIV reverse transcriptase, treating infection caused by the human immunodeficiency virus (HIV), as well as treating the resulting pathological conditions such as acquired immunodeficiency syndrome (AIDS). Treatment of AIDS, or treatment of HIV infection, by definition includes, without limitation, treatment and prevention of a wide range of HIV-infection conditions: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic forms, current and potential exposure to HIV -in through blood transfusion, exchange of body fluids, bites, stabbing incidents or exposure to blood during surgical procedures.

For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, rectally, in dosage compositions containing conventional non-toxic pharmaceutically suitable adjuvants and carriers, in forms for dosages that are well known to people with an average knowledge of pharmaceuticals.

The crystalline forms of Efavirenz described herein can be formulated into pharmaceutical compositions and used for therapeutic and prophylactic procedures, as described in US Patent 5,519,021, which is incorporated herein by reference. These methods include combining forms of the present invention with one or more agents useful in the treatment of AIDS, such as other HIV reverse transcriptase inhibitors, HIV protease inhibitors, antiviral agents, immunomodulators, antibiotics, anti-infectives or vaccines.

As used herein, "HIV reverse transcriptase inhibitor" refers to nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, delavirdine (Pharmacia and Upjohn U90152S), nevirapine (Boehinger Ingelheim), Ro 18893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst) , ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.) and MEN 10979 (Menarini Farmaceutici).

As used herein, "HIV protease inhibitors" refer to compounds that inhibit HIV protease. Examples include, but are not limited to, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343 ), palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP- 61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors described in WO 93/07128, WO 94/19329, WO 94/22840 and PTC application no. USA 96/03426.

The crystalline forms of Efavirenz of the present invention can be administered in oral dosage forms such as tablets, capsules (including sustained release or time programmed release preparations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.

Solid dosage forms (pharmaceutical preparations) suitable for administration generally contain from about 1 mg to about 1000 mg of crystalline Efavirenz per dosage unit.

For oral administration in a solid form such as a tablet or capsule, crystalline Efavirenz may be combined with a non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. .

It is recommended that in addition to the active ingredient, solid dosage forms contain various additional ingredients, called "excipients". Among other things, these excipients include diluents, binders, lubricants, glidants and disintegrators. Coloring agents can also be added. "Diluting agents", as used herein, are agents which convert a mixture into a formulation, thereby producing a tablet of a size practical for compression. Examples of diluents are lactose and cellulose. "Binders", as used herein, are agents that increase the cohesive properties of the powder substance, which allows the tablet to remain intact after compression, and improves the fluidity of the powder. Examples of typical binding agents are lactose, starch and various sugars. "Lubricants", as used herein, have several roles, including preventing tablet adhesion to compression equipment and improving the fluidity of the granulation prior to compression or encapsulation. Lubricants are mostly hydrophobic substances. Excessive use of lubricants can lead to a preparation with reduced decomposition and/or delayed dissolution of the medicinal substance. "Glidans", as used herein, are substances that improve the fluidity of a granular substance. Examples of glidans include talc and colloidal silicon dioxide. "Disintegrators", as used herein, are substances or mixtures of substances that are added to the preparation to promote the breakdown of the solid dosage form after administration. Substances that serve as disintegrators include starches, clays, celluloses, algins, gums, and cross-linked polymers. A group of disintegrators called "superdisintegrators" are usually used in small doses in solid dosage forms, typically 1 to 10% by weight relative to the total weight of the dosage unit. Croscarmellose, crospovidone and sodium starch glycolate are examples of cross-linked cellulose, cross-linked polymer and cross-linked starch. Sodium starch glycolate swells seven to twelve times in less than 30 seconds, leading to effective breakdown of the granules containing it.

Disintegrants preferably used in the present invention are selected from the group consisting of modified starches, croscarmellose sodium, carboxymethylcellulose calcium and crospovidone. A more preferred disintegrant in this invention is a modified starch such as sodium starch glycolate.

Preferred carriers include capsules or compressed tablets containing the solid pharmaceutical dosage forms described herein. Recommended capsule or compressed tablet forms generally contain a therapeutically effective amount of Efavirenz and one or more disintegrants in an amount greater than about 10% by weight relative to the total weight of the capsule ingredients or the total weight of the tablet.

Recommended preparations in capsule form may contain Efavirenz in an amount of about 5 to about 1000 mg per capsule. Recommended preparations in the form of compressed tablets contain Efavirenz in an amount of about 5 mg to about 800 mg per tablet. More recommended preparations contain about 50 to about 200 mg per capsule or compressed tablet. Preferably, the capsule or compressed tablet as a pharmaceutical dosage form contains a therapeutically effective amount of Form 1, 2, 3 or 4 of Efavirenz; surfactant; disintegrator; binding agent; lubricant; possibly an additional pharmaceutically suitable excipient, such as diluents, glidans and the like; wherein the disintegrator is selected from among modified starches, croscarmallose sodium, carboxymethylcellulose calcium and crospovidone.

In general, liquid pharmaceutical compositions for oral administration contain agents that are HIV reverse transcriptase inhibitors in a range of about 0.1 to about 15% by weight. It is more recommended that the proportion of the medicinal substance be in the range of 1 to about 10% by mass in the preparation.

For oral administration in liquid form, crystalline Efavirenz may be combined with any oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like. In the recommended liquid preparation, the liquid carrier consists of essential polyol esters of medium chain fatty acids. The term polyol esters of medium chain fatty acids includes esters and mixed esters of glycerol, propylene glycol or other open chain polyols such as polyethylene glycol, reacted with medium chain fatty acids, wherein these acids have a chain length between 6 and 12 carbon atoms. Triglycerides or diglycerides of C8-C10 fatty acids, which are available on the market as fractionation products of coconut oil, are particularly recommended for preparations. Preparations of this description which are available on the market are sold under the commercial names "Miglyol" and "Captex 300", and their typical composition is described as about 68% C8 fatty acid triglycerides (caprylic) and about 28% C10 fatty acid triglycerides (caprylic ), with smaller amounts of triglycerides C6 and C14 fatty acids.

The medium-chain fatty acid ester component, when present, serves as a carrier - solvent for the active agent during the preparation of the composition of the invention, and is present in the range of about 50 to about 99 wt%, more preferably from 70 to 99 wt%.

It is recommended that the liquid preparation containing polyol esters also contains a sweetener, which is useful for mitigating the oily taste of medium-chain fatty acid esters, and thus significantly contributes to a better taste of the preparation.

The sweetener can be chosen from sugars such as sucrose, mannitol, sorbitol, xylitol, lactose, etc., or sugar substitutes, such as cyclamate, saccharin, aspartame, etc. If one of the sugar substitutes is chosen as a sweetener, the amount that the benefits in the preparation will be generally less than in the case of using sugar. Taking this into account, the sweetener can be used in the composition in the range of 0.1 to 50 wt%, more preferably in the range of 0.5 to 30 wt%.

More recommended sweeteners are sugars, especially sucrose. The particle size of the sucrose crushed into powder used has a significant influence on the final physical appearance of the preparation and on its palatability. The recommended particle size of the sucrose component, when used, is in the range of 200 to less than 325 mesh, according to the US standard.

In another preferred liquid pharmaceutical preparation, Efavirenz is combined with a liquid carrier that is a vegetable oil selected from the group consisting of olive oil, peanut oil, soybean oil, corn oil, safflower oil, sunflower oil, canola oil, or walnut oil. These vegetable oils are commercially available from numerous sources, which are well known to those skilled in the art.

Vegetable oil as an ingredient serves as a solvent - a carrier for the active ingredient in the preparations of the invention and is present in the composition of the preparation in the range of 50 to 99 wt%, more preferably from 70 to 99 wt%.

It is recommended that pharmaceutical preparations containing vegetable oil should also contain a sweetener that is useful for mitigating the oily taste of the vegetable oil, thus significantly contributing to the acceptability of the taste of the preparation.

Liquid preparations may also contain other ingredients commonly used to make pharmaceutical preparations. One example of such ingredients is lecithin. Its use in the preparations of the invention, as an emulsifying agent, in the range of 0.1 to 0.5% by mass, may contribute to a better absorption of the active ingredient of the medicine. Other examples of ingredients that can be used are antimicrobial preservatives such as benzoic acid and parabens; suspending agents, such as colloidal silica; antioxidants; topical oral anesthetics; aromas; and colors.

The selection of some of these optional ingredients and the scope of their use in the compositions of the invention is a matter of expertise, which will become clearer from the attached working examples.

Crystalline Efavirenz can also be bound to suitable polymers as targeted drug carriers. These polymers include polyvinylpyrrolidine pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, crystalline Efavirenz can be bound to a class of biodegradable polymers useful in achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polyacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Efavirenz crystalline gelatin capsules contain Efavirenz and the liquid or solid preparations described herein. Gelatin capsules can also contain carriers in powder form, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and others. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be prepared in such a way that they release the products in a prolonged manner, which achieves a sustained release of the drug over several hours. Tablets can be coated with sugar or film, to mask any unpleasant taste, and to protect the tablet from the atmosphere, or they can be enteric-coated, so that they can be selectively broken down in the digestive tract.

In general, water, a suitable oil, saline, aqueous dextrose (glucose) solution, and related sugar and glycol solutions, such as propylene glycol or polyethylene glycols, are suitable carriers for parenteral solutions. Solutions for parenteral solutions are prepared by dissolving crystalline Efavirenz in a carrier and, if necessary, adding buffer substances. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, individually or in combination, are suitable stabilizing agents. Citric acid and its salts can also be used, as well as sodium EDTA. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., which is a standard reference text in the field. Useful pharmaceutical dosage forms for the administration of the compounds of this invention are illustrated as follows:

Capsules

A large number of different capsules can be prepared by filling standard two-piece hard gelatin capsules with 100 mg of the active ingredient in powder form, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

A mixture of the active ingredient in a digestible oil, such as soybean, cottonseed or olive oil, can be prepared and injected via a positive displacement pump into the gelatin, resulting in soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be rinsed and dried.

Pills

A large number of tablets can be prepared by usual procedures, so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. A suitable coating can be applied to improve taste or delay absorption.

Suspension

An aqueous suspension may be prepared for oral administration so that each 5 mL contains 25 mg of finely dissolved active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Preparations for injection

Parenteral preparations suitable for use in the form of injections can be prepared by mixing 1.5 wt.% of the active ingredient in 10 vol.% propylene glycol and water. The solution is sterilized by conventional techniques.

Nasal spray

The aqueous solution is prepared so that each milliliter contains 10 milligrams of the active ingredient, 1.8 mg of methylparaben, 0.2 mg of propylparaben and 10 mg of methylcellulose. The solution is filled into ampoules of 1 mL.

Pulmonary inhaler

A homogeneous mixture of the active ingredient in polysorbate 80 is prepared so that the final concentration of the active ingredient is 10 mg per container, and the final concentration of polysorbate 80 in the container is 1 wt.%. The mixture is filled into tanks, valves are mounted on them and the required amount of dichlorotetrafluoroethane is added under pressure.

Combination of ingredients (a) and (b)

Form 1, Form 2, Form 3, Form 4 and Form 5 as therapeutic agents of ingredient (a) of the present invention may appear independently in any dosage form, such as those described above, and may also be administered in various combinations, such as described above. In the following description, ingredient (b) is to be understood as representing one or more agents, as previously described. Accordingly, if ingredients (a) and (b) are processed jointly or independently, each agent of ingredient (b) may also be processed jointly or independently.

The ingredients (a) and (b) of the present invention can be formulated into a common preparation, in a common dosage unit (that is, combined together in a single capsule, tablet, powder, liquid form, etc.) as a combination product. When ingredients (a) and (b) are not formulated in a common dosage unit, then ingredient (a) may be administered simultaneously with ingredient (b), or in any order; for example, ingredient (a) of this invention may be given first, followed by ingredient (b), or the order may be reversed. If ingredient (b) contains more than one agent, e.g. one RT inhibitor and one protease inhibitor, these agents can be administered simultaneously or in any order. When they are not applied simultaneously, it is recommended that the application of ingredients (a) and (b) follow within 1 hour. It is recommended that the route of administration of ingredients (a) and (b) be oral. The terms oral agent, oral inhibitor, oral compound and the like refer to compounds that can be administered orally. it is easily desirable that both ingredient (a) and ingredient (b) are administered in the same way (for example both orally) and in the same dosage unit, if desired they can be given in different ways (that is, for example, one ingredient of a combination of preparations can given orally, and the other ingredient intravenously) and in different dosage forms.

A medical practitioner skilled in the art will appreciate that the dosage of the combination treatment of this invention may vary depending on a variety of factors, such as the pharmacodynamic properties of the individual agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of symptoms, the type comparative therapies, frequency of therapy and desired effect, as described above.

A trained medical practitioner will easily determine the appropriate dosage of ingredients (a) and (b) of this invention based on this disclosure. As a guideline, a typical daily dose can be about 100 milligrams to about 1.5 g of each ingredient. If ingredient (b) represents more than one compound, then a typical daily dose is about 100 mg to about 1.5 g of each agent from ingredient (b). For guidance, when ingredient (a) and ingredient (b) are used in combination, the dose of each ingredient can be reduced to 70-80% compared to the usual dose of the ingredient when it is used individually, as a stand-alone agent for the treatment of HIV infection, and due to the synergistic effect of the combination.

The combination products of the present invention may be prepared so that, although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized as much as possible. In order to reduce contact, for example, when the product is administered orally, one active ingredient can be enteric coated. By enteric coating one of the active ingredients, it is possible not only to reduce the contact between the combined active ingredients, but also to control the release of one of these ingredients in the digestive system so that one of these ingredients is not released in the stomach, but in the intestines. The following form of this invention in which peroral administration is preferred provides for a combination of products where one of the active ingredients is coated with a substance that enables prolonged release in the digestive system and at the same time serves to reduce physical contact between the combined active ingredients. Furthermore, the sustained-release ingredient can be additionally enteric-coated, so that the release of this ingredient takes place only in the intestines. The following approach involves the preparation of a combination product wherein one ingredient is coated with a polymer for sustained and/or enteric release, and the other ingredient is coated with a polymer such as low viscosity hydroxypropyl methylcellulose or any other suitable substance known in the art, for the purpose of further separating the active ingredients. The polymer coating serves to form an additional barrier to interaction with another ingredient. In any composition in which contact between ingredients (a) and (b) is prevented by coating or some other substance, contact between individual substances of ingredient (b) can also be prevented.

Dosage forms of the combination product of the present invention in which one active ingredient is enteric-coated may be in tablet form, such that the enteric-coated ingredient and the other active ingredient are mixed together and compressed into a single tablet layer, or such that the enteric-coated ingredient is compressed into a single tablet layer, and the second active ingredient is pressed into an additional layer. If desired, if one wants to further separate the two layers, it is possible to place one or two placebo layers, so that the placebo layer is between the layers of active ingredients. In addition, the dosage forms of this invention can be in the form of capsules in which one active ingredient is pressed into a tablet or in the form of numerous microtablets, particles, granules or non-perils, which are then enterically coated. These enteric-coated microtablets, particles, granules or non-perils are then encapsulated or compressed into a capsule together with a granulation or other active ingredient.

These, as well as other means of reducing contact between the ingredients of the combination products of the present invention, whether administered in a single dosage form or in separate forms but simultaneously in the same manner, will be readily apparent to those skilled in the art, according to this disclosure.

The present invention also includes pharmaceutical kits useful for treating HIV infection, containing a therapeutically effective amount of a pharmaceutical composition comprising a compound of ingredient (a) and one or more compounds of ingredient (b), in one or more sterile containers. Sterilization of the container can be carried out by conventional methods well known in the art. Ingredient (a) and ingredient (b) can be in the same sterile container or in separate sterile containers. Sterile containers for substances may contain separate containers, or one or more multi-part containers, if desired. Ingredient (a) and ingredient (b) may be separate, or physically combined in a single dosage form, as described above. Such kits may further contain, as appropriate, one or more of a variety of conventional pharmaceutical kit ingredients, such as, for example, one or more pharmaceutically acceptable carriers, additional compound mixing containers, etc., as known to those skilled in the art. Instructions provided either as inserts or as labels, stating the amounts of ingredients to be applied, application guidelines and/or instructions for mixing ingredients, may also be an integral part of the kit.

It should be appreciated that, in light of the foregoing, numerous modifications and variations of this invention are possible. Therefore, within the scope of the patent claims, it is possible to practice the invention in ways different from those specifically described here.

ANALYTICAL PROCEDURES

X-ray powder refraction

X-ray powder diffraction data for Efavirenz were obtained with a Philips Model 3720 automatic powder diffractometer. Samples were batched using a Model PW 1775 multi-position sample changer. The diffractometer was equipped with a variable slit (θ-compensating slit), scintillation counter, and graphite monochromator. The radiation source was CuKα (40 kV, 30 mA). Data were collected at room temperature from 2 to 60 degrees 2θ; the step size was 0.02 degrees; the counting time was 0.5 s per step. The samples were prepared on glass sample holders as a thin layer of dispersed substance without solvent.

Differential scanning calorimetry

Thermal properties of Efavirenz were determined by differential scanning calorimetry, TA Instruments DSC 910, and data analysis was performed with a TA Instruments Thermal Analyzer 2100. Samples are placed in sealed aluminum pans for analysis, and an empty aluminum pan serves as a reference reading. A heating rate of 5°C per minute to 10°C per minute within the temperature range of 25 to 200°C is used. The instrument is calibrated with an indium standard.

EXAMPLES

The following examples describe the preparation of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Example 1

Preparation of N-(4-chlorophenyl)-2,2-dimethyl propanamide

4-chloroaniline (52.7 kg, 413 mol) is dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15 °C. Trimethylacetyl chloride (52.2 kg, 448 mol) was added to the resulting thick solution over 1 h, while maintaining the temperature below 40°C. After 30 minutes of mixing at 30°C, the thick solution is cooled to -10°C and kept like that for 2 hours. The product is collected by filtration, washed with a solution of 90/10 water/methanol (175 kg), then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: m.p. 152-153°C;

1HNMR (300 MHz, CDCl3) δ 7.48 (d, J = 9 Hz, 2H) 7.28 (d, J = 9 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.

Example 2

Preparation of 4-chloro-2-trifluoroacetyl-aniline, hydrochloride hydrate

N-(4-chlorophenyl)-2,2-dimethyl propanamide (36.7 kg, 173 mol) was added to a solution of TMEDA (20.2 kg, 174 mol) in anhydrous t-butyl methyl ether (271.5 kg) and cooled to -20°C. . 2.7 N n-butyllithium in hexane (101.9 kg, 393 mol) was added to the cold thick solution while maintaining the temperature below 5°C. After standing for 2 h at 0 to 5°C, the solution is cooled below -15°C, and then quickly reacted with ethyl trifluoroacetate (34.5 kg, 243 mol). After 30 min., the resulting solution is quenched in 3N HCl (196 L, 589 mol) while maintaining the temperature below 25°C. After removing the aqueous phase, the organic solution is concentrated by distilling approximately 200 L of solvent. Add acetic acid (352 kg) while distilling 325 kg of solvent in a vacuum of 100 mm. After cooling the solution to 30°C, 12 N HCl (43.4 kg, 434 mol) was added and the mixture was heated to 65 to 70°C for 4 hours. The resulting thick solution is cooled to 5°C and the product is collected by filtration, washed with ethyl acetate (50.5 kg) and dried in vacuo to give 42.1 kg (87%) of the title compound as a white crystalline solid: m.p. 159-162°C;

1HNMR (300 MHz, DMSO-d6) d 7.65-7.5 (complex, 2H), 7.1 (d, J = 8 Hz, 1H), 7.0 (brs, 3H); 19F NMR (282 MHz, DMSO-d6) δ -69.5.

Example 3

Preparation of N-((4'-methoxy)benzyl)-4-chloro-2-trifluoroacetylaniline

To a thick solution of 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate (40.0 kg, 144 mol) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) until pH 7.0 was reached. After removing the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution is heated to reflux and the water/toluene azeotrope (30 L) is distilled. The solution is cooled to room temperature and washed with saturated salt solution (80 kg). The organic solution is concentrated in vacuo to a volume of 35-40 L, then diluted with THF (52 kg). The weight fraction of the title compound in toluene/THF is 43%, calculated by HPLC. The yield, according to HPLC mass% analysis, is 47.7 kg (96%). The analytical sample is obtained by removing the solvent in vacuo and recrystallization from heptane: m.p. 82-84°C;

1HNMR (300 MHz, CDCl3) δ 9.04 (s,1H), 7.74 (d, J = 2 Hz, 1H), 7.35 (dd, J = 2.9 Hz), 7.24 (d, J = 8 Hz, 2H), 6.91 (d, J = 8 Hz, 2H), 6.75 (d, J = 9 Hz, 1H), 4.43 (d, J = 6 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 119.9, 117.0, 114.5, 114.4, 111.3, 55.3, 46.6.

Example 3a

Synthesis of (1R,2S)-pyrrolidinyl norephedrine

(1R,2S)-norephedrine (68.6 kg, 454 mol) was added to a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 mol). The mixture is heated to 90°C and 1,4-dibromobutane (113.4 kg, 525 mol) is added over 2 hours. The reaction is kept under reflux for 5 h, then cooled to 40°C. Water (181 kg) is added and the phases are separated at 30°C. 12 N HCl (54.3 kg, 543 mol) was added to the organic phase. The solution is heated to reflux and 150 L of distillate is removed at 200 to 300 mm. Toluene (39.5 kg) is added at 70°C and the resulting thick solution is cooled to 0-5°C for recrystallization. The product is collected, washed twice with toluene (39 kg each time) and dried under nitrogen to give 83.6 kg of the title compound as the hydrochloride salt. The hydrochloride salt is taken up in toluene (392 kg) and water (42 kg) and treated with 30% NaOH (approx. 55 kg, 414 mol) until a pH greater than 12 is reached. After removal of the lower aqueous phase, the organic solution is partially concentrated by distilling 140 L of solvent, which gives a 20 wt% solution of the title compound in toluene. The calculated yield is 50 kg (75%). The analytical sample is obtained by concentrating the toluene solution of the title compound in vacuo, and then by recrystallization from heptane: m.p. 46-48°C.

Example 3b

Preparation of cyclopropylacetylene

A mixture of 5-chloro-1-pentyne (23.0 kg, 224 mol) and anhydrous THF (150 kg) is cooled to -20°C. n-hexyllithium (2.3 eq.; 158 kg 30 wt%) in hexane is added to the mixture at a rate that prevents the temperature from rising above 5°C (approximately 2 hours). During the second half of the n-hexyllithium addition, the temperature must be maintained above -5°C, to prevent organolithium accumulation and the dangerous exothermic induction reaction. The reaction is allowed to stand at -5 to 0°C for 2 hours, until GC analysis shows at least 99% conversion. Then toluene (35 to 40 kg) is added and the reaction is concentrated in vacuo until the volume is reduced to ~1/3 of the initial volume. The mixture is heated during concentration (to ~40°C) in order to maintain the appropriate distillation rate. The mixture is then cooled to 15 to -20°C and a solution of ammonium chloride (11 to 12 kg) in 50 to 60 L of water is added, at a rate that does not raise the temperature above 10°C. After separation of the aqueous layer (approximately 70 kg), the reaction mixture is passed through a tower containing 15 kg of 3Å molecular sieves until the water content is ~300 ppm or less, by Karl Fisher analysis. The dried organic solution is then distilled through a column packed with steel wool, at atmospheric pressure, to collect cyclopropylacetylene as a solution in THF/toluene/hexane. The calculated yield is 14.0 kg.

Example 4

Preparation of (S)-5-chloro-α-(cyclopropyl-ethynyl)-2-[(4-methoxyphenyl)methyl]-amino]α-(trifluoromethyl)benzenemethanol

Triphenylmethane (100 g) is added to a toluene solution of (1R,2S)-pyrrolidinyl norephedrine (80 kg, contains 60.7 mol of (1R,2S)-pyrrolidinyl norephedrine). The solution is concentrated in vacuo to approximately half of the initial volume. Anhydrous THF (35 kg) was added and the solution was cooled using a cooling attachment to -50°C. When the temperature reaches -20°C, n-hexyllithium (33 wt% in hexanes, 33.4 kg, 119.5 mol) is added while maintaining the temperature below 0°C. A solution of cyclopropylacetylene (30 wt% in THF/hexane/toluene; contains about 4 kg, 65 mol of cyclopropylacetylene) is added to the resulting red solution while maintaining the internal temperature below -20°C. The resulting solution is left to stand at -45 to -50°C for 1 hour. A solution of N-((4'-methoxy)benzyl)-4-chloro-2-trifluoroacetylaniline (43 wt% in THF/toluene; contains about 10 kg, 28.8 mol of N-((4'-methoxy)benzyl) is added to the cold solution )-4-chloro-2-trifluoroacetylaniline) while maintaining the reaction temperature below -40°C. After standing the mixture at -43 +/- 3°C for 1 h, the reaction is quenched in 140 kg of 1N HCl, previously cooled to 0°C. The organic layer is separated and extracted twice with 25 kg of 1N HCl, twice with 40 kg of water, then concentrated in vacuo to a volume of about 29 L. Toluene (47 kg) is added and the solution is concentrated to a volume of 28 to 30 L Heptane (23 kg) is added, the mixture is cooled and kept at -5°C for 4 hours. The product is filtered, washed twice with 10 kg of heptane each and dried in vacuo to give 10 kg (85%) of the title compound as an off-white solid: m.p. 163-165°C; [α]25D +8.15° (c 1.006, MeOH);

1HNMR (300 MHz, CDCl3) δ 7.55 (brs, 1H), 7.23 (d, J = 8 Hz, 2H), 7.13 (dd, J = 3.9 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 6.59 (d, J = 8 Hz, 1H), 4.95 (bs, 1H), 4.23 (s, 2H), 3.79 (s, 3H), 2.39 (m, 1H), 1.34 (m, 1H), 0.84 (m, 2H), 0.76 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 158.9, 145.5, 130.6, 130.3, 130.2, 128.6, 125.9, 122.0, 121.6, 119.5, 114.8, 114.1, 94.0, 75.2, 74.7, 70.3, 8.0, 8.5, - 55. 0.6; 19F NMR (282 MHz, CDCl3) δ -80.19.

Example 5

Preparation of (S)-6-chloro-4-(cyclopropyl-ethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl)-3,1-benzoxazine

To a solution of heptane (295.5 kg) and ethyl acetate (32.5 kg) was added p-chloranil (57 kg, 232 mol) and (S)-5-chloro-α-(cyclopropylethynyl)-2-[(4-methoxyphenyl)methyl] -amino]-α-(trifluoromethyl)benzenemethanol (89 kg, 217 mol). The mixture is refluxed with vigorous shaking for 5.5 h, then diluted with ethyl acetate (64.1 kg) and cooled to 30°C. Tetrachlorohydroquinone is removed by filtration and washed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate is partially concentrated by distilling 260 L of solvent, then diluted with heptane (177 kg) and cooled to -10 to -15°C. The resulting thick solution is filtered, the product is washed with heptane (41 kg) and dried on a filter to less than 20% by weight of heptane (according to the loss on drying). The yield, calculated by HPLC, is 71 kg (80%). The analytical sample was obtained by pulverizing the sample with 1N NaOH, followed by recrystallization from hexane/ethyl acetate: m.p. 130-131.7°C;

1HNMR (300 MHz, DMSO-d6) δ 7.46 (d, J = 9 Hz, 2H), 7.28-7.21 (m, 3H), 7.0 (d, J = 9 Hz, 2H), 6.85 (d, J = 9 Hz, 1H), 5.52 (s, 1H), 3.78 (s, 3H), 1.52-1.47 (m, 1H), 0.90-0.84 (m, 2H), 0.72-0.68 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 160.3, 143.8, 129.6, 129.3, 128.9, 125.8, 123.1, 121.7, 118.1, 117.8, 113.8, 93.6, 80.9, 74.1, 70.3, 55.2 - 8.0, 8.4; 19F NMR (282 MHz, CDCl3) δ -157.5.

Example 6

(S)-5-chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol

Crude (S)-5-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl)-3,1-benzoxazine (71 kg, calculated dry weight) was charged into a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61 L). The mixture is heated to 60°C, resulting in a clear solution, and then cooled to 30°C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29 L) was added to the methanol solution over 20 min, maintaining the temperature below 35°C. After 30 min, excess borohydride is quenched with acetone (5.8 kg), the solution is diluted with water (175 L) and neutralized to pH 8 to 9 with acetic acid. The obtained thick solution is cooled to about 0°C, filtered and the product is washed with water and then dried in vacuo at 40°C. The crude product is again brought into the form of a thick solution with a mixture of toluene (133 kg) and heptane (106 kg) at first at 25°C, then with cooling below -10°C. The product is filtered, washed with heptanes (41 kg) and dried in vacuo at 40°C, yielding 44.5 kg (88%) as an off-white/pale yellow crystalline solid. The analytical sample is recrystallized from t-butyl methyl ether/heptane: m.p. 141-143°C; [α]25D -28.3° (c 0.106, MeOH);

1HNMR (300 MHz, CDCl3) δ 7.54 (d, J = 2 Hz, 1H), 7.13 (dd, J = 9, 2 Hz, 1H), 6.61 (d, J = 9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-1.35 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSO-d6) δ 146.7, 129.4, 129.0, 124.3, 118.4, 118.07 , 118.05, 92.3, 72.6, 71.0, 8.2, 8.1 -1.1; 19F NMR (282 MHz CDCl3) δ -80.5.

Example 7

Preparation of (S)-6-chloro-4-(cyclopropyl-ethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one

(S)-5-chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptane (32 kg) and THF (52 kg) at less than - 10°C. Phosgene (~8.0 kg, 80 mol) is introduced directly below the surface for approximately 1 h, while maintaining the temperature below 0°C. The resulting thick solution is heated to 20-25°C and kept like that for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred for about 30 min. Heptanes (97 kg) are added and ~140 L of solvent is distilled off under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution was washed with 5% aqueous sodium bicarbonate (15 L) and then with water (15 L). The solution is heated to 50°C and filtered into a clean reactor, followed by washing with 40 kg of heptane. The solution is concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10°C. The product is filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100°C, yielding 16.0 kg (95%) as an off-white to slightly pink solid. HPLC: 99.8 surface%: wt. 139-141°C; [α]25D -94.1° (c 0.300, MeOH);

1HNMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J = 2.5, 7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1.

Examples 8-16 specifically talk about the preparation of individual forms of Efavirenz of this invention, as well as the procedures for carrying out mutual conversions of these forms (Scheme 5). The following examples are intended to illustrate the present invention, and should not be construed as limiting the scope of the invention.

Scheme 5

[image]

Example 8

Direct crystallization of Form 1

Efavirenz (800 g, 2.5 mol) was dissolved in THF (1.2 L) and heptane (6.8 L). The solution is clarified by filtering through #1 Whatman paper. The THF is then removed by distillation at atmospheric pressure, and the volume is maintained by constant replacement with fresh heptane. When the THF level is <1%, the solution is cooled to 70 °C and sieved. The solution is further cooled, and crystallization begins at 64°C. The sample shows the presence of Form 1, according to XRD. The thick solution is further cooled to 30°C and filtered. The wet cake is dried at 65°C in a vacuum oven, with nitrogen, until the loss on drying is 0.36%, which gives 640 g of product (80% yield).

Example 9

Crystallization of Form 2, conversion to Form 1

Efavirenz (450 g, 1.4 mol) was prepared as a thick solution in heptane (3.5 L) and heated at reflux until complete dissolution. The solution is allowed to cool to 73°C, at which point it is filtered through #1 Whatman paper and cooled to 6°C. The thick solution is filtered and the wet cake is washed with 300 mL of heptane. The wet cake (389 g) is dried in a tray vacuum oven at 100°C for 15 hours, yielding 388 g (86% yield) of Form 1.

Example 10

Crystallization of Form 4, conversion to Form 1

Efavirenz (32 g, 0.1 mol) was dissolved in 390 mL of heptane and 20 mL of THF at 60°C. The solution is allowed to cool and seeded at 45°C with 50 mg of DMP 266. After crystallization, the solvent is removed in vacuo and replaced with fresh heptane. The thick solution is cooled to 0°C and filtered. XRD shows that it is Form 4. This is followed by drying in a vacuum oven at 80°C for 16 hours, which gives 26 g of Form 1 (82% yield).

Example 11

Crystallization of Form 2, conversion to Form 3, conversion to Form 1

Efavirenz (105 g, 0.33 mol) was prepared as a thick solution in 1.2 L of heptane and heated at reflux until dissolved. The solution is allowed to cool to 75°C, filtered through #1 Whatman paper and cooled. The diluted solution crystallizes, and the sample is filtered. X-ray powder diffraction showed that it was Form 2. The thick solution was stirred at room temperature for 24 hours, and the resulting thick solution was diluted with 200 mL of heptane, filtered and dried under vacuum at room temperature, yielding 82.5 g ( 79%). The solid is identified as Form 3 by x-ray powder diffraction. A 5 g sample is dried at 90°C for 24 hours, and the resulting solid is identified as Form 1 by x-ray powder diffraction.

Example 12

Converting Form 1 to Form 3

Form 1 Efavirenz (105 g, 0.33 mol) was prepared as a thick solution in 1.0 L of heptane at room temperature for seven days. Form 1 is not found in the sample by XRD. The peaks shown are the same as those obtained starting from Form 2, although the relative intensities show a slight difference.

Example 13

Converting Form 2 to Form 4

Form 2 Efavirenz (50 g, 0.16 mol) was prepared as a thick solution in 580 mL of heptane. Add THF (7 mL, 1% THF in heptane is obtained), heat to 40°C and after 50 minutes the sample of the thick solution is filtered; XRD (x-ray powder diffraction) still shows Form 2. Add THF (28 mL, total 32 mL, yield 5% THF in heptane) in four portions. After the final portion is added, the mixture is cooled to 28°C, the point at which a very thick solution forms, confirmed by XRD to be Form 4.

Example 14

Converting Form 1 to Form 4

Form 1 Efavirenz (10 g, 0.03 mol) was prepared as a thick solution in 90 mL of heptane. The thick solution is heated to 35°C. THF was added in 2 mL portions. After a total of 6 mL is added (giving a ~6% THF solution), the solution becomes very thick. XRD shows that it is Form 4.

Example 15

Conversion of Form 2 to Form 1 by heating the thick solution to 70°C

Form 2 of Efavirenz (3 g, 0.01 mol) was prepared as a thick solution in heptane (42 mL), heated to 70°C and held for 2 hours. The thick solution is cooled to room temperature and the sample is filtered for XRD, which shows the presence of only Form 1.

Example 16

Conversion of Form 3 to Form 1 by heating the thick solution to 70°C

Form 1 of Efavirenz (3 g, 0.01 mol) was prepared as a thick solution in heptane (42 mL) and kept for 48 hours. XRD shows Form 3. The thick solution is then heated to 70°C for 2 hours, cooled to room temperature and the sample is filtered for XRD, which shows Form 1.

Example 17

Direct crystallization of Form 5

Form 1 Efavirenz (approximately 70 g) was prepared as a slurry in 1 L of 1% vol/vol THF/heptane at room temperature. Undissolved solids were removed by filtration, and the mother liquor was seeded at room temperature with Form 5. Crystals formed slowly and were isolated by filtration, yielding 0.92 g of Form 5. The solid was identified as Form 5 by x-ray powder diffraction. .

Alternatively, Form 1 Efavirenz (approximately 70 g) is prepared as a slurry in 1.5 L of 1% vol/vol THF/heptane and heated to 40°C. The solution is filtered warm (40°C) to remove undissolved solids and the mother liquor is sieved with Form 5 at 40°C. Along with cooling the solution to room temperature, Form 5 crystallized. The solid was isolated by filtration at room temperature (9.43 g).

Alternatively, Form 1 Efavirenz (approximately 70 g) is prepared as a slurry in 1 L of warm heptane and 10 mL of THF is added to adjust the solvent ratio to 1% vol/vol THF/heptane. The thick solution is then heated to complete dissolution at 85°C. Along with cooling, the solution is periodically seeded with Form 5 until its dissolution stops (63°C), then it is allowed to cool to 45°C and filtered. The isolated solid was Form 1. The solution was cooled to room temperature overnight, and crystals of Form 5 were then collected by filtration (15.41 g).

Example 18

Form 5 to Form 1 conversion

Form 5 is dried at 95°C for 3 days, in a vacuum oven, with nitrogen, which gives Form 1, which is established by x-ray powder diffraction.

Claims (20)

1. Form 1 of crystalline Efavirenz. 2. The compound of Claim 1 characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.0 ± 0.2, 6.3 ± 0.2, 10.3 ± 0.2, 10.8 ± 0.2, 14.1 ± 0.2, 16.8 ± 0.2, 20.0 ± 0.2, 20.5 ± 0.2, 21.1 ± 0.2 and 24.8 ± 0.2. 3. The compound of Claim 1 or 2, characterized in that it is characterized by a differential scanning calorimetric thermogram peaking at about 138°C to 140°C. 4. Form 2 of crystalline Efavirenz. 5. The compound of Claim 4 characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2. 6. The compound of Claim 4 or 5, characterized by a differential scanning calorimetry thermogram peaking at about 116°C to about 119°C. 7. Form 3 of crystalline Efavirenz. 8. The compound of Claim 7 characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 7.1 ± 0.2, 7.3 ± 0.2, 11.0 ± 0.2, 13.8 ± 0.2, 20.9 ± 0.2, 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2. 9. The compound of Claim 7 or 8, characterized by a differential scanning calorimetry thermogram peaking at about 108°C to about 110°C. 10. Form 4 of crystalline Efavirenz. 11. The compound of Claim 10 characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 3.6 ± 0.2, 6.3 ± 0.2, 9.7 ± 0.2, 11.0 ± 0.2, 12.7 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 19.2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2 and 24.3 ± 0.2. 12. The compound of Claim 10 or 11, characterized by a differential scanning calorimetric thermogram peaking at about 95°C to about 100°C. 13. Form 5 of crystalline Efavirenz. 14. The compound of Claim 13 characterized by an x-ray powder diffraction pattern having four or more 2θ values selected from the group consisting of 10.2 ± 0.2, 11.4 ± 0.2, 11.6 ± 0.2, 12.6 ± 0.2, 19.1 ± 0.2, 20.6 ± 0.2, 21.3 ± 0.2, 22.8 ± 0.2, 24.8 ± 0.2, 27.4 ± 0.2, 28.2 ± 0.2 and 31.6 ± 0.2. 15. The compound of Claim 13 or 14, characterized by a differential scanning calorimetric thermogram peaking at about 108°C to about 110°C. 16. Pharmaceutical preparation, characterized in that it contains a therapeutically effective amount of Ospoj from Claim 1, 4, 7, 10 or 13 and a pharmaceutically suitable carrier. 17. The pharmaceutical composition of Claim 16, characterized in that it is contained in a capsule or compressed tablet as a dosage form, wherein the therapeutically effective amount is about 1 mg to about 1000 mg of Form 1, 2, 3, 4 or 5 crystalline Efavirenz. 18. A method for inhibiting viral replication by a virally encoded reverse transcriptase, characterized in that it comprises administering the compound of Claim 1, 4, 7, 10 or 13 in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active substance medicine. 19. The method of claim 18, characterized in that the compound is administered to a human or an animal for the purpose of inhibiting reverse transcriptase in vivo. 20. A method of treating HIV infection, characterized by the fact that it comprises the application, in combination, to a host in need, of a therapeutically effective amount of: a) compounds from Claims 1, 4, 7, 10 or 13; and b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.