WO2015138933A1 - Solid state forms of dolutegravir sodium - Google Patents

Abstract

Solid state forms of Dolutegravir sodium, processes for preparation thereof and pharmaceutical compositions thereof are provided.

Description

SOLID STATE FORMS OF DOLUTEGRAVIR SODIUM

Cross Reference to Related Applications

This application claims the benefit of U.S. Provisional Application No. 61/952,481, filed 13 March 2014, U.S. Provisional Application No. 61/977,247, filed 9 April 2014, U.S. Provisional Application No. 61/979,175, filed 14 April 2014, U.S. Provisional Application No. 62/028,075, filed 23 July 2014, U.S. Provisional Application No. 62/047,347, filed 8

September 2014, U.S. Provisional Application No. 62/079,246, filed 13 November 2014, U.S. Provisional Application No. 62/084, 161, filed 25 November 2014 and European Patent Application No. 14200344.1, filed 24 December 2014, the contents of each of which are incorporated herein by reference in their entireties for all purposes.

Field of the Invention

The present invention relates to solid state forms of Dolutegravir sodium, processes for preparation thereof and pharmaceutical compositions thereof.

Background of the Invention

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.

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.

The sodium salt of Dolutegravir is described in WO2006/1 16754. A crystalline form of this sodium salt or a hydrate thereof are disclosed in WO2010/068253. Dolutegravir potassium salt and solid state forms thereof are described in WO20150009927. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Dolutegravir, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms) of an active

pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving

formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, low content of residual solvent, a lower degree of hygroscopicity, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Dolutegravir sodium, particularly those having improved solubility and/or dissolution characteristics. Summary of the Invention

The present invention relates to solid state forms of Dolutegravir sodium, to processes for preparation thereof, and to pharmaceutical compositions comprising these solid state forms.

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 (for example, Dolutegravir potassium) and solid state forms thereof or another solvate or a hydrate form of Dolutegravir sodium.

In another embodiment, 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.

In another embodiment 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 further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Dolutegravir sodium according to the present invention. Typically, 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 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.

Any of the solid state forms as defined herein and /or combinations thereof as well as the pharmaceutical compositions of the solid state forms of Dolutegravir sodium can be used as medicaments, particularly for the treatment of HIV infection.

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.

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

Dolutegravir sodium of the present invention and /or combinations thereof, or at least one of the above pharmaceutical compositions, to a subject suffering from HIV infection, or otherwise in need of the treatment. Brief Description of the Figures

Figure 1 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of Dolutegravir sodium Form II.

Figure 2 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of Dolutegravir sodium Form III.

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 5 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of

Dolutegravir sodium Form VI.

Figure 6 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of Dolutegravir sodium Form VII.

Figure 7 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form VIII. Figure 8 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form IX.

Figure 9 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form X n- butanol solvate prepared according to example 20.

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 14 shows a solid-state ¹³C NMR spectrum of Dolutegravir sodium Form V in the 100-200 ppm range.

Figure 15 shows a solid-state ¹³C 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 17 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form X n- butanol solvate prepared according to example 19. Figure 18 shows a powder X-ray diffraction pattern of Dolutegravir sodium Form X 1,2-PG (1 : 1) solvate prepared according to example 21.

Figure 19 shows a 1H-NMR Spectrum of Dolutegravir sodium 1 ,2-PG (1 :1) solvate prepared according to Example 22.

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 22 shows an X-ray powder diffractogram of Dolutegravir sodium 1 ,2-PG (1 :1) solvate prepared according to Example 22.

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 24 shows a comparison of XRPD of Dolutegravir sodium 1,2-PG (1 : 1) solvate prepared according to Example 22 following slurry in DMSO (bottom trace), with anhydrous Dolutegravir sodium as disclosed in WO2010/068253 (top trace).

Figure 25 shows a chiral GC-FID chromatogram analysis of 1,2-PG after suspending Dolutegravir sodium 1,2-PG (1 : l)-solvate in Methanol.

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 27 shows an X-ray powder diffractogram of Dolutegravir sodium hydrate: comparative example 23, dried (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.

Figure 30 shows a solid-state C NMR spectrum of Dolutegravir sodium Form X 1,2- PG (1 : 1) solvate in the 100-200 ppm range.

Figure 31 shows a solid-state C NMR spectrum of Dolutegravir sodium Form X n- butanol solvate in the 0-200 ppm range.

Figure 32 shows a solid-state C NMR spectrum of Dolutegravir sodium Form X n- butanol solvate in the 100-200 ppm range. Detailed Description of the Invention

The present invention relates to Dolutegravir sodium, to solid state forms thereof, such as crystalline Forms II, III, IV, V, VI, VII, VIII, IX, X and XI, to processes for preparation thereof and to pharmaceutical compositions comprising at least one of, or a combination of these solid state forms. The invention also relates to the conversion of the Dolutegravir sodium and its solid state forms to Dolutegravir or other Dolutegravir salts and solid state forms thereof.

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. As is well-known in the art, 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. In any event, 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 Dolutegravir salt, e.g., 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 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 (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other, salts, solid state (or polymorphic) forms. As used herein in this context, 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. Thus, 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. Accordingly, in some embodiments of the invention, 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.

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.

As used herein, the term "DTG" refers to Dolutegravir. As used herein, the term "butanol solvate" refers to n-butanol solvate of Dolutegravir sodium Form X.

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

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, unless stated otherwise, PXRD peaks reported herein are preferably measured using CuK _α radiation, λ = 1.5418A.. Further, unless indicated otherwise, XRPD peaks are reported as degrees 2-theta values with standard errors of ± 0.2 degrees 2-theta.

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

As used herein, 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, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, 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.

As used herein, the expression "wet crystalline form" refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.

As used herein, the expression "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. As used herein, the term "residual solvent" refers to minor amount of unbound solvents, i.e. solvents that are not part of the crystal structure.

As used herein, and unless stated otherwise, the term "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).

The term "solvate", as used herein and unless indicated otherwise, 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

"hydrate." The solvent content can be measured, for example, by GC, ^IH-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.

The amount of solvent employed in a chemical process, e.g., a reaction or a

crystallization may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, 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. In another context, 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.

As used herein the term 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.

As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

As used herein, and unless indicated otherwise, the term "thermo-dynamical stability" in relation to solid state forms of Dolutegravir sodium refers to resistance of the solid state form to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than 20%, 10%, 5%, 1%, or 0.5% (w/w) conversion of crystalline Dolutegravir sodium to any other solid state form of

Dolutegravir sodium as measured by PXRD. In some embodiments, the conversion is 1%- 20%, 1%-10% or l%-5% (w/w).

As used herein 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.

As used herein 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):

(i) having characteristic diffraction peaks at 6.4, 9.2, 13.8, 19.2 and 21.8±0.2 degrees two theta in an X-ray powder diffraction pattern; and

(ii) having characteristic infrared absorption spectra at 1641, 1536, 1503 and 1424cm^"1±2 cm^"1.

As used herein the monohydrate form of Dolutegravir sodium, as disclosed in

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 ¹³C-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. According to TGA measurement, the NMP solvent is well incorporated in the crystal structure which is desolvated at the temperature range of about 100-200°C showing weight lost of about 17-18% . This weight lost demonstrates monosolvate of NMP (1 : 1 NMP to DTG- Na).

As discussed above, crystalline form II of Dolutegravir sodium has some advantages. For example, 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. Furthermore, Dolutegravir sodium is not soluble in most solvent systems and as a result using NMP is crucial for chemical purification. For example, 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. sodium (4R,12aR)-9- ((2,4-difluorobenzyl)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].

In addition, 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,

20.1 and 21.9 degrees 2- theta ± 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 28 and combinations of these data.

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,

19.2 and 24.3 degrees two theta ± 0.2 degrees two theta.

Pure crystalline Form III of Dolutegravir sodium might be characterized as ethanol solvate. 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 ¹³C-NMR spectrum with signals at about 180.4, 136.1, 128.8, 120.5, and 76.6 ± 0.2 ppm; a solid-state ¹³C NMR spectrum as depicted in Figure 13; a solid-state ¹³C 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. Preferably Form V contains less than 1% of water or any other solvent as measured by TGA, KF, GC or any other similar methods.

Preferably 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.

As discussed above, 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. In addition, 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.

Alternatively 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 ¹³C-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 ¹³C 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.

Alternatively, 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. According to TGA measurement, 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 ¹³C-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 ¹³C 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.

Preferably, 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 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_\/ Ka₂ radiation with wavelength 1.5419 A (weighted mean of Cu Και and Cu Ka₂)).

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 (XRPD peaks are recorded using copper Κα^ Κα₂ radiation with wavelength 1.5419 A (weighted mean of Cu Koti and Cu Ka₂)).

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 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

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 (XRPD peaks are recorded using copper Kaj/ Ka₂ radiation with wavelength 1.5419 A (weighted mean of Cu Kai and Cu Ka₂)). 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)-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.

As discussed above, crystalline form X of Dolutegravir sodium has some advantages. For example, 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. In addition, it is preferable to work with "green solvent" (class A solvent) such as n-BuOH which is a pharmaceutically acceptable solvent with a maximum permitted amount in the final drug substance of NMT 5000ppm. Also, owing to low desolvation temperature (~50°C), it may also be used to remove other solvents from the crystal structure of the active ingredient.

As mentioned above 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. In addition, 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,

18.7 and 19.3 degrees 2- theta ± 0.2 degrees 2- theta; a PXRD pattern as depicted in figure 10; and combinations of these data.

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. In particular, 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

Dolutegravir with an appropriate salt having the desired metal, to obtain the corresponding salt.

In another embodiment 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. Typically, 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.

In another embodiment 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

Dolutegravir sodium of the present invention and/or combinations thereof, or at least one of the above pharmaceutical compositions, to a subject suffering from HIV infection, or otherwise in need of the treatment.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Powder X-ray diffraction pattern ("PXRD") method:

The analyses were performed on ARL (SCINTAG) powder X-Ray diffractometer model X'TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.

Samples according to examples 22 and 23 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).

Ή-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. 6.1 a. The sample was measured in solid form, by placing the 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

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 nm)

Differential Scanning Calorimetry (DSC)

Instrument: Mettler-Toledo DSC 822E (Mettler-Toledo GmbH, GieBen,

Germany)

Aluminium crucible: 40 (with perforated lid)

Lid: perforated

Temperature range: 30°C to 350°C

Heating rate: 10°C/ min

Nitrogen flush: 50 mL / min

Software: STARe Version 1 1.0

Interpretation: Endothermic mode Thermo gravimetric Analysis (TGA)

Chiral Gas Chromatography (GO 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

Examples

Reference examples

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) can for example be prepared by processes disclosed in US8217034 and Dolutegravir sodium Form I can for example be prepared by processes disclosed in WO 2010/068253. For example, 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).

Example 1: Preparation of Dolutegravir sodium Form II

About 20 mg of 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.

Example 2: Preparation of Dolutegravir sodium Form II

20 ml glass vial was charged with 0.5 g Dolutegravir sodium (form I) and 12.5 ml NMP (extra dry). The mixture was heated by heat gun (2 minutes), clear yellow solution was obtained. The mixture was mixed at room temperature over night. The precipitated solid was filtrated, sticky off white solid was obtained, which was dried at 60°C under reduced pressure over night. Crystalline Form II was obtained as confirmed by PXRD measurement.

Example 3: Preparation of Dolutegravir sodium Form HI

50 mg of Dolutegravir sodium Form II was exposed to vapors of Ethanol abs. for 7 days at RT. PXRD measurement for the powder confirmed Form III content.

Example 4: Preparation of Dolutegravir sodium Form IV

50 mg of Dolutegravir sodium Form II was exposed to vapors of IP A for 7 days at RT. PXRD measurement for the powder confirmed Form IV content.

Example 5: Preparation of Dolutegravir sodium Form V

20 ml glass vial was charged with 0.5 g Dolutegravir sodium Form I and 12.5 ml NMP (extra dry). The mixture was heated by heat gun (2 minutes), clear yellow solution was obtained.

The mixture was mixed at room temperature overnight. The precipitated solid was filtrated, sticky off white solid was obtained, which was dried at 60 °C under reduced pressure (1020 mbar) for 1 month. Crystalline Form V was obtained as confirmed by PXRD

measurement.

Example 6: Preparation of Dolutegravir sodium Form VI

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.

Example 7: Preparation of Dolutegravir sodium 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.

Example 8: Preparation of Dolutegravir sodium 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.

Example 9: Preparation of Dolutegravir sodium Form VII

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.

Example 11: Preparation of Dolutegravir sodium Form VIII

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.

Example 13: Preparation of Dolutegravir sodium Form X (butanol solvate)

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.

Example 14: Preparation of Dolutegravir sodium Form XI

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%.

After 4.5 h of drying, the obtained product was tested by XRD to confirm Dolutegravir-

Sodium Form V content.

Example 16: Preparation of Dolutegravir sodium Form V

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%.

After 6 h of drying, the obtained product was tested by XRD to confirm Dolutegravir- Sodium Form V content.

Example 17: Preparation of Dolutegravir sodium Form V

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%.

After 6 h of drying, the obtained product was tested by XRD. According to XRD results, mainly Dolutegravir-Sodium Form V was obtained with some minor content of Form II (1.5% NMP was determined by HPLC). Example 18: Preparation of Dolutegravir sodium Form II

100 ml glass reactor (CBT) was charged with 6 g Dolutegravir free acid in 10 V NMP (60 ml). Sodium methoxide (NaOMe 3.15 ml, 1.02 eq, 25% sol in MeOH) was added, clear solution was obtained. The mixture was mixed at room temperature overnight. In the morning, precipitation was formed which was filtrated (slow filtration) and washed with 3.3 V N- methyl-2-pyrrolidone (NMP 20 ml), sticky white solid was obtained. The product was dried at the oven at 80°C over weekend. About 5.2 g Dolutegravir-Sodium form II was obtained (91% Yield). Example 19; Preparation of Dolutegravir sodium Form X (butanol solvate)

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.

Example 20: Preparation of Dolutegravir sodium Form X (butanol solvate)

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.

Example 21: Preparation of Dolutegravir sodium Form X (1,2-PG solvate)

Dolutegravir-Sodium Form VI (0.5g, 1.Oeq) was slurried at room temperature in propylene glycol (racemate, 5mL) and stirred for 24 hours.

The obtained slurry was collected by vacuum filtration and dried in vacuum oven at 50 °C overnight to obtain Dolutegravir-Sodium (0.28g) which was analyzed by XPRD and found to be Form X as depicted in Figure 18.

Example 22: Preparation of Dolutegravir 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 23 (Comparative Example): Preparation of Dolutegravir 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

Ή-NMR Spectroscopy of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 22

The sample was analyzed in a 400 MHz-NMR spectrometer. As solvent, DMSO-d6 was used. The ¹ H-NMR spectrum is Figure 19. The signals are summarized below (*= signals of 1 ,2-PG; **=signals of Dolutegravir ):

0.98 (d, J=1.00 Hz, 3 H)*; 1.23 (d, J=7.04 Hz, 3 H)**; 1.37 (d, J=l 1.34 Hz, 1 H)**; 1.79 -

1.91 (m, 1 H)**; 2.48 (dt, J=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, J=13.88, 4.89 Hz, 1 H)**; 4.28 (m, J=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, J=5.87, 5.87 Hz, 1 H)**; 5.15 (m, J-4.1 1 , 4.1 1 Hz, 1 H)**; 7.01 (m, J=8.36, 8.36 Hz, 1 H)**; 7.19 (m, J=10.46, 9.48, 2.74 Hz, 1

H)**; 7.34 (m, J=8.70, 8.70, 6.84 Hz, 1 H)**; 7.85 (s, 1 H)**; 10.72 (t, J=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: 1 ,2-PG = 1 : 1 equivalent ratio.

FT-IR Spectroscopy of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 22

The solid-state FT-IR spectrum of Dolutegravir sodium 1 ,2-PG solvate prepared according to Example 22 is shown in Figure 20 and that of the non-solvated anhydrous Dolutegravir sodium in Figure 21.

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 (Example 22) (WO2010/068253)

* Characteristic bands. Chemical Purity of Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 22

The chemical purity of the product of example 22 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 22

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 22

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 22

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:

Angle Relative Intensity (2Θ) ± 0.2 °2θ %

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%

most characteristic peaks [° 2Θ] ± 0.2 °2Θ

sample

Primary characterising peaks Secondary characterising peaks

Dolutegravir sodium 1 ,2-

12.9 19.3 21.5 24.2 29.4 6.4 19.0 19.7 24.4 29.9

PG (1 : 1) solvate

for comparison:

Dolutegravir sodium

6.4 9.2 13.8 14.6 15.2 17.6 19.2 21.8 24.1 28.7

(anhydrous)* ¹

Dolutegravir sodium

8.0 9.3 1 1.3 16.0 22.8 15.4 18.7 19.1 19.8 26.8

(hydrate)^*2

* ' claim 18 of WO 2010/068253 and Figure 24 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.

These 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 22 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 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.

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 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 μπι 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 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 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^rd 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.

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 0.1 1

2ⁿ 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 22 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, osmolarity 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:

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: Relative Solubility of

Dolutegravir sodium 1 ,2- weighed

solvent PG (1 : 1) solvate vs

amount

anhydrous DTG-Na

[mg/ml]

[mg/ml]

5 min. 15 min. 60 min.

25 142% 123% 1 1 1%

buffer pH 2.1

70 149% 132% 1 15%

25 60% 1017% 127%

buffer pH 4.5

70 70% 152% 125%

25 N/A 146% 123%

buffer pH 6.8

70 250% 130% 1 10%

25 350% 170% 156%

FaSSIF

70 265% 169% 139%

deionized 25 108% 107% 112%

water 70 1 10% 106% 101%

Enantiomeric ratio of 1,2-PG in Dolutegravir sodium 1,2-PG (1:1) solvate prepared according to Example 22

1 mg Dolutegravir sodium 1,2-PG (1 : 1) solvate prepared according to Example 22 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 25) and 27:73 for the second sample was determined, i.e. a 1 :3 (S)/(R) ratio.

Solubility of Dolutegravir sodium form V

In a 1 st experiment, about 3 mg of Dolutegravir Sodium form I samples (obtained according to the processes disclosed in WO 2010/068253) were suspended by stirring each in 20 mL of following solutions: 0.1N HC1, pH1.2 and 50 raM Phosphate buffer, pH-5.0. About 25 mg of Dolutegravir Sodium form I was suspended by stirring in 5 mL of HPLC grade water.

The tests were performed on saturated solutions equilibrated 0.5hour at 25°C.

After 0.5 h, samples were withdrawn, filtered through a disposable 0.2 μιη filter, diluted and analyzed by HPLC/UV. In a 2nd experiment about 5 mg of Dolutegravir Sodium portions of form V were suspended by stirring each in 20 mL of following solutions: 0.1N HCL, pH1.2 and 50 mM Phosphate buffer, pH-5.0. About 35 mg of Dolutegravir Sodium form V was suspended by stirring in 4 mL of HPLC grade water.

The tests were performed on saturated solutions equilibrated 0.5hour at 25°C.After 0.5 h, samples were withdrawn, filtered through a disposable 0.2 μιη filter, diluted and analyzed by HPLC/UVperformed according to the conditions below:

Column: Cortecs CI 8 2.7um 4.6"= 150mm

Part no. 186007378, Serial no.01063424515814, Lot no.0106342451

Buffer: 0.002% EDTA, 0.002M NH4H2P04 pH7.0,

Eluent: A- 90% Buffer, 10% ACN

Eluent B- 50% MeOH, 50% ACN

Mobile phase: 50A : 50B

Diluent: 30% Buffer, 70% MeOH

Flow: 0.8 ml/min

Detector: 256nm, Injection volume: 5ul,

T column: 30C, T autosampler: IOC

The results are summarized in the table below:

Further aspects and embodiments of the present invention are set out in the following numbered paragraphs:

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

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

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

4. Dolutegravir sodium 1 ,2-propylene glycol solvate according to any of paragraphs 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 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.

6. 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 1-7 characterized by the absence of peaks at 9.2° and at 9.3° degrees 2-theta ± 0.2 degrees 2- theta.

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

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 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.

A crystalline form of dolutegravir sodium according to paragraph 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.

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.

A crystalline form of dolutegravir sodium according to paragraph 16 wherein the solvate is with an organic solvent. A crystalline form of dolutegravir sodium according to paragraph 17 wherein the solvate is with a C₃-C₆ alkane diol.

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

A crystalline form of dolutegravir sodium according to paragraph 19 wherein the solvate contains (R)-l,2-propylene glycol and (S)-l,2-propylene glycol.

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 according to any of paragraphs 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.

Use of 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.

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

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.

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

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

Claims

Crystalline Form X of Dolutegravir sodium, characterized by a PXRD pattern having peaks at about 6.3, 7.9, 12.6, 19.8 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta.

Crystalline Form X of Dolutegravir sodium according to Claim 1 , further characterized by a PXRD pattern having one, two, three, four or five additional peaks selected from about 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 characterized by data selected from: a solid state ^I3C-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 ¹³C NMR spectrum substantially as depicted in Figure 15 or Figure 16, or combinations of these data.

Crystalline Form X of Dolutegravir sodium according to any of Claims 1-3, in the form of an n-butanol solvate.

Crystalline Form X of Dolutegravir sodium according to any of Claims 1-4, further characterised by a PXRD pattern substantially as depicted in Figure 9 or Figure 17.

Crystalline Form X of Dolutegravir sodium characterized by data selected from: a solid state ¹³C-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 substantially as depicted in Figure 29 or Figure 30; or combinations of these data.

Crystalline Form X of Dolutegravir sodium according to any of Claims 1 , 2 or 6 in the form of a propylene glycol solvate.

Crystalline Form X of Dolutegravir sodium according to any of Claims 1, 2, 6 or 7 further characterised by a PXRD pattern substantially as depicted in Figure 18 or 22.

Crystalline Dolutegravir sodium Form X characterized by a PXRD pattern having peaks at about: 12.9, 19.3, 21.5, 24.2 and 29.4 degrees 2-theta ± 0.2 degrees 2-theta.

Crystalline Dolutegravir sodium Form X according to Claim 9, 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.

1 1. Crystalline Dolutegravir sodium Form X according to any of Claims 9-10, having characteristic infrared absorption bands at 1086, 1250, 1279, 1427, 1506, 1525, 1624, 3230 and 3380 cm^"1 ± 2 cm^"1.

12. Crystalline Dolutegravir sodium Form X according to any of Claims 9-1 1, 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.

13. Crystalline Dolutegravir sodium Form X according to any of Claims 9-12, in the form of a 1 ,2-propylene glycol solvate.

14. Crystalline Dolutegravir sodium Form X according to Claim 13, wherein the ratio of Dolutegravir sodium to 1 ,2-propylene glycol is about 1 : 1.

15. Crystalline Dolutegravir sodium in the form of a 1 ,2-propylene glycol solvate.

16. Crystalline Dolutegravir sodium according to Claim 15, characterized by data according to any of Claims 9-14.

17. Crystalline Form II of Dolutegravir sodium, 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 substantially as depicted in Figure 1 ; a solid state ¹³C-NMR spectrum with signals at about 175.6, 173.3, 130.6, 128.0, and 1 16.4 ± 0.2 ppm; a solid-state ¹³C NMR spectrum as depicted in figure 1 1 or Figure 12; or combinations thereof.

18. Crystalline Form II of Dolutegravir sodium according to Claim 17, further characterized by an XRPD pattern 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.

19. Crystalline Form II of Dolutegravir sodium according to any of Claims 17-18, in the form of an N-methyl-2-pyrrolidone solvate.

20. Crystalline Form V of Dolutegravir sodium, 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 substantially as depicted in Figure 4; by a solid state ¹³C-NMR spectrum with signals at about 180.4, 136.1, 128.8,

120.5, and 76.6 ± 0.2 ppm; a solid-state ¹³C NMR spectrum substantially as depicted in Figure 13 or Figure 14; or combinations thereof.

21. Crystalline Form V of Dolutegravir sodium according to Claim 20, further characterized by the PXRD pattern 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.

22. Crystalline Form V of Dolutegravir sodium according to any of Claims 20-21 which is anhydrous, preferably wherein the crystalline form contains less than 1% of water or any other solvent.

23. Crystalline Dolutegravir sodium according to any of Claims 1-22, which is substantially free of any of any other solid state form of dolutegravir sodium.

24. Crystalline Dolutegravir sodium according to any of Claims 1-23 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 of any other solid state forms of dolutegravir sodium. 25. Use of crystalline Dolutegravir sodium defined in any of Claims 1-24 for the preparation of: dolutegravir, another dolutegravir salt, another crystalline form of dolutegravir sodium, or another solvate or hydrate form of dolutegravir sodium.

26. A pharmaceutical composition comprising crystalline Dolutegravir sodium as defined in any of Claims 6-16 and 20-24 and at least one pharmaceutically acceptable excipient.

27. Use of crystalline Dolutegravir sodium as defined in any of Claims 6-16 and 20-24 for the preparation of a pharmaceutical composition. 28. A process for preparing a pharmaceutical composition comprising combining crystalline Dolutegravir sodium as defined in any of Claims 6-16 and 20-24 with at least one pharmaceutically acceptable excipient.

29. Crystalline Dolutegravir sodium as defined in any of Claims 6-16 and 20-24 for use as a medicament.

30. Crystalline Dolutegravir sodium as defined in Claim 29 wherein the medicament is for the treatment of HIV- 1 infection.

31. A method of treating HIV infection comprising administering a therapeutically effective amount of any one of the crystalline forms of Dolutegravir sodium as defined in any of Claims 6-16 and 20-24, or a pharmaceutical composition according to Claim 26 to a subject suffering from HIV infection, or otherwise in need of the treatment.

32. Use of crystalline Dolutegravir sodium Form X as defined in any of Claims 1-5,

preferably wherein Form X is a butanol solvate, as an intermediate for the purification of Dolutegravir sodium, or as a processing aid for the purification of Dolutegravir sodium.

33. Use of crystalline Dolutegravir sodium Form X as defined in any of Claims 1, 2 or 6-16, preferably wherein Form X is a propylene glycol solvate for the preparation of a pre-mix for a formulation of Dolutegravir sodium, preferably wherein the pre-mix is for a liquid formulation of Dolutegravir sodium.

34. Use of crystalline Dolutegravir sodium Form II as defined in any of Claims 17-19,

preferably wherein the Form II is an N-methyl-2-pyrrolidone solvate, as an intermediate for the purification of Dolutegravir or a pharmaceutically acceptable salt therof, or as a processing aid for the purification of Dolutegravir or a pharmaceutically acceptable salt thereof, preferably wherein the pharmaceutically acceptable salt is Dolutegravir sodium.

35. A process for reducing isomeric impurity sodium (4R,12aR)-9-((2,4- difluorobenzyl)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 of Dolutegravir sodium comprising slurrying Dolutegravir sodium in a solvent comprising N-methyl-2-pyrrolidone, precipitating and optionally isolating the crystalline Dolutegravir sodium Form II as defined in any of Claims 17-19.