WO2016102078A1 - Formes solides de dolutégravir sodique - Google Patents

Formes solides de dolutégravir sodique Download PDF

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Publication number
WO2016102078A1
WO2016102078A1 PCT/EP2015/055257 EP2015055257W WO2016102078A1 WO 2016102078 A1 WO2016102078 A1 WO 2016102078A1 EP 2015055257 W EP2015055257 W EP 2015055257W WO 2016102078 A1 WO2016102078 A1 WO 2016102078A1
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Prior art keywords
dolutegravir sodium
dolutegravir
propylene glycol
solvate
sodium
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PCT/EP2015/055257
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English (en)
Inventor
Wolfgang Albrecht
Jens Geier
David PÉREZ
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Ratiopharm GmbH
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Ratiopharm GmbH
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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

  • the present invention relates to solid state form of Dolutegravir sodium 1,2-propylene glycol solvate, processes for preparation thereof and pharmaceutical compositions thereof.
  • Dolutegravir sodium belongs to the chemical class of tricyclic
  • carbamoylpyridones and 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[l',2':4,5]pyrazino[2,l-b][l,3]oxazin-7-olate.
  • Dolutegravir sodium has the following chemical structure:
  • Dolutegravir is a novel HIV-1 integrase strand transfer inhibitor selected for its activity against integrase inhibitor (INI) resistance and its potential for higher genetic barrier to resistance in vitro.
  • 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
  • Dolutegravir is known from WO2006/116764 as a compound possessing antiviral activity, in particular an inhibitory activity against HIV integrase.
  • the sodium salt of Dolutegravir is described in WO2006/116764.
  • a crystalline form of this sodium salt in anhydrous form, as well as a monohydrate thereof are apparently reported in WO2010/068253.
  • the present invention addresses a need in the art by providing new crystalline forms of dolutegravir sodium, that may have advantageous properties selected from at least one of: chemical and/or polymorphic purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as thermal and mechanical stability to polymorphic conversion, stability to desolvation and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
  • Dolutegravir is practically insoluble and even the known non-solvated
  • an object of the invention is to provide a solid state form of Dolutegravir sodium, which shows good solubility and/or dissolution characteristics.
  • the present invention relates to a Dolutegravir sodium 1,2-propylene glycol (1,2-PG) solvate (DTG-Na-1,2-PG solvate).
  • the present invention further relates to a crystalline form of Dolutegravir sodium.
  • the crystalline form of Dolutegravir sodium may be characterized by 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.
  • the present invention also relates to the use of the dolutegravir sodium or crystalline forms thereof as defined herein for preparing dolutegravir, another dolutegravir salt (for example, dolutegravir potassium), another crystalline form of dolutegravir sodium, or another solvate or a hydrate form of dolutegravir sodium.
  • a further aspect of the present invention provides the use of a dolutegravir sodium or a crystalline form thereof as defined herein for the preparation of a pharmaceutical composition.
  • a yet further aspect of the present invention provides dolutegravir sodium or a crystalline form thereof as defined herein for use as a medicament, preferably for the treatment of HIV- 1 infection. Also encompassed by the present invention are pharmaceutical compositions comprising the dolutegravir sodium or crystalline form thereof as defined herein.
  • DFG refers to Dolutegravir
  • DTG-Na refers to Dolutegravir sodium salt
  • DTG-Na 1,2-PG DTG-Na 1,2-PG
  • 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
  • room temperature refers to a temperature of about 18°C to about 28°C, preferably about 18°C to about 25°C, and more preferably about 18°C to about 22°C, and most preferably about 20°C,
  • salts and solid state forms of dolutegravir sodium of the invention are substantially free of any other salts, polymorphic forms, or of specified polymorphic forms of dolutegravir sodium, respectively.
  • substantially free is meant that the forms of the present invention contain 20% (w/w) or less, 10% (w/w) or less, 5% (w/w) or less, 2% (w/w) or less, particularly 1% (w/w) or less, more particularly 0.5% (w/w) or less, and most particularly 0.2% (w/w) or less of any other forms of dolutegravir or salts of dolutegravir, or any other polymorphs or a specified polymorph of dolutegravir sodium (such as dolutegravir sodium hydrate or anhydrous dolutegravir sodium as disclosed in
  • 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).
  • 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.
  • additional features 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
  • XRPD peaks are recorded using copper ⁇ ⁇ / Ka 2 radiation with wavelength 1.5419 A (weighted mean of Cu ⁇ ⁇ and Cu Ka 2 ). Further, unless indicated otherwise, XRPD peaks are reported as degrees 2-theta values with standard errors of + 0.2 degrees 2-theta.
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in" a particular figure. Such data include, for example, powder X-ray diffractograms. 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 a dolutegravir sodium referred to herein as being characterized by graphical data "as depicted in" a figure will thus be understood to include any crystal forms of the dolutegravir sodium characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the figure.
  • solvate refers to a crystal form containing one or more solvents in the crystal structure, wherein the solvent can include organic solvents as well as water.
  • the solvent is water, the solvate may be referred to as a
  • hydrate The solvent content can be measured, for example, by GC, 1H-NMR, TGA or by monitoring the weight increase during dynamic vapor sorption (DVS) test.
  • anhydrous refers to crystalline dolutegravir sodium as disclosed in WO2010/068253.
  • the dolutegravir sodium form is a solvate, preferably wherein the solvent is 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)-l,2- propylene glycol.
  • FIGURE 1 1H-NMR Spectrum of Dolute gravir sodium 1,2-PG (1: 1) solvate prepared
  • FIGURE 2 Solid-state FT-IR spectrum of Dolutegravir sodium 1,2-PG solvate prepared
  • FIGURE 3 Solid-state FT-IR spectrum of anhydrous Dolutegravir sodium according to
  • FIGURE 4 X-ray powder diffractogram of Dolutegravir sodium 1 ,2-PG (1: 1) solvate
  • FIGURE 5 X-ray powder diffractogram of Dolutegravir sodium 1,2-PG (1: 1) solvate
  • FIGURE 6 Comparison of XRPD of Dolutegravir sodium 1,2-PG (1: 1) solvate prepared according to Example 1 following slurrying in DMSO (bottom trace), with anhydrous Dolutegravir sodium as disclosed in WO2010/068253 (top trace)
  • FIGURE 7 Chiral GC-FID chromatogram analysis of 1,2-PG after suspending Dolutegravir sodium 1,2-PG (1: 1)- solvate in Methanol
  • FIGURE 8 X-ray powder diffractogram of Dolutegravir sodium hydrate: comparative
  • FIGURE 9 X-ray powder diffractogram of Dolutegravir sodium hydrate: comparative
  • dolutegravir sodium 1,2-propylene glycol solvate (DTG-Na- 1,2-PG solvate).
  • 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
  • dolutegravir sodium to 1,2-propylene glycol of about 1: 1.
  • the dolutegravir sodium 1,2-propylene glycol solvate contains (S)- 1,2- propylene glycol and (R)- 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.
  • 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.
  • the dolutegravir sodium 1,2-propylene glycol solvate may be alternatively or additionally characterized by having characteristic infrared absorption bands at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm "1 + 1 cm "1 .
  • 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 289°C and optionally a sharp exotherm at about 296°C.
  • Dolutegravir sodium 1,2-propylene glycol solvate may be prepared by contacting dolutegravir sodium with 1,2-propylene glycol.
  • 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.
  • 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.
  • 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.
  • Crystalline dolutegravir sodium according to this aspect of the present invention is preferably in the form of a solvate, preferably with an organic solvent. More preferably, the solvent is a C3-C6 alkane diol, most preferably propylene glycol. When the solvent is propylene glycol, the solvate can contain (R)-l,2-propylene glycol and (S)- 1,2-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 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.
  • the present invention further provides the use of dolutegravir sodium or dolutegravir sodium 1,2-propylene glycol solvate as defined in any of the embodiments described herein for the preparation of a pharmaceutical composition, and a pharmaceutical composition comprising said dolutegravir sodium or dolutegravir sodium 1,2-propylene glycol solvate.
  • a pharmaceutical composition comprising dolutegravir sodium or dolutegravir sodium 1,2- propylene glycol solvate as described herein can be prepared by a process comprising combining a dolutegravir sodium or a crystalline form thereof as defined in any of Claims 1-20 with at least one pharmaceutically acceptable excipient.
  • the invention additionally provides dolutegravir sodium or dolutegravir sodium 1,2- propylene glycol solvate as described herein for use as a medicament, preferably for the treatment of HIV- 1 infection.
  • the chiral gas chromatography was carried out in order to determine the enantiomeric ratio of the propylene glycol which is bound to dolutegravir sodium.
  • test substance 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 HCl, 0.01 N HCl, 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 HCl, 0.01 N HCl, 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. 3 r experiment: approx.
  • 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
  • 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.
  • Example 1 The solid-state FT-IR spectrum of Dolutegravir sodium 1,2-PG solvate prepared according to Example 1 is shown in Figure 2 and that of the non- solvated anhydrous Dolutegravir sodium in Figure 3.
  • Dolutegravir sodium 1,2-PG (1:1) solvate Anhydrous Dolutegravir sodium
  • 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%.
  • the x-ray powder diffractogram of Dolutegravir sodium 1,2-PG (1: 1) solvate is shown in Figures 4 and 5 (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. This results allow the conclusion that the crystal structure of Dolutegravir sodium 1,2-PG (1: 1) solvate belongs to a different type than the structures of anhydrous and hydrate form.
  • Figure 6 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.
  • 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, osmolality approx. 270 + 10 mOsmol/kg and buffer capacity approx. 12 mEq/L/pH).
  • Dolutegravir sodium was also with deionized water and was compared with the kinetic solubility of anhydrous Dolutegravir sodium:

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Abstract

La présente invention concerne le solvate de 1,2 propylène-glycol de carabmoylpyridone tricyclique de dolutégravir sodique, des formes solides de celui-ci, des procédés pour les préparer, et des compositions pharmaceutiques contenant le solvate de 1,2-propylène-glycol de dotégravir sodique
PCT/EP2015/055257 2014-12-24 2015-03-13 Formes solides de dolutégravir sodique Ceased WO2016102078A1 (fr)

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Cited By (2)

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WO2017029642A2 (fr) 2015-08-19 2017-02-23 Laurus Labs Private Limited Nouveaux polymorphes du dolutégravir et leurs sels
WO2017046131A1 (fr) * 2015-09-15 2017-03-23 Ratiopharm Gmbh Procédés de préparation de formes à l'état solide de dolutégravir de sodium

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EA030003B1 (ru) 2012-12-21 2018-06-29 Джилид Сайэнс, Инк. Полициклическое карбамоилпиридоновое соединение и его фармацевтическое применение для лечения вич-инфекции
TW201613936A (en) 2014-06-20 2016-04-16 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
NO2717902T3 (fr) 2014-06-20 2018-06-23
US10189860B2 (en) * 2014-07-29 2019-01-29 Lek Pharmaceuticals D.D. Hydrates of dolutegravir sodium
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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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2017029642A2 (fr) 2015-08-19 2017-02-23 Laurus Labs Private Limited Nouveaux polymorphes du dolutégravir et leurs sels
US10597404B2 (en) 2015-08-19 2020-03-24 Laurus Labs Ltd. Polymorphs of dolutegravir and salts thereof
US10647729B1 (en) 2015-08-19 2020-05-12 Laurus Labs Limited Polymorphs of dolutegravir and salts thereof
US10654872B1 (en) 2015-08-19 2020-05-19 Laurus Labs Limited Polymorphs of dolutegravir and salts thereof
WO2017046131A1 (fr) * 2015-09-15 2017-03-23 Ratiopharm Gmbh Procédés de préparation de formes à l'état solide de dolutégravir de sodium

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