WO2013132314A1 - Phosphate de type ténofovir, procédés de préparation et composition pharmaceutique de celui-ci - Google Patents

Phosphate de type ténofovir, procédés de préparation et composition pharmaceutique de celui-ci Download PDF

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Publication number
WO2013132314A1
WO2013132314A1 PCT/IB2013/000467 IB2013000467W WO2013132314A1 WO 2013132314 A1 WO2013132314 A1 WO 2013132314A1 IB 2013000467 W IB2013000467 W IB 2013000467W WO 2013132314 A1 WO2013132314 A1 WO 2013132314A1
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Prior art keywords
tenofovir disoproxil
phosphate
gms
disoproxil phosphate
solution
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PCT/IB2013/000467
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English (en)
Inventor
Ravindra Babu BOLLU
Venkata Krishna Kishore JAMMULA
Satish Kumar Pannalal JAIN
Sandeep Joharilal KACHHWAHA
Venkata Sunil Kumar Indukuri
Seeta Ramanjaneyulu Gorantla
Satyanaarayana CHAVA
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Laurus Labs Private Limited
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Publication of WO2013132314A1 publication Critical patent/WO2013132314A1/fr

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    • 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
    • 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

Definitions

  • the present invention generally relates to a compound Tenofovir phosphate salt, processes for their preparation and pharmaceutical compositions containing the same.
  • Tenofovir disoproxil also known as 9-[(i?)-2-[[bis[[(isopropoxycarbonyl)oxy] methoxy]phosphinyl] methoxy]propyl]adenine (CipHsoNsOioP), is represented by the structure of Formula I:
  • Tenofovir disoproxil is approved as its fumarate salt and is a potent antiviral agent, available in the market under the brand name VIREAD ® in the form of 300mg of oral tablets and in combination with other antiviral agents.
  • U.S. Patent No. 5,922,695 discloses phosphonomethoxy nucleotide analogs such as tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof.
  • the '695 patent further discloses a process for preparation of tenofovir disoproxil as its fumarate salt form by reaction of tenofovir disoproxil with fumaric acid in isopropanol.
  • Patent No. 8,049,009 discloses tenofovir disoproxil hemifumarate and process for preparation of the same.
  • Patent publication No. WO 2009/074351 discloses crystalline solid forms of tenofovir disoproxil and an organic acid, wherein the organic acid is selected from the group consisting of succinic acid, tartaric acid, saccharic acid, citric acid, oxalic acid and salicylic acid; and processes for the preparation thereof.
  • CN Publication No. 101712692 (“the '692 publication”) discloses salts of tenofovir disoproxil including hydrochloric acid, sulfuric acid, phosphoric acid, toluene sulfonic acid, salicylic acid, benzoic acid, formic acid, citric acid, fumaric acid, maleic acid, malic acid.
  • the '692 publication does not describe the physical characteristics of the salts of tenofovir disoproxil so obtained.
  • the entirety of the '692 publication is incorporated herein by reference.
  • the present invention encompasses tenofovir disoproxil phosphate, processes for the preparation and pharmaceutical composition containing the same.
  • the present invention provides tenofovir disoproxil phosphate.
  • the present invention provides crystalline tenofovir disoproxil phosphate.
  • the present invention provides crystalline tenofovir disoproxil phosphate, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 1.
  • XRD X-Ray diffraction
  • the present invention provides crystalline tenofovir disoproxil phosphate, characterized by one or more X-Ray diffraction (XRD) peaks at about 5.5, 12.3, 13.5, 15.7, 16.3, 16.9, 22.3, 22.6, 24, 25, 25.3 and 32° ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides crystalline tenofovir disoproxil phosphate, characterized by a predominant endotherm peak at about 147°C as measured by a differential scanning calorimetric (DSC) thermogram.
  • DSC differential scanning calorimetric
  • the present invention provides a process for preparation of crystalline tenofovir disoproxil phosphate, comprising:
  • one or more solvents is selected from the group consisting of water, alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and the like and mixtures thereof.
  • the present invention provides a process for preparation of crystalline tenofovir disoproxil phosphate, comprising:
  • g) isolating the tenofovir disoproxil phosphate.
  • one or more solvents is selected from the group consisting of water, alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and the like and mixtures thereof; wherein the C alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixtures thereof.
  • one or more solvents is selected from the group consisting of water, alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and the like and mixtures thereof.
  • the present invention provides a pharmaceutical composition comprising tenofovir disoproxil phosphate, prepared by the processes of the present invention, together with one or more pharmaceutically acceptable excipients.
  • Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of Tenofovir disoproxil phosphate.
  • Figure 2 is the characteristic differential scanning calorimetric (DSC) theremogram of tenofovir disoproxil phosphate.
  • Solid state physical properties of an active pharmaceutical ingredient affect the commercial usefulness of the API.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound may also affect its behavior on compaction and its storage stability.
  • the present invention provides tenofovir disoproxil phosphate compound with increased solubility in water as compared to the tenofovir disoproxil fumarate. Increased solubility leads to improved bioavailability when the drug is administered to a patient, and, thus, allows reduced required dosages.
  • One embodiment of the invention is crystalline Form of tenofovir disoproxil phosphate, which is more readily soluble than tenofovir disoproxil fumarate.
  • the present invention provides a compound tenofovir disoproxil phosphate, particularly crystalline tenofovir disoproxil phosphate (herein after referred to as "Form ⁇ ).
  • the tenofovir disoproxil phosphate of the present invention can be represented by the following molecular structure:
  • the present invention provides crystalline tenofovir disoproxil phosphate as characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 1.
  • XRD X-Ray diffraction
  • the present invention further provides crystalline tenofovir disoproxil phosphate as characterized by one or more X-Ray diffraction (XRD) peaks at about 5.5, 12.3, 13.5, 15.7, 16.3, 16.9, 22.3, 22.6, 24, 25, 25.3 and 32° ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the crystalline tenofovir disoproxil phosphate of the present invention can be characterized by, for example, X-ray powder diffraction pattern and/or melting point.
  • the powder XRPD spectrum for crystalline tenofovir disoproxil phosphate is presented in Figure 1.
  • the present invention provides crystalline tenofovir disoproxil phosphate as characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 2.
  • DSC differential scanning calorimetric
  • the present invention provides crystalline tenofovir disoproxil phosphate as characterized by a predominant endotherm peak at about 147°C as measured by a differential scanning calorimetric (DSC) thermogram.
  • DSC differential scanning calorimetric
  • crystalline tenofovir disoproxil phosphate exhibits a predominant endotherm peak at about 147°C as measured by a Differential Scanning Calorimeter (DSC Q200, TA instrumentation, Waters) at a scan rate of 2°C per minute with an Indium standard.
  • DSC Q200 Differential Scanning Calorimeter
  • TA instrumentation Waters
  • Indium standard an Indium standard.
  • the endotherm measured by a particular differential scanning calorimeter is dependent upon a number of factors, including the rate of heating (i.e., scan rate), the calibration standard utilized, instrument calibration, relative humidity, and upon the chemical purity of the sample being tested.
  • an endotherm as measured by DSC on the instrument identified above may vary by as much as ⁇ 1 °C or even ⁇ 2°C.
  • the present invention provides a process for preparation of crystalline tenofovir disoproxil phosphate, comprising:
  • starting tenofovir disoproxil can be prepared either from the corresponding tenofovir disoproxil acid addition salts by neutralization or from the reaction by tenofovir with chloro methyl isopropyl carbonate in presence of a base.
  • the tenofovir disoproxil salt as mentioned above can be prepared by any method known in the art and thereafter adjusting the pH with a base to produce tenofovir disoproxil, which is immediately processed through the subsequent steps defined above.
  • the pH adjustment can be made by the addition of about 1 molar equivalent of a suitable base. Examples of such base comprise but not limited to, all bases that neutralizes the acid, e.g. sodium hydroxide and the like.
  • tenofovir disoproxil can be prepared by reaction of tenofovir with chloro methyl isopropyl carbonate in presence of a base in an organic solvent.
  • Tenofovir can be prepared by any known method, for example tenofovir may be synthesized as disclosed in U.S. Patent No. 5,922,695 or our Indian pending Patent application No. 3791/CHE/2010.
  • the organic solvent may be selected from amides such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidinone and the like and mixtures thereof; hydrocarbons such as cyclohexane, toluene, xylene, and the like and mixtures thereof; and the base include, but is not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triemylamine and the like and mixtures thereof.
  • the organic solvent is N-methyl pyrrolidinone and the base is triethylamine.
  • tenofovir can be purified before the reaction with chloro methyl isopropyl carbonate (CMIC).
  • CMIC chloro methyl isopropyl carbonate
  • the purification may be carried out by mixing tenofovir crude compound in water and adjusting the pH to about 4 to about 7 with a suitable base.
  • suitable base include but are not limited to hydroxide base, carbonate base, bicarbonate base and the like; preferably sodium hydroxide, sodium carbonate, sodium bicarbonate; more preferably sodium hydroxide.
  • the resultant reaction mixture may be washed with a water immiscible organic solvent, wherein the water immiscible organic solvent is selected from the group consisting of ⁇ methylene chloride, chloroform, toluene, methyl tertiary butyl ether and the like; preferably methylene chloride.
  • the product containing aqueous layer may be acidified to about 2 to about 4 with a suitable acid such as hydrochloric acid, hydrobromic acid and the like and isolating the pure tenofovir product.
  • the reaction of tenofovir with chloromethyl isopropyl carbonate may be carried out at a temperature of about 40°C to about 70°C.
  • the reaction may take from about 2 hours to about 10 hours depending upon the solvent, base and temperature chosen.
  • a reaction carried out with N-methyl pyrrolidinone, triemylamine base at temperature 50°C to 55°C is completed about 3 hours.
  • the solid bi-product salts that are produced may be removed, such as by filtration and then the filtrate may be washed with water.
  • the resultant product layer containing tenofovir disoproxil can be further processed directly in the same reaction vessel without isolating the tenofovir disoproxil base.
  • the solvent from the product layer may be concentrated under vacuum to get tenofovir disoproxil base as residue by any method known in the art and then converted further to the tenofovir disoproxil phosphate of the invention.
  • the one or more solvents in a) of the foregoing process may be selected from the group consisting of alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidinone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4- dioxane and the like;
  • the one or more solvents selected from the group consisting of methanol, methylene chloride, cyclohexane, tetrahydrofuran, methyl tertiary butyl ether, dimethyl ether, dimethyl formamide, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, nitromethane, nitroethane, chloroform, water or mixture thereof.
  • the reaction may be heated to dissolve or mixing the tenofovir disoproxil in the one or more solvents.
  • the temperature suitable for dissolving or mixing the tenofovir disoproxil in the one or more solvents depends on the solvent used and the amount of tenofovir disoproxil in the solution.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution is heated at about 30°C to about 80°C.
  • the orthophosphoric acid can range from about 0.5 to about 2 mole equivalents per mole of starting tenofovir disoproxil, preferably about 1.0 to about 1.5 moles.
  • the orthophosphoric acid can be added either as a solution in one or more solvents defined above or it may be added directly to the solution of tenofovir disoproxil in one or more solvents.
  • the sequence of addition of orthophosphoric acid is not particularly critical.
  • the phosphoric acid salt formation can be carried out in any known manner, for example, the orthophosphoric acid can be added into tenofovir disoproxil or tenofovir disoproxil may be added to the orthophosphoric acid.
  • the precipitation of tenofovir disoproxil phosphate may be carried out by crystallization, solvent precipitation, concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like.
  • the reaction may be cooled at a temperature from about 25°C or less such that the tenofovir disoproxil phosphate can be recovered by conventional techniques, for example filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the drying can be carried out at a temperature ranging from about 30°C to about 50°C.
  • the drying can be carried out for any desired time until the required product purity is achieved, e.g., a time period ranging from about 1 hour to about 10 hours.
  • the present invention provides tenofovir disoproxil phosphate thus obtained may be purified by dissolving the tenofovir disoproxil phosphate in a C ⁇ alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixtures thereof, with methanol being preferred.
  • the solvent may be heated to obtain a solution at a temperature of from about ambient temperature to about reflux temperature.
  • adding water to the resultant solution and the reaction solution may be cooled at a temperature from about 20°C or less such that the tenofovir disoproxil phosphate can be isolated by conventional techniques.
  • the tenofovir disoproxil phosphate recovered using the process of the present invention is substantially in crystalline Form.
  • the crystalline tenofovir disoproxil phosphate can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure.1 or a DSC thermogram substantially in accordance with Figure. 2.
  • XRD X-Ray diffraction
  • the present invention provides crystalline tenofovir disoproxil phosphate having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC.
  • the tenofovir disoproxil phosphate obtained by the process as described above may have an increased solubility as compared to the commercially available tenofovir disoproxil fumarate.
  • Table I shows comparison study for solubility of tenofovir disoproxil phosphate of the invention and tenofovir disoproxil fumarate.
  • the present invention provides a tenofovir disoproxil phosphate, obtained by the above process, as analyzed using the high performance liquid chromatography ("HPLC") with the conditions described below:
  • Buffer solution disodiumhydrogen phosphate in water and pH at 5.5.
  • Mobile phase A mixture of 700 ml of buffer, 275 ml of methanol and 25 ml tertiary butanol.
  • Mobile phase B mixture of 300 ml of buffer, 675 ml of methanol and 25 ml tertiary butanol.
  • tenofovir disorpoxil phosphate is prepared according to Scheme I:
  • Tenofovir disoproxil phosphate salt as obtained by the '692 publication has several limitations, which includes:
  • the process herein described arrives at a tenofovir disoproxil phosphate, which includes optimized isolation techniques; for instance, tenofovir disoproxil phosphate obtained from a mixture of one or more of solvent or a mixture with water of the invention, not only reduced the contamination of the impurity of Formula 2, but also improved the particle size, with d(0.9) >120.
  • the optimized isolation techniques include:
  • tenofovir disoproxil phosphate disclosed herein for use in the pharmaceutical compositions of the present invention can independently have a D50 and D90 particle size less than about 200 microns, preferably less than about 150 microns, more preferably less than about 100 microns, still more preferably less than about 50 microns and most preferably less than about 25 microns.
  • Dx means that X% of the particles have a diameter less than a specified diameter D.
  • a D50 of about 200 microns means that 50% of the micronized particles in a composition have a diameter less than about 200 microns.
  • any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the tenofovir disoproxil phosphate into any desired particle size range set forth above.
  • the tenofovir disoproxil phosphate of the present invention is useful as it is stable under conditions of high relative humidity and elevated temperatures.
  • the present invention provides a pharmaceutical composition comprising the tenofovir disoproxil phosphate described above and at least one pharmaceutically acceptable excipient.
  • the present invention provides the use of tenofovir disoproxil phosphate, for the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition can be useful for the treatment of viral infections.
  • the pharmaceutical composition of the present invention can be in a solid or a non- solid form. If the pharmaceutical composition is in a non-solid form, the tenofovir disoproxil phosphate in the composition can present as a solid in the non-solid pharmaceutical composition, e.g., as a suspension.
  • the pharmaceutical composition can be prepared by a process comprising combining the above-described tenofovir disoproxil phosphate with at least one pharmaceutically acceptable excipient.
  • the tenofovir disoproxil phosphate can be obtained by any of the processes of the present invention as described above.
  • the pharmaceutical composition can be used to make appropriate dosage forms such as tablets, powders, capsules, suppositories, sachets, troches and lozenges.
  • compositions of the invention may be combination products comprising one or more additional pharmaceutically active components in addition to tenofovir disoproxil phosphate.
  • compositions include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, macrocrystalline cellulose, silicified macrocrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium oxide, magnesium carbonate, calcium carbonate, mannitol, sorbitol, xylitol and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl celluloses, hydroxypropyl starch, hydroxypropylmethyl celluloses and pregelatinized starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, polacrilin potassium, croscarmellose sodium and colloidal silicon dioxide; lubricants such as stearic acid, talc, magnesium stearate, calcium stearate and zinc stearate; gli
  • composition includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof.
  • composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a “composition” may contain a single compound or a mixture of compounds.
  • compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • excipient means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on.
  • the excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, nontoxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable excipient as used in the specification and claims includes both one and more than one such excipient.
  • the temperature was further raised to 75-80°C and diethyl p- toluene sulfonyloxy methyl phosphonate (DESMP, 250 gms) was charged. After stirring at the same temperature for 4 hours HPLC analysis revealed a conversion of 70-78%.
  • the reaction mass was allowed to cool to 70°C and solvent removed under vacuum to afford a thick residue.
  • the residue was allowed to cool to ambient temperature and aqueous hydrobromic acid (650 ml) was charged.
  • the temperature was raised to 90-95°C and stirred for 2 hours at same temperature. After completion of the de-alkylation reaction, the reaction mass was allowed to cool to ambient temperature and stirred for another 30 minutes at same temperature.
  • the precipitate was filtered and the wet cake washed with methylene chloride (300 ml). The bottom organic layer was separated and the pH of the aqueous layer adjusted to 2.5 to 3.0 with 50% sodium hydroxide solution, at 20-25°C. The reaction mass stirred for 1 hour at 20- 25°C, cooled to 0-5°C and then stirred for 4 hours. The precipitated product was filtered and the wet cake was sequentially washed with chilled water (100 ml) and then with chilled acetone (100 ml) to provide crude Tenofovir.
  • a mixture of tenofovir (100 gms), triethyl amine (68 gms) and cyclohexane (800 ml) were stirred at 80-85°C and water, completely, removed by azeotropic distillation.
  • the reaction mixture was allowed to cool to 65 °C and concentrated under vacuum, while mamtaining temperature below 65 °C. Released the vacuum and in the presence of nitrogen atmosphere the residue was allowed to cool to ambient temperature.
  • N- methylpyrrolidinone (300 ml), triethyl amine (64 gms) and tetrabutylammom ' um bromide (53 gms) were charged to the residue at 25-30°C.
  • the crude product (105 gms, obtained from Example 3) in methanol (550 ml) was stirred, at 40-50°C, for 1 hour.
  • the reaction mass was allowed to cool to 10°C and stirred for 60 minutes.
  • the precipitated material was filtered off and the wet cake washed with chilled methanol (100 ml).
  • the wet product was dried at 35-40°C for 6 hours under vacuum to provide the title compound.
  • Phosphoric acid content 1 .9 %w/w (by potentiometry method)
  • the DSC is set forth in Figure 2
  • Table 1 shows physicochemical properties of Tenofovir disoproxil phosphate and Tenofovir disoproxil fumarate.
  • a mixture of tenofovir (100 gms), triethyl amine (68 gms) and cyclohexane (800 ml) were stirred at 80-85°C Dean-Stark apparatus for 2 hours and water, completely, removed by azeotropic distillation.
  • the reaction mixture was allowed to cool to 65 °C and concentrated under vacuum, while mamtaining temperature below 65°C. Released the vacuum and in the presence of nitrogen atmosphere the residue was allowed to cool to ambient temperature.
  • N-methylpyrrolidinone (300 ml), triethyl amine (64 gms) and tetrabutylammonium bromide (53 gms) were charged to the residue at 25-30°C.
  • a mixture of tenofovir (6.0 Kg), triethylamine (4.08 Kg) and cyclohexane (48 Lit) were stirred at 80-85°C, with azeotropic removal of water.
  • the reaction mixture was allowed to cool to 65°C and concentrated under vacuum, while maintaining temperature below 65 °C.
  • the vacuum released and in the presence of nitrogen atmosphere the residue was allowed to cool to ambient temperature.
  • N- Methylpyrrolidone (18 Lit), triethyl-unine (3.84 Kg) and tetrabutylammonium bromide (3.18 Kg) were charged to the residue at 25-30°C.
  • composition for the preparation of tenofovir disoproxil phosphate tablets with tenofovir disoprbxil phosphate obtained from Example 4.

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Abstract

La présente invention concerne un phosphate de type ténofovir disoproxil et un procédé pour sa préparation. La présente invention concerne également une composition pharmaceutique utilisant le phosphate de type ténofovir disoproxil de l'invention.
PCT/IB2013/000467 2012-03-05 2013-03-04 Phosphate de type ténofovir, procédés de préparation et composition pharmaceutique de celui-ci WO2013132314A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2860184A1 (fr) * 2013-10-09 2015-04-15 Zentiva, k.s. Sel dihydrogénophosphate du Ténofovir disoproxil
CN104610360A (zh) * 2015-02-13 2015-05-13 山东新时代药业有限公司 一种富马酸替诺福韦二吡呋酯的制备方法
WO2016003194A1 (fr) * 2014-07-01 2016-01-07 Hanmi Pharm. Co., Ltd. Phosphate de ténofovir disoproxil, et composition pharmaceutique de celui-ci comprenant un délitant de sel non métallique et un lubrifiant de sel non-métallique
KR101811030B1 (ko) * 2016-10-21 2017-12-20 한미약품 주식회사 테노포비어 디소프록실 인산염과, 비금속염 붕해제 및 비금속염 활택제를 포함하는 약학 조성물

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