WO2016102078A1

WO2016102078A1 - Solid state forms of dolutegravir sodium

Info

Publication number: WO2016102078A1
Application number: PCT/EP2015/055257
Authority: WO
Inventors: Wolfgang Albrecht; Jens Geier; David PÉREZ
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2014-12-24
Filing date: 2015-03-13
Publication date: 2016-06-30
Anticipated expiration: 2017-06-24
Also published as: WO2015138933A1

Abstract

The present invention relates to the tricyclic carbamoylpyridone Dolutegravir sodium 1,2-propylene glycol solvate, solid state forms thereof, processes for their preparation and pharmaceutical compositions containing Dolutegravir sodium 1,2-propylene glycol solvate.

Description

SOLID STATE FORMS OF DOLUTEGRAVIR SODIUM

Field of the Invention

The present invention relates to solid state form of Dolutegravir sodium 1,2-propylene glycol solvate, processes for preparation thereof and pharmaceutical compositions thereof.

Background of the Invention

Dolutegravir sodium (DTG-Na) 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.

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.

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. In particular, Dolutegravir is practically insoluble and even the known non-solvated

(anhydrous) sodium salt of dolutegravir is practically insoluble (solubility below 0.1 mg/ml) in 0.1 N HC1 (pH 1.2). At an increasing pH, for example to pH 6.8 in phosphate buffer the solubility of the sodium salt of dolutegravir slightly increases but the salt still remains only very slightly soluble. The solvate Dolutegravir sodium hydrate shows the same low solubility as the foregoing.

Thus, an object of the invention is to provide a solid state form of Dolutegravir sodium, which shows good solubility and/or dissolution characteristics.

It is a further object of the present invention to prepare a stable solvate of Dolutegravir sodium that can be used in pharmacological formulations. Summary of the Invention

In one aspect, the present invention relates to a Dolutegravir sodium 1,2-propylene glycol (1,2-PG) solvate (DTG-Na-1,2-PG solvate).

CH₃

I

² (1 ,2-propylene glycol; Propane- 1 ,2-diol)

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.

As used herein, the term "DTG" refers to Dolutegravir.

As used herein, the terms "DTG-Na" refers to Dolutegravir sodium salt, and DTG-Na 1,2-PG"

As used herein, unless indicated otherwise, reference to 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.

As used herein, the term "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,

In some embodiments, 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. In any embodiment of the present invention, by "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

WO2010/068253, or other polymorphs of dolutegravir sodium- 1,2-propylene glycol solvate). In other embodiments, 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). These expressions, e.g., "any combination thereof contemplate that the skilled person may characterize a crystal form using any combination of the recited characteristic analytical data. For example, 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. Alternatively, 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.

Unless indicated otherwise, XRPD peaks are recorded using copper Κ ι/ Ka₂ radiation with wavelength 1.5419 A (weighted mean of Cu Κ ι and Cu Ka₂). 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. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. 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.

As used herein, unless indicated otherwise, IR absorption bands are reported as cm^"1 with standard errors of + 1 cm^"1.

As used herein, unless indicated otherwise the term "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. When 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. The term "anhydrous" as used herein, and unless stated otherwise, refers to crystalline dolutegravir sodium as disclosed in WO2010/068253. In the preferred embodiments of the present invention, 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.

Description of Drawings

FIGURE 1 : 1H-NMR Spectrum of Dolute gravir sodium 1,2-PG (1: 1) solvate prepared

according to Example 1

FIGURE 2: Solid-state FT-IR spectrum of Dolutegravir sodium 1,2-PG solvate prepared

according to Example 1

FIGURE 3: Solid-state FT-IR spectrum of anhydrous Dolutegravir sodium according to

WO2010/068253

FIGURE 4: X-ray powder diffractogram of Dolutegravir sodium 1 ,2-PG (1: 1) solvate

prepared according to Example 1 FIGURE 5: X-ray powder diffractogram of Dolutegravir sodium 1,2-PG (1: 1) solvate

prepared according to Example 1 (enlarged Y- scale)

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

example 2, wet (top) compared to Dolutegravir sodium hydrate as disclosed in

WO2010/068253 (bottom)

FIGURE 9: X-ray powder diffractogram of Dolutegravir sodium hydrate: comparative

example 2, dried (top) compared to Dolutegravir sodium hydrate as disclosed in

WO2010/068253 (bottom)

Detailed Description of the Invention

In one aspect of the present invention, there is provided 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.

Preferably, the Dolutegravir sodium 1,2-propylene glycol solvate has a ratio of

dolutegravir sodium to 1,2-propylene glycol of about 1: 1.

Preferably, 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.

Moreover, 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. In a preferred embodiment, 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. Preferably 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. In a preferred embodiment, 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. 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 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.

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.

Having thus described the invention with reference to particular preferred embodiments those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The following examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way.

The following parameters and experimental conditions have been used for analysis of the crystalline forms of the invention and the prior art forms.

¹H-Nuclear Magnetic Resonance (NMR) Spectroscopy

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400 MHz. FT (Fourier Transform) Infrared (IR) Spectroscopy Instrument: Thermo Nicolet, Avatar 330 FT-IR. Smart Endurance Diamond-ATR.

Software: Omnic Vers. 6.1a. The sample was measured in solid form, by placing sample in the sample holder and directly carrying out the measurement.

High Performance Liquid Chromatography (HPLC / Ultra Violet Detection (UV)

Instrument: Agilent 1100/1200 Binary pump

Column: YMC Triart CI 8 100*3mm sub 3u

Column temp.: 40.0 °C

Flow [mL/min]: 0.6

Injection volume: 2 L

Solvent A: Acetonitrile

Solvent B: 0.2% Formic acid + 0.1% HFBA (hepta

fluoro butyric acid

Gradient

time [min] Solvent B [%]

3.20 30.0

4.00 15.0

4.50 15.0

4.70 60.0

6.50 60.0

Detector: UV (λ = 258 urn)

X-ray powder diffraction

Samples were measured on a D8 Advance powder X-ray diffractometer (Bruker AXS, Karlsruhe, 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, Karlsruhe, Germany). radiation Cu Κ ι/ ₂ (wavelength 1.5419 A - weighted mean of Cu Κ ι and Cu K ₂)

source 34 kV / 40 mA

detector Vantec-1 (electronic window: 3°) Κβ filter Ni (diffracted beam) measuring circle diameter 435 mm

detector window slit 12 mm

anti- scatter slit (diffracted beam) 8 mm

divergence slit v6.00 (variable)

Soller slit (incident /diffracted beam) 2.5°

2Θ range 2° < 2Θ < 55° step size 0.016

step time 0.2 s

Differential Scanning Calorimetry (DSC)

Thermogravimetric Analysis (TGA)

Chiral Gas Chromatography (GC) by Flame Ionization Detector (FID)

The chiral gas chromatography was carried out in order to determine the enantiomeric ratio of the propylene glycol which is bound to dolutegravir sodium.

Sample preparation: 1 mg of sample in 1 mL methanol

Solubility Determination in Aqueous Solvents

1^st 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 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 μιη disposable filter, 50 μΐ of the clear filtrate were diluted with 950 μΐ DMSO and 2 μΐ thereof were analyzed by HPLC/UV.

2^nd experiment: 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 μιη disposable filter, 50 μΐ of the clear filtrate were diluted with 950 μΐ DMSO and 2 μΐ thereof were analyzed by HPLC/UV. 3^r experiment: approx. 210 mg and 75 mg (exactly weighed) 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 μιη disposable filter. The clear filtrates were analyzed by HPLC either without further processing or after dilution with DMSO (100 μΐ filtrate + 900 μΐ DMSO). 2 μΐ thereof were analyzed by HPLC/UV.

Examples Example 1 (DTG sodium-l,2-PG solvate)

Racemic 1,2-propylene glycol (1,2-PG), purchased from Sigma Aldrich(water content below 0.2%) and met USP testing specification.

1 g (2.4 mmol) Dolutegravir free acid according to WO2010/068253 was suspended in racemic 1,2-PG (45 mL) at room temperature (RT). The flask was placed in an oil bath with an oil temperature kept at 90°C. A solution of 0.27 g (2.8 mmol, 1.17 eq.) sodium tert-butylate (sodium tert-butoxide) in 7.5 mL racemic 1,2-PG was added portionwise to the suspension. After completion of the addition, a clear yellow solution was obtained. The temperature of the solution was slowly cooled down to RT by switching off the heating of the oil bath. A white solid started to precipitate. The solution was left overnight at room temperature without stirring for the complete precipitation. It was isolated by filtration, washed with acetone and dried at 40°C / 10 mbar for 24 hours. The solvate was obtained in 96% yield.

A second batch with 3.0g Dolutegravir free acid as starting material was prepared and used for stability investigations ("stability batch"). Example 2 (Comparative Example DTG sodium-hydrate)

A 100 ml round bottom flask was charged with 3.0 g (7.2 mmol) dolutegravir free acid. After addition of 60 ml tetrahydrofuran / water (80/20 vol/vol), the mixture was stirred at room temperature until the solid was completely dissolved. Thereafter, 3.6 ml 2N aqueous NaOH (1 equivalent) was added in portions. After completion, the mixture was stirred at room temperature for 2 hours. The solid was filtered off and washed with 15 ml tetrahydrofuran / water (80/20 vol/vol) and with 15 ml tetrahydrofuran.

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.

1H NMR analysis showed that the dried product contained no organic solvent (tetrahydrofuran). The dried product lost up to 1.8% weight when it was stored in an environment with a relative humidity of 0% at 25 °C. This weight loss is ascribed to water contained in the dried product.

Results

¹H-NMR Spectroscopy of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent, DMSO-d6 was used. The 1H-NMR spectrum is Figure 1. The signals are summarized below (*= signals of 1,2-PG; **=signals of Dolutegravir ):

0.98 (d, 7=1.00 Hz, 3 H)*; 1.23 (d, 7=7.04 Hz, 3 H)**; 1.37 (d, 7=11.34 Hz, 1 H)**; 1.79 - 1.91 (m, 1 H)**; 2.48 (dt, 7=3.62, 1.91 Hz, 7 H) (DMSO); 3.09 - 3.18 (m, 1 H)**; 3.19 - 3.27 (m, 1 H)*; 3.30 (Water); 3.50 - 3.57 (m, 1 H)*; 3.75 - 3.83 (m, 1 H)**; 3.91 - 3.99 (m, 1 H)**; 4.14 (m, 7=13.88, 4.89 Hz, 1 H)**; 4.28 (m, 7=13.69, 3.13 Hz, 1 H)**; 4.35 - 4.38 (m, 1 H)*; 4.40 - 4.45 (m, 1 H)*; 4.47 - 4.52 (m, 2 H)**; 4.79 (m, 7=5.87, 5.87 Hz, 1 H)**; 5.15 (m, 7=4.11, 4.11 Hz, 1 H)**; 7.01 (m, 7=8.36, 8.36 Hz, 1 H)**; 7.19 (m, 7=10.46, 9.48, 2.74 Hz, 1 H)**; 7.34 (m, 7=8.70, 8.70, 6.84 Hz, 1 H)**; 7.85 (s, 1 H)**; 10.72 (t, 7=5.87 Hz, 1 H)**.

The integration values of the methyl groups from DTG-Na (1.23 ppm) and 1,2-PG (0.98 ppm) were 3.08 and 3.07 resp. It corresponds with a DTG-Na: l,2-PG = 1: 1 equivalent ratio.

FT-IR Spectroscopy of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to

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.

The absorption bands of the solvate and of anhydrous DTG-Na are summarized in Table 1. Most characteristic differences between the spectra of the new, solvated form and anhydrous DTG-Na are the OH-absorption bands of 1,2-PG (3380 and 3230 cm^"1), the carbonyl group (1624 cm^"1 (solvate) vs. 1637 cm^"1 (anhydrous form) as well as the aromatic -C=C-groups (range between 1500 and 1600 cm^"1).

Dolutegravir sodium 1,2-PG (1:1) solvate Anhydrous Dolutegravir sodium

1057 3072 1034 2941

1086* 3230 [br] 1066 2966

1099 3381[br] 1093 2976

1107

Characteristic bands.

Chemical Purity of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

The chemical purity of the product of example 1 was analysed by HPLC/UV and yielded a purity of 99.85% (stability batch >99.9 %).

Analysis of purity 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:

Differential Scanning Calorimetry (DSC) of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

The differential scanning calorimetry of the Dolutegravir sodium 1,2-PG (1: 1) solvate revealed a broad endotherm, which is believed to correspond to desolvation of the 1,2 PG, followed by a sharp endotherm and subsequently a sharp exotherm. The results are summarized in the table below:

Thermogravimetric Analysis (TGA) of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

The 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:

X-ray Powder Diffraction of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

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:

Angle Relative Intensity

° (2Θ) + 0.2 °20 %

6,4 100,0%

7,9 2,0%

9,9 0,2%

12,9 10,1%

16,0 0,2%

16,9 0,1%

17,9 0,2%

19,0 5,0%

19,3 4,4%

19,7 4,3%

20,8 1,0%

21,5 3,6%

21,9 0,4%

24,2 6,8%

24,4 3,1%

25,3 1,4%

25,7 0,8%

25,9 0,9%

26,3 0,9%

27,9 0,5%

29,4 4,6%

29,9 2,0%

** claim 18 of WO 2010/068253 and Figure 6 below (top XRPD trace)

*² claim 24 of WO 2010/068253

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.

In order to verify that the product of example 1 indeed contains ionic bound sodium it was converted into the known anhydrous form of Dolutegravir sodium without addition of any sodium source: Approx. 200 mg of Dolutegravir sodium 1,2-PG solvate prepared according to Example 1 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 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.

Samples of Dolutegravir sodium 1,2-PG (1: 1) solvate (Stability batch) were stored 4 weeks in open and closed containers at 25°C / 60% relative humidity (r.h.), at 30°C / 65% r.h. XRPD analysis, performed after 4 weeks demonstrated no change in solid state for all samples in the open container (i.e. with exposure to humidity).

Solubility of Dolutegravir sodium 1,2-PG (1:1) solvate in Aqueous Solvents

Two experiments in three solvents were performed. In a 1^st experiment, 75 mg (accurately weighed) sample were suspended in 3 ml solvent and the dissolved amount was determined after 15 min and 1 h. In a 2^nd experiment, 140 mg sample were suspended in 1 ml of the same solvents and the dissolved amount was determined after 1 h. All experiments were carried out 37°C. The results are summarized:

Solubility [mg/ml]

Experiment Water 0.01 N HC1 0.1 N HC1

(deionized) pH 2.1 pH 1.2

1^st experiment

15 min 3.8 2.4 0.15

1 h 3.7 2.3 0.11

2^nd experiment

1 h 3.3 2.3 0.50

In a comparative experiment, 70 mg dolutegravir sodium hydrate and anhydrous Dolutegravir sodium (as disclosed in WO2010/068253) were suspended in 1 ml solvent (water, 0.1 N HC1 (pH 1.2) and 50 mM phosphate buffer (pH 6.8). After 1 h, a sample was withdrawn, filtered through a disposable 0.2 μιη filter and the filtrate was analyzed by HPLC/UV. This results, which are summarized in the table below, show that the aqueous solubility of Dolutegravir sodium hydrate is approximately as low as that of anhydrous Dolutegravir sodium in at pH 1.2 and pH 6.8. In distilled water, the solubility of the hydrated form is even lower than that of the anhydrous form.

In a further experiment, the kinetic solubility of Dolutegravir sodium 1,2-PG (1: 1) solvate prepared by a process according to Example 1 was investigated in different solvent systems (at physiological buffers, and in the Biorelevant dissolution medium, "FaSSIF, FeSSIF & FaSSGF Powder" [i.e. a Fasted State Simulated Intestinal Fluid (FaSSIF) 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). and also with deionized water and was compared with the kinetic solubility of anhydrous Dolutegravir sodium:

weighed solubility [mg/ml]

amount FaSSIF deionized water

Sample

[mg/ml]

5 15 60 5 15 60

min min min min min min

Dolutegravir 25 0.56 0.51 0.42 3.85 3.78 3.87

sodium 1,2-

70 0.82 0.49 0.39 3.66 3.58 3.46

PG (1: 1)

solvate

anhydrous 25 0.16 0.30 0.27 3.55 3.52 3.46

Dolutegravir

70 0.31 0.29 0.28 3.32 3.39 3.44

sodium

The above results show the significantly higher solubility of Dolutegravir sodium 1,2-PG (1: 1) solvate relative to anhydrous Dolutegravir sodium, which can be summarized as follows:

Enantiomeric ratio of 1,2-PG in Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 1

1 mg Dolutegravir sodium 1,2-PG (1: 1) solvate prepared according to Example 1 was dissolved in 1ml methanol and was analyzed by chiral gas chromatography. Two different batches were analyzed. An enantiomeric ratio of (S)/(R) of 24:76 for the first sample (Figure 7) and 27:73 for the second sample was determined, i.e. a 1:3 (S)/(R) ratio.

Claims

1. Dolutegravir sodium 1,2-propylene glycol solvate.

2. Dolutegravir sodium 1,2-propylene glycol solvate according to Claim 1 in the form of a crystalline solid.

3. Dolutegravir sodium 1,2-propylene glycol solvate according to Claim 1 or Claim 2 which contains dolutegravir sodium (S)- 1,2-propylene glycol solvate and dolutegravir sodium (R)- 1,2-propylene glycol solvate.

4. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 1-3 wherein the ratio of dolutegravir sodium to 1,2-propylene glycol is about 1: 1.

5. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 1-4 having a ratio of dolutegravir sodium (S)- 1,2-propylene glycol solvate to dolutegravir sodium (R)- 1,2-propylene glycol solvate of about 1:3.

6. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 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.

7. Dolutegravir sodium 1,2-propylene glycol solvate according to Claim 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.

8. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 1-7

characterized by the absence of peaks at 9.2° and at 9.3° degrees 2-theta + 0.2 degrees 2- theta.

9. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 1-8 having characteristic infrared absorption bands at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm^"1 + 2 cm^"1.

10. Dolutegravir sodium 1,2-propylene glycol solvate according to any of Claims 1-9 having a DSC thermogram comprising a broad endo therm 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.

11. 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.

12. A crystalline form of dolutegravir sodium according to Claim 11 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.

13. A crystalline form of dolutegravir sodium according to any of Claims 11 or 12

14. A crystalline form of dolutegravir sodium according to any of Claims 11-13 having

characteristic infrared absorption bands at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm^"1 + 2 cm^"1.

15. A crystalline form of dolutegravir sodium according to any of Claims 11-14 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.

16. A crystalline form of dolutegravir sodium according to any of Claims 11-15 wherein the crystalline form is a solvate.

17. A crystalline form of dolutegravir sodium according to Claim 16 wherein the solvate is with an organic solvent.

18. A crystalline form of dolutegravir sodium according to Claim 17 wherein the solvate is with a C3-C6 alkane diol.

19. A crystalline form of dolutegravir sodium according to Claim 18 wherein the solvate is with propylene glycol.

20. A crystalline form of dolutegravir sodium according to Claim 19 wherein the solvate

contains (R)-l,2-propylene glycol and (S)-l,2-propylene glycol.

21. Dolutegravir sodium or a crystalline form thereof according to any of Claims 1-20 being substantially free of any of any other solid state form of dolutegravir sodium.

22. Dolutegravir sodium or a crystalline form thereof according to any of Claims 1-21

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.

23. Use of dolutegravir sodium or a crystalline form thereof as defined in any of Claims 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.

24. A pharmaceutical composition comprising a dolutegravir sodium or a crystalline form thereof as defined in any of Claims 1-22 and at least one pharmaceutically acceptable excipient.

25. Use of a dolutegravir sodium or a crystalline form thereof as defined in any of Claims 1-22 for the preparation of a pharmaceutical composition.

26. A process for preparing a pharmaceutical composition comprising combining a dolutegravir sodium or a crystalline form thereof as defined in any of Claims 1-22 with at least one pharmaceutically acceptable excipient.

27. Dolutegravir sodium or a crystalline form thereof as defined in any of Claims 1-22 for use as a medicament.

Dolutegravir sodium or a crystalline form thereof as defined in Claim 27 wherein the medicament is for the treatment of HIV-1 infection.