WO2017042735A1 - Forme amorphe d'un inhibiteur de la protéase du vih - Google Patents

Forme amorphe d'un inhibiteur de la protéase du vih Download PDF

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Publication number
WO2017042735A1
WO2017042735A1 PCT/IB2016/055393 IB2016055393W WO2017042735A1 WO 2017042735 A1 WO2017042735 A1 WO 2017042735A1 IB 2016055393 W IB2016055393 W IB 2016055393W WO 2017042735 A1 WO2017042735 A1 WO 2017042735A1
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WIPO (PCT)
Prior art keywords
atazanavir
free base
amorphous form
solvent
atazanavir free
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PCT/IB2016/055393
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English (en)
Inventor
Prasada Raju Vnkv VETUKURI
Goverdhan Gilla
Ravindra Vedantham
Yuvasai Krishna KAMMA
Krishna Prasad CHIGURUPATI
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Granules India Limited
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Publication of WO2017042735A1 publication Critical patent/WO2017042735A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom

Definitions

  • the present invention relates to stable amorphous form of a HIV protease inhibitor, namely, Atazanavir.
  • the present invention preferably relates to stable amorphous form of Atazanavir free base.
  • the present invention also relates to an improved process for the preparation of Atazanavir sulfate from amorphous Atazanavir free base.
  • the present invention also relates to solid dispersion/premix comprising amorphous Atazanavir free base and a pharmaceutically acceptable excipient.
  • Atazanavir trade name Reyataz (formerly known as BMS-232632), is an antiretroviral drug of the protease inhibitor (PI) class, approved by the FDA in June of 2003. Like other antiretrovirals, it is used to treat infection of human immunodeficiency virus (HIV). Unlike most protease inhibitors, Atazanavir appears not to increase cholesterol, triglycerides, or blood sugar levels, which is a problem to various degrees with all other Pis. Furthermore, the good oral bioavailability and favorable pharmacokinetic profile enables Atazanavir to be the first once-a-day protease inhibitor to treat AIDS. This can provide a benefit for people seeking a simplified dosing regimen.
  • PI protease inhibitor
  • Atazanavir is an aza-peptidomimetic HIV-1 protease inhibitor, bearing an aza- dipeptide isostere structure.
  • the focus of its synthesis is to construct the aza-dipeptide skeleton with desired stereochemistry.
  • the chemical name of Atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(l,l-dimethylethyl)-8-hydroxy-4,l l-dioxo-9-(phenylmethyl)-6-[[4- (2-pyridinyl)phenyl] methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1: 1) and the molecular formula is C 38 H 52 N 6 0 7 .H 2 S0 4 with a molecular weight of 802.9.
  • the structural formula of Atazanavir sulfate is:
  • US Patent No. 5,849,911 discloses Atazanavir for the first time.
  • This patent also discloses process for preparing Atazanavir by treating l-[4-(pyridin-2-yl)-phenyl]-4(S)- hydroxy-5(S)-2,5-bis[tert-butoxycarbonyl)amino]-6-phenyl-2-azahexane with hydrochloric acid in THF to give l-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2- azahexane trihydrochloride followed by reacting the obtained compound with N- (methoxycarbonyl)-L-tert-leucine to give Atazanavir.
  • the process is shown in the scheme given below:
  • Amorphous forms can be thought of as liquids that have been solidified by the removal of thermal energy or a solvent, in a manner that circumvents crystallization.
  • the amorphous form can have different solubility, stability, and mechanical behavior that can be exploited by pharmaceutical scientists.
  • the solubility of a given solid is a sum of crystal packing energy, cavitation, and solvation energy. Different crystalline forms of a given drug will have different crystal packing energies.
  • the amorphous forms of the same drug require minimal packing energy disruption when dissolving due to absence of an ordered crystal lattice.
  • the amorphous forms provide the maximal solubility advantage as compared to the crystalline forms of a drug.
  • the "apparent solubility" and dissolution advantage offered by these systems is a vital approach to enhance bioavailability of poorly water soluble drugs.
  • amorphous forms are more soluble than crystalline forms, they are usually associated with their own problems.
  • One such problem is that amorphous forms are very often unstable and revert to a crystalline form after short periods.
  • An unstable amorphous form such as this is therefore not suitable for pharmaceutical use, where it is essential to have a stable physical form of the compound.
  • Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Polymorphism is the ability of a substance to exist in several different amorphous forms. Different forms of amorphous pharmaceuticals with readily discernible physical and chemical characteristics and some marked differences in their pharmaceutical performance have been reported.
  • amorphous materials do not exhibit long-range periodic atomic ordering, different amorphous phases of the same chemical substance can exhibit significant structural differences in their short-range atomic arrangement. These differences may lead to different physical and chemical properties such as density, stability, processability, dissolution and even bioavailability.
  • Polymorphism in pharmaceuticals is reviewed in Hancock et al. (Journal of Pharmacy and Pharmacology 2002, 54: 1151-1152), the content of which is hereby incorporated by reference.
  • the identification and characterization of various morphic or amorphic forms of a pharmaceutically active compound is of great significance in obtaining medicaments with desired properties including a specific dissolution rate, milling property, bulk density, thermal stability or shelf-life.
  • the stable amorphous form of Atazanavir free base disclosed herein possesses improved physicochemical properties including advantageous solubility properties.
  • Atazanavir free base can be prepared in amorphous Form.
  • the amorphous form has been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.
  • the amorphous Form of Atazanavir free base obtained by the process of the invention may be used in development of composition of Atazanavir or Atazanavir sulfate.
  • the main objective of the present invention is to provide stable amorphous form of a
  • HIV protease inhibitor namely, Atazanavir.
  • the preferred objective of the present invention is to provide stable amorphous form of Atazanavir free base.
  • Still another preferred objective of the present invention is to provide a stable solid dispersion/premix comprising amorphous Atazanavir free base and a pharmaceutically acceptable excipient.
  • the present invention provides amorphous form of Atazanavir free base which is highly stable.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by X-ray powder diffraction pattern as depicted in Figure 1.
  • the present invention provides stable amorphous form of Atazanavir free base further characterized by DSC as depicted in Figures 2, 3 and 4.
  • the present invention provides stable amorphous form of Atazanavir free base having DSC melting point in the range of 140-165°C.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by a TGA profile substantially as shown in Figure 5 or 6.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) providing a solution of Atazanavir in a suitable solvent or mixture of solvents; and b) obtaining the amorphous form of Atazanavir.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) providing a solution of Atazanavir in a suitable solvent or mixture of solvents; and b) spray drying or vaccum drying the step a) solution to obtain amorphous form of Atazanavir.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) suspending Atazanavir in a suitable organic solvent and removing the solvent to obtain residue;
  • the present invention provides a process for the preparation of Atazanavir sulfate which comprises converting stable amorphous Atazanavir free base to Atazanavir sulfate.
  • the present invention provides a process for the preparation of Atazanavir sulfate which comprises:
  • step b) spray drying or Vaccum drying the step a) solution to obtain amorphous Atazanavir free base
  • the present invention provides a process for the preparation of Atazanavir sulfate Form- A, which comprises:
  • the present invention provides stable amorphous
  • Atazanavir free base premix comprising Atazanavir free base and at least one pharmaceutically acceptable excipient.
  • Fig. l Represents X-ray powder diffraction pattern of stable amorphous form of Atazanavir free base.
  • Fig.2 Represents Differential Scanning Calorimetry (DSC) thermogram of stable amorphous form of Atazanavir free base.
  • Fig.3 Represents Differential Scanning Calorimetry (DSC) thermogram of stable amorphous form of Atazanavir free base.
  • Fig.4 Represents Differential Scanning Calorimetry (DSC) thermogram of stable amorphous form of Atazanavir free base which is prepared according to example-2.
  • DSC Differential Scanning Calorimetry
  • Fig.5 Represents TGA curve of stable amorphous form of Atazanavir free base.
  • Fig.6 Represents TGA curve of stable amorphous form of Atazanavir free base.
  • the present invention provides amorphous form of Atazanavir free base which is highly stable.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by X-ray powder diffraction pattern as depicted in Figure 1.
  • the present invention provides stable amorphous form of Atazanavir free base further characterized by DSC as depicted in Figures 2, 3 and 4.
  • the present invention provides stable amorphous form of Atazanavir free base having DSC melting point in the range of 140-165°C. In yet another preferred embodiment, the present invention provides stable amorphous form of Atazanavir free base characterized by DSC which is having an endothermic peak at about 145+2°C as depicted in Figures 2 and 3.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by DSC which is having an endothermic peak at about 156+2°C as depicted in Figure 4.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by a TGA profile substantially as shown in Figures 5 or 6. In yet another preferred embodiment, the present invention provides stable amorphous form of Atazanavir free base characterized by a TGA profile with a weight loss of about 1.63% between about 30°C and about 120°C as depicted in Figure 5.
  • the present invention provides stable amorphous form of Atazanavir free base characterized by a TGA profile with a weight loss of about 2.31% between about 30°C and about 120°C as depicted in Figure 6.
  • the amorphous Form of the present invention is characterized by DSC in order to determine the transition temperature.
  • the transition temperature of the different batches is between about 140°C and about 165°C, wherein the variability is largely due to Loss on drying or due to the variation in TGA and also due to residual solvent effects.
  • the amorphous Form obtained as per the process of the present invention has a transition temperature around 145°C, which has loss on drying of 2.33%, results in amorphous which has a transition temperature of around 156°C. This amorphous Form has loss on drying of 1.63% results in the stable amorphous Atazanavir free base which finally melts at a temperature in the range of 207-212°C.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) providing a solution of Atazanavir in a suitable solvent or mixture of solvents; and b) obtaining the amorphous form of Atazanavir.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) providing a solution of Atazanavir in a suitable solvent or mixture of solvents; and b) spray drying or vaccum drying the step a) solution to obtain amorphous form of Atazanavir.
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base which comprises the steps of: a) suspending Atazanavir in a suitable organic solvent and removing the solvent to obtain residue;
  • the present invention provides a process for the preparation of stable amorphous form of Atazanavir free base, which comprises the steps of: a) providing a solution of pharmaceutically acceptable salts of Atazanavir in a suitable solvent,
  • step i) converting the solution obtained in step i) to Atazanavir free base
  • the present invention provides a process for the preparation of Atazanavir sulfate which comprises converting amorphous Atazanavir free base to Atazanavir sulfate.
  • the present invention provides a process for the preparation of Atazanavir sulfate which comprises:
  • step b) spray drying or Vaccum drying the step a) solution to obtain amorphous Atazanavir free base
  • the present invention provides a process for the preparation of Atazanavir sulfate Form- A, which comprises:
  • Atazanavir sulfate optionally converting Atazanavir sulfate to Atazanavir free base.
  • the present invention provides Atazanavir free base premix having enhanced stability and dissolution properties and process for preparation thereof.
  • Atazanavir used as starting material for the preparation of stable amorphous Atazanavir free base of the present invention may be obtained by any of processes reported in literature or any known form of the Atazanavir or its pharmaceutically acceptable salt. According to the present inventors' knowledge, there have not been any published reports which disclose the physiochemical properties of amorphous Atazanavir free base.
  • suitable solvents used in the present invention are selected from water or "alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n- butanol and t-butanol and the like or "hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents” such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, sec -butyl acetate, and the like or "nitrile solvents” such as ace
  • the suitable anti-solvent comprises one or more of hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane and the like; aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like; ethers like diethyl ether, di-tert- butylether, pet-ether, diisopropyl ether, methyltert-butyl ether, dibutyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, dimethoxyethane and the like or mixtures thereof.
  • the term "obtaining” or “isolating” means isolating the amorphous form of Atazanavir free base by way of solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/antisolvent method, slurry, cooling, seeding, filtration, filtration under vacuum, centrifugation, decantation, distillation, evaporation, evaporation under reduced pressure.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the process involves obtaining an amorphous form of Atazanavir free base by removal of solvent.
  • the isolation of amorphous form may be affected by removing the solvent.
  • suitable techniques which may be used for the removal of solvent include using a rotational distillation device like a Buchi Rotavapor, spray drying, vacuum drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
  • Atazanavir free base to Atazanavir sulfate in a solvent mixture of acetone and acetonitrile is carried out by the methods known in the art.
  • the amorphous Atazanavir free base obtained by the process disclosed herein is stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling.
  • the premix of the present invention is prepared by combining Atazanavir free base or its with suitable premixing agents in pharmaceutically acceptable proportions to yield desired characteristics of good stability and formulation properties wherein the premixing agent is selected from a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone (also called povidone or PVP), polyvinyl alcohol, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, hypromellose phthalate (HPMCP), lactose monohydrate, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, sugars, water soluble and water insoluble polymers and combinations comprising one or more of the foregoing hydrophilic carriers.
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • lactose monohydrate polyvinyl acetate
  • maltodextrins cyclodextrins
  • gelatins sugars
  • sugars water soluble and water insoluble
  • the polymers used in the present invention are selected from N- vinyl lactams, such as homopolymers or copolymers of N- vinyl pyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N- vinyl pyrrolidone and vinyl acetate or vinyl propionate); cellulose esters or cellulose ethers, such as alkylcelluloses (e.g., methylcellulose or ethylcellulose), hydroxyalkylcelluloses (e-g-, hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose), and cellulose phthalates or succinates (e.g., cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose acetate succinate); high molecular polyalkylene oxides, such as polyethylene oxide, polypropylene oxide, and copoly
  • Non-limiting examples of preferred polymers for the invention include polyvinylpyrrolidone (PVP) K17, PVP K25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10, Ethocel 14, Ethocel 20, copovidone (vinylpyrrolidone-vinyl acetate copolymer 60/40), polyvinyl acetate, methacrylate/methacrylic acid copolymer (Eudragit) L100-55, Eudragit LlOO, Eudragit S lOO, polyethylene glycol (PEG) 400, PEG 600
  • stable relates to a compound which after storage for up to 2 weeks, more suitably up to 4 weeks, still more suitably up to 12 weeks, or at least 12 weeks and especially up to 6 months, particularly at least 6 months at 25°C and 60% relative humidity, 40°C and 75% relative humidity or at 50°C and ambient humidity, when protected from moisture is at least 95% chemically identical to the starting sample and retains an amorphous form.
  • solid dispersion refers to a solid product comprising a polymeric matrix and a drug.
  • the matrix can be either crystalline or amorphous.
  • the drug can be dispersed molecularly, in amorphous particles, for instance clusters, or in crystalline particles.
  • a solid dispersion is in any of the following forms, or any combination thereof: a) a simple eutectic mixture, b) a solid solution (continuous, discontinuous, substitutional, interstitial, amorphous), c) a glass solution, and d) an amorphous precipitation in a crystalline carrier.
  • certain more complex combinations can be encountered, i.e. in the same sample some molecules are present in clusters while some are molecularly dispersed.
  • the process consistently provides amorphous form which is free from crystallinity.
  • Atazanavir free base (50.0g) was dissolved in methylene chloride (2500 mL) at 25- 35°C. The obtained solution was spray dried by using rotavapour at 45-50°C under vacuum and sample was further dried under vacuum at 45-50°C to obtain stable amorphous form.
  • Example 2 Process for the preparation of stable amorphous form of Atazanavir free base: Atazanavir free base (2.0 g) was dissolved in methylene chloride (200 mL) at 25-35°C.
  • the obtained solution was cooled to 10°C and spray dried the solution in rotavapor at below 60°C and further dried at 55-60°C to obtain stable amorphous form. It is further analyzed on differential scanning calorimeter (DSC) and it shows endotherm at 156.4°C further it is converted to crystalline form and obtained endotherm at 209.42°C.
  • DSC differential scanning calorimeter
  • Example 3 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in methylene chloride (100 mL) at 25-35°C. The obtained solution was cooled to 10°C and distilled the solvent completely under vacuum at below 30°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 4 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in methanol (100 mL) at 25-35°C. The obtained solution was heated to 65-70°C and cooled to below 10°C and distilled the solvent completely under vacuum at below 50°C and further dried at 50-60°C to obtain stable amorphous form.
  • Example 5 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in THF (100 mL) at 40-45°C. The obtained solution was cooled to below 10°C and distilled the solvent completely under vacuum at below 30°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 6 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in methylene chloride (100 mL) at 25-35°C and distilled the solvent completely under vacuum at below 30°C and further dried at 25-35°C to obtain stable amorphous form.
  • Example 7 Process for the preparation of stable amorphous form of Atazanavir free base: Atazanavir free base (5.0g) was dissolved in chloroform (100 niL) at 25-35°C. The obtained solution was heated to 64-68°C and mass was transferred to precooled RBF at 0- 10°C and maintain for 30 minutes and filtered the solid to obtain stable amorphous form.
  • Example 8 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (lOO.Og) was dissolved in methylene chloride (2000 mL) at 25- 35°C. The obtained solution was cooled to 10°C and distilled the solvent completely under vacuum at below 55°C and further dried at 50-55°C to obtain stable amorphous form.
  • Example 9 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in 1,4-Dioxane (100 mL) at 70-75°C. The obtained solution was transferred to pre-cooled RBF at 10-15°C and distilled the solvent completely under vacuum at below 60°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 10 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (5.0g) was dissolved in THF (20 mL) at 60-65°C. The obtained solution was transferred to pre-cooled RBF at 10-15°C and distilled the solvent completely under vacuum at below 55°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 11 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (20.0 g) was dissolved in methylene chloride (400 mL) at 25-
  • Example 12 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (20.0 g) was dissolved in methanol (400 mL) at 25-35°C. The obtained solution sprayed into spray dryer below 65°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 13 Process for the preparation of stable amorphous form of Atazanavir free base:
  • Atazanavir free base (200.0 g) was dissolved in methylene chloride (4000 mL) at 25- 35°C. The obtained solution distilled in rotavapour below 65°C and further dried at 55-60°C to obtain stable amorphous form.
  • Example 14 Process for the preparation of Atazanavir sulfate:
  • Atazanavir free base (50.0 g) was dissolved in methylene chloride (500 mL) and filtered through filter bed. Distilled out the solvent completely at a temperature below 55°C and co-distilled the solvent with acetone (100 mL) at below 55°C under reduced pressure. Slurry was made in acetone (900 mL) and acetonitrile (100 mL) at room temperature. To the prepared slurry was added sulfuric acid (6.95g) and maintained for 3 hrs. Filtered the solid and washed with acetone (50mL) and dried at 50-55°C to get Atazanavir sulfate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une forme amorphe stable d'un inhibiteur de la protéase du VIH, à savoir l'atazanavir. La présente invention concerne, de préférence, une forme amorphe stable de la base libre de l'atanazavir. La présente invention porte également sur un procédé perfectionné pour la préparation de sulfate d'atazanavir à partir de la base libre de l'atazanavir amorphe. La présente invention concerne aussi une dispersion solide/un prémélange comprenant de la base libre d'atazanavir amorphe et un excipient de qualité pharmaceutique.
PCT/IB2016/055393 2015-09-09 2016-09-09 Forme amorphe d'un inhibiteur de la protéase du vih WO2017042735A1 (fr)

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IN4775CH2015 2015-09-09
IN4775/CHE/2015 2015-09-09

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461347B2 (en) * 2011-08-05 2013-06-11 Scinopharm Taiwan, Ltd. Process for preparing form A of atazanavir sulfate
WO2014125270A1 (fr) * 2013-02-12 2014-08-21 Cipla House Procédé de production de sulfate d'atazanavir

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461347B2 (en) * 2011-08-05 2013-06-11 Scinopharm Taiwan, Ltd. Process for preparing form A of atazanavir sulfate
WO2014125270A1 (fr) * 2013-02-12 2014-08-21 Cipla House Procédé de production de sulfate d'atazanavir

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