SK18182000A3 - Crystalline efavirenz - Google Patents

Abstract

The potent reverse transcriptase inhibitor Efavirenz is produced in crystalline form. Crystalline Efavirenz exists in several physical forms which are designated Forms 1, 2, 3, 4 and 5 and are characterized by x-ray powder diffraction and differential scanning calorimetry. Pharmaceutical compositions and methods are useful for the treatment of the human immunodeficiency virus (HIV).

Description

Technical field

Effective reverse transcriptase inhibitor Efavirenz is produced in crystalline form. Crystalline Efavirenz exists in several physical forms, designated as Forms 1, 2, 3, 4, and 5, and characterized by X-ray powder diffraction and differential scanning calorimetry. The pharmaceutical preparations and methods are useful in the treatment of human immunodeficiency virus (HIV) infection.

BACKGROUND OF THE INVENTION

Reverse transcription is a common feature of retroviral replication. Viral replication requires virus-encoded reverse transcriptase to produce copies of the DNA sequences of the viral RNA genome reverse transcription sequences. Reverse transcriptase is therefore a clinically relevant target for chemotherapy of retroviral infections because inhibition of virus-encoded reverse transcriptase disrupts viral replication.

Efavirenz is a compound that is effective in the treatment of human immunodeficiency virus (HIV) infection. HIV is a retrovirus causing progressive destruction of the human immune system with subsequent development of AIDS. Effective treatment by inhibiting HIV reverse transcriptase has been shown both for nucleoside inhibitors such as azidothymidine and non-nucleoside inhibitors. Benzoxazinones such as Efavirenz have been shown to act as non-nucleoside inhibitors of HIV reverse transcriptase. The compound Efavirenz is known by its chemical name (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, which is represented by formula (I):

Efavirenz is not only a highly potent reverse transcriptase inhibitor, but is also effective against HIV 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, they are essential for the production, purification and preparation of the crystalline preparation. forms which exhibit chemical and physical benefits.

The treatment or prevention of the above diseases is accomplished by administering 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 using the preparation alone as a component of a pharmaceutical preparation, or in combination with other antiviral and immunomodulatory agents, antibiotics and vaccines. The compound may be administered enterally or parenterally in solid or liquid dosage forms.

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9 • · · 9

9 99

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99

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To date, Efavirenz has not been known to exist in crystalline polymorphic form. Therefore, there is a need for stable crystalline drug forms and reliable and reproducible preparation procedures.

Description of the invention

In one aspect, the present invention relates to a crystalline Efavirenz compound. Related aspects relate to novel crystalline forms of a compound designated as Form 1, Form 2, Form 3, Form 4 and Form 4 and Form 5. These forms were characterized and distinguished from each other by differential scanning calorimetry (DSC) and X-ray powder diffraction analysis.

Other aspects of the invention include pharmaceutical preparations of the crystalline Efavirenz compound and its five forms. The crystalline products of the invention can 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. The crystalline products may be administered in pharmaceutical preparations which may be combined with other antiviral and immunomodulatory agents, antibiotics or vaccines.

Another method of the present invention includes a method of inhibiting reverse transcriptase, comprising administering an amount of crystalline Efavirenz sufficient to contact the reverse transcriptase with an effective inhibitory amount of the active drug substance.

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In particular aspects, the invention encompasses methods of treating retroviral infections, such as infections caused by human immunodeficiency virus, and disorders involving viral replication, comprising administering a pharmaceutical composition comprising the novel crystalline forms of the Efavirenz compound of the present invention.

Another object of the present invention is to provide a novel method of treating HIV infection comprising administering a therapeutically effective combination of Forms 1, 2, 3, 4, or 5 of Efavirenz with one or more compounds selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease to needs this treatment.

Brief description of the pictures

The invention is illustrated by reference to the accompanying drawings described below.

Figure 1 shows the powder X-ray diffractogram of Form 1 of crystalline Form (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

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

Figure 3 shows the X-ray powder diffraction pattern of Form 3 of crystalline form (S) -6-chloro-4-cycloyl

Propylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 4 shows the powder X-ray diffractogram of Form 4 of crystalline Form (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 of crystalline Form (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 crystalline Form (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 crystalline Form (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 crystalline Form (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

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

0000 0000 0 0 00 00 0 0 0 0 0 0 0 0 0 0 0

Figure 10 is a differential calorimetric thermogram of Form 5 of crystalline Form (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 provides Form 1 of the crystalline Efavirenz compound.

In a preferred embodiment, Form 1 of crystalline Efavirenz is in substantially pure form.

In another preferred embodiment, Form 1 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 another preferred embodiment, Form 1 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with that found in Figure 1.

In another preferred embodiment, Form 1 of crystalline Efavirenz is characterized by a differential scanning calorimetry thermogram having a peak from about 138 ° C to about 140 ° C.

In another preferred embodiment, Form 1 of the crystalline Efavirenz compound is characterized by a differential scanning calorimetric thermogram that is substantially in accordance with the finding of Figure 5.

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In another more preferred embodiment, Form 1 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 further characterized by a differential scanning calorimetry thermogram having a peak from about 138 ° C to about 140 ° C.

In another more preferred embodiment, Form 1 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with that found in Figure 1 and is further characterized by a differential scanning calorimetry thermogram that is substantially consistent with that found in Figure 5. .

A second embodiment of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of Form 1 crystalline Efavirenz and a pharmaceutically acceptable carrier.

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

In a more preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet dosage form, wherein the therapeutically effective amount is

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from about 50 mg to about 200 mg of Form 1 crystalline Efavirenz.

In another more preferred embodiment, the pharmaceutical composition is contained in a capsule or compressed into a tablet containing more than 10% by weight of the disintegrant to the total dry weight of the dosage form.

In another preferred embodiment, the pharmaceutical preparation is in liquid form.

In a more preferred embodiment, the liquid form comprises about 0.1% to about 15% by weight of Form 1 crystalline Efavirenz, and a liquid vehicle comprising about 50% to about 99% of a medium chain fatty acid polyol ester.

In an even more preferred embodiment, the formulation is contained in a soft gelatin capsule by weight of about 0.1% to about 15% of Form 1 crystalline Efavirenz, and a liquid vehicle comprising about 50% to about 99% of medium chain fatty acid polyol esters. it further comprises a sweetening agent in the range of about 0.1% to about 50% by weight.

In another more preferred embodiment, the pharmaceutical formulation, which is in liquid form, comprises from about 0.1% to about 10% Form 1 of crystalline Efavirenz, and a liquid vehicle comprising about 50% to about 99% by weight of vegetable oil.

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

In another more preferred embodiment, the pharmaceutical formulation in liquid form comprises from about 0.1% to about 10% of Form 1 crystalline Efavirenz, and the liquid vehicle comprising from about 50% to about 99% by weight of the vegetable oil comprises a sweetening agent ranging from 1.0% to about 50% by weight.

In a third embodiment, the pharmaceutical dosage form in capsule or compressed tablet comprises:

a) a therapeutically effective amount of Form 1 crystalline Efavirenz;

(a) a surfactant;

(a) a disintegrant;

(a) a binding substance; and

g) a lubricant.

In a preferred embodiment, the therapeutically effective amount is from 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 provides a method of inhibiting viral replication by virus-encoded reverse transcriptase, comprising the use of Form 1 of crystalline Efavirenz in an amount sufficient to provide contact with HIV reverse transcription. ··· · ··· · · · · ·················

- 10 criptases with an effective inhibitory amount of the active drug substance.

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

In a fifth embodiment, the present invention provides a method of treating a human immunodeficiency virus infection comprising administering to a subject in need thereof a therapeutically effective amount of Form 1 crystalline Efavirenz.

In a preferred embodiment, Form 1 of crystalline Efavirenz is administered at a dose of from about 1 to about 1000 mg per dose.

In a more preferred embodiment, Form 1 of crystalline Efavirenz is administered at a dose of from about 50 to about 200 mg per dose.

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

In a seventh embodiment, Form 1 of the crystalline Efavirenz compound is prepared by a method comprising:

1) recrystallizing Efavirenz from a suitable solvent;

2) isolating the crystals; and

3) drying the crystals to an appropriate temperature to obtain Form 1 crystalline Efavirenz in a substantially pure form.

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In a more preferred embodiment, a suitable solvent is heptane or a mixture of tetrahydrofuran and heptane, the crystals are isolated by filtration, the temperature is from about 70 ° C to about 95 ° C, and substantially pure means greater than 90% purity.

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

In a ninth embodiment, Form 1 of the crystalline Efavirenz compound is prepared by mixing the coarse material of Form 2 of the crystalline Efavirenz compound and Form 3 of the crystalline Efavirenz compound, or mixtures thereof in a hydrocarbon solvent.

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

In a preferred embodiment, Form 2 of crystalline Efavirenz is in substantially pure form.

In another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 or more 2Ô 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 another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with the finding shown in Figure 2.

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In another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by a differential scanning calorimetric thermogram having a peak from about 116 ° C to about 119 ° C.

In another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by a differential scanning calorimetric thermogram that is substantially in accordance with the finding of Figure 6.

In another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 further characterized by a differential scanning calorimetric thermogram having a peak from about 116 ° C to about 119 ° C.

In another preferred embodiment, Form 2 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with that of Figure 2 and is further characterized by a differential scanning calorimetry thermogram having a peak from about 116 ° C to about 119 ° C.

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

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

In another preferred embodiment, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is from about 0.1% to about 15% of Form 2 of the crystalline Efavirenz compound.

In a twelfth embodiment, the present invention provides a method of inhibiting viral replication by virus-encoded reverse transcriptase, comprising using 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 provides a method for treating viral diseases, such as human immunodeficiency virus infection, and further uses in other indications, comprising administering a therapeutically effective amount of Form 2 crystalline Efavirenz to an individual in need of such treatment or prevention.

In a preferred embodiment, Form 2 of the crystalline Efavirenz compound is administered at a dose of from about 1 to about 1000 mg per dose.

In a fourteenth embodiment of the invention, Form 2 of the crystalline Efavirenz compound is prepared by the rapid crystal process 14

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lysis from a saturated alkane solution of Efavirenz.

In a preferred embodiment, the rapid crystallization comprises:

1) dissolving Efavirenz in a suitable solvent at an appropriate temperature to form a saturated solution;

1) filtering the saturated solution; and

3) rapidly cooling the saturated solution to form Form 2 of the crystalline Efavirenz compound.

In a more preferred embodiment, a suitable solvent is heptane, a suitable temperature is from about 70 ° C to about 80 ° C, and rapid cooling of the saturated solution involves contacting the saturated solution with a cold surface.

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

In another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with the finding shown in Figure 3.

In another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by a differential 15

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a partial scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C.

In another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by a differential scanning calorimetric thermogram that is substantially consistent with the finding of Figure 7.

In another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 or more 2S 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 further characterized by a differential scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C.

In another preferred embodiment, Form 3 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with that of Figure 3, and is further characterized by a differential scanning calorimetry thermogram having a peak from about 108 ° C to about 100 ° C. 110 ° C.

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

In a preferred embodiment, the pharmaceutical preparation is contained in a capsule or compressed into a tablet dosage form, wherein the therapeutically effective amount is from

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about 1 mg to about 1000 mg of Form 3 crystalline Efavirenz.

In another preferred embodiment, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is from about 0.1% to about 15% of Form 3 of the crystalline Efavirenz compound.

In a seventeenth embodiment, the present invention provides a method of inhibiting viral replication by virus-encoded reverse transcriptase, comprising using Form 3 of crystalline Efavirenz in an amount sufficient to contact an HIV reverse transcriptase with an effective inhibitory amount of the active drug substance.

In an eighteenth embodiment, the present invention provides a method of treating a human immunodeficiency virus infection comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of Form 3 crystalline Efavirenz.

In a preferred embodiment, Form 3 of the crystalline Efavirenz compound is administered at a dose of from about 1 to about 1000 mg per dose.

In a nineteenth embodiment, Form 3 of the crystalline Efavirenz compound is prepared by mixing the coarse material of Form 1 of the crystalline Efavirenz compound, Form 2 of the crystalline Efavirenz compound, or mixtures thereof in a hydrocarbon solvent, and isolating the crystals.

In a preferred embodiment, the hydrocarbon is heptane and the crystals are isolated by filtration.

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In a twentieth form, the present invention provides Form 4 crystalline Efavirenz.

In a preferred embodiment, Form 4 of crystalline Efavirenz is in substantially pure form.

In another preferred embodiment, Form 4 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 and 19, 2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2, and 24.3 ± 0.2.

In another preferred embodiment, Form 4 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with the finding shown in Figure 4.

In another preferred embodiment, Form 4 of crystalline Efavirenz is characterized by a differential scanning calorimetry thermogram having a peak from about 95 ° C to about 100 ° C.

In another preferred embodiment, Form 4 of crystalline Efavirenz is characterized by a differential scanning calorimetric thermogram that is substantially in accordance with the finding of Figure 8.

In another preferred embodiment, Form 4 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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, · · · ·· · φ · · ······································

16.1 ± 0.2 and 19.2 ± 0.2, 19.5 ± 0.2, 20.6 ± 0.2 and 24.3 ± 0.2, and further characterized by a differential scanning calorimetric thermogram having a peak from about 95 ° C to about 100 ° C.

In another preferred embodiment, Form 4 of crystalline Efavirenz is characterized by an X-ray powder diffraction finding that is substantially consistent with that of Figure 4 and is further characterized by a differential scanning calorimetric thermogram having a peak from about 95 ° C to about 95 ° C. 100 ° C.

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

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

In another preferred embodiment, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is from about 0.1% to about 15% of Form 4 of the crystalline Efavirenz compound.

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

In a twenty-third embodiment, the present invention provides a method of treating a human immunodeficiency virus infection comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of Form 4 crystalline Efavirenz.

In a preferred embodiment, Form 4 of crystalline Efavirenz is administered at a dose of from about 1 to about 1000 mg per dose.

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

In a twenty-fifth embodiment, Form 4 of crystalline Efavirenz is prepared by a method comprising:

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

1) distilling the final solution to form a preparation in a solvent from which Efavirenz crystallizes as Form 4 crystals; and

3) isolating the crystals.

In a preferred embodiment, a suitable solvent is heptane, the solution comprises tetrahydrofuran and Efavirenz, the solvent comprises from about 1% to about 10% tetrahydrofuran in heptane, and the isolation comprises filtration.

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

In a preferred embodiment, Form 5 of crystalline Efavirenz is in substantially pure form.

In another preferred embodiment, Form 5 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 another preferred embodiment, Form 5 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding that is substantially consistent with the finding shown in Figure 9.

In another preferred embodiment, Form 5 of crystalline Efavirenz is characterized by a differential scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C.

In another preferred embodiment, Form 5 of the crystalline Efavirenz compound is characterized by a differential scanning calorimetry thermogram that is substantially consistent with the finding of Figure 10.

In another preferred embodiment, Form 5 of the crystalline Efavirenz compound is characterized by an X-ray powder diffraction finding comprising 4 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 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, and further characterized by a differential scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C.

In another preferred embodiment, Form 5 of crystalline Efavirenz is characterized by an X-ray powder diffraction finding that is substantially consistent with that of Figure 9, and is further characterized by a differential scanning calorimetry thermogram having a peak from about 108 ° C to about 110 ° C.

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

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

In another preferred embodiment, the pharmaceutical composition is in liquid form, wherein the therapeutically effective amount is from about 0.1% to about 15% of Form 5 of the crystalline Efavirenz compound.

In a twenty-eighth embodiment, the present invention provides a method of inhibiting viral replication by virus-encoded reverse transcriptase, comprising the use of Form 5 of crystalline Efavirenz in an amount of

A sufficient amount of the HIV reverse transcriptase to contact an effective inhibitory amount of the active drug substance.

In a twenty-ninth embodiment, the present invention provides a method of treating human immunodeficiency virus infection comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of Form 5 crystalline Efavirenz.

In a preferred embodiment, Form 5 of crystalline Efavirenz is administered at a dose of from about 1 to about 1000 mg per dose.

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

In a thirty-first embodiment, the present invention provides a method of treating an HIV infection, which comprises combining a therapeutically effective amount to a subject in need of such treatment:

(a) Form 1, 2, 3, 4 or 5 of the crystalline Efavirenz compound; and

a) 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 provides 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 represented by formula (I):

Synthesis of (S) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1'-benzoxazin-2-one can be accomplished using commercially available 4-chloroaniline. After reaction with pivaloyl chloride in the presence of hydroxide to give the corresponding amide, acidification with a mineral acid is carried out with alkyl lithium and ethyl trifluoroacetate to form the trifluoro ketone salt (Scheme 1).

Scheme 1

Pivaloyl-CI 1) Bui / EtTF 2

NaOH 2) HCl / HOaZ x

The free base is then reacted with benzyl alcohol in the presence of an acid to form benzylamine,

Which is alkylated in the presence of a chiral indicator by cyclopropylethynyl lithium to form a chiral alcohol (Scheme 2).

Scheme 2

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

Scheme 3

(I)

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Methods for the synthetic preparation of Efavirenz are further described in U.S. Pat. Patent Application No. 60/032980, which is hereby incorporated by reference.

Five forms identified as Form 1, Form 2, Form 3, Form 4, and Form 5 have been identified. Each Form is distinguishable from other forms by X-ray powder diffraction (XRD) analysis and differential scanning calorimetry (DSC). Each form can be isolated in substantially pure form under the conditions described. Further, the forms can be interconverted by the methods described herein.

Form 1 is the thermodynamically most stable form. It has a melting point of from about 138 ° C to about 140 ° C, which is the most of all 4 molds. Due to the increased stability it is commonly used for drug preparation. All other forms can be converted to Form 1 during drying at a temperature of about 60 ° C to about 110 ° C. The conversion and drying are preferably carried out in a drying oven at a temperature of from about 70 ° C to about 110 ° C under reduced pressure. More preferably, the temperature is from about 75 ° C to about 85 ° C. 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 coarse material at a temperature of from about 65 ° C to about 75 ° C. Heptane is the most preferred hydrocarbon for this conversion. However, Form 4 cannot be converted to Form 1 under these conditions because it is soluble at about 70 ° C. Form 1 can be directly crystallized from heptane when the saturated solution is adjusted.; · ·;;;;;;;;

· .. ·· .. · · .. ·,

- 26 to a temperature of about 60 ° C to about 75 ° C and maintained at this temperature until crystallization of Form 1 has begun.

Form 2 can be obtained by rapid crystallization.

Rapid crystallization can be achieved by filtering a saturated heptane solution of Efavirenz at a temperature from about 60 ° C to about 75 ° C, and crystallization preferably occurs upon contact of the solution with a cooler surface. Form 2 has a melting point of from about 116 ° C to about 119 ° C by differential scanning calorimetry and therefore has exceptional stability. The needles are generally larger than the other forms. Form 2 is free of a variety of impurities common to the processes that produce Efavirenz. Form 2 is therefore an important tool for the commercial production of Efavirenz, which relates to the purification of the second crop and the regeneration of series in which the drug specification has failed. The larger crystal size further confers numerous advantages to this process, such as shortening of filtration and drying and improving the flowability of the coarse solution. Form 2 can be converted to Form 1 by heating in an oven at a temperature of about 95 ° C to 100 ° C for about 15 hours. Alternatively, Form 1 can be prepared from Form 2 by mixing the coarse Form 2 material in heptane heated to about 70 ° C and maintaining these conditions for 2 hours. The preferred concentration of this coarse material is about 12 ml of solvent per gram of Form 2 of Efavirenz. Form 2 can also be converted to Form 3 by mixing the crude product in heptane at room temperature for about 8 to about 24 hours. Form 2 can be converted to Form 4 by mixing the crude Form 2 product in heptane at a concentration of approximately 10 mL of solvent per gram of compound ·· ····

Efavirenz and adding THF to achieve a concentration of from about 4 to about 6 mL of THF in about 100 mL of heptane / THF solution.

Form 3 can be obtained by mixing the hydrocarbon coarse material of Form 1 or Form 2 at a temperature of about 25 ° C. Heptane is the most preferred hydrocarbon. Form 2 generally converts more rapidly to Form 3 than Form 1. This conversion takes about 8 to 24 hours. The conversion of Form 1 to Form 3 takes at least about 48 hours. Form 3 has a melting point of approximately 108 ° C to 110 ° C by differential scanning calorimetry and is the most stable form in the solution of crude products of Efavirenz at room temperature. Form 3 can be converted to Form 1 by drying at a temperature of about 85 ° C to 90 ° C for 12 to 24 hours. Conversion of Form 3 to Form 1 can also be achieved by heating the heptane crude product at a concentration of about 10 mL to 14 mL of solvent per gram of Efavirenz Form 3 at about 65 ° C to 75 ° C and maintaining the material at that temperature for 2 hours. .

Form 4 has a melting point of from about 95 ° C to 100 ° C according to differential scanning calorimetry. After drying, Form 4 has the most suitable morphology, which is advantageous for processing the crystalline material. Furthermore, Form 4 has a preferred crystalline shape and may therefore be particularly suitable for preparing the formulation. The crystals can be obtained from a hydrocarbon crude material of Form 1 or Form 2 by adding a cyclic ether such as tetrahydrofuran (THF) to obtain a concentration of 4 to 6% THF in a hydrocarbon (w / w) solvent. Heptane is

- 28 The most preferred hydrocarbons. It can be directly crystallized from about 5% THF in heptane solution. The solubility of Efavirenz in THF / heptane mixtures is generally high, so certain methods are preferably used to maximize yield. Once crystallization of Form 4 occurs, the THF concentration is preferably reduced to less than 1%, which is achieved by solvent exchange with heptane. Form 4 can also be obtained by crystallization from a saturated solution of methylcyclohexane. Recrystallization from heptane generally results in Form 4, 1, 2 or mixtures thereof. Since Form 4 is the most common form resulting from crystallization from hydrocarbon / THF mixtures, it is a form that is isolated in the commercial drug formulation as a wet material. Form 4 can be converted to Form 1 by drying the crystals at a temperature of about 80 ° C to about 100 ° C for about 12 to 24 hours, preferably in a vacuum dryer. For large-scale preparation of Form 1 from Form 4, it is preferred to heat the wet Form 4 material to about 30 ° C to 50 ° C to remove most of the solvent. Then, the temperature can be raised to about 80 ° C to 100 ° C to complete the conversion.

Form 5 has a melting point of from about 108 ° C to 110 ° C according to differential scanning calorimetry. Form 5 was determined to be the most thermodynamically stable crystalline form below 40 ° C. Form 5 is highly crystalline and additionally has a property which allows the preferential elimination of impurities, which is an advantage of the process. The crystals may be obtained from solutions in which either Form 1 or Form 4 has already been isolated. The possible interconversion of the forms of the present invention can be further understood from Scheme 4.

· · · · · · ···· · · • • · • • • • • • • · • · · · • • • • • • • • · · • · • · • • • • • · • • • · • • • ···· • · • · • · · · · · ·

Crude material in heptane, room temperature, 12 hr.

Form 3> Form

4 ------------ Saturated solution up to 75 ^e C

Form 2

Coarse material

------------------ ► Form 4 in heptane + 5% THF

Slow crystallization

Dried at a temperature of 90 ^eC

Diluted solution ______Form 5

Form 1

· · • · • ·· • ··· • · • · • · ···· • • • · · • · ·· • · e ···· · · · · · · ·· ···

definitions

The following abbreviations are used: THF means tetrahydrofuran, GC means gas chromatography, DMSO means dimethylsulfoxide, TMEDA means N, N, Ν ', 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. Preferred solvent mixed systems are preferably solvent mixed systems containing tetrahydrofuran and hydrocarbons.

As used herein, a coarse material means a saturated solution of Efavirenz and an additional amount of Efavirenz to form a heterogeneous solution of Efavirenz and a solvent.

The present invention describes Form 1 of Efavirenz, Form 2 of Efavirenz, Form 3 of Efavirenz, Form 4 of Efavirenz, and Form 5 of Efavirenz in substantially pure form. As used herein, the term " substantially pure " means a compound having a purity greater than 90% including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100 percent.

Upon dissolution, it loses its crystalline structure and is a compound of Efavirenz. However, all of the Efavirenz compound referred to herein as a solution form of the present invention can be used to prepare liquid preparations in which the drug is dissolved or suspended. Crystalline The Efavirenz compound can additionally be incorporated into solid formulations.

A therapeutically effective amount of the crystalline Efavirenz compound is combined with a pharmaceutically acceptable carrier to form the pharmaceutical compositions of the invention. By a therapeutically effective amount is meant an amount that when administered alone or with another therapeutic agent is effective to prevent, suppress, or ameliorate the disease or condition, or the progression of the disease or condition. The combination of the compounds described herein is preferably a synergistic combination. Synergy, as described, for example, 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. The synergistic effect is best demonstrated at suboptimal concentrations of the compounds. Synergy may be related to lower cytotoxicity, increased antiviral effect, or some other beneficial effects of combination therapy compared to single component therapy.

The compounds of the present invention are useful in the inhibition of human immunodeficiency virus (HIV) infection and in the treatment of subsequent pathological conditions, such as acquired immunodeficiency syndrome (AIDS). Treatment of AIDS or treatment of HIV infection is defined as including, but not limited to, a wide range of conditions caused by HIV infection: AIDS, ARC (AIDS-related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV blood transfusion in exchange ·· ···· · · · ·

• Body fluids, stings, accidental needles, or exposure to blood during surgery. • • • • • • • •

For these reasons, the compounds of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular and intrasternal injections, or by infusion), by inhalation spray, rectally, in unit dosage formulations well known to those skilled in the pharmaceutical art.

The crystalline forms of Efavirenz described herein can be formulated into pharmaceutical preparations and used in therapeutic and prophylactic methods as described in US Patent 5519021, which is hereby incorporated by reference. These methods involve ingesting the forms of the present invention in combination with one or more agents that are useful in the treatment of AIDS. Such useful agents include other reverse transcriptase inhibitors, HIV protease inhibitors, antiviral drugs, immunomodulatory agents, antibiotics, anti-infective agents, or vaccines.

As used herein, the term HIV reverse transcriptase inhibitor refers to both nucleoside and non-nucleoside HIV reverse transcriptase (RT) inhibitors. Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, dd1, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, delavirdine (Pharmacia aad Upjohn U90152S), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly), MKC-442 (Triangle), HBY 097 (Hoechst), ACT (Korean Research ·· ················· · · · ·· 99 ·

Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.) and MEN 10979 (Menarini Pharmaceuticals).

As used herein, the term "HIV protease inhibitor" refers to compounds that inhibit HIV protease. Examples of these compounds include, but are not limited to, saquinavir (Roche, Ro 31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex / GIaxo Wellcome), nephlinavir (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), PD177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn) and ABT-378 . Other examples include cyclic protease inhibitors disclosed in WO 93/07128, WO 94/19329, WO 94/22840 and PCT Application No. US 96/03426.

The crystalline forms of the Efavirenz compound of the present invention can be administered in oral dosage forms such as tablets, capsules (both also include sustained-release or time-release formulations), pills, powders, granules, elixirs, elixirs, suspensions. , syrups and emulsions.

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

For oral administration in solid form, such as tablets or capsules, the compound may be a crystalline compound

- 34 ···································

Efavirenz combined with a non-toxic, pharmaceutically acceptable carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like.

Solid dosage forms may contain, in addition to the active ingredient, a variety of other substances referred to herein as excipients. Such excipients include, but are not limited to, diluents, binders, lubricants, glidants, and disintegrants. Coloring agents may also be incorporated. Diluents, as used herein, are agents that give the formulation a volume so that the tablet has a practical size for compression. Examples of diluents are lactose and cellulose. Binding agents, as used herein, are agents that impart cohesive properties to a compressed formulation and ensure that the tablet remains intact after compression. They also improve the liquid properties of the powder. Examples of typical binding agents are lactose, starch and various sugars.

Lubricants, as used herein, have several functions that include preventing tablet adhesion to the compression device and improving granulation flow prior to compression or encapsulation. Lubricants are in most cases hydrophobic materials. Excessive use of lubricants may result in a formulation with reduced disintegration and / or delayed dissolution of the drug substance. Glidants, as used herein, are substances that improve the flow characteristics of the granulation material. Examples thereof include talc and colloidal silicone dioxide.

- 35 ·· ···· ···· ·· ··

Disintegrants, as used herein, are substances or mixtures of substances added to a formulation to facilitate the breakdown or disintegration of a solid dosage form after administration. Materials that serve as disintegrants include starches, clays, cellulose, algines, gums, and crosslinked polymers. The class of disintegrants referred to as superdisintegrants is generally used in low concentration in solid dosage form, typically from 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 and cross-linked polymer, respectively, and cross-linked starch, respectively. Sodium starch glycolate swells 7 to 12 times in less than 30 seconds while effectively disintegrating the granulations it contains.

The disintegrant preferably used in the present invention is selected from the group consisting of modified starches, croscarmellose sodium, calcium carboxymethylcellulose and crospovidone. A preferred disintegrant in the present 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.

Preferred capsules or compressed tablet forms generally comprise 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 content or to the total weight of the tablet.

·· ·· ·· ····

- 36 · · 36 36 36 • 36 36 36 36 36 36 36 36 36 36 36 36 36

Preferred capsule preparations may contain Efavirenz in an amount of from about 5 to about 1000 mg per capsule. Preferred compressed tablet formulations comprise Efavirenz in an amount of from about 5 mg to about 800 mg per tablet. Most preferably, the preparations contain about 50 mg up to about 200 mg per capsule or compressed tablet. A capsule or compressed tablet pharmaceutical dosage form comprises a therapeutically effective amount of Efavirenz Form 1, 2, 3 or 4; surfactant; a disintegrant; a binding agent; a lubricant; optionally other pharmaceutically acceptable excipients such as diluents, glidants and the like; wherein the disintegrant is selected from modified starches, croscarmellose sodium, calcium carboxymethylcellulose and crospovidone.

Liquid pharmaceutical preparations for oral administration generally have an HIV reverse transcriptase inhibitor content of from about 0.1% to about 15% by weight. More preferably, the drug substance content in the formulation is from about 1 to about 10% by weight.

When administered orally in liquid form, the crystalline Efavirenz compound may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In a preferred liquid formulation, the liquid vehicle consists exclusively of medium chain polyol fatty acid esters. The term polyol medium chain fatty acid esters refers to esters and mixed esters of glycerol, propylene glycol, and other open-chain polyols such as polyethylene glycol, which are reacted with medium chain fatty acids, wherein said acid has a chain length of 6 to 12 carbon atoms. Particularly preferred for compositions are triglycerides or diglycerides of C _e -Cio fatty acids commercially available from fractionation of coconut oil. Commercially available products of this disclosure are sold under the trade names Miglyol and Captex 300, which are described to have a typical composition of about 68% triglycerides of C 8 fatty acids (caprylic) and 28% triglycerides of C 10 fatty acids (carp) with less triglycerides. Cg and Cu fatty acids.

When a medium chain fatty acid ester component is present, it serves as a solubilizing vehicle for the active ingredient in the preparation of the preparation of the invention and has a content in the preparation of from about 50% to about 99% by weight, but more preferably from 70% to 99%. mass.

The liquid preparation containing the polyol esters preferably contains a sweetener which is useful for reducing the oily taste of the medium chain fatty acid ester and thus contributing significantly to improving the taste of the formulation.

The sweetener may be selected from sugars such as sucrose, mannitol, sorbitol, xylitol, lactose, etc., or sugar substitutes such as cyclamate, saccharin, aspartame, and the like. When sugar substitutes are selected as sweeteners, the amount in the preparation is significantly lower than in sugars. For this reason the sweetener can be used in ·· ····

The composition is in the range of from 0.1 to 50% by weight, and more preferably in the range of from 0.5 to 30% by weight.

Preferred sweeteners are sugars and especially sucrose. It has been found that the particle size of the sucrose powder used has a significant effect on the physical appearance of the final preparation and its final taste. When a sucrose component is used, the preferred particle size is in the range of 200 to less than 325 according to the US Standard Screen.

In another preferred liquid pharmaceutical formulation, Efavirenz is combined with a liquid vehicle 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 chestnut oil. These vegetable oils are commercially available from a variety of sources well known to those skilled in the art.

The vegetable oil component serves as a solubilizing vehicle for the active ingredient in the preparation of the present invention and is present in the preparation in the range of from 50% to 99% by weight, more preferably from 70% to 99% by weight.

Pharmaceutical preparations containing polyol esters preferably contain a sweetener which is useful for reducing the oily taste of the medium chain fatty acid ester, and which thus contributes significantly to improving the taste of the formulation.

9 9 9 9 9 9 9 99 99 · · «« «« «« «• • • • • • • • • • • • • · ···

The liquid preparations may also contain other ingredients used routinely in the preparation of pharmaceutical preparations. One example of such ingredients is lecithin. Its use as an emulsifying agent in the range of from 0.05% to 1%, more preferably from 0.1% to 0.5% by weight in the compositions of the present invention may improve the absorption of the active drug substance. Other examples of ingredients that may be used are antimicrobial preservatives such as benzoic acid or parabens, suspending agents such as colloidal silicone dioxide, antioxidants, topical oral anesthetics, flavoring agents and coloring agents.

The choice of these optional ingredients and their concentrations in the formulations of the present invention depends on the experience in the art, and this will be better appreciated in the working examples below.

The crystalline Efavirenz compound may also be coupled with soluble polymers such as drug carriers with targeting capability. These polymers include a copolymer of polyvinylpyrrolidone pyran, polyhydroxypropylmethacrylamide phenol, polyhydroxyethyl aspartamidephenol, or polyethylene oxide polylysine substituted palmitolyl residues. In addition, the crystalline Efavirenz compound may be associated with a class of biodegradable polymers useful for achieving controlled drug release, e.g. block copolymers of hydrogels.

• · • · ···· • · • • • · · • • • · • · · · • 9 • • • • • · • · · · · • • • · · · · e · · · · · • ·

The gelatin capsules of the crystalline Efavirenz compound comprise Efavirenz and the liquid or solid preparation described herein. Gelatin capsules may also contain powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents may be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained release formulations to ensure continuous release of the drug over several hours. Tablets may be coated with sugar or film to mask unpleasant taste and protect the tablet from atmospheric influences, or may be enteric coated for selective disintegration in the gastrointestinal tract.

Suitable carriers for parenteral solutions are generally water, a suitable oil, saline, aqueous dextrose (glucose), sugar-related solutions and glycols such as propylene glycol or polyethylene glycols. Solutions for parenteral administration are prepared by dissolving the crystalline Efavirenz compound in a carrier and buffering agents are added if necessary. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid alone or in combination are suitable stabilizers. Citric acid and its salts as well as sodium EDTA may also be used. Parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in the publication

Remington's Pharmaceutical Sciences, Mack Publishing Co., which is a standard reference publication in the art.

·· ·· «·

Useful pharmaceutical dosage forms for administration of the compounds of the present invention may be illustrated as follows:

capsule

A plurality of unit capsules can be prepared by filling standard two-piece hard gelatin capsules with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsules

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

tablets

A large number of tablets may be prepared by conventional procedures such that the dosage unit comprises 100 mg of active ingredient, 0.2 mg of colloidal silicone dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. To improve taste and slow down

Appropriate coatings may be applied for absorption. suspensions For oral filing can be ready water suspension so that every 5 ml contains 25 mg all right

divided active ingredient, 200 mg of sodium carboxymethylcell 42; V; j; ·; g _e · · · · · · · • · · · · · · · W »9 9 t culosis, 5 mg of sodium benzoate, 1.0 grams of sorbitol solution, USP, and 0.025 mg of vanillin.

Injectable preparations

A parenteral preparation suitable for injection may be prepared by mixing 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Nasal spray

The aqueous solution is prepared such that each milliliter contains 10 mg of active ingredient, 1.8 mg of methylparaben, 0.2 mg of propylparaben, and 10 mg of methylcellulose. The solution is dispensed into 1 ml vials.

Pulmonary inhalation preparation

A homogeneous mixture of the active ingredient in polysorbate 80 is prepared such that the final concentration of active ingredient is 10 milligrams per vial and the final concentration of polysorbate 80 is 1% by weight. The mixture is divided into vials, the flaps are squeezed into vials, and the required amount of dichlorotetrafluoroethane is added under pressure.

Combination of components (a) and (b)

The therapeutic component (a) of Form 1, Form 2, Form 3, Form 4, and Form 5 of the present invention may be independently in any dosage form, such as those described above. In the following description, it is intended that component (b) represents one or more of the substances described above. Therefore, when components (a) and (b) are used equally or independently, each substance of component (b) may be used in the same manner or independently.

• · · · · · · · · · · · ·

Components (a) and (b) of the present invention may be formulated together in a single dosage unit (i.e., combined together in one capsule, tablet, powder or liquid, etc.) as a combination product. If components (a) and (b) are not prepared together in a single dosage unit, component (a) may be administered at the same time as component (b), or in any other order; for example, component (a) of the invention may be administered first followed by component (b), or may be administered in reverse order. If component (b) contains more than one substance, e.g. one RT inhibitor and one protease inhibitor, these may be co-administered or in any order. Unless administered at the same time, preferably component (a) and component (b) are administered in less than one hour. The route of administration of components (a) and (b) is preferably oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, refer to compounds that can be orally administered. Although it is preferred to administer components (a) and (b) in the same manner (i.e., orally), the dosage form, if desired, may be administered in different ways (i.e., one component of the combination product may be administered orally and another component). can be administered intravenously).

As appreciated by those skilled in the art, the dosage of the combination therapy of the present invention may vary depending on various factors such as the pharmacodynamic characteristics of the particular substance and the route of administration, the age, health and weight of the recipient, the type and extent of symptoms, concomitant treatment, frequency of administration, and desired effect as described above.

·· ·· ····

Self-dosing of components (a) and (b) of the present invention will be readily ascertainable by those skilled in the art depending upon the present invention. Generally speaking, a daily dosage of about 100 milligrams to about 1.5 grams of each component can be used. When component (b) represents more than one compound, a typical daily dosage may be from about 100 milligrams to about 1.5 grams of each of the ingredients of (b). Generally speaking, when the compounds of component (a) and component (b) are administered in combination, the dose of each component may be reduced by 70 to 80% relative to the usual dose of the component when administered alone as the sole agent for the treatment of HIV infection. the synergic effect of the combination.

The combination products of the invention can be prepared such that although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized. To minimize this contact, for example, when the product is administered orally, one of the components may be enteric coated. By enteric coating of one of the active ingredients, it is not only possible to minimize contact between the combined active ingredients, but it is also possible to control the release of one of these ingredients in the gastrointestinal tract so that one of these ingredients is not released in the stomach but rather in the intestine. Another embodiment of the present invention, where oral administration is required, provides a combination product wherein one of the active ingredients is coated with a sustained release material that permits sustained release in the gastrointestinal tract and also serves to minimize physical contact of the combined active ingredients. *

- 45 t · 9 · zlož zlož ζ zlož iek iek iek... Iek.... Iek iek In addition, the sustained release component of the active ingredient may be enteric coated, so that the release of this component occurs only in the intestine. Another approach involves preparing a combination of a product in which one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polymer, such as low viscosity hydroxypropyl methylcellulose, or other materials known in the art to separate the active compounds. . The polymer serves as a sufficient barrier to interaction with another component. In any formulation in which contact between components (a) and (b) is prevented by a coating or by the use of some other material, contact between the individual substances of component (b) may also be prevented.

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated may be in the form of tablets such that the enteric coated component and the other active ingredient are mixed together and then compressed into a tablet, or the enteric coated component is compressed into one tablet layer and the other the active ingredient is compressed into another layer. Optionally, one or more placebo layers may be present to further separate the two layers so that the placebo layer is between the layers of the active ingredients. In addition, the dosage forms of the present invention may be in the form of capsules wherein one active ingredient is compressed into a tablet, or may be in the form of a variety of microtablets, particles or granules, which are then enteric coated. These entrically coated microtablets, particles or granules are then placed in capsules or compressed into capsules together with a granulate of the other active ingredient.

• · · · ·

These, as well as other methods of minimizing contact between the components of the combination products of the present invention, whether used in a single dosage form or in separate forms but at the same time or administered in the same manner, will easily be based on the present invention. understandable to persons skilled in the field.

Pharmaceutical kits useful for treating HIV infection, comprising a therapeutically useful amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b) in one or more sterile containers are also within the scope of the present invention. Sterilization of the container may be accomplished by conventional sterilization methods well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. If desired, sterile material containers may contain separate containers or one or more multi-part containers. Component (a) and component (b) may be separated or physically combined into an individual dosage form or unit as described above. Such kits may further comprise, if desired, one or more different components of a conventional pharmaceutical kit, such as one or more pharmaceutically acceptable carriers, additional vials for mixing the ingredients, etc., as will be apparent to those skilled in the art. Instructions may also be placed in the kit, either inserted or in the form of a sticker, indicating the number of ingredients to be administered, the directions of administration and / or the guidelines for mixing the ingredients.

··························································································Iel 9

9999 99 9 9 99 9 9 9

Of course, in light of the above, various modifications and modifications of the present invention are possible. Therefore, it should be understood that, within the scope of the appended claims, the use of the invention is other than as specifically described herein.

Analytical methods

X-ray powder diffraction

The X-ray powder diffraction data of Efavirenz was obtained on a Philips Model 3720 automated powder diffractometer. The samples were analyzed in serial mode using a Model PW 1775 sample exchanger. The diffractometer was equipped with a variable slot (θ-compensating slot), scintillation counter and graph. The radiation was CuKα (40 kV, 30 mA). Data were collected at room temperature from 2 to 60 degrees 28; the step size was 0.02 degrees; the counting time was 0.5 seconds per step. The samples were prepared on a glass sample holder in the form of a thin layer of powdered material without solvent.

Differential scanning calorimetry

The thermal properties of Efavirenz were characterized by differential scanning calorimetry using a TA Instrument DSC 910, with data analysis using the TA Instruments Thermal Analyzer 2100. Samples were placed in sealed aluminum analysis pans with an empty aluminum dish as reference. Heat was used 5 ° C per minute or 10 ° C ·· ····

- 48 per minute over a temperature range of 25 ° C to 200 ° C.

The instrument was calibrated with an indium standard.

DETAILED DESCRIPTION OF THE INVENTION

The following examples show 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) was 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), and the mixture was then cooled to 15 ° C. To the resulting crude was added trimethylacetyl chloride (52.2 kg, 448 mol) for 1 hour while maintaining the temperature below 40 ° C. After stirring at 30 ° C for 30 minutes, the crude material was cooled to -10 ° C and held at that temperature for 2 hours. The product was then collected by filtration, washed with 90/10 water / methanol (175 kg), then dried under vacuum to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153 ° C; ^X H NMR (300 MHz, CDC13) δ 7.48 (d, J = 9 Hz, 2H), 7.28 (d, J = 9 Hz, 2H); ¹³ C NMR (75 MHz, CDCl 3) d 176.7, 136, 6, 129, 1, 128, 9, 121.4, 39, 6, 27, 6.

Example 2

Preparation of 4-chloro-2-trifluoroacetylaniline 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 ·· ····

with anhydrous t-butyl methyl ether (271.5 kg) and the mixture was cooled to -20 ° C. To the cold coarse material was added 2.7 N n-butyllithium (101.9 kg, 393 moles) maintaining the temperature below 5 ° C. After 2 hours at 0-5 ° C, the solution was cooled to -15 ° C and then rapidly reacted with ethyl trifluoroacetate (34.5 kg, 243 moles). After 30 minutes, the resulting solution was poured into 3N HCl (196 L, 589 mol) maintaining the temperature below 25 ° C. After removal of the aqueous phase, the organic solution was concentrated by distillation of approximately 200 L of solvent. Acetic acid (352 kg) was added after distillation of 325 kg of solvent under 100 mm vacuum. After cooling to 30 ° C, 12 N HCl (43.4 kg, 434 moles) was added and the mixture was heated to 65-70 ° C and maintained under these conditions for 4 hours. The resulting crude material was cooled to 5 ° C and the product collected by filtration, washed with ethyl acetate (50.5 kg) and dried under vacuum to give 42.1 kg (87%) of the title compound as a crystalline solid: mp 159 -162 ° C; ^X H NMR (300 MHz, DMSO-d) d 7.65-7.5 (complex, 2H), 7.1 (d, J = 8 Hz, 1H), 7.0 (br s, 3H) ; ¹⁹ F NMR (282 MHz, DMSO-d ₅ ) δ -69.5.

Example 3

Preparation of N - ((4'-methoxy) benzyl) -4-chloro-2-trifluoroacetyl aniline.

To the crude 4-chloro-2-trifluoroacetylaniline hydrochloride hydrate (40.0 kg, 144 moles) in toluene (140 kg) and water (50 L) was added 30% NaOH (18 kg) to pH 7.0. After removal of the aqueous phase, 4-methoxybenzyl alcohol (20 kg, 144 mol) and TsOH (1.0 kg, 5.3 mol) were added. The solution was heated to reflux and the water / toluene azeotrope (30 L) was distilled. The solution was cooled to ·· ····

- 50 φ φφ

• · Φ φ φ Φ ΦΦΦ φ φ Φ φ φ φ φ φ • φ φ φ φ φφφφ • · φφ

• Room temperature and washed with saturated brine (80 kg). • • • • • • • • • • • • • • • • • • • • • • • • • • • • • The organic solution was concentrated in vacuo to a volume of 35-40 L, and then diluted with THF (52 kg). The weight percent of the title compound in toluene / THF was calculated by HPLC as 43%. Yield based on weight percent from HPLC analysis was 47.7 kg (96%). An analytical sample was obtained by removing the solvent in vacuo and recrystallizing from heptane: mp 82-84 ° C; ^X H NMR (300 MHz, CDC1 ₃₎ δ 9.04 (s, 1H), 7.74 (d, J = 2 Hz,

1 Η), 7.35 (dd, J = 2, 9 Hz), 7.24 (d, J = 8 Hz, 2H), 6.91 (d, J = 8Hz, 2 H), 6, 75 (d, J = 9Hz) 1 H), 4.43 (d, J = 6) Hz, 2 H, 3.79 (s, 3 H); ¹³ C NMR (75 MHz CDCI3) 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.

To a mixture of n-butanol (227 kg), water (144 kg) and potassium carbonate (144 kg, 1043 moles) was added (1R, 2S) -norephedrine (68.6 kg, 454 moles). The mixture was heated to 90 ° C and 1,4-dibromobutane (113.4 kg, 525 mol) was added over 2 hours. The reaction was refluxed for 5 hours and then cooled to 40 ° C. Water (181 kg) was added and the phases were separated at 30 ° C. To the organic phase was added 12 N HCl (54.3 kg, 543 moles). The solution was heated to reflux and 150 L of distillate was removed at 200-300 mm. Toluene (39.5 kg) was added at 70 ° C and the resulting crude was cooled to 0-5 ° C for crystallization. The product was collected, washed twice with toluene (39 kg each) and dried under nitrogen to give the title compound as its hydrochloride salt. The hydrochloride salt was added to

9999

- 51 ·· 99

9

999

99 9

99

999999

99

99

99

9 99

9999

999

999

99

9 99

99

99999 toluene (392 kg) and water (42 kg) and treated with 30% NaOH (approximately 55 kg, 414 moles) to pH above 12. After removal of the lower aqueous phase, the organic solution was partially concentrated by distillation of 140 L of solvent to form a solution. 20% by weight of the title compound in toluene. The calculated yield was 50 kg (75%). An analytical sample was obtained by concentrating the toluene solution of the title compound in vacuo followed by recrystallization from heptane: mp 46-48 ° C.

Example 3b

Preparation of cyclopropylacetylene.

A mixture of 5-chloro-1-pentene (23.0 kg, 224 moles) and anhydrous THF (150 kg) is cooled to -20 ° C. To the mixture is added n-hexyllithium (2.3 eq; 158 kg 30% by weight) in hexane at a rate such that the temperature does not exceed 5 ° C (about 2 hours). During the second half of the n-hexyllithium addition, the temperature must remain above -5 ° C to prevent organolithium accumulation and induction of a dangerous exothermic reaction. The reaction is run at 5 to 0 ° C for 2 hours until analysis by gas chromatography shows at least 99% conversion. Toluene (35-40 kg) is then added and the product is concentrated in vacuo until the volume is reduced to approximately 1/3 of the original volume. The mixture is heated (to about 40 ° C) for a period of concentration to maintain a good degree of distillation. The mixture is then cooled to 15 to -20 ° C and then a solution of ammonium chloride (11 to 12 kg) in 50 to 60 L of water is added at a rate that does not allow the temperature to rise above 10 ° C. When the aqueous phase is separated (approximately 70 kg), the reaction mixture is circulated through a column containing 15 kg of 3A molecular sieve until a water content of approximately 300 ppm or less is determined by analysis

·· • · • ·· • ··· · · ···· • • · · • • • • • · • • • • • • · • • • · • • ···· · · · · · · · · • ·

Karel Fisher. The dried organic solution is then distilled at atmospheric pressure through a steel wool column and cyclopropylacetylene is collected as a solution in THF / toluene / hexane. The calculated yield is 14.0 kg.

Example 4

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

To a toluene solution of (1R, 2S) -pyrrolidinyl norephedrine (80 kg containing 60.7 moles of (1R, 2S) -pyrrolidinyl norephedrine) was added triphenylmethane (100 g). The solution was concentrated in vacuo to approximately half the original volume. Anhydrous THF (35 kg) was added and the solution was cooled to -50 ° C with a cooling jacket. Upon reaching -20 ° C, n-hexyllithium (33% in hexane, 33.4 kg, 119.5 moles) was added while maintaining the temperature below 0 ° C. To the resulting red solution was added a solution of cyclopropylacetylene (30 wt% in THF / hexane / toluene; containing about 4 kg, 65 moles of cyclopropylacetylene) while maintaining the internal temperature below -20 ° C. The resulting solution was maintained at -45 to -50 ° C for 1 hour. To the cold solution was added a solution of N - ((4'-methoxy) benzyl) -4-chloro-2-trifluoroecetylaniline (43% w / w in THF / toluene) containing approximately 10 kg, 28.8 moles of N - ((4 ') (methoxy) benzyl) -4-chloro-2-trifluoroecetylaniline) while maintaining the reaction temperature below -40 ° C. After incubating the mixture at -43 ° C +/- 3 ° C for 1 hour, the reaction was terminated by pouring into 140 kg of 1N HCl, pre-cooled to 0 ° C. The organic layer was separated and extracted twice with 40 kg of water, then concentrated in vacuo to a volume of approximately 29 L. Toluene (47 kg) was added and the solution was concentrated to a volume of 28 to 28 L.

1. Add heptane (23 kg) and cool and maintain at 5 ° C for 4 hours. The product was filtered off, washed twice with 10 kg portions of heptane and dried in vacuo to give 10 kg (85%) of the title compound as a white solid: mp 163-165 ° C; (a) ² D + 8.15 ° (c 1.006, MeOH); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (brs, 1H), 7.23 (d, J = 8 Hz,

H), 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); ¹³ C NMR (75 MHz, CDCl 3) 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, 6, 55.3, 48.0, 8.6, 8.5, -0.6; ^1? F NMR (282 MHz, CDCl ₃ ) δ -80.19.

Example 5

Preparation of (S) -6-chloro-4- (cyclopropylethynyl) -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-chloroaniline (57 kg, 232 moles) and (S) -5-chloro-α- (cyclopropylethynyl) -2 - [(4-methoxyphenyl)]. methyl] -amino α- (trifluoromethyl) benzenemethanol (89 kg, 217 moles). The mixture was heated under reflux with good stirring for 5.5 hours, then diluted with ethyl acetate (64.1 kg) and cooled to 30 ° C. Tetrachloro p-hydroquinone was removed by filtration and washed with a mixture of heptane (104.7 kg) and ethyl acetate (31 kg). The filtrate was partially concentrated by distillation of 260 L of solvent, then diluted with heptane (177 kg) and cooled to -10 to -15 ° C. The resulting coarse material was filtered and the product was washed with heptane (41 kg) and dried on the filter to less

· · • · • · · • · · · ·· • · • · ···· • • ·· • · • · • ·· • ···· · · · · · · · · · · ·

as 20 weight percent heptane (loss on drying). The yield calculated by HPLC was 71 kg (80%). An analytical sample was obtained by triturating the sample with 1N NaOH followed by recrystallization from hexane / ethyl acetate: mp 130-131.7 ° C; ^X H NMR (300 MHz, DMS0-d 6) 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) 1 H), 0.90-0.84 (m, 2H), 0.72-0.68 (m, 1H); ¹³ C NMR (75 MHz, DMSO-d 6) 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, 8.5, 8.4, -1.07; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ

-157.5.

Example 6 (S) -5-chloro-α- (cyclopropylethynyl) -2-amino-α-trifluoromethyl benzenemethanol.

Crude (S) -6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4-trifluoromethyl-2- (4'-methoxyphenyl) -3,1-benzoxazine (71 kg of calculated dry weight) was added to the mixture methanol (301 kg), 30% NaOH (121 kg) and water (61 L). The mixture was heated to 60 ° C to give a clear solution and then cooled to 30 ° C. To the methanolic solution was added a solution of sodium borohydride (3.2 kg, 84.2 moles) in 0.2 N NaOH (29 L) for 20 minutes while maintaining the temperature below 35 ° C. After 30 minutes the excess borohydride was quenched with acetone (5.8 kg) and the solution was diluted with water (175 L) then neutralized to pH 8-9 with acetic acid. The resulting crude material was cooled to about 0 ° C, filtered and the product was washed with water and then dried under vacuum at 40 ° C. The crude product was washed with a mixture of toluene (133 kg) and heptane (106 kg).

- 55 ·· ··· · · · ··· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · at 25 ° C followed by cooling to -10 ° C. The product was filtered off, washed with heptane (41 kg) and dried under vacuum at 40 ° C to give

44.5 kg (88%) of a white-colored / slightly yellow crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether / heptane: mp 141-143 ° C; (a) ²⁵ D

-28.3 ° (c 0.106, MeOH); ^X H NMR (300 MHz, CDC1 ₃₎ 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); ¹³ C NMR (75 MHz, DMSO-d ₆ ) 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; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ -80.5.

Example 7

Preparation of (S) -6-chloro-4- (cyclopropylethynyl) -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 moles) was dissolved in a mixture of heptane (32 kg) and THF (52 kg) at a temperature of below -10 ° C. Phosgene (about 8 kg, 80 moles) was added below the surface for about 1 hour while maintaining the temperature below 0 ° C. The resulting coarse material was heated to 20-25 ° C and held at this temperature for 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution was stirred for approximately 30 minutes. Heptane (97 kg) was added and approximately 140 L of solvent was distilled under reduced pressure. Heptane (97 kg) and THF (22 kg) were added and the solution was washed with 5% aqueous sodium bicarbonate (15 L) followed by water (15 L). The solution was heated to 50 ° C and filtered into a clean reactor followed by washing with 40 kg of heptane. The solution was concentrated under reduced pressure,

· · · · • · ···· ·· · • · • • · • • · • · • · · · • • • • · T • • · • · • • • · · • • • · • · • · • · • ···· · · · · · · · · · · ·

diluted with heptane (22 kg) and cooled to -10 ° C. The product was filtered off, washed with heptane (37 kg) and dried under vacuum at 90-100 ° C to give 16.0 kg (95%) of a white to slightly violet color. HPLC: 99.8 area%: mp 139-141 ° C; (a) ²⁵ D -94.1 ° (c 0.300,

MeOH); NMR (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) ); ¹³ C NMR (100 MHz, DMSO-d 6) 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; ¹⁹ F NMR (282 MHz, DMSO-d 6) δ

-81,1.

Scheme 5

Example 11

Example 17 Example 18

Do not dilute solution________Forma 5 ________________ »

Form 1 ·· ····

Examples 8-16 relate specifically to the preparation of each of the forms of the present invention as well as methods for effecting the mutual transformation 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.

Example 8

Direct crystallization of Form I.

Efavirenz (800 g, 2.5 mol) was dissolved in THF (1.2 L) and heptane (6.8 L). The solution was clarified by filtration through Whatman No. 1 filter paper. 1. THF was then removed at atmospheric pressure, keeping the volume constant with fresh heptane. When the THF level was below 1%, the solution was cooled to 70 ° C and settled. The solution was further cooled and crystallization was started at 64 ° C. X-ray diffractometry revealed that the sample was Form I. The crude product was further cooled to 30 ° C and filtered off. The wet material was dried at 65 ° C in a vacuum oven under a stream of nitrogen until dry loss of 0.36%, resulting in 640 g of product (80% yield).

Example 9

Crystallization of Form 2, Conversion to Form 1.

Efavirenz (450 g, 1.4 mol) was added to heptane (3.5 L) and heated to reflux until complete dissolution. The solution was cooled to 73 ° C and filtered through Whatman # 1 filter paper at this temperature. 1 and further cooled to 6 ° C. The crude product was filtered off and the wet material was washed with 300 mL of heptane. The wet material (389 g) was dried in a vacuum oven at ·· ····

- 58 ° C at 15 ° C for 15 hours, resulting in 388 g Form 1 (86% yield).

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 was cooled and 50 mg of DMP 266 was added at 45 ° C. After crystallization, the solvent was removed in vacuo and replaced with fresh heptane. The crude product was cooled to 0 ° C and filtered. X-ray diffractometry was found to be Form IV. The product was dried in a vacuum oven at 80 ° C for 16 hours to give 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 added to 1.2 L of heptane and heated to reflux until dissolution. The solution was cooled to 75 ° C and filtered through Whatman No. 1 filter paper. 1 and cooled. The crude product was crystallized and filtered off. X-ray diffractometry revealed to be Form 2. The crude product was stirred at room temperature for 24 hours and the resulting concentrated crude was diluted with 200 mL of heptane, filtered and dried under vacuum at room temperature to give 82.5 g ( 79%). The solid was identified as Form 3 by X-ray diffractometry. Five grams of the sample were dried at 90 ° C for 24 hours and the resulting solid was identified as Form I by X-ray diffractometry.

· · • · • ·· • ··· · · • · • · ···· • • · · • · • · · · • • · • · • · • · ···· · · · · · · · · · ·

Example 12

Conversion of Form 1 to Form 3

Efavirenz Form I (105 g, 0.33 mol) was added to 1.0 L heptane at room temperature for 7 days. X-ray diffractometry revealed that Form 1 was absent.

reaction They differed. with Form 2, also when relative intensity is slightly Example 13 transformation Form 2 to Form 4th Form 2 compounds Efavirenz (50 g. 0.16 mol) was added to 580 ml heptane. Added THF (7 ml, v · CO lead

to 1% THF in heptane), the solution was heated to 40 ° C and after 50 minutes a sample of the crude product was filtered off and X-ray diffraction still showed Form 2. THF (28 ml, total volume 32 ml) was added in four portions. resulted in a 5% THF concentration in heptane). After addition of the last portion, the mixture was cooled to 28 ° C, at which temperature a very concentrated crude product was formed, which was Form 4 by X-ray diffractometry.

Example 14

Conversion of Form 1 to Form 4

Efavirenz Form 1 (10 g, 0.03 mol) was added to 90 mL of heptane. The crude material was heated to 35 ° C. THF was added in 2 mL portions. Addition of a total amount of 6 mL (the resulting solution was approximately 6% THF) resulted in the formation of a highly concentrated crude product which was Form 4 by X-ray diffractometry.

- 60 ·· ····

Example 15

Conversion of Form 2 to Form 1 by heating the crude product to 70 ° C.

Efavirenz Form 2 (3 g, 0.01 mol) was added to heptane (42 mL), heated to 70 ° C and held for 2 hours. The crude product was cooled to room temperature and the sample was filtered for X-ray diffractometry, which showed only Form 1.

Example 16

Conversion of Form 3 to Form 1 by heating the crude product to 70 ° C.

Efavirenz Form 1 (3 g, 0.01 mol) was added to heptane (42 mL) for 48 hours. X-ray diffractometry showed Form 3. The crude product was heated to 70 ° C, maintained at this temperature for 2 hours, cooled to room temperature, and the sample was filtered for X-ray diffractometry, which showed Form 1.

Example 17

Direct Crystallization of Form 5.

Efavirenz Form 1 (approximately 70 g) was added at room temperature to 11 1% w / w.

THF / heptane. The undissolved solid was removed by filtration and the mother liquor was incubated at room temperature with Form 5. Slow crystals formed which were isolated by filtration, resulting in 0.92 g of Form 5. The solid was identified as Form 5 by X-ray diffraction. .

Alternatively, Efavirenz Form 1 (approximately 70 g) was added to 1.5 L of 1% w / w. THF / heptane and heated to 40 ° C. The solution was hot filtered (40 ° C) to remove any undissolved solids and the mother liquor was incubated with Form 5 at 40 ° C. After cooling to room temperature, Form 5 crystallized. The solid was isolated by filtration at room temperature (9.43 g).

Alternatively, Efavirenz Form 1 (approximately 70 g) was added to 1 L of warm heptane and 10 mL of THF was added to adjust the solvent ratio to 1% w / w. THF / heptane. The crude product was then heated to 85 ° C until complete dissolution. Once the solution was cooled, it was added periodically to the Mold until dissolution stopped (63 ° C), then cooled to 45 ° C and filtered. The isolated solid was Form 1. The solution was then cooled to room temperature and incubated overnight and Form 5 crystals were then collected by filtration (15.41 g).

Example 18

Conversion of Form 5 to Form 1

Form 5 was dried at 95 ° C for 3 days in a vacuum oven under a stream of nitrogen, resulting in Form 1, which was identified by X-ray powder diffraction.

Claims (20)

PATENT CLAIMS · · • · • · · • • • t • · • · • · ···· • • • · · • • • • • · • • • · • · • e • • • ·· · · • · • · • · · · • · · 7V tftf'ZOOO Form 1 of crystalline Efavirenz. Compound according to claim 1, characterized by an X-ray powder diffraction finding comprising 4 or more 23 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. A compound according to claim 1 or 2, characterized by a differential scanning calorimetric thermogram having a peak from about 138 ° C to about 140 ° C. 4. Form 2 of crystalline Efavirenz. A compound according to claim 4, characterized by an X-ray powder diffraction pattern comprising 4 or more 23 values selected from the group consisting of 6.8 ± 0.2, 9.2 ± 0.2, 3 ± 0.2, 16.2 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 24.1 ± 0.2 and 28.0 ± 0.2. The compound of claim 4 or 5, characterized by a differential scanning calorimetric thermogram having a peak from about 116 ° C to about 119 ° C. 7. Form 3 of crystalline Efavirenz. A compound according to claim 7 which is characterized by an X-ray powder diffraction finding comprising 4 or more 23 values selected from the group consisting of 7.1 ± 0.2, 7.3 ± 0.2, 11%, 0 ± · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 63 0.2, 13.8 ± 0.2, 20, 9 ± 0.2, 23.3 ± 0.2, 27.9 ± 0.2 and 33.5 ± 0.2. The compound of claim 7 or 8, characterized by a differential scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C. 10. Form 4 of crystalline Efavirenz. A compound according to claim 10, characterized by an X-ray powder diffraction finding comprising 4 or more 29 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 and 19.2 ± 0.2, 19.5 ± 0, 2, 20.6 ± 0.2 and 24.3 ± 0.2. The compound of claim 7 or 8, characterized by a differential scanning calorimetry thermogram having a peak from about 95 ° C to about 100 ° C. 13. Form 5 of crystalline Efavirenz. A compound according to claim 13, characterized by an X-ray powder diffraction finding comprising 4 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. The compound of claim 13 or 14, characterized by a differential scanning calorimetric thermogram having a peak from about 108 ° C to about 110 ° C. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the claims 1, 4, 7, 10, or 13, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 16, contained in a capsule or compressed tablet dosage form, wherein the therapeutically effective amount is from about 1 mg to about 1000 mg of Forms 1, 2, 3, 4 or 5 of crystalline Efavirenz. A method of inhibiting viral replication by virus-encoded reverse transcriptase, comprising providing the compound of claims 1, 4, 7, 10, or 13 in an amount sufficient to contact the HIV reverse transcriptase with an effective inhibitory amount of the active drug substance. The method of claim 18, wherein the compound is administered to a human or animal to inhibit HIV reverse transcriptase in vivo. 20. A method of treating HIV infection comprising combining to an individual in need of such treatment with a therapeutically effective amount: (a) a compound as claimed in claims 1, 4, 7, 10 or 13 b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors. • 0 • · • 0 • · · • • 0 • · • • • • 0 • · • · · · • • • s • • • 0 • • • • • • • 0 0 · • · 00 • · ·· ·