WO2008108630A1

WO2008108630A1 - Polymorphic forms of efavirenz

Info

Publication number: WO2008108630A1
Application number: PCT/NL2008/000055
Authority: WO
Inventors: Evanthia Dova
Original assignee: ULTIMORPHIX TECHNOLOGIES BV
Current assignee: ULTIMORPHIX TECHNOLOGIES BV
Priority date: 2007-03-02
Filing date: 2008-02-22
Publication date: 2008-09-12
Anticipated expiration: 2009-09-02

Abstract

The present invention provides novel crystalline forms of Efavirenz, designated Efavirenz form ULT-I and ULT-2 respectively, methods for the preparation of Efavirenz form ULT-I and ULT-2 respectively and the use of Efavirenz form ULT-I and ULT-2 in pharmaceutical applications, in particular in anti-HIV medicaments. The crystalline form of Efavirenz form ULT-I and ULT-2 can be used in combination with other anti-HIV medicaments such as Tenofovir DF and Emtricitabine.

Description

Title: Polymorphic forms of Efavirenz

The present invention relates to novel polymorphs of Efavirenz, processes for their preparation and pharmaceutical compositions containing them as well as their use as a medicament and for the treatment of ailments.

Efavirenz :

Efavirenz is a HIV reverse transcriptase inhibitor and described in U.S. Patent No. 5,519,021. Efavirenz is chemically known as, (4S) -6- chloro-4- (cyclopropylethyny] ) -1, 4-dihydro-4- (trifluoromethyl) -2H-3, 1-benzoxazin- 2-one, C14H9NC1F3O2, MW 315.675, CAS [154598-52-4]

Efavirenz has the following structural formula:

Efavirenz is used for the preparation of a medicament having non-nucleoside HIV-I reverse transcriptase inhibiting activity that is useful in the prevention or treatment of infection by HIV and the treatment of AIDS. Efavirenz is sold commercially as SUSTIVA(R) or STOCRIN ® by Bristol Myers Squibb. Efavirenz is also combined with Truvada and sold as Atripla.

Polymorphs :

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterised as the ability of a drug substance to exist as two or more crystalline forms that have different arrangements and/or conformations of the molecules in the crystalline lattice.

The present invention relates to the solid state physical properties of Efavirenz. These properties can be influenced by controlling the conditions under which Efavirenz is obtained in solid form. Solid state physical properties affect the ease with which the material is handled during processing into a pharmaceutical product such as a tablet or capsule formulation. The physical properties impact the sort of excipients, for instance, to add to an Efavirenz formulation. Furthermore, the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have therapeutic consequences. The rate of dissolution is also a consideration in liquid forms of medicine as well. The solid state form of a compound may also affect its storage conditions .

These practical physical characteristics are influenced by the particular solid form of a substance. One solid form may give rise to thermal behaviour different from that of the amorphous material or other solid forms. Thermal behaviour is measured in the laboratory by such techniques as thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some solid forms from others. A particular solid form may also give rise to distinct physical properties that may be detectable by powder X-ray crystallography, solid state ¹³C NMR spectrometry and infrared and Raman spectrometry.

Polymorphic forms of Efavirenz:

Several solid forms of Efavirenz are known in the art.

WO patent application publication No. 98/33782 disclosed three crystalline forms of Efavirenz , Form I, Form II and Form III.

WO patent application publication No. 99/64405 disclosed five crystalline forms of Efavirenz, Form 1, Form 2, Form 3 Form 4 and Form 5.

WO2006018853 discloses another form (Hl) of Efavirenz. WO2006030299 describes methods for the preparation of

Form I and Form II of Efavirenz using solvent-antisolvent technology to improve on existing preparative methodologies.

WO2006040643 describes novel forms of Efavirenz depicted as [alpha], [beta], [gamma], [gammal] , [gamma2] , [omega], [delta] , N, 0 and P and to an amorphous from of Efavirenz as well as methods for their preparation.

WO2006029079 describes the preparation of Efavirenz Form 1 and its crystallisation from heptane/ethylacetate.

The present invention relates to two novel crystalline forms of Efavirenz. The present inventors have identified two novel crystalline forms, herein depicted as ULT-I and ULT-2, respectively.

Description of the Drawings:

Figure IA illustrates the X-Ray Powder Diffraction pattern of

Efavirenz Form ULT-I.

Figure IB illustrates the DSC thermogram of Efavirenz Form

ULT-I.

Figure 1C illustrates the TGA/SDTA thermogram of Efavirenz

Form ULT-I.

Figure 2A illustrates the X-Ray Powder Diffraction pattern of

Efavirenz Form ULT-2.

Figure 2B illustrates the DSC thermogram of Efavirenz Form

ULT-2.

Figure 2C illustrates the TGA/SDTA thermogram of Efavirenz

Form ULT-2.

Crystalline Efavirenz form ULT-I:

Thus, in one aspect, the present invention provides crystalline Efavirenz herein defined as Form ULT-I, characterized by the selection of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeen X-ray powder diffraction peaks selected from the group consisting of 7.0, 9.3, 11.6, 12.5, 13.1, 14.5, 16.5, 18.0, 19.7, 20.8, 21.9, 22.9, 23.4, 24.3, 28.1, 29.4, 30.5 degrees two-theta +/- 0.3 degrees two-theta, more preferably 0.2 degrees two-theta, even more preferably 0.1 degrees two-theta, most preferably 0.05 degrees two-theta.

In another embodiment Form ULT-I can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 1:

*For normalized intensity values: L = 0-25, M = 25-60, H = 60-100.

In another embodiment, Form ULT-I can be characterized by an XRPD substantially according to Fig IA.

In another embodiment, Form ULT-I can be characterized by a DSC substantially according to Fig IB.

In another embodiment, Form ULT-I can be characterized by a TGA substantially according to Fig 1C.

In another embodiment, Form ULT-I of the present invention can be characterized by DSC with an endothermic event with an onset at 107.3 °C and a characterizing peak at 119.9 ⁰C, optionally followed by an exothermic event with a characterizing peak at 124.4 ⁰C, optionally followed by a second endothermic event with an onset at 131.6 ⁰C and a characterizing peak at 138.5 ⁰C. From thermal analysis it is concluded that solid form

ULT-I is anhydrous. It is further concluded that solid form ULT-I melts and recrystallizes to a solid form with melting peak at about 139 ⁰C.

In another embodiment, form ULT-I is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect, "substantially free from other amorphous, crystalline and/or polymorphic forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.

The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-I of Efavirenz comprising the steps of dissolving Efavirenz in a solvent selected from the group consisting of 1,3 Butanediol, Chlorobenzene, Chloroform, Cyclohexanol, Cyclopentanone, p- Cymene , Decane, Dibutylether, 1, 2-Dichloroethane , Diethylene glycol diethyl ether, Diethylene glycol dimethylether, Diethyloxalate, 1, 2-Dimethoxyethane , 2, 6-Dimethyl-4-heptanone , N,N-Dimethylacetamide , cis-1, 2-Dimethylcyclohexaan , N, N- Dimethylformamide , Dimethylsulfoxide, Dipropylene glycol, 3- Ethoxy-1-propanol , -(-) Ethyl L-lactate, Ethylpropionate, 4- Hydroxy-4-methyl-2-pentanon , Methanol, l-Methoxy-2-propanol , 5-Methyl-2-hexanone, 1-Nitropropane , 1, 2-Propanediol , 2- Propanol, Propylene glycol methyl ether acetate, Tetrahydrofurfurylalcohol, Tetrahydropyran-2-methanol, 2,2,2- Trifluoroethanol or mixtures thereof and crystallizing Efavirenz Form ULT-I by cooling/evaporation crystallisation.

In certain embodiments, a co-solvent is used in an amount between about 5 vol. % co-solvent (and about 95 vol. % solvent) and about 40 vol. % co-solvent (and about 60 vol. % solvent), preferably between about 10 vol. % co-solvent (and about 90 vol. % solvent) and about 35 vol. % co-solvent (and about 65 vol. % solvent), more preferably between about 15 vol. % co-solvent ( and about 85 vol. % solvent) and about 30% co-solvent (and about 70 vol. % solvent) and most preferably between about 20 vol. % co-solvent (and about 80 vol. % solvent) and about 25 % co-solvent (and about 75 vol. % solvent) . In a preferred embodiment, water is used as a second solvent (or antisolvent) .

Crystalline Efavirenz form ULT-2:

Thus, in one aspect, the present invention provides crystalline Efavirenz herein defined as Form ULT-2, characterized by the selection of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen X-ray powder diffraction peaks selected from the group consisting of 7.3, 11.0, 13.8, 14.6, 16.9, 19.2, 20.9, 21.8, 23.3, 23.9, 25.0, 27.7, 29.0, and 30.4 degrees two-theta +/- 0.3 degrees two-theta, more preferably 0.2 degrees two- theta, even more preferably 0.1 degrees two-theta, most preferably 0.05 degrees two-theta.

In another embodiment Form ULT-2 can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 2:

*For normalized intensity values: L = 0-25, M = 25-50, H 50-100. In another embodiment, Form ULT-2 can be characterized by an XRPD substantially according to Fig 2A.

In another embodiment, Form ULT-2 can be characterized by a DSC substantially according to Fig 2B.

In another embodiment, Form ULT-2 can be characterized by a TGA substantially according to Fig 2C.

In another embodiment, Form ULT-2 of the present invention can be characterized by DSC with an endothermic event with an onset at 111.7 ⁰C and a characterizing peak at 117.4°C ⁰C, optionally followed by an exothermic event with a characterizing peak at 121.5 ⁰C, optionally followed by a second endothermic event with an onset at 134.0 ⁰C and a characterizing peak at 139.4 ⁰C.

From thermal analysis it is concluded that solid form ULT-2 is anhydrous. It is further concluded that solid form ULT-2 melts and recrystallizes to a solid form with melting peak at about 139 ⁰C.

In another embodiment, form ULT-2 is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect, "substantially free from other amorphous, crystalline and/or polymorphic forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms are present in the form according to the invention.

The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-2 of Efavirenz comprising the steps of dissolving Efavirenz in hexafluorobenzene and crystallizing Efavirenz Form ULT-2.

Pharmaceutical formulations comprising ULT-I and/or ULT2.

The present invention further relates to pharmaceutical formulations comprising the novel crystalline forms of Efavirenz. Pharmaceutical formulations of the present invention contain the crystalline form according to the present invention, such as ULT-I and or ULT-2 as disclosed herein. The invention also provides pharmaceutical compositions comprising the crystal form according to the present invention. Pharmaceutical formulations of the present invention contain the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s) .

The pharmaceutical formulations according to the invention, may further comprise, in addition to the forms ULT- 1 and/or ULT-2, additional pharmaceutical active ingredients, preferably Anti-HIV agents and more preferably Tenofovir DF and/or Emtricitabine.

In addition to the active ingredient (s) , the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel (R) ) , micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit (R) ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol) , carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel (R) ) , hydroxypropyl methyl cellulose (e.g.

Methocel (R) ) , liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone (R) ) , pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A l.ubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste. Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability. According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

For infections of the eye or other external tissues, e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base .

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent) , it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tweenδ 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.

Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc) . Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient .

Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate .

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) , inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art. A composition for tabletting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.

A tabletting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.

As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.

Moreover, the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection. The crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Allen et al.,

Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed.

The present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof. A pharmaceutical composition of the present invention comprises the crystalline form ULT-I and/or ULT-2. The crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition. The invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compounds of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Examples Experimental conditions

X-ray Diffraction:

XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings. Data collection was carried out at room temperature using monochromatic CuK (alpha) radiation in the two-theta region between 1.5 ° and 41.5 °. The diffraction pattern of each well is collected in two two-theta ranges (1.5 ° < 2θ < 21.5 ° for the first frame, and 19.5 ° < 2θ < 41.5 ° for the second) with an exposure time of 120 s for each frame. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors. Typically XRPD data are collected with a variance of about 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees. This has consequences for when X-ray peaks are considered overlapping.

Thermal analysis:

Melting properties were obtained from DSC thermograms, recorded with a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland) . The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6°C; delta-H(f) = 28.45 J/g) . Samples were sealed in standard 40 microliter aluminium pans and heated in the DSC from 25°C to 300°C, at a heating rate of 20°C/min. Dry N₂ gas, at a flow rate of 50 ml/min, was used to purge the DSC equipment during measurement.

Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA. Monitoring of the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve. The TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25⁰C to 300⁰C at a heating rate of 20°C/min. Dry N₂ gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.

Examples ULT-I

Crystallization of Efavirenz form ULT-I on milliliter scale. From cyclopentanone :

As a part of high-throughput experimentation, a small quantity, about 2.8 mg of the starting material was placed in a plate well. The starting material was stock-dosed in methanol. The solvent was removed by evaporation under 2OkPa for about 19 h and the starting material was dry. The solvent cyclopentanone was added in small amounts to the well containing the dry starting material at room temperature to a total volume of 40 microliter. The solution was heated and maintained at 60⁰C for 30 minutes. Following, controlled cooling was applied with a cooling rate of about l°C/h to a final temperature of 25°C and remained at this temperature for Ih. Subsequently, the solvent was evaporated under pressure of 20 kPa at RT for 96 h. The resulting residue was analyzed by X-ray powder diffraction and TGA and identified as efavirenz form ULT-I.

More solvents and combinations of solvents that led to formation of efavirenz form ULT-I are:

Alternative crystallization conditions were tested: cooling rate of 30°C/h, final temperature of 5 ⁰C, ageing time of 48h. The solvents as listed above yielded again Efavirenz ULT-I

ULT-2

Crystallization of Efavirenz form ULT-2 on milliliter scale. From hexafluorobenzene:

A small quantity, about 82 mg of the starting material was placed in a HPLC vial. The solvent hexafluorobenzene was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 200 microliter. Subsequently, the solution was heated to 60⁰C for 60 min and it was filtered at this temperature. The filtrated solution was cooled with l.l°C/h to a temperature of 5°C where it remained for 72h. Subsequently, the solvent was evaporated from the vial under 20 kPa pressure at 20-25 ⁰C for 25h. The resulting residue was analyzed by X-ray powder diffraction, DSC and TGA and identified as efavirenz form ULT-2.

Claims

1. Crystalline Efavirenz Form ULT-I and/or ULT-2.

2. Crystalline Efavirenz Form ULT-I, characterized by one or more of: one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeen X-ray powder diffraction peaks selected from the group consisting of 7.0, 9.3, 11.6, 12.5, 13.1, 14.5, 16.5,

18.0, 19.7, 20.8, 21.9, 22.9, 23.4, 24.3, 28.1, 29.4, 30.5 degrees two-theta +/- 0.3 degrees two-theta, more preferably 0.2 degrees two-theta, even more preferably 0.1 degrees two-theta, most preferably 0.05 degrees two-theta - DSC with an onset at 107.3 ⁰C and a characterizing peak at 119.9 ⁰C and optionally at 124.4 ⁰C

3. Crystalline Efavirenz Form ULT-I according to claim 1, characterized by one or more of: - a XRPD pattern substantially as set out in Table 1 and/or Fig IA; a DSC thermogram substantially as set out in Fig IB.

4. Method for the preparation of form ULT-I comprising the steps of mixing Efavirenz with solvents or mixtures thereof selected from the group consisting of 1,3 Butanediol, Chlorobenzene, Chloroform, Cyclohexanol, Cyclopentanone, p-Cymene, Decane, Dibutylether, 1, 2-Dichloroethane, Diethylene glycol diethyl ether, Diethylene glycol dimethylether, Diethyloxalate, 1, 2-Dimethoxyethane, 2, 6-Dimethyl-4-heptanone,

N,N-Dimethylacetamide, cis-1, 2-Dimethylcyclohexaan, N,N-Dimethylformamide, Dimethylsulfoxide, Dipropylene glycol, 3-Ethoxy-l-propanol, -(-) Ethyl L-lactate, Ethylpropionate, 4-Hydroxy-4-methyl-2-pentanon, Methanol, l-Methoxy-2-propanol, 5-Methyl-2-hexanone, 1-Nitropropane, 1, 2-Propanediol, 2-Propanol, Propylene glycol methyl ether acetate, Tetrahydrofurfurylalcohol, Tetrahydropyran-2-methanol, 2, 2, 2-Trifluoroethanol and crystallizing Efavirenz Form ULT-I.

5. Crystalline Efavirenz Form ULT-2, characterized by one or more of: - one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen X-ray powder diffraction peaks selected from the group consisting of 7.3, 11.0, 13.8, 14.6, 16.9, 19.2, 20.9, 21.8, 23.3, 23.9, 25.0, 27.7, 29.0, and 30.4 degrees two-theta +/- 0.3 degrees two-theta, more preferably 0.2 degrees two-theta, even more preferably 0.1 degrees two-theta, most preferably 0.05 degrees two- theta;

DSC with an onset at 111.7 °C and a characterizing peak at 117.4°C ⁰C and optionally at 121.5 ⁰C.

6. Crystalline Efavirenz Form ULT-2 according to claim 1, characterized by one or more of: a XRPD pattern substantially as set out in Table 2 and/or Fig 2A;

- a DSC thermogram substantially as set out in Fig 2B.

7. Method for the preparation of form ULT-2 comprising the steps of mixing Efavirenz with hexafluorobenzene and crystallizing Efavirenz Form ULT-2.

8. Pharmaceutical formulation comprising Efavirenz Form ULT-I and/or ULT-2.

9. Use of Efavirenz Form ULT-I and/or ULT-2 as a medicament.

10. Use of Efavirenz Form ULT-I and/or ULT-2 in the preparation of a medicament for the treatment of HIV.

11. Use of Efavirenz Form ULT-I and/or ULT-2 in the treatment of HIV.

12. Use of Efavirenz Form ULT-I and/or ULT-2 in combination with another pharmaceutical ingredient, preferably an anti HIV agent, preferably Tenofovir DF and/or Emtricitabine.