WO2009064174A1 - Forme polymorphe du ténofovir disoproxil fumarate, son procédé de préparation et son utilisation - Google Patents

Forme polymorphe du ténofovir disoproxil fumarate, son procédé de préparation et son utilisation Download PDF

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WO2009064174A1
WO2009064174A1 PCT/NL2008/000250 NL2008000250W WO2009064174A1 WO 2009064174 A1 WO2009064174 A1 WO 2009064174A1 NL 2008000250 W NL2008000250 W NL 2008000250W WO 2009064174 A1 WO2009064174 A1 WO 2009064174A1
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degrees
ult
tenofovir
theta
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PCT/NL2008/000250
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Evanthia Dova
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Ultimorphix Technologies B.V.
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Publication of WO2009064174A1 publication Critical patent/WO2009064174A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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

Definitions

  • the present invention relates to a novel crystalline form of Tenofovir disoproxil fumarate (Tenofovir DF), methods for the preparation and the formulation and application in the field of medicine, in particular antiviral medicines.
  • Teofovir DF Tenofovir disoproxil fumarate
  • Tenofovir disoproxil fumarate also known as Viread(R), Tenofovir DF, Tenofovir 5 disoproxil, TDF, Bis-POC-PMPA (U.S. Pat. Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) is a prodrug of Tenofovir.
  • Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor
  • Tenofovir disoproxil DF is available as Viread(R) (Gilead Science, Inc.). Tenofovir is also seen as a medicament against hepatitis, in particular hepatitis B. 5 Among the anti-HIV drugs which have been developed are those which target the
  • RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs).
  • NRTIs nucleoside/nucleotide RT inhibitors
  • NRTIs non-nucleoside RT inhibitors
  • PIs protease inhibitors
  • NNRTIs non-nucleoside RT inhibitors
  • one of the PIs is often ritonavir, given at a low sub-therapeutic dose, which acts as an effective inhibitor of the elimination of the other Pl(s) in the regimen, resulting in maximal suppression of the virus and thereby reducing the emergence of resistance.
  • Tenofovir DF is described inter alia in WO99/05150 and EP998480.
  • This crystalline form is characterized as having XRPD peaks at about 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4.
  • these crystals are described as opaque or off- white and exhibit a DSC absorption peak at about 118 0 C with an onset at about 116 0 C and an IR spectrum showing characteristic bands expressed in reciprocal centimeters at approximately 3224, 3107-3052, 2986-2939, 1759, 1678, 1620, 1269 and 1102.
  • Bulk densities have been described of about 0.15-0.30 g/mL, usually about 0.2-0.25 g/mL.
  • Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases 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 Tenofovir DF. These properties can be influenced by controlling the conditions under which Tenofovir DF 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 a Tenofovir DF 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.
  • polymorphic form of a substance.
  • One polymorphic form may give rise to thermal behavior different from that of the amorphous material or other polymorphic forms. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • a particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13 C NMR spectrometry and infrared and Raman spectrometry.
  • the present invention relates to a novel crystalline form of Tenofovir DF.
  • the present inventors have identified a novel crystalline forms, herein depicted as ULT-3. Surprisingly, it has been found that the form according to the invention is more stable and is less prone to conversion into other solid forms than the known solid forms.
  • Figure 1 A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-3.
  • Figure 1B illustrates the DSC pattern of Tenofovir DF Form ULT-3
  • Figure 1C illustrates the TGA pattern of Tenofovir DF Form ULT-3.
  • the present invention provides crystalline Tenofovir DF herein defined as Form ULT-3, characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four or even more preferably five or six X-ray powder diffraction peaks selected from the group consisting of 7.0; 13.2; 17.8; 23.8; 25.9 and 30.6 degrees two-theta +/- 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees.
  • Form ULT-3 can, in a preferred embodiment, be further characterized by an X-ray powder diffraction peak at 18.7 degrees two-theta +/- 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees.
  • Form ULT-3 can, in a more preferred embodiment, be further characterized by the selection of at least one, preferably at least two, more preferably three X-ray powder diffraction peaks from the group consisting of 9.7; 11.3 and 20.2 degrees two-theta +/- 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees.
  • Form ULT-3 can, in an even more preferred embodiment, be further characterized by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four and most preferably five, X-ray powder diffraction peaks from the group consisting of 10.2; 14.1 ; 19.3; 21.2 and 25.4 degrees two-theta +/- 0.3 degrees - A -
  • two-theta preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees..
  • Form ULT-3 can be characterized by the following set of XRPD peaks and, optionally by the associated intensities:
  • Form ULT-3 can be characterized by an XRPD substantially according to Fig 1A.
  • Form ULT-3 can be characterized by a DSC substantially according to Fig 1B.
  • Form ULT-3 can be characterized by a TGA substantially according to Fig 1C.
  • Form ULT-3 of the present invention can also be characterized by DSC with an onset at 102.6 0 C and a characterizing peak at 114.2 0 C. From the thermal analysis it is concluded that solid form ULT-3 is anhydrous.
  • form ULT-3 is in a substantially pure form, preferably substantially free from other amorphous, crystalline and/or polymorphic forms.
  • substantially pure relates to at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% pure.
  • substantially free from other amorphous, crystalline and/or polymorphic forms means that no more than 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, crystalline and/or polymorphic forms is present in the form according to the invention.
  • form ULT-3 does not contain a peak in its XRPD at 25.0 two theta.
  • the present invention further relates to a method for the preparation of the crystalline form ULT-3 of Tenofovir DF comprising the steps of dissolving Tenofovir DF in methanol and crystallizing Tenofovir DF Form ULT-3 by evaporation of the solvent.
  • compositions comprising ULT-3.
  • the present invention further relates to pharmaceutical formulations comprising the novel crystalline forms of Tenofovir DF.
  • compositions of the present invention contain one or more of the crystalline forms according to the present invention, such as ULT-3 as disclosed herein.
  • the invention also provides pharmaceutical compositions comprising one or more of the crystal forms according to the present invention.
  • Pharmaceutical formulations of the present invention contain the various crystal forms according to the present invention as active ingredients, optionally in a mixture with other crystal form(s) according to the present invention.
  • the pharmaceutical formulations can be used against HIV and/or hepatitis, in particular hepatitis B.
  • the pharmaceutical formulations according to the invention may further comprise, in addition to one or more of the form ULT-3, additional pharmaceutical ingredients, preferably Anti-HIV agents and more preferably Efavirenz 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 sulfate, sugar,
  • 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 aluminum 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 aluminum 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, crospovidone (e.g.
  • 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 lubricant 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.
  • 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
  • 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. 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, which 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.
  • the present invention also provides pharmaceutical formulations comprising one or more of the crystalline forms 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 one or more forms of the crystalline forms selected from the group consisting of ULT-3.
  • the crystalline forms 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 forms of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV.
  • X-rav Diffraction Spectrometry 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.
  • DSC822e instrument Metal-Toledo GmbH, Switzerland.
  • Samples were sealed in standard 40 microliter aluminum pans and heated in the DSC from 25°C to 300 0 C, at a heating rate of 20°C/min.
  • Dry N 2 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.
  • 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°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 H- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
  • a small quantity, about 14.9 mg of the starting material was placed in a HPLC vial.
  • the solvent 2,2,2-trifluoroethanol was added in small amounts to the vial containing the dry starting material at room temperature to a total volume of 200 microliter.
  • the vial was shaken and the qualitative solubility was assessed visually.
  • the solvent was evaporated from the vial under vacuum at 20-25 0 C.
  • the evaporation time and pressure was 22.5 hr at 20 KPa.
  • the resulting residue was analyzed by X-ray powder diffraction, DSC and TGA and identified as Tenofovir DF form ULT-3.

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Abstract

La présente invention concerne une nouvelle forme cristalline du ténofovir disoproxil fumarate (ténofovir DF), appelée forme ULT-3, des procédés pour la préparer et son utilisation dans des applications pharmaceutiques, en particulier dans des médicaments anti-VIH. La forme cristalline du ténofovir DF peut être utilisée en combinaison avec d'autres médicaments anti-VIH tels que l'éfavirenz et l'emtricitabine.
PCT/NL2008/000250 2007-11-14 2008-11-11 Forme polymorphe du ténofovir disoproxil fumarate, son procédé de préparation et son utilisation WO2009064174A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012027972A1 (fr) * 2010-08-30 2012-03-08 杭州和素化学技术有限公司 FORME CRISTALLINE α DU TÉNOFOVIR DISOPROXIL FUMARATE, PROCÉDÉ POUR LA PRÉPARER ET SON UTILISATION
CN104288118A (zh) * 2014-07-08 2015-01-21 南京卡文迪许生物工程技术有限公司 富马酸替诺福韦二吡呋酯片剂及其制备方法
WO2015051875A1 (fr) 2013-10-09 2015-04-16 Zentiva, K.S. Sel dihydrogénophosphate de ténofovir disoproxil
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004569A1 (fr) * 1996-07-26 1998-02-05 Gilead Sciences, Inc. Analogues de nucleotides
WO2007013086A1 (fr) * 2005-07-26 2007-02-01 Hetero Drugs Limited Nouveaux polymorphes de tenofovir disoproxil fumarate
WO2007013085A1 (fr) * 2005-07-26 2007-02-01 Hetero Drugs Limited Procede innovant pour analogues acycliques de nucleotide phosphonate
CN101066980A (zh) * 2007-05-08 2007-11-07 黑龙江加州国际投资咨询有限公司 富马酸泰诺福韦酯新晶型及其药用制剂
WO2008007392A2 (fr) * 2006-07-12 2008-01-17 Matrix Laboratories Limited Procédé amélioré destiné à préparer du ténofovir
WO2008140302A1 (fr) * 2007-05-14 2008-11-20 Ultimorphix Technologies B.V. Formes polymorphes de ténofovir disoproxil fumarate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004569A1 (fr) * 1996-07-26 1998-02-05 Gilead Sciences, Inc. Analogues de nucleotides
WO2007013086A1 (fr) * 2005-07-26 2007-02-01 Hetero Drugs Limited Nouveaux polymorphes de tenofovir disoproxil fumarate
WO2007013085A1 (fr) * 2005-07-26 2007-02-01 Hetero Drugs Limited Procede innovant pour analogues acycliques de nucleotide phosphonate
WO2008007392A2 (fr) * 2006-07-12 2008-01-17 Matrix Laboratories Limited Procédé amélioré destiné à préparer du ténofovir
CN101066980A (zh) * 2007-05-08 2007-11-07 黑龙江加州国际投资咨询有限公司 富马酸泰诺福韦酯新晶型及其药用制剂
WO2008140302A1 (fr) * 2007-05-14 2008-11-20 Ultimorphix Technologies B.V. Formes polymorphes de ténofovir disoproxil fumarate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CENTER FOR DRUG EVALUATION AND RESEARCH: "Application Number: 21-356", 2001, XP002507928, Retrieved from the Internet <URL:http://www.fda.gov/cder/foi/nda/2001/21-356_Viread_chemr.pdf> [retrieved on 20081212] *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012027972A1 (fr) * 2010-08-30 2012-03-08 杭州和素化学技术有限公司 FORME CRISTALLINE α DU TÉNOFOVIR DISOPROXIL FUMARATE, PROCÉDÉ POUR LA PRÉPARER ET SON UTILISATION
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
WO2015051875A1 (fr) 2013-10-09 2015-04-16 Zentiva, K.S. Sel dihydrogénophosphate de ténofovir disoproxil
CN104288118A (zh) * 2014-07-08 2015-01-21 南京卡文迪许生物工程技术有限公司 富马酸替诺福韦二吡呋酯片剂及其制备方法

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