WO2015138933A1 - Formes à l'état solide de dolutegravir sodium - Google Patents

Formes à l'état solide de dolutegravir sodium Download PDF

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WO2015138933A1
WO2015138933A1 PCT/US2015/020497 US2015020497W WO2015138933A1 WO 2015138933 A1 WO2015138933 A1 WO 2015138933A1 US 2015020497 W US2015020497 W US 2015020497W WO 2015138933 A1 WO2015138933 A1 WO 2015138933A1
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Prior art keywords
dolutegravir sodium
dolutegravir
crystalline
sodium
theta
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PCT/US2015/020497
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English (en)
Inventor
Sigalit Levi
Limor TESSLER-SHAMIS
Kerem GOREN
Jonathan ENAV
Ivgenya FRAGIN
Wolfgang Albrecht
Jens Geier
David Perez
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Assia Chemical Industries Ltd.
Ratiopharm Gmbh
Teva Pharmaceuticals Usa, Inc.
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Application filed by Assia Chemical Industries Ltd., Ratiopharm Gmbh, Teva Pharmaceuticals Usa, Inc. filed Critical Assia Chemical Industries Ltd.
Publication of WO2015138933A1 publication Critical patent/WO2015138933A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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

Definitions

  • Dolutegravir sodium has the chemical name sodium (4R,12aS)-9- ⁇ [(2,4- difluorophenyl)methyl]carbamoyl ⁇ -4-methyl-6,8-dioxo-3 ,4,6,8, 12,12a-hexahydro-2H- pyrido[ ,2':4,5]pyrazino[2,l-b][l ,3]oxazin-7-olate.
  • Dolutegravir sodium has the following chemical structure:
  • Dolutegravir is known from WO2006/1 16764 as a compound possessing antiviral activity, in particular an inhibitory activity against HIV integrase.
  • TIVICAY Dolutegravir is marketed as TIVICAY by GlaxoSmithKline (GSK). TIVICAY is reported to be a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
  • HIV-1 human immunodeficiency virus type 1
  • INSTI integrase strand transfer inhibitor
  • the present invention encompasses the use of any one of the above described solid state forms of Dolutegravir sodium and /or combinations thereof for the preparation of pharmaceutical compositions.
  • the present invention encompasses processes to prepare said pharmaceutical compositions of Dolutegravir sodium comprising combining any one of the above solid state forms and /or combinations thereof and at least one pharmaceutically acceptable excipient.
  • Figure 3 shows a powder X-ray diffraction pattern ("powder XRD” or "PXRD”) of Dolutegravir sodium Form IV.
  • Figure 4 shows a powder X-ray diffraction pattern ("powder XRD” or "PXRD”) of Dolutegravir sodium Form V.
  • Figure 10 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form XI.
  • Figure 1 1 shows a solid-state C NMR spectrum of Dolutegravir sodium Form II in the 0-200 ppm range.
  • Figure 12 shows a solid-state C NMR spectrum of Dolutegravir sodium Form II in the 100-200 ppm range.
  • Figure 13 shows a solid-state C NMR spectrum of Dolutegravir sodium Form V in the 0-200 ppm range.
  • Figure 15 shows a solid-state 13 C NMR spectrum of Dolutegravir sodium Form X n- butanol solvate in the 0-200 ppm range.
  • Figure 16 shows a solid-state C NMR spectrum of Dolutegravir sodium Form X n- butanol solvate in the 100-200 ppm range.
  • Figure 20 shows a solid-state FT-IR spectrum of Dolutegravir sodium 1 ,2-PG solvate prepared according to Example 22.
  • Figure 21 shows a solid-state FT-IR spectrum of anhydrous Dolutegravir sodium according to WO2010/068253.
  • Figure 23 shows an X-ray powder diffractogram of Dolutegravir sodium 1 ,2-PG (1 : 1) solvate prepared according to Example 22 (enlarged Y-scale).
  • Figure 26 shows an X-ray powder diffractogram of Dolutegravir sodium hydrate: comparative example 23, wet (top) compared to Dolutegravir sodium hydrate as disclosed in WO2010/068253 (bottom).
  • Figure 28 shows a powder X-ray diffraction pattern ("powder XRD” or "PXRD”) of Dolutegravir sodium pure Form III.
  • Figure 29 shows a solid-state C NMR spectrum of Dolutegravir sodium Form X 1,2- PG (1 : 1) solvate in the 0-200 ppm range.
  • the Dolutegravir sodium and solid state forms of the present invention may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density.
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which can not necessarily be described by reference to numerical values or peak positions alone.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person.
  • a crystal form of Dolutegravir salt e.g., Dolutegravir sodium
  • graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Dolutegravir salt, e.g., Dolutegravir sodium, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • a solid state form may be referred to herein as polymorphically pure or as substantially free of any other, salts, solid state (or polymorphic) forms.
  • the expression “substantially free of any other forms” will be understood to mean that the solid state form contains 20% (w/w) or less, 10% or less, 5% or less, 2% or less, or 1% or less, more particularly 0.5% or less, 0.2% or less of any other forms of the subject compound or salts of Dolutegravir as measured, for example, by PXRD.
  • solid state of Dolutegravir sodium described herein as substantially free of any other solid state forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject solid state form of Dolutegravir sodium.
  • the described solid state forms of Dolutegravir sodium may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10%) (w/w) of one or more other solid state forms of Dolutegravir sodium.
  • the crystalline Dolutegravir sodium contains less than 10%) (w/w), less than 5% (w/w), less than 2%, less than 1%, less than 0.5%, less than 0.2% or less than 0.1%) of other polymorphs or of a specified polymorph of Dolutegravir sodium (such as other polymorphs of Dolutegravir sodium- 1 ,2-propylene glycol solvate).
  • a solid state form may be referred to herein as being characterized by data selected from two or more different data groupings, for example, by a powder XRD pattern having a group of specific peaks; or by a powder XRD pattern as shown in a figure depicting a diffractogram, or by "a combination thereof (or “combinations thereof,” or “any combination thereof).
  • a powder XRD pattern having a group of specific peaks
  • a powder XRD pattern as shown in a figure depicting a diffractogram
  • the skilled person may characterize a crystal form using a group of three, four or five characteristic powder XRD peaks, and supplement that characterization with one or more additional features observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity, or even the absence of a peak at some position in the powder XRD pattern.
  • the skilled person may in some instances characterize a crystal form using a group of three, four or five characteristic powder XRD peaks and supplement that characterization with one or more additional features observed using another analytical method, for example, using one or more characteristic peaks in a solid state IR spectrum, or characteristics of the DSC thermogram of the crystal form that is being characterized.
  • TDG Dolutegravir
  • butanol solvate refers to n-butanol solvate of Dolutegravir sodium Form X.
  • DTG-Na refers to Dolutegravir sodium salt
  • DTG-Na 1 ,2-PG refers to Dolutegravir sodium 1 ,2-propylene glycol solvate
  • 1 ,2-propylene glycol (1,2-PG) includes racemic 1,2-PG, (R)- 1 ,2-PG or mixtures of (R)- 1 ,2-PG and (S)- 1,2-PG in any proportion.
  • the term "isolated" in reference to solid state forms of Dolutegravir sodium of the present invention corresponds to solid state form of Dolutegravir sodium that is physically separated from the reaction mixture in which it is formed.
  • a thing e.g., a reaction mixture
  • room temperature often abbreviated "RT.”
  • RT room temperature
  • room temperature is from about 18°C to about 30°C, about 18°C to about 28°C, about 20°C to about 30°C, about 18°C to about 25°C, about 18°C to about 22°C, or about 22°C to about 27°C, or about 25°C, or about 20°C.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, typically about 16 hours.
  • dry crystalline form refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples of such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.
  • residual solvent refers to minor amount of unbound solvents, i.e. solvents that are not part of the crystal structure.
  • anhydrous in relation to crystalline Dolutegravir sodium relates to crystalline Dolutegravir sodium which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than 1% (w/w) of either water or organic solvents as measured for example by TGA or by F (Karl Fischer).
  • solvate refers to a crystal form that incorporates a solvent in the crystal structure.
  • the solvent can include organic solvents as well as water. When the solvent is water, the solvate is often referred to as a
  • the solvent content can be measured, for example, by GC, I H-NMR, TGA or by monitoring the weight increase during dynamic vapor sorption (DVS) test.
  • the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
  • crystallization may be referred to herein as a number of "volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.
  • non-hygroscopic in relation to crystalline Dolutegravir sodium refers to less than 0.2% (w/w) absorption of water at 25°C and 75% RH, preferably for 4 weeks or more, by the crystalline Dolutegravir sodium as determined for example by TGA.
  • Water can be for example atmospheric water.
  • reduced pressure refers to a pressure of about 10 mbar to about 50 mbar.
  • Dolutegravir sodium as measured by PXRD is 1%- 20%, 1%-10% or l%-5% (w/w).
  • Dolutegravir also referred to as Dolutegravir free acid refers to a crystalline form which may be characterized by data selected from one or more of the following: PXRD pattern having characteristic diffraction peaks at 5.4° ⁇ 0.2°, 10.7° ⁇ 0.2°, 12.3° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 16.4° ⁇ 0.2° two theta; infrared absorption spectra having characteristic peaks at 1658cm "1 ⁇ 2cm “1 , 1628cm “1 ⁇ 2cm “1 , 1540cm “1 ⁇ 2cm “1 and 1498cm “1 ⁇ 2cm “1 and combinations of these data.
  • Form I of Dolutegravir sodium also referred to as the anhydrous form as disclosed in WO2010/068253, is characterized by having one or more physical properties selected from the group consisting of (i) and (ii):
  • WO2010/068253 is characterized by having one or more physical properties selected from the group consisting of (i) and (ii):(i) having characteristic diffraction peaks at 8.0° ⁇ 0.2°, 9.3° ⁇ 0.2°, 1 1.3° ⁇ 0.2°, 16.0° ⁇ 0.2°, and 22.8° ⁇ 0.2°degrees two-theta in an X-ray powder diffraction pattern; and (ii) having characteristic infrared absorption spectra at 1637cm "1 ⁇ 2cm “ 1536cm "1 ⁇ 2cm “1 , 1501cm “1 ⁇ 2cm “1 and 1422cm “1 ⁇ 2cm “1 .
  • the present invention encompasses solid state forms of Dolutegravir sodium, in particular crystalline forms of Dolutegravir sodium.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form II.
  • the crystalline Form II of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.9, 7.8, 1 1.9, 13.1 and 17.7 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 1 ; a solid state 13 C-NMR spectrum with signals at about 175.6, 173.3, 130.6, 128.0, and 1 16.4 ⁇ 0.2 ppm; a solid-state C NMR spectrum as depicted in figure 1 1 ; a solid-state C NMR spectrum as depicted in Figure 12; and combinations of these data.
  • Crystalline Form II of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 5.9, 7.8, 1 1.9, 13.1 and 17.7 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 12.3, 19.1 , 19.5, 20.7, 21.5, and 24,9 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form II of Dolutegravir sodium may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by an X-ray powder diffraction pattern having peaks at 5.9, 7.8, 1 1.9, 13.1 and 17.7 degrees two theta ⁇ 0.2 degrees two theta and an X-ray powder diffraction pattern as depicted in Figure 1.
  • Crystalline Form II of Dolutegravir sodium can be an N-methyl-2-pyrrolidone (NMP) solvate.
  • NMP N-methyl-2-pyrrolidone
  • crystalline form II of Dolutegravir sodium has some advantages.
  • crystalline form II of Dolutegravir sodium may be used in the preparation of other crystalline forms of Dolutegravir sodium, such as forms V and X, which may be the final drug substance.
  • Dolutegravir sodium is not soluble in most solvent systems and as a result using NMP is crucial for chemical purification.
  • Dolutegravir sodium may be purified with more than 95%, more than 97%, more than 99% purity, preferably with less than 0.4%, less than 0.2%, less than 0.1% (w/w) isomeric purity [i.e.
  • Dolutegravir sodium may be purified in the preparation of form II with only losing less than 40%, less than 30%, less than 20%», less than 10%, less than 5% (w/w) of the starting material (Dolutegravir sodium).
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form III.
  • the crystalline Form III of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.4, 7.9, 12.8, 20.1 and 21.5 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 2; and combinations of these data.
  • This crystalline FormTII of Dolutegravir sodium may comprise a mixture of Form III and Form II as described above.
  • Crystalline Form III of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 6.4, 7.9, 12.8, 20.1 and 21.5 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 6.0, 19.2, 19.5 and 24.3 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form III of Dolutegravir sodium may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by an X-ray powder diffraction pattern having peaks at 6.4, 7.9, 12.8, 20.1 and 21.5 degrees two theta ⁇ 0.2 degrees two theta and an X-ray powder diffraction pattern as depicted in Figure 2.
  • Pure crystalline Form III of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.4, 7.9, 12.8,
  • Pure crystalline Form III of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 6.4, 7.9, 12.8, 20.1 and 21.9 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 10.0, 18.6,
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form IV.
  • the crystalline Form IV of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 11.8, 13.1, 19.1, 21.2 and 23.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 3; and combinations of these data.
  • Crystalline Form IV of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 1 1.8, 13.1, 19.1 , 21.2 and 23.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 7.8, 17.4, 24.6 and 25.4 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form IV of Dolutegravir sodium may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by an X-ray powder diffraction pattern having peaks at 1 1.8, 13.1, 19.1, 21.2 and 23.2 degrees two theta ⁇ 0.2 degrees two theta and an X-ray powder diffraction pattern as depicted in Figure 3.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form V.
  • the crystalline Form V of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 8.2, 18.6, 19.3, 21.4 and 24.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in Figure 4; a solid state 13 C-NMR spectrum with signals at about 180.4, 136.1, 128.8, 120.5, and 76.6 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum as depicted in Figure 13; a solid-state 13 C NMR spectrum as depicted in Figure 14; and combinations of these data.
  • Crystalline Form V of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 8.2, 18.6, 19.3, 21.4 and 24.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 6.5, 15.8, 21.9, 25.1 and 27.7 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form V of Dolutegravir sodium may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by an X-ray powder diffraction pattern having peaks at 8.2, 18.6, 19.3, 21.4 and 24.2 degrees two theta ⁇ 0.2 degrees two theta and an X-ray powder diffraction pattern as depicted in Figure 4.
  • Crystalline Form V of Dolutegravir sodium may be anhydrous.
  • Form V contains less than 1% of water or any other solvent as measured by TGA, KF, GC or any other similar methods.
  • crystalline Form V of Dolutegravir sodium is polymorphically pure which contains less than 10%, 5%, 1% or 0.5% of other DTG Na polymorphic forms.
  • the crystalline Form V of Dolutegravir sodium is preferably in the form of a crystalline solid.
  • crystalline form V of Dolutegravir sodium has some advantages.
  • Form V exhibits improved solubility preferably higher than anhydrous form I. Solubility has a significant impact on performance of a molecule. Improvement of solubility, especially for product which is defined as insoluble can affect dramatically the bioavailability of the drug.
  • Form V exhibits processing advantage for example Form V may present improved wettability preferably higher than Form I. Form V has a higher tendency to absorb water. This improved hydrophilic character can increase the compatibility of the API, and present better dissolution profile which could increase its bioavailability, relative to Form I.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form VI.
  • the crystalline Form VI of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 11.9, 13.1, 14.2, 19.9 and 24.5 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in Figure 5; and combinations of these data.
  • Crystalline Form VI of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 1 1.9, 13.1, 14.2, 19.9 and 24.5 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 16.6, 19.9, 22.9, 23.7, and 27.0 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form VI of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 1 1.9, 13.1 , 14.2, 19.9 and 24.5 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 16.6, 19.9, 22.9, 23.7, 26.2, and 27.0 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form VII.
  • the crystalline Form VII of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 9.1 , 1 1.2, 15.1, 18.2 and 22.4 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 6; and combinations of these data.
  • Crystalline Form VII of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 9.1 , 1 1.2, 15.1, 18.2 and 22.4 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 19.0, 21.4, 23.3, 26.1 , 26.4 and 28.2 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form VIII.
  • the crystalline Form VIII of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 3.9, 7.6, 10.0, 1 1.5 and 15.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 7; and combinations of these data.
  • Crystalline Form VIII of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 3.9, 7.6, 10.0, 1 1.5 and 15.2 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 13.2, 13.7, 19.2, 23.4 and 27.8 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form IX.
  • the crystalline Form IX of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.4, 7.3, 9.2, 14.6 and 17.4 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 8; and combinations of these data.
  • Crystalline Form IX of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 6.4, 7.3, 9.2, 14.6 and 17.4 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 1 1.6, 12.9, 19.2, 20.0 and 23.4 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form X.
  • the crystalline Form X of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 6.3, 7.9, 12.6, 19.8 and 24.1 degrees 2- theta ⁇ 0.2 degrees 2- theta; a PXRD pattern as depicted in Figure 9;; and combinations of these data.
  • crystalline Form X of Dolutegravir sodium may also be defined by a PXRD pattern as depicted in Figure 17.
  • Crystalline Form X of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 6.3, 7.9, 12.6, 19.8 and 24.1 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 19.0, 24.3, 18.7, 21.4 and 25.5 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form X of Dolutegravir sodium may be characterized by each of the above characteristics alone and/or by all possible combinations, e.g. by an X-ray powder diffraction pattern having peaks at 6.3, 7.9, 12.6, 19.8 and 24.1 degrees 2- theta ⁇ 0.2 degrees 2- theta and an X-ray powder diffraction pattern as depicted in Figure 9 or Figure 17.
  • Crystalline Form X of Dolutegravir sodium may be a solvate.
  • Form X can be for example an n- butanol solvate or a propylene glycol solvate.
  • the present invention encompasses an n-butanol solvate of Dolutegravir sodium.
  • the crystalline n- butanol solvate of Dolutegravir sodium can be characterized by data selected from one or more of the following: a solid state 13 C-NMR spectrum with signals at about 135.9, 132.9, 120.9, 1 1 1.2, and 6 2.6 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum as depicted in
  • Figure 15 excluding the peak at about 67.6, which may relate to an impurity; a solid-state C NMR spectrum as depicted in Figure 16; and combinations of these data.
  • crystalline n- butanol solvate of Dolutegravir sodium may also be defined by a solid-state 13C NMR spectrum as depicted in Figure 31 and Figure 32.
  • the Dolutegravir sodium butanol solvate has a ratio of Dolutegravir sodium to butanol of about 1 : 1.
  • the Butanol solvent is well incorporated in the crystal structure which is desolvated at the temperature range of about 100-200°C showing weight loss, of about 14-15% . This weight loss demonstrates monosolvate of Butanol (1 : 1 Butanol to DTG-Na).
  • the present invention encompasses a 1 ,2-propylene glycol solvate.
  • the crystalline propylene glycol solvate of Dolutegravir sodium can be characterized by data selected from one or more of the following: a solid state 13 C-NMR spectrum with signals at about 178.6, 161.6, 135.6, 132.4 and 104.0 ⁇ 0.2 ppm; a solid-state 13C NMR spectrum as depicted in Figure 29; a solid-state 13 C NMR spectrum as depicted in Figure 30; and combinations of these data.
  • the Dolutegravir sodium 1 ,2-propylene glycol solvate is preferably in the form of a crystalline solid.
  • the Dolutegravir sodium 1,2-propylene glycol solvate has a ratio of
  • the Dolutegravir sodium 1,2- propylene glycol solvate may contain (S)- 1,2-propylene glycol and (R)- 1 ,2-propylene glycol .
  • the 1,2-propylene glycol may be in the form of a mixture of (R)- 1,2-propylene glycol and (S)- 1 ,2-propylene glycol.
  • the ratio of (S)- 1 ,2-propylene glycol to (R)- 1 ,2-propylene glycol in the solvate is preferably about 1 :3.
  • the Dolutegravir sodium 1 ,2-propylene glycol solvate may be characterized by having XRPD peaks at about: 12.9, 19.3, 21.5, 24.2 and 29.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • the Dolutegravir sodium, 1,2-propylene glycol solvate may be further characterized by having additional XRPD peaks at about 6.4, 19.0, 19.7, 24.4 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2- theta( XRPD peaks are recorded using copper Ka ⁇ / Ka 2 radiation with wavelength 1.5419 A (weighted mean of Cu ⁇ and Cu Ka 2 )).
  • Dolutegravir sodium 1 ,2-propylene glycol solvate can be characterized by the absence of peaks at 9.2° and at 9.3° degrees 2-theta ⁇ 0.2 degrees 2-theta (XRPD peaks are recorded using copper ⁇ ⁇ 2 radiation with wavelength 1.5419 A (weighted mean of Cu Koti and Cu Ka 2 )).
  • Dolutegravir sodium 1,2-propylene glycol solvate may be alternatively or
  • the Dolutegravir sodium 1 ,2-propylene glycol solvate may also be alternatively or additionally characterized by having a DSC thermogram comprising a broad endotherm at about 120°C to about 220°C, optionally a sharp endotherm having an onset at about 271°C with a peak at about 289°C and optionally a sharp exo therm at about 296°C.
  • Dolutegravir sodium 1 ,2-propylene glycol solvate may contain about one equivalent of solvent, as depicted by TGA.
  • Dolutegravir sodium 1,2-propylene glycol solvate may be prepared by contacting
  • the Dolutegravir sodium 1,2-propylene glycol solvate can be prepared by a process comprising reacting Dolutegravir free acid with a sodium alkoxide in the presence 1 ,2-propylene glycol as solvent.
  • the sodium alkoxide is sodium tert-butoxide.
  • the reaction is preferably conducted in a temperature range of about 60 to about 150°C, preferably about 60 to about 120°C, more preferably about 80 to about 100 °C, and most preferably about 85 to about 90°C.
  • the sodium alkoxide is added to a suspension of Dolutegravir in 1 ,2- propylene glycol, preferably wherein the 1 ,2-propylene glycol is in racemic form.
  • a further aspect of the present invention provides a crystalline form of Dolutegravir sodium having characteristic X-ray powder diffraction peaks at about: 12.9, 19.3, 21.5, 24.2 and 29.4 degrees 2-theta ⁇ 0.2 degrees 2-theta, and optionally additional characteristic XRPD peaks at about 6.4, 19.0, 19.7, 24.4 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Crystalline Dolutegravir sodium may be alternatively or additionally characterized by the absence of peaks at 9.2° and at 9.3° degrees 2-theta ⁇ 0.2 degrees 2-theta (XRPD peaks are recorded using copper Kaj/ Ka 2 radiation with wavelength 1.5419 A (weighted mean of Cu Kai and Cu Ka 2 )).
  • Crystalline Dolutegravir sodium may be alternatively or additionally characterized by having characteristic infrared absorption bands in the solid-state FT-IR spectrum at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm “1 ⁇ 1 cm "1 .
  • Crystalline Dolutegravir sodium may be alternatively or additionally characterized by having a DSC thermogram comprising a broad endotherm at about 120°C to about 220°C, optionally a sharp endotherm having an onset at about 271°C with a peak at 289°C and optionally a sharp exotherm at about 296°C.
  • Dolutegravir sodium is preferably in the form of a solvate, preferably with an organic solvent. More preferably, the solvent is a C 3 -C 6 alkane diol, most preferably propylene glycol. When the solvent is propylene glycol, the solvate can contain (R)-l,2-propylene glycol and (S)-l,2-propylene glycol.
  • the crystalline form of Dolutegravir sodium having characteristic X-ray powder diffraction peaks at about: 12.9, 19.3, 21.5, 24.2 and 29.4 degrees 2-theta ⁇ 0.2 degrees 2-theta according to this aspect of the present invention may be prepared by contacting Dolutegravir sodium with racemic 1 ,2-propylene glycol, for example, the Dolutegravir sodium may be formed by the reaction of Dolutegravir with a sodium alkoxide in the presence of racemic 1 ,2- propylene glycol.
  • crystalline form X of Dolutegravir sodium has some advantages.
  • form X in particular in the form of an n- butanol solvate, may be used in the preparation of other crystalline forms of Dolutegravir sodium such as form V.
  • "green solvent” class A solvent
  • n-BuOH is a pharmaceutically acceptable solvent with a maximum permitted amount in the final drug substance of NMT 5000ppm.
  • ⁇ 50°C low desolvation temperature
  • form X can also be prepared as a propylene glycol solvate.
  • Propylene glycol is used in a wide variety of pharmaceutical formulations and is generally regarded as relatively nontoxic material.
  • This solvate may have a particular advantage in the preparation of Dolutegravir sodium as a pre-mix or pre-formulation, especially should the final drug product be administered in an oral liquid form, e.g. syrup.
  • form X as propylene glycol solvate as defined in any embodiment of the present invention may exhibit high solubility preferably higher than anhydrous form I. Solubility has a significant impact on performance of a molecule. Improvement of solubility, especially for product which is defined as insoluble can affect dramatically the bioavailability of the drug.
  • the present invention comprises a crystalline form of Dolutegravir sodium designated as Form XI.
  • the crystalline Form XI of Dolutegravir sodium salt can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 5.5, 6.2, 1 1.3,
  • Crystalline Form XI of Dolutegravir sodium may be further characterized by the PXRD pattern having peaks at 5.5, 6.2, 1 1.3, 18.7 and 19.3 degrees 2- theta ⁇ 0.2 degrees 2- theta; and also having one, two, three, four or five additional peaks selected from 7.1, 12.7, 21.1, 23.1 and 27.1 degrees two theta ⁇ 0.2 degrees two theta.
  • the present invention also provides the use of any one of the solid state forms of Dolutegravir sodium salt for preparing Dolutegravir, other Dolutegravir salts and solid state forms thereof or another solvate or a hydrate form of Dolutegravir sodium.
  • the present invention provides the use of forms II and X (e.g. butanol solvate) of Dolutegravir sodium or combinations thereof for preparing Dolutegravir sodium form V.
  • the present invention further provides a process for preparing other Dolutegravir salts or solid state forms.
  • the process comprises preparing any one of the Dolutegravir sodium solid state forms of the present invention or solvate or a hydrate form of Dolutegravir sodium and converting it to Dolutegravir or Dolutegravir salt.
  • the conversion can be done, for example, by a process comprising acidifying any one or a combination of the above described solid state forms or solvate or a hydrate form of Dolutegravir sodium, and reacting the obtained
  • the present invention encompasses any one of the above described solid state forms of Dolutegravir sodium and/or combinations thereof for use in the preparation of pharmaceutical compositions, preferably for the treatment of HIV infection.
  • the present invention further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Dolutegravir sodium according to the present invention.
  • the pharmaceutical compositions comprising any one of the above described solid state forms of Dolutegravir sodium and/or combinations thereof and at least one pharmaceutically acceptable excipient.
  • the present invention comprises a process for preparing the above mentioned pharmaceutical compositions.
  • the pharmaceutical compositions can be prepared by a process comprising combining any one of the above described solid state forms of Dolutegravir sodium and/or combinations thereof and at least one pharmaceutically acceptable excipient.
  • the present invention encompasses the use of any one of the above described solid state forms of Dolutegravir sodium and/or combinations thereof for the preparation of pharmaceutical compositions.
  • the present invention also provides the use of any one of the solid state forms of Dolutegravir sodium of the present invention and/or combinations thereof, or at least one of the above pharmaceutical compositions for the manufacture of a medicament for treating HIV infection.
  • any one of the solid state forms as defined herein and/or combinations thereof, as well as the pharmaceutical compositions of Dolutegravir sodium can be used as medicaments, particularly for the treatment of HIV infection.
  • the present invention also provides a method of treating HIV infection, comprising administering a therapeutically effective amount of any one of the solid state forms of
  • Powder X-ray diffraction pattern (“PXRD”) method:
  • Samples according to examples 22 and 23 were measured on a D8 Advance powder X- ray diffractometer (Bruker AXS, Düsseldorf, Germany) in a rotating PMMA sample holder (diameter: 25 mm; depth: 1 mm) in reflection mode (Bragg-Brentano geometry). Conditions of the measurements are summarized in the following Table. Raw data were analyzed with the program EVA (Bruker AXS, Düsseldorf, Germany).
  • Aluminium crucible 40 (with perforated lid)
  • the chiral gas chromatography was carried out in order to determine the enantiomeric ratio of the propylene glycol which is bound to Dolutegravir sodium.
  • the starting material can be prepared by any known method for the preparation of Dolutegravir and Dolutegravir sodium.
  • Dolutegravir also referred to as Dolutegravir free acid
  • Dolutegravir sodium Form I can for example be prepared by processes disclosed in WO 2010/068253.
  • a slurry mixture of Dolutegravir (0.9 g, 1 eq), EtOH (16 mL) and water (1 mL) was heated to 80 ° C and stirred for 30 min. NaOH 2N (1.22 mL, 1.05 eq) was added dropwise and the mixture became completely clear then precipitation was obtained.
  • the solution was cooled to room temperature and stirred for 2 hours.
  • the product was collected by vacuum filtration, washed with EtOH (5 mL) and dried to obtain 0.83 g of slightly yellow solid (88% yield).
  • Dolutegravir sodium Form I was dissolved in 0.5 ml of N- methyl-2- pyrrolidone (NMP) using a heat gun for 1 min. Afterwards, 0.3 ml of cyclohexane was added to the solution which was then kept closed for 2 days at room temperature. The precipitated material was filtrated off and washed with NMP, dried for 1 day at 40°C and for 4 hours at 40°C using vacuum and another drying for more 3 days at 50°C using vacuum. Crystalline Form II was obtained as confirmed by PXRD measurement.
  • NMP N- methyl-2- pyrrolidone
  • Dolutegravir sodium Form II 50 mg was exposed to vapors of Ethanol abs. for 7 days at RT. PXRD measurement for the powder confirmed Form III content.
  • Dolutegravir (0.5g; 1.0 eq) was slurried at room temperature in THF (2.5 mL) followed by dropwise addition of 2N NaOH aq (0.63 mL; 1.05eq). The obtained mixture was stirred at room temperature overnight. The precipitate was collected by vacuum filtration, washed with THF (10 mL) and dried in vacuum oven at 50 °C (16h) to obtain Dolutegravir-Sodium (0.25g) which was analyzed by XRPD and found to be Form VI.
  • Dolutegravir (0.5g; 1.0 eq) was slurried at room temperature in THF (2.5 mL). The reaction mixture was warmed to reflux followed by dropwise addition of 2N NaOH aq (0.63 mL; 1.05eq). The obtained mixture was cooled to room temperature and stirred for overnight. The precipitate was collected by vacuum filtration, washed with THF (5 mL) and dried in vacuum oven at 50 °C (16h) to obtain Dolutegravir-Sodium (0.4g) which was analyzed by XRPD and found to be Form VI.
  • Dolutegravir (2 g; 1.0 eq) was slurried at room temperature in THF (10 mL) followed by dropwise addition of 2N NaOH aq (2.5 mL; 1.05eq). The obtained mixture was stirred at room temperature overnight. The precipitate was collected by vacuum filtration, washed with THF (10 mL) and dried in vacuum oven at 50 °C (16h) to obtain Dolutegravir-Sodium (1.66 g) which was analyzed by XRPD and found to be Form VI as presented in Figure 5.
  • Dolutegravir (0.5g; 1.0 eq) was slurried at room temperature in THF (2.5 mL). The reaction mixture was warmed to reflux followed by dropwise addition of 2N NaOH aq (0.63 mL; 1.05eq). The obtained mixture was cooled to room temperature and stirred for overnight. The precipitate was collected by vacuum filtration, washed with THF (5 mL) to obtain Dolutegravir-Sodium (0.49 g) which was analyzed by XRPD and found to be Form VII as presented in Figure 6.
  • Example 10 Preparation of Dolutegravir sodium Form VII
  • Dolutegravir (2 g; 1.0 eq) was slurried at room temperature in THF (10 mL) followed by dropwise addition of 2N NaOH aq (2.5 mL; 1.05eq). The obtained mixture was stirred at room temperature overnight. The precipitate was collected by vacuum filtration, washed with THF (10 mL) to obtain Dolutegravir-Sodium which was analyzed by XRPD and found to be Form VII.
  • Dolutegravir-Sodium Form VI (0.3g; 1.0 eq) was dissolved at 150 °C in Benzyl alcohol (9.0 mL). The obtained clear yellow solution was cooled to room temperature and stirred for 24 h. The precipitate was collected by vacuum filtration and dried in vacuum oven at 50 °C overnight to obtain Dolutegravir-Sodium (0.13g) which was analyzed by XPRD and found to be Form VIII, Example 12: Preparation of Dolutegravir sodium Form IX
  • Dolutegravir-Sodium Form VI (0.3g; 1.0 eq) was dissolved at 150 °C in Benzyl alcohol (9.0 mL). The obtained clear yellow solution was cooled to 100 °C and methyl isobutyl ketone (MIBK ) (6.0 mL) was added. The obtained slurry was stirred at room temperature overnight. The precipitate was collected by vacuum filtration to obtain Dolutegravir-Sodium (0.28g) which was analyzed by XPRD and found to be Form IX.
  • MIBK methyl isobutyl ketone
  • Dolutegravir-Sodium Form VI (0.3g; 1.0 eq) was slurried at room temperature in n- Butanol (3.0 mL) and stirred for 24 h. The obtained slurry was collected by centrifuge filtration and dried in vacuum oven at 50 °C overnight to obtain Dolutegravir-Sodium (0.16g) which was analyzed by XPRD and found to be Form X.
  • Dolutegravir-Sodium Form VI (0.3g; 1.0 eq) was slurried at room temperature in iso- Butanol (3.0 mL) and stirred for 24 h. The obtained slurry was collected by centrifuge filtration to obtain Dolutegravir-Sodium (0.46g) which was analyzed by XPRD and found to be Form XI.
  • Example 15 Preparation of Dolutegravir sodium Form V Fluid-Bed Dryer was charged with 5 g Dolutegravir-Sodium Form X (BuOH solvate). The dryer was heated directly to 60°C, working under static air flow of 10. The humidity percent was measured intermittently during the process and was found to be between 45% and 50%.
  • Fluid-Bed Dryer was charged with 4.7 g Dolutegravir-Sodium Form X (BuOH solvate). The dryer was heated directly to 80°C, working under static air flow of 10. The humidity percent was measured intermittently during the process and was found to be between 56% and 68%.
  • Fluid-Bed Dryer was charged with 5.4 g Dolutegravir-Sodium Form II (NMP solvate). The dryer was heated directly to 80°C, working under static air flow of 10. The humidity percent was measured intermittently during the process and was found to be between 56% and 68%.
  • Dolutegravir-Sodium Form VI (0.3g, l .Oeq) was slurried at room temperature in n- Butanol (1.5mL) and stirred for 24 hours. The obtained slurry was collected by centrifuge filtration and dried in vacuum oven at 50 °C overnight to obtain Dolutegravir-Sodium (0.2g) which was analyzed by XPRD and found to be Dolutegravir-Sodium Form X as depicted in Figure 17.
  • Dolutegravir-Sodium Form II (lg) was slurried in 10 ml n-BuOH at RT for 24 hours. The product was vacuum filtrated, washed with 10 mL n-BuOH and dried overnight in vacuum oven at 60 °C to obtain Dolutegravir-Sodium (0.79g) which was analyzed by XPRD and found to be Form X as depicted in Figure 9.
  • Dolutegravir-Sodium Form VI (0.5g, 1.Oeq) was slurried at room temperature in propylene glycol (racemate, 5mL) and stirred for 24 hours.
  • the resulting wet solid was separated in two portions. One sample was analyzed immediately and the second portion was dried overnight at 85°C / 35 mbar in a drying oven, and subsequently analyzed.
  • Dolutegravir sodium 1,2-PG (1:1) solvate Anhydrous Dolutegravir sodium (Example 22) (WO2010/068253)
  • thermogravimetric analysis of the Dolutegravir sodium 1,2-PG (1 :1) solvate revealed a relative weight loss of 15.6% (stability batch 15.3%) , which occurred at a temperature range between approx. 50°C and 200°C. Theoretically, a loss of exactly one equivalent of 1,2-PG corresponds to a weight loss of 17.2%.
  • 1,2-PG content TGA analysis of Dolutegravir sodium 1 ,2-PG (1 :1) solvate (Stability batch) after 4 weeks storage at 25°C / 60% relative humidity (r.h.), at 30°C / 65% r.h. and at 40°C / 75% r.h. under open conditions and with closed cap. The results are shown below:
  • the x-ray powder diffractogram of Dolutegravir sodium 1,2-PG (1 : 1) solvate is shown in Figures 22 and 23 (enlarged y-scale).
  • the diffractogram is characterized by the following signals:
  • Dolutegravir sodium 1,2-PG (1 : 1) solvate may also be characterised by the absence of peaks at 9.2° and at 9.3°, respectively.
  • Dolutegravir sodium 1,2-PG solvate prepared according to Example 22 was mixed with 1 mL DMSO and the suspension was stirred for 24 hours at 500 rpm at RT. The solid was filtered off and dried overnight at 50°C/10mbar in a drying oven and analysed by means of XRPD.
  • Figure 24 presents a comparison of the diffractogram of the isolated product with that of anhydrous Dolutegravir sodium, which corresponds to the solid state form, disclosed in WO 2010/068253.
  • Solubility Determination in Aqueous Solvents 1 experiment 75 mg (exactly weighed) test substance (DTG-Na - non-solvated, anhydrous form as disclosed in WO2010/068253 and DTG-Na- 1 ,2-PG solvate) was weighed into a glass vial, followed by addition of 3 ml solvent (0.1 N HC1, 0.01 N HC1, or water). A stirring bar was added, the vial was fixed in a block heater at 37°C and the suspension was stirred with approx. 250 rpm. After 15 min and 1 h, samples were withdrawn, filtered through a 0.2 ⁇ disposable filter, 50 ⁇ of the clear filtrate were diluted with 950 ⁇ DMSO and 2 ⁇ thereof were analyzed by HPLC/UV.
  • test substance 140 mg (exactly weighed) test substance (DTG-Na non-solvated anhydrous form as disclosed in WO2010/068253 and DTG-Na-1,2-PG solvate) was weighed into a glass vial, followed by addition of 1 ml solvent (0.1 N HC1, 0.01 N HC1, or water). A stirring bar was added, the vial was fixed in a block heater at 37°C and the suspension was stirred with approx. 250 rpm. After 1 h, samples were withdrawn, filtered through a 0.2 ⁇ disposable filter, 50 ⁇ of the clear filtrate were diluted with 950 ⁇ DMSO and 2 ⁇ thereof were analyzed by HPLC/UV.
  • solvent 0.1 N HC1, 0.01 N HC1, or water
  • test substance (DTG-Na non- solvated anhydrous form as disclosed in WO2010/068253 and DTG-Na- 1,2-PG solvate) were weighed into a glass vial, followed by addition of 3 ml solvent (0.1 N HC1, 0.01 N HC1, or water). A stirring bar was added, the vial was fixed in a block heater at 37°C and the suspension was stirred with approx. 250 rpm. After 5 min, 15 min and 60 min, samples were withdrawn and filtered through a 0.2 ⁇ disposable filter. The clear filtrates were analyzed by HPLC either without further processing or after dilution with DMSO (100 ⁇ filtrate + 900 ⁇ DMSO). 2 ⁇ thereof were analyzed by HPLC/UV.
  • DMSO 100 ⁇ filtrate + 900 ⁇ DMSO
  • Fasted State Simulated Intestinal Fluid containing a complex of bile salt (sodium taurocholate) and phospholipid (lecithin) in a 4: 1 molar ratio and physiologically relevant surfactants present in GI fluids]
  • FaSSIF composition - taurochlorate bile salt 3 mM; lecithin phospholipid, 0.75 mM; sodium dihydrogen phosphate, 28.65 mM; hydrochloric acid, q.s. pH 6.5; sodium chloride 105.85 mM, having pH 6.5, osmolarity approx. 270 ⁇ 10 mOsmol/kg and buffer capacity approx. 12 mEq/L/pH).
  • Buffer 0.002% EDTA, 0.002M NH4H2P04 pH7.0,
  • Dolutegravir sodium 1 ,2-propylene glycol solvate according to any of paragraphs 1-4 having a ratio of dolutegravir sodium (S)-l,2-propylene glycol solvate to dolutegravir sodium (R)-l,2-propylene glycol solvate of about 1 :3.
  • Dolutegravir sodium 1 ,2-propylene glycol solvate according to any of paragraphs 1-5 having characteristic X-ray powder diffraction peaks at about: 12.9, 19.3, 21.5, 24.2 and 29.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Dolutegravir sodium 1 ,2-propylene glycol solvate according to paragraph 6 further characterized by having X-ray powder diffraction peaks at about: 6.4, 19.0, 19.7, 24.4 and 29.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
  • Dolutegravir sodium 1 ,2-propylene glycol solvate according to any of paragraphs 1-9 having a DSC thermogram comprising a broad endotherm at about 120°C to about 220°C, optionally a sharp endotherm having an onset at about 271°C with a peak at 289°C and optionally a sharp exotherm at about 296°C.
  • a crystalline form of dolutegravir sodium according to any of paragraphs 1 1 or 12 characterized by the absence of peaks at 9.2° and at 9.3° degrees 2-theta ⁇ 0.2 degrees 2- theta.
  • a crystalline form of dolutegravir sodium according to any of paragraphs 1 1-13 having characteristic infrared absorption bands at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm “1 ⁇ 2 cm “1 .
  • a crystalline form of dolutegravir sodium according to any of paragraphs 1 1-14 having a DSC thermogram comprising a broad endotherm at about 120°C to about 220°C, optionally a sharp endotherm having an onset at about 271°C with a peak at 289°C and optionally a sharp exotherm at about 296°C.
  • a crystalline form of dolutegravir sodium according to any of paragraphs 1 1-15 wherein the crystalline form is a solvate.
  • Dolutegravir sodium or a crystalline form thereof according to any of paragraphs 1-20 being substantially free of any other solid state form of dolutegravir sodium.
  • Dolutegravir sodium or a crystalline form thereof containing 20% (w/w) or less, 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, 1% (w/w) or less, 0.5% (w/w) or less, or 0.2% (w/w) or less of any other solid state forms of dolutegravir sodium.
  • dolutegravir sodium or a crystalline form thereof as defined in any of paragraphs 1-22 for the preparation of: dolutegravir, another dolutegravir salt, another crystalline form of dolutegravir sodium, or another solvate or hydrate form of dolutegravir sodium.
  • a pharmaceutical composition comprising a dolutegravir sodium or a crystalline form thereof as defined in any of paragraphs 1-22 and at least one pharmaceutically acceptable excipient.
  • a process for preparing a pharmaceutical composition comprising combining a dolutegravir sodium or a crystalline form thereof as defined in any of paragraphs 1 -22 with at least one pharmaceutically acceptable excipient.

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Abstract

Des formes à l'état solide de Dolutegravir sodium, leurs procédés de préparation et des compositions pharmaceutiques de celles-ci sont divulgués.
PCT/US2015/020497 2014-03-13 2015-03-13 Formes à l'état solide de dolutegravir sodium WO2015138933A1 (fr)

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WO2017208105A1 (fr) 2016-05-30 2017-12-07 Lupin Limited Nouvelle forme cristalline de dolutégravir sodique
WO2019048808A1 (fr) 2017-09-07 2019-03-14 Cipla Limited Nouveaux polymorphes du dolutégravir sodique
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US11202780B2 (en) 2014-06-20 2021-12-21 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

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