WO2008108630A1 - Formes polymorphes de l'efavirenz - Google Patents

Formes polymorphes de l'efavirenz Download PDF

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Publication number
WO2008108630A1
WO2008108630A1 PCT/NL2008/000055 NL2008000055W WO2008108630A1 WO 2008108630 A1 WO2008108630 A1 WO 2008108630A1 NL 2008000055 W NL2008000055 W NL 2008000055W WO 2008108630 A1 WO2008108630 A1 WO 2008108630A1
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ult
efavirenz
degrees
theta
form ult
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PCT/NL2008/000055
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English (en)
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Evanthia Dova
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Ultimorphix Technologies B.V.
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Publication of WO2008108630A1 publication Critical patent/WO2008108630A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • 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 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.
  • 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.
  • 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 .
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular solid form may also give rise to distinct physical properties that may be detectable by powder X-ray crystallography, solid state 13 C NMR spectrometry and infrared and Raman spectrometry.
  • 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
  • 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.
  • Figure IA illustrates the X-Ray Powder Diffraction pattern
  • Figure IB illustrates the DSC thermogram of Efavirenz Form
  • FIG. 1C illustrates the TGA/SDTA thermogram of Efavirenz
  • Figure 2A illustrates the X-Ray Powder Diffraction pattern of
  • FIG. 2B illustrates the DSC thermogram of Efavirenz Form
  • FIG. 2C illustrates the TGA/SDTA thermogram of Efavirenz
  • 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.
  • Form ULT-I can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 1:
  • Form ULT-I can be characterized by an XRPD substantially according to Fig IA.
  • Form ULT-I can be characterized by a DSC substantially according to Fig IB.
  • Form ULT-I can be characterized by a TGA substantially according to Fig 1C.
  • 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 0 C, optionally followed by an exothermic event with a characterizing peak at 124.4 0 C, optionally followed by a second endothermic event with an onset at 131.6 0 C and a characterizing peak at 138.5 0 C. 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 0 C.
  • form ULT-I is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound.
  • 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
  • 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) .
  • water is used as a second solvent (or antisolvent) .
  • 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.
  • Form ULT-2 can be characterized by the following set of XRPD peaks and, optionally, by the associated intensities listed in Table 2:
  • Form ULT-2 can be characterized by an XRPD substantially according to Fig 2A.
  • Form ULT-2 can be characterized by a DSC substantially according to Fig 2B.
  • Form ULT-2 can be characterized by a TGA substantially according to Fig 2C.
  • Form ULT-2 of the present invention can be characterized by DSC with an endothermic event with an onset at 111.7 0 C and a characterizing peak at 117.4°C 0 C, optionally followed by an exothermic event with a characterizing peak at 121.5 0 C, optionally followed by a second endothermic event with an onset at 134.0 0 C and a characterizing peak at 139.4 0 C.
  • 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 0 C.
  • form ULT-2 is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound.
  • 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.
  • compositions 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.
  • additional pharmaceutical active ingredients preferably Anti-HIV agents and more preferably Tenofovir DF and/or Emtricitabine.
  • 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.
  • microcrystalline cellulose e.g. Avicel (R)
  • micro fine cellulose lactose
  • lactose starch
  • pregelatinized starch calcium carbonate, calcium sul
  • 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.
  • 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.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose (R) ) , colloidal silicon dioxide, croscarmellose sodium,
  • 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.
  • a dosage form such as a tablet
  • 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.
  • 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.
  • 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.
  • a viscosity enhancing agent 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.
  • 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.
  • 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.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base .
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • 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.
  • 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 Tween ⁇ 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.
  • 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.
  • 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.
  • compositions and dosage forms may be prepared by wet granulation.
  • 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.
  • 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.
  • 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.
  • 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.,
  • 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.
  • 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 ° ⁇ 2 ⁇ ⁇ 21.5 ° for the first frame, and 19.5 ° ⁇ 2 ⁇ ⁇ 41.5 ° for the second) with an exposure time of 120 s for each frame.
  • 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.
  • Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA.
  • 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 25 0 C to 300 0 C at a heating rate of 20°C/min. Dry N 2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
  • 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.
  • the solution was heated to 60 0 C 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.
  • the solvent was evaporated from the vial under 20 kPa pressure at 20-25 0 C for 25h.
  • the resulting residue was analyzed by X-ray powder diffraction, DSC and TGA and identified as efavirenz form ULT-2.

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Abstract

La présente invention a pour objet de nouvelles formes cristallines de l'efavirenz, appelées respectivement formes ULT-I et ULT-2 de l'efavirenz, des procédés pour la préparation respectivement des formes ULT-I et ULT-2 de l'efavirenz et l'utilisation des formes ULT-I et ULT-2 de l'efavirenz dans des applications pharmaceutiques, notamment dans des médicaments anti-VIH. La forme cristalline des formes ULT-I et ULT-2 de l'efavirenz peuvent être utilisées combinées à d'autres médicaments anti-VIH comme le ténofovir DF et l'emtricitabine.
PCT/NL2008/000055 2007-03-02 2008-02-22 Formes polymorphes de l'efavirenz WO2008108630A1 (fr)

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US90437407P 2007-03-02 2007-03-02
US60/904,374 2007-03-02

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz
US8383811B2 (en) 2008-12-22 2013-02-26 Hetero Research Foundation Process for preparing efavirenz polymorph

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Publication number Priority date Publication date Assignee Title
WO1998033782A1 (fr) * 1997-02-05 1998-08-06 Merck & Co., Inc. Procede de cristallisation d'un inhibiteur de transcriptase inverse utilisant un antisolvant
WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
WO2006018853A2 (fr) * 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006030299A1 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Processus de preparation de polymorphes d'efavirenz
WO2006040643A2 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033782A1 (fr) * 1997-02-05 1998-08-06 Merck & Co., Inc. Procede de cristallisation d'un inhibiteur de transcriptase inverse utilisant un antisolvant
WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
WO2006018853A2 (fr) * 2004-08-19 2006-02-23 Hetero Drugs Limited Nouveaux polymorphes d'efavirenz
WO2006030299A1 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Processus de preparation de polymorphes d'efavirenz
WO2006040643A2 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Formes polymorphes d'efavirenz et processus de leur fabrication

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8383811B2 (en) 2008-12-22 2013-02-26 Hetero Research Foundation Process for preparing efavirenz polymorph
WO2011032634A1 (fr) 2009-09-16 2011-03-24 Archimica Gmbh Sels d'éfavirenz, leur procédé de préparation et de libération du sel
DE102009041443A1 (de) 2009-09-16 2011-03-31 Archimica Gmbh Salze des 6-Chlor-4-(cyclopropylethinyl)-1,4-dihydro-4-(trifluormethyl)-2H-3,1-benzoxazin-2-ons und deren Synthese, Aufreinigung und Anwendung als Vorstufen für Efavirenz
EP2471783A1 (fr) 2010-12-23 2012-07-04 Esteve Química, S.A. Nouvelle forme polymorphe de l'éfavirenz

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