EA042594B1 - CRYSTALLINE FORM OF BITEGRAVIR SODIUM - Google Patents

Description

The field of technology to which the invention belongs

The invention relates to a crystalline form of bitegravir sodium and to a method for its preparation. In addition, the present invention relates to a pharmaceutical composition comprising said crystalline form of bitegravir sodium, preferably in a predetermined and/or effective amount, at least one pharmaceutically acceptable excipient and optionally one or more additional antiviral agents. The pharmaceutical composition of the present invention can be used as a medicine, in particular for the treatment and/or prevention of HIV-1 infections.

State of the art

Bitegravir is an integrase strand transfer inhibitor for human immunodeficiency virus type 1 (HIV-1) (INSTI). It is indicated for the treatment of HIV-1 infection in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir alafenamide and emtricitabine. Bitegravir has the chemical name (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)2,3,4,5,7,13,13a-octahydro-2, 5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate (IUPAC name) or (2R,5S, 13aR)-8-hydroxy-7 ,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13а-octahydro2,5-methanopyrido[1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide and is described by the following chemical structural formula (I):

About F

OH OH

Formula (I)

The method for producing bitegravir is disclosed in example 42 in WO 2014/100323 A1. WO 2015/196116 A1 discloses a crystalline form of bitegravir sodium, designated as form I. Although the application notes that the use of certain solvents such as methanol, ethanol, water, isopropyl acetate, acetonitrile, tetrahydrofuran, methyl isobutyl ketone and any mixture thereof gives different polymorphs, Form I is the only crystalline form disclosed in this application.

Different solid phase forms of the active pharmaceutical ingredient often have different characteristics. Differences in the physicochemical characteristics of solid phase forms can be important for improving pharmaceutical compositions, for example, pharmaceutical preparations with an improved dissolution profile or with improved stability or shelf life can be made available due to an improved solid phase form of the active pharmaceutical ingredient. The handling or use of the active pharmaceutical ingredient during the preparation procedure may also be improved. Thus, novel solid phase forms of the active pharmaceutical ingredient may have desirable processing characteristics. They may be easier to handle, better stored and/or better purified than previously known solid state forms.

The thermodynamically most stable polymorph of an active pharmaceutical ingredient is often used to formulate a drug product, and phase transitions can be attenuated to the extent possible during standard pharmaceutical procedures such as compaction, milling and wet granulation. However, a huge disadvantage associated with the thermodynamically most stable form of the drug substance is the fact that it is the least soluble form, resulting in reduced bioavailability. This is critical for sparingly soluble compounds such as bitegravir. Therefore, the use of a metastable drug polymorph may be desirable due to its particular characteristics, in particular higher solubility and hence bioavailability, as well as better performance during milling and compression, or less hygroscopicity. However, it is important to exclude any possible solid form transitions that may occur in the metastable polymorph during pharmaceutical processing or storage, as these can greatly affect the safety and efficacy of the drug product. Therefore, not every metastable polymorph of an active pharmaceutical ingredient can be used to prepare a pharmaceutical composition.

It is an object of the present invention to provide an improved bitegravir sodium polymorph that is kinetically stable, eg does not undergo phase transitions during standard pharmaceutical processing and storage, and at the same time has high solubility and dissolution rates.

The essence of the invention

In the present invention, the above problem is solved with the metastable bitegravir sodium polymorph, hereinafter also referred to as form II. Form II of the present invention has been found to be monotropically related to the known form I in WO 2015/196116 A1, the latter being the highest melting form. According to measurements from to

- 1 042594 by DSC at a heating rate of 10 K/min, the transition temperature at which Form II of the present invention is converted to Form I of WO 2015/196116 A1 is well over 300°C. This unusually high transition temperature is indicative of the high kinetic stability of Form II of the present invention and shows that the likelihood of solid form changes during standard pharmaceutical processing and during storage is vanishingly small. On the other hand, form II has a higher solubility than form I. Therefore, bitegravir sodium form II of the present invention combines the favorable characteristics of high physical stability and high solubility, and is therefore the preferred solid form of bitegravir sodium for the preparation of a pharmaceutical composition. Other favorable characteristics of form II bitegravir sodium are low hygroscopicity and good characteristics during milling and compression, which make it particularly suitable for the preparation of a pharmaceutical composition.

Abbreviations. ______________________________________________________

PXRD powder x-ray FTIR infrared Fourier spectroscopy ATR broken total reflection DSC differential scanning calorimetry TGA thermogravimetric analysis

Definitions.

The term bitegravir as used in the present invention means (2R,5S,13aR)-7,9dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,13,13a-octahydro -2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-8-olate (IUPAC name) or (2R,5S,13aR)-8- hydroxy-7,9-dioxo-N-(2,4,6trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4, 5]pyrazino[2,1-b][1,3]oxazepine10-carboxamide of formula (I) disclosed above in the present invention.

The term bitegravir sodium as used herein means the sodium salt of bitegravir having a chemical structure in which about 1 mole of bitegravir is bonded to 1 mole of sodium via ionic interaction of deprotonated bitegravir with Na ⁺ . Bitegravir sodium can be represented by the chemical structure of formula (II) below in the present invention.

The term bitegravir sodium form I as used in the present invention means the crystalline form of bitegravir sodium as disclosed in WO 2015/196116 A. Bitegravir sodium form I can be characterized by a powder X-ray pattern containing reflections at 2theta angles equal to (5.5 ± 0.3 )°, (16.1±0.3)°, (22.1±0.3)°, (23.3±0.3)° and (28.5±0.3)°, when measured at temperature in the range from 20 to 30°C using radiation Cu-K-alpha ₁ , ₂ having a wavelength equal to 0.15419 nm.

When used in the present invention, the term measured at a temperature in the range from 20 to 30°C means the measurement under standard conditions. Typically, standard conditions mean a temperature in the range of 20 to 30°C, i. e. room temperature. Standard conditions may mean a temperature of about 22°C.

Typically, standard conditions may further mean measurement at 20-80% RH, preferably 30-70% RH, more preferably 40-60% RH, and most preferably 50% RH.

The term reflection in relation to X-ray powder imaging as used in the present invention means peaks in an X-ray pattern that are formed at certain diffraction angles (Bragg angles) by enhancing interference of X-rays scattered by parallel planes of atoms in a solid material that are distributed in an orderly and repetitive manner in far positional order. . Such a solid material is classified as a crystalline material, and an amorphous material is defined as a solid material in which there is no long-range order and only short-range order, resulting in broad scattering. According to the literature, the long-range order, for example, extends over about 100-1000 atoms, while the short-range order extends over only a few atoms (see Fundamentals of Powder Diffraction and Structural Characterization of Materials by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers , 2003, page 3).

When used in the present invention, the term amorphous means the solid form of the compound, which is not crystalline. An amorphous compound does not have long-range order and does not result in a distinct X-ray diffraction pattern with reflections.

The term is basically the same when applied to X-ray powder imaging, meaning that changes in the positions of the reflections and in the relative intensities of the reflections must be taken into account. For example, the typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, preferably in the range of ±0.1° 2-theta. Thus, under standard conditions for most diffractometers, the reflectance, which is usually at 6.5° 2-theta, for example, can range from 6.3 to 6.7° 2

- 2042594 theta, preferably from 6.4 to 6.6° 2-theta. In addition, one skilled in the art should understand that the relative intensities of reflections vary from instrument to instrument, as well as vary with degree of crystallinity, preferred orientation, sample preparation, and other factors known to those skilled in the art, and should only be considered quality measure.

The term is basically the same when applied to Fourier infrared spectroscopy, meaning that changes in peak positions and in relative peak intensities should be taken into account. For example, the typical accuracy of wavenumber values is in the range of ±2 cm ^-1 . Thus, under standard conditions for most infrared spectrometers, the peak at 3055 cm ^-1 , for example, can range from 3053 to 3057 cm ^-1 . The differences in relative intensities are usually smaller than for radiography. However, one of skill in the art should understand that slight differences in peak intensities due to differences in crystallinity, sample preparation, and other factors can also appear in infrared spectroscopy. Therefore, the relative peak intensities should be considered only a qualitative measure.

The term is basically the same when applied to Raman spectroscopy, meaning that changes in peak positions and in relative peak intensities should be taken into account. For example, the typical accuracy of wavenumber values is in the range of ±4 cm ^-1 . Thus, under standard conditions for most Raman spectrometers, the peak at 1641 cm ^-1 , for example, can range from 1637 to 1645 cm ^-1 . The differences in relative intensities are usually smaller than for radiography. However, one of skill in the art should understand that slight differences in peak intensities due to differences in crystallinity, sample preparation, and other factors can also show up in Raman spectroscopy. Therefore, the relative peak intensities should be considered only a qualitative measure.

When used in the present invention, the term generally does not contain another physical form in relation to a composition containing a specific physical form of bitegravir sodium, means that the composition contains no more than 20%, preferably no more than 10%, more preferably no more than 5%, even more preferably not more than 2% and most preferably not more than 1% by weight of any other physical form of bitegravir sodium, based on the weight of the composition.

The term physical form as used herein means any crystalline and/or amorphous phase of a compound.

When used in the present invention, the term solvate means a crystalline form of a molecule, atom and/or ion, which additionally contains the molecules of the solvent or solvents included in the structure of the crystal lattice.

The crystalline forms of bitegravir sodium in the present invention can be considered as characterized by the X-ray powder diffraction, FTIR spectrum or Raman spectrum shown in the drawing. One of skill in the art understands that factors such as changes in instrument type, response and changes in sample directionality, sample concentration, sample purity, sample history, and sample preparation technique can lead to changes such as those associated with accurate reflection and peak positions and their intensities. However, it is within the skill of the art to compare the graphical data in the drawings of the present invention with the graphical data generated for an unknown physical form and confirm that the two sets of graphical data refer to the same crystal form.

When used in the present invention, the term mother liquor means the solution remaining after crystallization of the solid from the specified solution.

The predetermined amount when used in the present invention with respect to bitegravir sodium means the initial amount of bitegravir sodium used to prepare a pharmaceutical composition containing the desired dose of bitegravir.

The term "effective amount" as used herein in relation to bitegravir sodium includes an amount of bitegravir sodium which has the desired therapeutic and/or prophylactic effect.

When used in the present invention, the term roughly means a statistically significant range of value. Such a range, in order of magnitude, may vary by no more than 10%, more often no more than 5%, even more often no more than 1%, and most often no more than 0.1% of the specified value or range. Sometimes such a range may differ by no more than the experimental error typical of standard techniques used to measure and/or determine the indicated value or range.

The term pharmaceutically acceptable excipient as used in the present invention means substances that do not have significant pharmacological activity at a given dose and are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient.

- 3 042594

Brief description of the drawings

Fig. 1 illustrates a typical PXRD of bitegravir sodium form II of the present invention. The x-axis shows the scattering angle in °2-theta, and the y-axis shows the intensity of the scattered X-ray beam in the form of the number of detected protons.

Fig. 2 illustrates a typical PXRD of the bitegravir sodium 2,2,2-trifluoroethanol solvate of the present invention. The x-axis shows the scattering angle in °2-theta, and the y-axis shows the intensity of the scattered X-ray beam in the form of the number of detected protons.

Fig. 3 illustrates a comparison of a typical PXRD of bitegravir sodium crystalline form II according to the present invention (bottom) and a typical PXRD of bitegravir sodium form I from WO 2015/196116 A1 prepared in accordance with Reference Example 1 of the present invention (top). The x-axis shows the scattering angle in °2-theta. Form I PXRD is y-shifted to separate radiographs for clarity.

Fig. 4 illustrates a comparison of a typical PXRD of bitegravir sodium crystalline form II of the present invention (bottom) and a typical PXRD of bitegravir sodium 2,2,2-trifluoroethanol solvate of the present invention (top). The x-axis shows the scattering angle in °2-theta. PXRD solvate with 2,2,2-trifluoroethanol is shifted on the y-axis to separate X-ray patterns for clarity.

Fig. 5 illustrates a typical FTIR spectrum of bitegravir sodium form II of the present invention. The x-axis shows the wave numbers in cm ^-1 , the y-axis shows the relative intensity as a percentage of transmission.

Fig. 6 illustrates a typical FTIR spectrum of the bitegravir sodium solvate with 2,2,2-trifluoroethanol of the present invention. The x-axis shows the wave numbers in cm ^-1 , the y-axis shows the relative intensity as a percentage of transmission.

Fig. 7 illustrates a typical Raman spectrum of bitegravir sodium Form II of the present invention. The x-axis shows the wavenumbers in cm ^-1 , the y-axis shows the intensity of Raman scattering.

Fig. 8 illustrates a typical Raman spectrum of the bitegravir sodium solvate with 2,2,2-trifluoroethanol of the present invention. The x-axis shows the wave numbers in cm ^-1 , the y-axis shows the intensity of Raman scattering.

Fig. 9 illustrates a typical DSC curve of bitegravir sodium Form II of the present invention. The x-axis shows the temperature in degrees Celsius (°C), the y-axis shows the heat flow rate in watts per gram (W/g) with upward endothermic peaks.

Fig. 10 illustrates a typical DSC curve of bitegravir sodium solvate with 2,2,2 trifluoroethanol of the present invention. The x-axis shows the temperature in degrees Celsius (°C), the y-axis shows the heat flow rate in watts per gram (W/g) with upward endothermic peaks.

Fig. 11 illustrates a typical TGA curve of bitegravir sodium form II of the present invention. The x-axis shows the temperature in degrees Celsius (°C), the y-axis shows the mass (loss) of the sample in percent by weight (wt.%).

Fig. 12 illustrates a typical TGA curve of bitegravir sodium solvate with 2,2,2 trifluoroethanol of the present invention. The x-axis shows the temperature in degrees Celsius (°C), the y-axis shows the mass (loss) of the sample in percent by weight (wt.%).

Detailed description of the invention

The present invention relates to a metastable bitegravir sodium polymorph, in the present invention, also referred to as form II.

Although it is a metastable polymorph, the bitegravir sodium form II of the present invention has a high physical stability, for example, according to DSC measurement at a heating rate of 10 K/min, it converts to the thermodynamically more stable form I from WO 2015 /196116 A1 at temperatures well above 300°C. Form II of the present invention has a higher solubility, a fact which results in greater bioequivalence of a low solubility drug such as bitegravir. Therefore, Form II of the present invention combines the favorable characteristics of high physical stability and high solubility and is therefore an ideal solid form of bitegravir sodium for the preparation of an improved pharmaceutical composition, such as a pharmaceutical composition with increased bioavailability, which is safe and effective throughout its duration. expiration date.

- 4 042594

Bitegravir sodium can be described by the following chemical structure of formula (II):

Bitegravir sodium can be characterized by a molar ratio of bitegravir to sodium, preferably in the range of 1.0:0.7 to 1.0:1.3, more preferably in the range of 1.0:0.8 to 1.0 :1.2, even more preferably in the range of 1.0:0.9 to 1.0:1.1, and in particular the molar ratio is 1.0:1.0.

Form II of bitegravir sodium according to the present invention may be characterized by any of the following embodiments or by a combination of two or more of the following embodiments.

Thus, the first object of the present invention is the crystalline form of bitegravir sodium (form II), which can be characterized by a powder X-ray pattern containing reflections at 2-theta angles equal to (6.5±0.2)°, (7.5±0 .2)° and (18.8±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (18.8±0.2)° and (20.9±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (18.8±0.2)°, (19.4±0.2)° and (20.9± 0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (18.8±0.2)°, (19.4± 0.2)° and (20.9±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (18.8±0.2)°, (19.4± 0.2)°, (20.9±0.2)° and (26.5±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (18.1±0.2)°, (18.8± 0.2)°, (19.4±0.2)°, (20.9±0.2)° and (26.5±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (16.8±0.2)°, (18.1± 0.2)°, (18.8±0.2)°, (19.4±0.2)°, (20.9±0.2)° and (26.5±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (20.9±0.2)° and (26.5± 0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (20.9±0.2)°, (24.2± 0.2)° and (26.5±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (14.6±0.2)°, (14.6± 0.2)°, (14.6±0.2)°, (20.9±0.2)°, (24.2±0.2)°, (24.7±0.2)° and (26.5±0.2)°; or (6.5±0.2)°, (7.5±0.2)°, (13.0±0.2)°, (14.6±0.2)°, (16.8± 0.2)°, (18.1±0.2)°, (16.8±0.2)°, (18.1±0.2)°, (16.8±0.2)°, (18.1±0.2)°, (16.8±0.2)°, (18.1±0.2)°, (18.8±0.2)°, (19.4±0 .2)°, (18.8±0.2)°, (18.8±0.2)°, (18.8±0.2)°, (19.4±0.2)°, ( 19.4±0.2)°, (19.4±0.2)°, (20.9±0.2)°, (23.5±0.2)°, (24.2±0, 2)°, (24.7 ± 0.2)° and (26.5 ± 0.2)°, when measured at a temperature in the range from 20 to 30°C using Cu-Kalfa1, ₂ radiation, which has a wavelength , equal to 0.15419 nm.

In another embodiment, the present invention relates to a crystalline form of bitegravir sodium (Form II), which can be characterized by a powder X-ray pattern containing reflections at 2-theta angles equal to (6.5±0.1)°, (7.5±0 .1)° and (18.8±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (18.8±0.1)° and (20.9±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (18.8±0.1)°, (19.4±0.1)° and (20.9± 0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (18.8±0.1)°, (19.4± 0.1)° and (20.9±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (18.8±0.1)°, (19.4± 0.1)°, (20.9±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (18.1±0.1)°, (18.8± 0.1)°, (19.4±0.1)°, (20.9±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (16.8±0.1)°, (18.1± 0.1)°, (18.8±0.1)°, (19.4±0.1)°, (20.9±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (14.6±0.1)°, (16.8± 0.1)°, (18.1±0.1)°, (18.8±0.1)°, (19.4±0.1)°, (20.9±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (14.6±0.1)°, (16.8± 0.1)°, (18.1±0.1)°, (18.8±0.1)°, (19.4±0.1)°, (20.9±0.1)°, (24.2±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (14.6±0.1)°, (16.8± 0.1)°, (18.1±0.1)°, (18.8±0.1)°, (19.4±0.1)°, (20.9±0.1)°, (24.2±0.1)°, (24.7±0.1)° and (26.5±0.1)°; or (6.5±0.1)°, (7.5±0.1)°, (13.0±0.1)°, (14.6±0.1)°, (16.8± 0.1)°, (18.1±0.1)°, (18.8±0.1)°, (19.4±0.1)°, (20.9±0.1)°, (23.5±0.1)°, (24.2±0.1)°, (24.7±0.1)° and (26.5±0.1)°, when measured at a temperature in the range from 20 to 30°C using Cu- _Kalfa1,2 radiation having a wavelength of 0.15419 nm.

The powder X-ray diffraction pattern of bitegravir sodium form II according to the present invention is easily distinguished from the X-ray diffraction pattern of known Form I in WO 2015/196116 A1 (see also the overlay shown for this purpose in Fig. 3 in the present invention). Form II has, for example, reflection

- 5 042594 niami at 2-theta angles equal to (6.5±0.2)°, (7.5±0.2)° and (18.8±0.2)°, and form I does not have reflections in these ranges. On the other hand, form II has no reflections at (5.5 ± 0.2)° 2-theta, and form I has a very characteristic reflection (namely, the most intense reflection) in this range. Thus, another object of the present invention is the crystalline form of bitegravir sodium (form II), which is characterized by a powder X-ray pattern containing reflections at the 2-theta angles indicated above, but no reflection in the range from (5.5 ± 0.2) ° 2-theta, when measured at a temperature in the range of 20 to 30°C using Cu-K-alpha ₁ , ₂ radiation with a wavelength of 0.15419 nm.

In yet another embodiment, the present invention relates to a crystalline form of bitegravir sodium (Form II) having an X-ray powder pattern substantially the same as that shown in FIG. 1 in the present invention when measured at a temperature in the range of 20 to 30° C. using Cu-K-alpha ₁ , ₂ radiation having a wavelength of 0.15419 nm.

In another embodiment, the present invention relates to a crystalline form of bitegravir sodium (form II) characterized by an FTIR spectrum including peaks at wavenumbers equal to (3055±2) cm ^-1 , (2964±2) cm ^-1 and (1614± 2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 and (1525±2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 and (1435±2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 , (1435±2) cm ^-1 and (1315±2 ) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 , (1435±2) cm ^-1 , (1315±2 ) cm ^-1 and (1290±2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 , (1435±2) cm ^-1 , (1315±2 ) cm ^-1 (1290±2) cm ^-1 and (1252±2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 , (1435±2) cm ^-1 , (1315±2 ) cm ^-1 (1290±2) cm ^-1 , (1252±2) cm ^-1 and (1069±2) cm ^-1 ; or (3055±2) cm ^-1 , (2964±2) cm ^-1 , (1614±2) cm ^-1 , (1525±2) cm ^-1 , (1435±2) cm ^-1 , (1315±2 ) cm ^-1 , (1290±2) cm ^-1 , (1252±2) cm ^-1 , (1069±2) cm ^-1 and (998±2) cm ^-1 , when measured at a temperature in the range from 20 to 30°C using an ATR diamond cell.

In yet another embodiment, the present invention relates to a crystalline form of bitegravir sodium (Form II) characterized by an FTIR spectrum substantially the same as shown in FIG. 5 in the present invention when measured at a temperature in the range of 20 to 30°C using an ATR diamond cell.

In another embodiment, the present invention relates to a crystalline form of bitegravir sodium (Form II) characterized by a Raman spectrum including peaks at wavenumbers equal to (1641±4) cm ^-1 , (1436±4) cm ^-1 and (680 ±4) cm ^-1 ; or (1641±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 and (680±4) cm ^-1 ; or (1641±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 , (1328±4) cm ^-1 and (680±4) cm ^-1 ; or (1641±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 , (1328±4) cm ^-1 , (1254±4) cm ^-1 and (680±4 ) cm ^-1 ; or (1641±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 , (1328±4) cm ^-1 , (1254±4) cm ^-1 , (759±4 ) cm ^-1 and (680±4) cm ^-1 ; or (1641±4) cm ^-1 , (1474±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 , (1328±4) cm ^-1 , (1254±4 ) cm ^-1 , (759±4) cm ^-1 and (680±4) cm ^-1 ; or (1641±4) cm ^-1 , (1517±4) cm ^-1 , (1474±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4) cm ^-1 , (1328±4 ) cm ^-1 , (1254±4) cm ^-1 , (759±4) cm ^-1 and (680±4) cm ^-1 ; or (1641±4) cm ^-1 , (1586±4) cm ^-1 , (1517±4) cm ^-1 , (1474±4) cm ^-1 , (1436±4) cm ^-1 , (1404±4 ) cm ^-1 , (1328±4) cm ^-1 , (1254±4) cm ^-1 , (759±4) cm ^-1 and (680±4) cm ^-1 , when measured at a temperature in the range from 20 to 30°C and at a wavelength of 785 nm.

In yet another embodiment, the present invention provides a crystalline form of bitegravir sodium (Form II) having a Raman spectrum substantially the same as that shown in FIG. 7 in the present invention, when measured at a temperature in the range of 20 to 30°C and at a wavelength of 785 nm.

In one aspect, the present invention relates to a composition comprising bitegravir sodium form II of the present invention, which is substantially free of any other physical forms of bitegravir sodium. For example, a composition comprising bitegravir sodium form II of the present invention contains no more than 20 wt.%, preferably no more than 10 wt.%, more preferably no more than 5 wt.%, even more preferably no more than 2 wt.% and most preferably not more than 1% by weight of any other physical form of bitegravir sodium, based on the weight of the composition. Preferably, any other physical form of bitegravir sodium is selected from the group consisting of Form I of WO 2015/196116 A1, 2,2,2-trifluoroethanol solvate, defined as

- 6 042594 divided below in the present invention, or amorphous bitegravir sodium. Thus, in another preferred embodiment, the present invention relates to a composition comprising bitegravir sodium Form II as defined above in the present invention, characterized by a PXRD containing no reflection at 2-theta angles in the range of (5.5±0.2) ° and / or (5.8±0.2) °, when measured at a temperature in the range from 20 to 30 ° C using radiation Cu-K-alpha ₁ , ₂ having a wavelength equal to 0.15419 nm.

Surprisingly, it was found that a new crystalline form of bitegravir sodium can be obtained by crystallizing bitegravir sodium from 2,2,2-trifluoroethanol and using the conditions described below. Crystallization of bitegravir sodium from 2,2,2-trifluoroethanol under the conditions disclosed below in the present invention leads to the formation of a solvate with 2,2,2-trifluoroethanol, which can be further desolvated under the drying conditions disclosed below in the present invention to form the preferred Form II bitegravir -sodium, proposed in the present invention. Thus, the solvate with 2,2,2-trifluoroethanol is an intermediate product for obtaining form II bitegravir-sodium proposed in the present invention.

The solvate of bitegravir of the present invention may be characterized by any of the following embodiments or by combining two or more of the following embodiments.

In one aspect, the present invention relates to bitegravir sodium solvate, which can be characterized by a powder X-ray pattern containing reflections at 2-theta angles equal to (5.8±0.2)°, (16.8±0.2)° and ( 21.0±0.2)°; or (5.8±0.2)°, (16.8±0.2)°, (19.5±0.2)° and (21.0±0.2)°; or (5.8±0.2)°, (16.8±0.2)°, (17.5±0.2)°, (19.5±0.2)° and (21.0± 0.2)°; or (5.8±0.2)°, (15.9±0.2)°, (16.8±0.2)°, (17.5±0.2)°, (19.5± 0.2)° and (21.0±0.2)°; or (5.8±0.2)°, (9.1±0.2)°, (15.9±0.2)°, (16.8±0.2)°, (17.5± 0.2)°, (19.5±0.2)° and (21.0±0.2)°; or (5.8±0.2)°, (9.1±0.2)°, (12.5±0.2)°, (15.9±0.2)°, (16.8± 0.2)°, (17.5±0.2)°, (19.5±0.2)° and (21.0±0.2)°; or (5.8±0.2)°, (9.1±0.2)°, (12.5±0.2)°, (15.9±0.2)°, (16.8± 0.2)°, (17.5±0.2)°, (19.5±0.2)°, (21.0±0.2)° and (25.0±0.2)°; or (5.8±0.2)°, (9.1±0.2)°, (12.5±0.2)°, (15.9±0.2)°, (16.8± 0.2)°, (17.5±0.2)°, (19.5±0.2)°, (21.0±0.2)°, (22.3±0.2)° and (25.0±0.2)°;

when measured at a temperature in the range from 20 to 30°C using Cu- _Kalfa1,2 radiation having a wavelength of 0.15419 nm.

In another embodiment, the present invention relates to bitegravir sodium solvate, which can be characterized by a powder X-ray pattern containing reflections at 2theta angles equal to (5.8±0.1)°, (16.8±0.1)° and (21 .0±0.1)°; or (5.8±0.1)°, (16.8±0.1)°, (19.5±0.1)° and (21.0±0.1)°; or (5.8±0.1)°, (16.8±0.1)°, (17.5±0.1)°, (19.5±0.1)° and (21.0± 0.1)°; or (5.8±0.1)°, (15.9±0.1)°, (16.8±0.1)°, (17.5±0.1)°, (19.5± 0.1)° and (21.0±0.1)°; or (5.8±0.1)°, (9.1±0.1)°, (15.9±0.1)°, (16.8±0.1)°, (17.5± 0.1)°, (19.5±0.1)° and (21.0±0.1)°; or (5.8±0.1)°, (9.1±0.1)°, (12.5±0.1)°, (15.9±0.1)°, (16.8± 0.1)°, (17.5±0.1)°, (19.5±0.1)° and (21.0±0.1)°; or (5.8±0.1)°, (9.1±0.1)°, (12.5±0.1)°, (15.9±0.1)°, (16.8± 0.1)°, (17.5±0.1)°, (19.5±0.1)°, (21.0±0.1)° and (25.0±0.1)°; or (5.8±0.1)°, (9.1±0.1)°, (12.5±0.1)°, (15.9±0.1)°, (16.8± 0.1)°, (17.5±0.1)°, (19.5±0.1)°, (21.0±0.1)°, (22.3±0.1)° and (25.0±0.1)°;

when measured at a temperature in the range from 20 to 30°C using radiation Cu-Kalfa ₁ , ₂ having a wavelength equal to 0.15419 nm.

In yet another embodiment, the present invention relates to bitegravir sodium solvate having an x-ray powder diffraction pattern substantially the same as that shown in FIG. 2 in the present invention when measured at a temperature in the range of 20 to 30°C using Cu-K-alpha ₁ , ₂ radiation having a wavelength of 0.15419 nm.

In another embodiment, the present invention relates to a solvate of bitegravir, characterized by an FTIR spectrum, including peaks at wave numbers equal to (3069±2) cm ^-1 , (2933±2) cm' ¹ and (1526±2) cm'¹; or (3069±2) cm' ¹ , (2933±2) cm' ¹ , (1526±2) cm' ¹ and (1290±2) cm'¹; or (3069±2) cm' ¹ , (2933±2) cm' ¹ , (1623±2) cm' ¹ , (1526±2) cm' ¹ and (1290±2) cm'¹; or (3069±2) cm' ¹ , (2933±2) cm' ¹ , (1623±2) cm' ¹ , (1526±2) cm' ¹ , (1434±2) cm' ¹ and (1290±2 ) cm'¹; or (3069±2) cm' ¹ , (2933±2) cm' ¹ , (1623±2) cm' ¹ , (1526±2) cm' ¹ , (1434±2) cm' ¹ , (1290±2 ) cm' ¹ and (1207±2) cm'¹; or (3069±2) cm' ¹ , (2933±2) cm' ¹ , (1623±2) cm' ¹ , (1526±2) cm' ¹ , (1434±2) cm' ¹ , (1290±2 ) cm' ¹ , (1207±2) cm' ¹ and (1073±2) cm'¹; or

- 7 042594 (3069±2) cm ^-1 , (2933±2) cm ^-1 , (1623±2) cm ^-1 , (1526±2) cm ^-1 , (1434±2) cm ^-1 , (1290 ±2) cm ^-1 , (1207±2) cm ^-1 , (1073±2) cm ^-1 and (998±2) cm ^-1 ; or (3069±2) cm ^-1 , (2933±2) cm ^-1 , (1623±2) cm ^-1 , (1526±2) cm ^-1 , (1434±2) cm ^-1 , (1290±2 ) cm ^-1 , (1207±2) cm ^-1 , (1073±2) cm ^-1 , (998±2) cm ^-1 and (832±2) cm ^-1 , when measured at a temperature in the range from 20 to 30°C using an ATR diamond cell.

In yet another embodiment, the present invention relates to bitegravir sodium solvate having an FTIR spectrum substantially the same as that shown in FIG. 6 in the present invention when measured at a temperature in the range of 20 to 30°C using an ATR diamond cell.

In another embodiment, the present invention relates to a solvate of bitegravir-sodium, characterized by a Raman spectrum, including peaks at wave numbers equal to (1501±4) cm ^-1 , (1472±4) cm ^-1 and (1400±4) cm ^{- 1} ; or (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1400±4) cm ^-1 and (1328±4) cm ^-1 ; or (1645±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1400±4) cm ^-1 and (1328±4) cm ^-1 ; or (1645±4) cm ^-1 , (1587±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1400±4) cm ^-1 and (1328±4 ) cm ^-1 ; or (1645±4) cm ^-1 , (1587±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1436±4) cm ^-1 , (1400±4 ) cm ^-1 and (1328±4) cm ^-1 ; or (1645±4) cm ^-1 , (1587±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1436±4) cm ^-1 , (1400±4 ) cm ^-1 , (1328±4) cm ^-1 and (1294±4) cm ^-1 ; or (1645±4) cm ^-1 , (1587±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1436±4) cm ^-1 , (1400±4 ) cm ^-1 , (1328±4) cm ^-1 , (1294±4) cm ^-1 and (1211±4) cm ^-1 ; or (1645±4) cm ^-1 , (1587±4) cm ^-1 , (1501±4) cm ^-1 , (1472±4) cm ^-1 , (1436±4) cm ^-1 , (1400±4 ) cm ^-1 , (1328±4) cm ^-1 , (1294±4) cm ^-1 , (1211±4) cm ^-1 and (681±4) cm ^-1 , when measured at a temperature in the range from 20 to 30°C and at a wavelength of 785 nm.

In yet another embodiment, the present invention relates to bitegravir sodium solvate having a Raman spectrum substantially the same as that shown in FIG. 8 in the present invention, when measured at a temperature in the range of 20 to 30°C and at a wavelength of 785 nm.

In the above, the present invention describes a solvate, preferably a solvate with 2,2,2-trifluoroethanol, more preferably a monosolvate with 2,2,2-trifluoroethanol.

Another object of the present invention is a method for obtaining a crystalline form II of bitegravir sodium, proposed in the present invention, or a composition comprising form II of bitegravir sodium, as defined above, comprising:

(i) preparing a solution containing bitegravir sodium and 2,2,2-trifluoroethanol;

(ii) crystallization of bitegravir sodium from the solution obtained in step (i);

(iii) optionally isolating at least a portion of the crystals obtained in step (ii) from their mother liquor;

(iv) optionally washing the isolated crystals obtained in step (iii);

(v) drying the crystals obtained in any of steps (ii)-(iv), wherein the drying is carried out in an atmosphere having a temperature in the range of 50 to 150° C. and in a vacuum of about 1 to 50 mbar.

Bitegravir can be obtained in accordance with the instructions in WO 2014/100323 A1, in particular, in accordance with the instructions contained in example 42. The solution obtained in stage (i) of the above procedure can be obtained by reacting bitegravir in the presence of 2,2, 2-trifluoroethanol with an alkaline source of sodium, for example sodium hydroxide, which is preferably used as an aqueous solution. Alternatively, the solution in step (i) of the above process can be prepared using bitegravir sodium as starting material and dissolving bitegravir sodium in 2,2,2-trifluoroethanol. Bitegravir sodium starting material can be prepared by reacting bitegravir with an aqueous solution of sodium hydroxide in a suitable solvent such as water, ethanol, THF, or any mixture thereof. Bitegravir sodium, for example, can be prepared according to Reference Example 1 in the present invention. In WO 2015/196116 A1, in particular, in the specific example disclosed in the paragraph on adjacent pages 38 and 39, a method for obtaining bitegravir sodium is also described.

The solution obtained in step (i) in the above method of the present invention can be obtained at room temperature or by heating bitegravir sodium in trifluoroethanol to a temperature in the range of about 40° C. to a boiling point, for example, to a temperature in the range about 50 to 70°C. The concentration of bitegravir sodium in said solution is usually about 25 to 100 g/l, preferably about 40 to 60 g/l and most preferably about 50 to 55 g/l. The solution can optionally be filtered to remove any possible undissolved particles.

After obtaining a clear solution containing bitegravir sodium and 2,2,2-trifluoroethanol, bitegravir sodium is crystallized in the next step (ii). Crystallization is initiated by

- 8 042594 temperature of the solution obtained in stage (i) to a temperature in the range from -25 to 30°C, preferably from about -10 to 10°C. Optionally, bitegravir sodium Form II seed crystals can be added to initiate crystallization and/or to control the particle size distribution of the final resulting material. The amount of seed crystals can be in the range of about 1 to 10% by weight, based on the amount of bitegravir sodium contained in the solution. After the material has crystallized and the target end temperature of the resulting slurry has been established, the resulting slurry is preferably further agitated at said temperature for a period that allows for abundant crystallization and/or crystal maturation. Typically, the slurry is further agitated for a period ranging from about 1 to 48 hours, preferably from about 2 to 24 hours, and most preferably from about 3 to 12 hours, such as from 4 to 6 hours.

In the next step, optionally, at least a portion of the crystals are separated from their mother liquor. The crystals are preferably separated from their mother liquor by any conventional technique such as filtration, centrifugation, solvent evaporation or decantation, more preferably filtration or centrifugation, and most preferably filtration.

In another optional step, the separated crystals can be washed with a suitable solvent, for example an organic solvent selected from the group consisting of 2,2,2-trifluoroethanol or ethanol.

The material thus obtained was found to be a solvate of bitegravir sodium with 2,2,2-trifluoromethanol, which can be desolvated using the conditions disclosed below.

The crystals obtained in any of steps (ii)-(iv), preferably step (iii) or (iv), are then dried, where the drying is carried out at a temperature in the range from about 50 to 150°C, for example about 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C or 150°C and vacuum in the range of approx. 1 to 50 mbar , for example, in the range of about 10 to 30 mbar. Typically, drying is carried out over a period ranging from about 6 to 72 hours, preferably 10 to 48 hours, more preferably 12 to 24 hours. Drying is carried out until most of the 2,2,2-trifluoroethanol solvate, preferably all of the The 2,2,2-trifluoroethanol obtained in any of steps (ii)-(iv) of the above process is not desolvated to the desired form II of the bitegravir sodium of the present invention. Said transformation can be registered, for example, using PXRD. One indication that desolvation is complete and that drying can be reversed is the disappearance of the most intense reflection at (5.8 ± 0.2)° 2-theta on the PXRD of the 2,2,2-trifluoroethanol solvate, which is absent on the PXRD of pure phase II of bitegravir sodium.

As noted above, bitegravir sodium form II of the present invention combines the favorable characteristics of high physical stability and high solubility and is therefore the preferred solid form of bitegravir sodium for pharmaceutical formulation.

Although it is a metastable polymorph, in a DSC study performed at a heating rate of 10 K/min, bitegravir sodium form II of the present invention was found to be extremely resistant to thermal stress and its crystal structure only changed when heated at temperatures well above 300°C (see experimental part and Fig. 9 in the present invention). This phase transition in the solid phase was confirmed by high temperature microscopy and X-ray powder diffraction. For example, a Form II sample that was heated slightly above the transition temperature and then cooled to room temperature resulted in a PXRD corresponding to the Form I PXRD of WO 2015/196116 A1. Based on this thermal behavior, it can be concluded, firstly, that form II is extremely resistant to thermal stress and its crystal structure only changes when heated at temperatures to which the pharmaceutical is never heated during processing and storage, and secondly, that Form I and Form II are monotropically linked to Form I, which is a thermodynamically stable polymorph below its melting point (see Heat-of-Transition rule, A. Burger and R. Ramberger, On the Polymorphism of Pharmaceuticals and Other Molecular Crystals. I Microchim. Acta II, (1979) 259-271). The fact that bitegravir sodium form II of the present invention has a greater solubility than bitegravir sodium form I of WO 2015/196116 A1 is very valuable, since the higher solubility of form II also results in faster dissolution and, most importantly, to greater bioavailability, which is quite important for a sparingly soluble substance such as bitegravir. Therefore, bitegravir sodium Form II of the present invention is the preferred form for use in a pharmaceutical composition for administration to a patient in need of such treatment.

Thus, another object of the present invention is the use of form II bitegravir sodium, proposed in the present invention, as defined above, for the preparation of a pharmaceutical composition.

Another object of the present invention is a pharmaceutical composition comprising

- 9 042594 bitegravir sodium form II as defined above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient. Most preferably, the pharmaceutical composition of the present invention is in an oral solid dosage form such as a tablet or capsule. Preferably, the pharmaceutical composition of the present invention is a tablet, most preferably a film-coated tablet. In one embodiment, the tablet contains a film coating of a coating material containing polyvinyl alcohol (eg, partially hydrolyzed), iron oxide, talc, and titanium dioxide.

At least one pharmaceutically acceptable excipient contained in the pharmaceutical composition of the present invention is preferably selected from the group consisting of carriers, excipients, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavoring agents, binders, colorants, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials, and combinations thereof. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of fillers, diluents, lubricants, disintegrants, and coating materials. In one embodiment, all of these pharmaceutically acceptable excipients are contained in the pharmaceutical composition of the present invention.

In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In a preferred embodiment, all of these pharmaceutically acceptable excipients are contained in the pharmaceutical composition of the present invention.

The present invention preferably relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bitegravir sodium form II is selected from the group consisting of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg , 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg and 100 mg in terms of bitegravir. Most preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bitegravir sodium form II is 50 mg, based on bitegravir.

Another object of the present invention is a pharmaceutical composition comprising bitegravir sodium form II as defined above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient and optionally one or more additional active pharmaceutical ingredients. Most preferably, the pharmaceutical composition of the present invention is in an oral solid dosage form such as a tablet or capsule. Preferably, the pharmaceutical composition of the present invention is a tablet, most preferably a film-coated tablet. In one embodiment, the tablet contains a film coating of a coating material containing polyvinyl alcohol (eg, partially hydrolyzed), iron oxide, talc, and titanium dioxide.

At least one pharmaceutically acceptable excipient contained in the pharmaceutical composition of the present invention is preferably selected from the group consisting of carriers, excipients, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavoring agents, binders, colorants, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials, and combinations thereof. More preferably, the at least one pharmaceutically acceptable excipient is selected from the group consisting of fillers, diluents, lubricants, disintegrants, and coating materials. In one embodiment, all of these pharmaceutically acceptable excipients are contained in the pharmaceutical composition of the present invention.

In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In a preferred embodiment, all of these pharmaceutically acceptable excipients are contained in the pharmaceutical composition of the present invention.

The present invention preferably relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bitegravir sodium form II is selected from the group consisting of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg , 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg and 100 mg in terms of bitegravir. Most preferably, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of bitegravir sodium form II is 50 mg, based on bitegravir.

- 10 042594

In another preferred embodiment, one or more additional active pharmaceutical ingredients are/are selected from the group consisting of entry/fusion inhibitors, reverse transcriptase inhibitors (RTIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors, protease inhibitors (PIs), or their mixtures. In another preferred embodiment, the entry/fusion inhibitors are selected from the group consisting of enfuvirtide, maraviroc, vikriviroc, cenicriviroc and fostemsavir or mixtures thereof, the reverse transcriptase inhibitors (RTIs) are selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir, apricitabine, censavudine, elvucitabine, racivir, stampidine, zalcitabine, tenofovir disoproxil, tenofovir alafenamide, efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, doravirine or mixtures thereof, integrase strand transfer inhibitors (INSTI) selected from the group consisting of dolutegravir, elvitegravir , raltegravir and bitegravir or mixtures thereof, the maturation inhibitor is bevirimat and protease inhibitors (PIs) are selected from the group consisting of amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir, tipranavir or mixtures thereof.

In a particularly preferred embodiment, one or more additional active pharmaceutical ingredients are/are selected from the group consisting of emtricitabine or a pharmaceutically acceptable salt thereof and tenofovir alafenamide or a pharmaceutically acceptable salt thereof, most preferably one or more additional active pharmaceutical ingredients are emtricitabine and hemifumarate. tenofovir alafenamide.

In some embodiments, the pharmaceutical composition contains 50 mg of form II bitegravir sodium in terms of bitegravir, 25 mg of tenofovir alafenamide or its pharmaceutically acceptable salt in terms of tenofovir alafenamide and 200 mg of emtricitabine or its pharmaceutically acceptable salt in terms of emtricitabine. For example, in some embodiments, the pharmaceutical composition contains bitegravir sodium form II 52.5 mg, tenofovir alafenamide hemifumarate 28 mg, and emtricitabine 200 mg. In a particularly preferred embodiment, the pharmaceutical composition of the present invention is a bilayer tablet comprising a first layer comprising bitegravir sodium form II and a second layer comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof and emtricitabine or a pharmaceutically acceptable salt thereof. The present invention preferably relates to a bilayer tablet comprising a first layer comprising bitegravir sodium form II and a second layer comprising tenofovir alafenamide hemifumarate and emtricitabine.

The present invention preferably relates to the pharmaceutical composition described above, where the pharmaceutical composition must be administered once a day.

Another object of the present invention is the pharmaceutical composition described above for use as a medicine.

Another object of the present invention is a pharmaceutical composition as described above for use in the treatment or prevention of viral infections caused by DNA viruses, RNA viruses, herpes viruses (for example, CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (for example, HBV), papillomavirus, hantavirus, adenoviruses and HIV.

In a preferred embodiment, the present invention relates to a pharmaceutical composition as described above for use in the treatment and/or prevention of HIV-1 infections.

In another embodiment, the present invention relates to a method of treating or prophylactically preventing HIV-1 infections by administering the pharmaceutical composition described above to a patient in need of such treatment and/or prevention.

Another aspect of the present invention is a pharmaceutical composition as described above for the treatment of HIV-1 infections in combination with one or more additional active pharmaceutical ingredients selected from the group consisting of entry/fusion inhibitors, reverse transcriptase inhibitors (RTIs), strand transfer inhibitors. integrase (INSTI), maturation inhibitors, protease inhibitors (PIs), or mixtures thereof. In another preferred embodiment, the entry/fusion inhibitors are selected from the group consisting of enfuvirtide, maraviroc, vikriviroc, cenicriviroc, ibalizumab and fostemsavir or mixtures thereof, the reverse transcriptase inhibitors (RTIs) are selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine, amdoxovir, apricitabine, censavudine, elvucitabine, racivir, stampidine, zalcitabine, tenofovir disoproxil, tenofovir alafenamide, efavirenz, nevirapine, delavirdine, etravirine, rilpivirine, doravirine or mixtures thereof, integrase strand transfer inhibitors (INSTI) selected from the group consisting of dolutegravir , elvitegravir, raltegravir and bitegravir or mixtures thereof, the maturation inhibitor is bevirimat and the protease inhibitors (PIs) are selected from the group consisting of amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir, darunavir, tipranavir or mixtures thereof.

Treatment in combination with one or more additional active pharmaceutical ingredients may mean administering a pharmaceutical dosage form comprising

- 11 042594 bitegravir sodium form II according to the present invention and one or more additional active pharmaceutical ingredients in the same dosage form, for example as a fixed dose combination.

Alternatively, treatment in combination with one or more additional active pharmaceutical ingredients may mean administering separate pharmaceutical dosage forms, one comprising bitegravir sodium form II of the present invention and the other(s) comprising one or more additional active pharmaceutical ingredients. ingredients in separate dosage form(s). Typically, in such combination therapy, instructions are given that a pharmaceutical dosage form comprising bitegravir sodium form II of the present invention must be administered in combination with said separate dosage form(s) to effectively treat a viral infection, such as an HIV- 1.

The following non-limiting examples are illustrative of the disclosure and should not be construed as limiting the scope of the present invention in any way.

Example 1 Preparation of form II bitegravir sodium.

Bitegravir (1.50 g, for example prepared according to example 42 in WO 2014/100323 A1) was dissolved in trifluoroethanol (30 ml) with heating to 65°C. An aqueous solution of NaOH (1 M, 3.6 ml) was added dropwise to the solution. The solution was then cooled to 0°C for 4 hours, after which crystallization was observed at a temperature of about 40°C. The resulting suspension was further stirred at 0° C. for 3 hours, then the crystals were collected by filtration and dried in vacuo (30 mbar) at 50° C. for 15 hours to give bitegravir sodium crystalline II (1.30 g).

Examples

Powder radiography.

PXRD was obtained using a PANalytical X'Pert PRO diffractometer equipped with a dual theta/theta goniometer in transmission geometry using Cu-K-alpha ₁ , ₂ radiation (wavelength 0.15419 nm) with a focusing mirror and a PIXcel solid phase detector. The radiographs were recorded at a tube voltage of kV and a tube current of 40 mA using 2-theta increments of 0.013° increments of 40 s per step (255 channels) over a range of angles from 2 to 40° 2theta at normal conditions. Typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, preferably ±0.1° 2-theta. Thus, for most diffractometers under standard conditions, the Form II diffraction peak of bitegravir sodium, which is located at, for example, 7.5° 2-theta, can be in the range from 7.3 to 7.7° 2-theta, preferably in range from 7.4 to 7.6° 2-theta.

A typical X-ray pattern of Form II bitegravir sodium is shown in FIG. 1 in the present invention. The corresponding list of reflections is given below in Table. 1.

Table 1 PXRD reflections and corresponding relative intensities for form II bitegravir sodium ranging from 2 to 30° 2-theta; typical value accuracy

-theta is in the range of ±0.2° 2-theta, preferably ±0.1° 2-theta

Reflection position [° 2-theta] Relative intensity[%] Reflection position [° 2-theta] Relative intensity[%] 6.5 14 18.8 thirty 7.5 100 19.4 13 13.0 14 20.9 43 14.6 9 23.5 8 15.4 2 24.2 14 16.3 4 24.7 eleven 16.8 8 26.5 18 18.1 10 29.6 6

Infrared Fourier spectroscopy.

Form II bitegravir sodium was examined by FTIR spectroscopy. The FTIR spectrum was recorded (obtained) using a Golden Gate™ Single Reflection Diamond ATR MCP cell of a Bruker Tensor 27 FTIR spectrometer with a resolution of 4 cm ^-1 at a temperature in the range from 20 to 30°C. To record the spectrum, a sample of the substance at the tip of a spatula in powder form was applied to the diamond surface. Then the sample was pressed into the diamond using a sapphire tip and the spectrum was recorded. The spectrum of pure diamond was used as background. Typical accuracy of wavenumber values is in the range of ±2 cm ^-1 . Thus, under standard conditions for most infrared spectrometers, the Form II infrared peak of bitegravir sodium, which is, for example, at 1624 cm ^-1 can be in the range from 1622 to 1626 cm ^-1 .

A typical FTIR spectrum of form II bitegravir sodium of the present invention is shown in FIG. 5 and the corresponding list of peaks is given below in table. 2.

- 12 042594

table 2

List of FTIR peaks of form II bitegravir sodium of the present invention; typical accuracy of wavenumber values is in the range of ±2 cm ^-1

Wave number [cm ¹ ] Wave number [cm ^-1 ] Wave number [cm ^-1 ] 3055 1290 898 2964 1252 847 1647 1208 828 1614 1158 803 1525 1128 756 1435 1110 727 1404 1069 709 1362 998 677 1315 950 616

Raman Spectroscopy.

Form II bitegravir-sodium was investigated using Raman spectroscopy. The Raman spectrum was recorded on a Raman Rxn 1 Raman spectrometer with a PhAT sensor with a spot size of 6 mm and a maximum focal length of 250 mm manufactured by Kaiser Optical Systems using an Invictus laser with a wavelength of 785 nm, a power of 400 mW and a measurement duration of 15 s. The spectrum was recorded in the range from 1850 to 200 cm ^-1 with a resolution of 4 cm ^-1 under normal conditions. The typical accuracy of wavenumber values is in the range of about ±4 cm ^-1 . Thus, under standard conditions for most Raman spectrometers, the Raman peak, which is, for example, at 1641 cm ^-1 can be in the range from 1637 to 1645 cm ^-1 . A typical form II Raman spectrum of bitegravir sodium is shown in FIG. 7. The listed spectrum was corrected to the baseline using OPUS 7.0 software (Bruker Optik GmbH) using the concave rubber thread method using 15 iterations and 64 base points. The corresponding list of peaks is given below in table. 3.

Table 3

List of Raman peaks of bitegravir sodium form II of the present invention; typical accuracy of wavenumber values is in the range of ±4 cm ^-1

Wave number [cm ¹ ] Wave number [cm ¹ ] Wave number [cm ¹ ] 1641 1160 709 1626 1150 680 1586 1074 615 1517 1047 577 1474 1020 524 1436 1001 514 1404 981 415 1384 952 328 1363 918 307 1328 887 292 1294 818 258 1254 803 216 1211 759

Differential scanning calorimetry.

Form II bitegravir sodium was examined by DSC on a Mettler Polymer DSC R instrument. A sample (3.77 mg) was heated in a 40 μl aluminum dish with a perforated aluminum lid at 25 to 400°C at a rate of 10 K/min. Nitrogen was used as purge gas (purge rate 50 ml/min).

The Form II DSC curve has a small exothermic peak starting at about 313° C. and a peak at about 320° C. (see also FIG. 9 in the present invention). This peak is due to a phase change in the solid phase from Form II of the present invention to Form I of WO 2015/196116 A1.

Form I then begins to decompose at a temperature of about 370°C.

Thermogravimetric analysis.

Form II bitegravir sodium was tested by TGA on a Mettler TGA/DSC 1 instrument. A sample (11.64 mg) was heated in a 100 μl aluminum dish covered with an aluminum lid. The lid was automatically perforated at the start of the measurement. The sample was heated at a temperature from 25 to 300°C at a rate of 10 K/min. Nitrogen was used as purge gas (purge rate 50 ml/min).

- 13 042594

The Form II TGA curve shows a weight loss of only about 0.5 wt% up to a temperature of about 300° C. (see FIG. 11 in the present invention). Thus, it can be concluded that neither water nor organic solvents are part of the crystal structure, and the mass loss may rather be due to the release of residual solvent/water, which is weakly bound to the surface.

dissolution rate.

The initial dissolution characteristics of form II bitegravir sodium were compared with data for form I bitegravir sodium. Approximately 100 mg bitegravir-Na (Form I or Form II) was suspended at 24° C. in 10 ml of solvent. Two different solvents were used in this study: 0.1M aqueous HCl and phosphate buffer system (pH 6.8; prepared according to Kuster Thiel - Rechentafeln dur die chemische Analytik).

After stirring for 1 min, a sample was taken and filtered through a syringe filter. The resulting clear filtrate was analyzed by HPLC to determine the content of bitegravir. For HPLC, a YMC-Pack Pro C18 RS (150x4.6 mm) column was used while running at 0.8 ml/min. The determination was carried out at a wavelength of 254 nm. The mobile phases were an aqueous solution of sulfamic acid and acetonitrile, respectively, and they were used as components of the gradient mode.

It was found that after 1 min 0.186 mg/ml form II bitegravir sodium was dissolved in the buffer system at pH 6.8, while only 0.059 mg/ml form I bitegravir sodium was dissolved. In 0.1 M HCl, 0.220 mg/ml form II bitegravir sodium was dissolved, while only 0.085 mg/ml form I bitegravir sodium was dissolved.

Thus, form II bitegravir sodium is a storage stable (polymorphically stable according to XRPD for at least 1 month when stored at 40°C/75% RH), a rapidly dissolving crystalline form of bitegravir sodium, with unexpected advantages over form I bitegravir sodium.

Example 2 Preparation of bitegravir sodium solvate with trifluoroethanol.

Bitegravir (0.5 g, for example, prepared according to example 42 in WO 2014/100323 A1) was dissolved in trifluoroethanol (10 ml) by heating to 70°C. NaOH (1 M, 1.22 ml) was added to the aqueous solution and the solution was further stirred at 65° C. for 2 hours. The solution was then allowed to cool to room temperature and a suspension was obtained. The suspension was further stirred at room temperature for 5 hours and then the crystals were successively collected by centrifugation to give bitegravir sodium trifluoroethanol solvate.

Powder radiography.

PXRD was obtained using a PANalytical X'Pert PRO diffractometer equipped with a dual theta/theta goniometer in transmission geometry using Cu-K-alpha1,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a PIXcel solid phase detector. The radiographs were recorded at a tube voltage of kV and a tube current of 40 mA using 2-theta increments of 0.013° increments of 40 s per step (255 channels) over a range of angles from 2 to 40° 2theta at normal conditions. Typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, preferably ±0.1° 2-theta. Thus, for most diffractometers under standard conditions, the diffraction peak of bitegravir sodium solvate with 2,2,2-trifluoroethanol, which is, for example, at 5.8° 2-theta, can be in the range from 5.6 to 6.0° 2-theta, preferably in the range of 5.7 to 5.9° 2-theta.

A typical X-ray diffraction pattern of bitegravir sodium solvate with 2,2,2-trifluoroethanol is shown in FIG. 2 in the present invention. The corresponding list of reflections is given below in Table. 4.

- 14 042594

Table 4

PXRD reflections and corresponding relative intensities for bitegravir sodium solvate with 2,2,2-trifluoroethanol in the range from 2 to 30° 2-theta; typical accuracy of 2-theta values is in the range of ±0.2° 2-theta, preferably up to ±0.1° 2-theta

Reflection position [° 2-theta] Relative intensity[%] Reflection position [° 2-theta] Relative intensity[%] 5.8 100 21.0 44 9.1 3 21.4 3 11.6 1 22.3 7 12.5 3 23.5 14 15.9 10 23.7 9 16.8 39 24.1 2 17.5 23 24.6 3 18.1 4 25.0 14 18.8 8 27.8 4 19.5 31 28.2 9 20.0 3 29.6 5 20.4 6

Infrared Fourier spectroscopy.

Bitegravir sodium solvate with 2,2,2-trifluoroethanol was examined by FTIR spectroscopy. The FTIR spectrum was recorded (obtained) using a Golden Gate™ Single Reflection Diamond ATR MCP cell of a Bruker Tensor 27 FTIR spectrometer with a resolution of 4 cm ^-1 at a temperature in the range from 20 to 30°C. To record the spectrum, a sample of the substance at the tip of a spatula in powder form was applied to the diamond surface. Then the sample was pressed into the diamond using a sapphire tip and the spectrum was recorded. The spectrum of pure diamond was used as background. Typical accuracy of wavenumber values is in the range of about ±2 cm ^-1 . Thus, under standard conditions for most infrared spectrometers, the infrared peak of bitegravir sodium solvate with 2,2,2-trifluoroethanol, which is, for example, at 1623 cm ^-1 , can be in the range from 1621 to 1625 cm ^-1 .

A typical FTIR spectrum of the bitegravir sodium solvate with 2,2,2-trifluoroethanol of the present invention is shown in FIG. 5 and the corresponding list of peaks is given below in table. 5.

Table 5

List of FTIR peaks of bitegravir sodium solvate with 2,2,2-trifluoroethanol of the present invention; typical accuracy of wavenumber values is in the range of ±2 cm ^-1

Wave number [cm ¹ ] Wave number [cm ¹ ] Wave number [cm ¹ ] 3248 1313 900 3069 1290 832 2933 1251 802 1623 1207 767 1526 1157 747 1434 1106 711 1400 1073 679 1370 998 614 1344 952

Raman Spectroscopy.

Bitegravir sodium solvate with 2,2,2-trifluoroethanol was studied using Raman spectroscopy. The Raman spectrum was recorded on a Raman Rxn 1 Raman spectrometer with a PhAT sensor with a spot size of 6 mm and a maximum focal length of 250 mm manufactured by Kaiser Optical Systems using an Invictus laser with a wavelength of 785 nm, a power of 400 mW and a measurement duration of 15 s. The spectrum was recorded in the range from 1850 to 200 cm ^-1 with a resolution of 4 cm ^-1 under normal conditions. The typical accuracy of wavenumber values is in the range of about ±4 cm ^-1 . Thus, under standard conditions for most Raman spectrometers, the Raman peak, which is, for example, at 1645 cm ^-1 can be in the range from 1641 to 1649 cm ^-1 . A typical Raman spectrum of bitegravir sodium solvate with 2,2,2-trifluoroethanol is shown in FIG. 8. The reduced spectrum was corrected to the baseline using the OPUS 7.0 software (Bruker Optik GmbH) using the concave rubber thread method using 15 iterations and

- 15042594 base points. The corresponding list of peaks is given below in table. 6.

Table 6

List of Raman peaks of bitegravir sodium solvate with 2,2,2-trifluoroethanol proposed in the present invention;

typical accuracy of wavenumber values is in the range of ± 4 cm ^-1

Wave number [cm ¹ ] Wave number [cm ¹ ] Wave number [cm ^-1 ] 1645 1075 681 1587 1047 578 1501 1022 560 1472 999 521 1436 978 415 1400 955 375 1343 919 322 1328 902 293 1294 886 258 1252 862 218 1211 802 1159 711

Differential scanning calorimetry.

Bitegravir sodium solvate with 2,2,2-trifluoroethanol was analyzed by DSC on a Mettler Polymer DSC R instrument. speed 10 K/min. Nitrogen was used as purge gas (purge rate 50 ml/min).

The DSC curve of the 2,2,2-trifluoroethanol solvate has a broad endothermic peak starting at about 104°C and a peak at about 138°C followed by a less intense endothermic peak starting at about 155°C and a peak at about 162°C. These signals are due to the process of desolvation/dehydration, which leads to the conversion to the form II proposed in the present invention. The rest of the DSC curve exhibits essentially the same behavior as described for Form II above in Example 1, including an exothermic peak due to the solid phase transition to Form I starting at about 315°C and a peak at about 322°C. (see Fig. 10 in the present invention).

Thermogravimetric analysis.

Bitegravir sodium solvate with 2,2,2-trifluoroethanol was analyzed by TGA on a Mettler TGA/DSC 1 instrument. A sample (9.57 mg) was heated in a 100 μl aluminum dish covered with an aluminum lid. The lid was automatically perforated at the start of the measurement. The sample was heated at a temperature from 25 to 300°C at a rate of 10 K/min. Nitrogen was used as purge gas (purge rate 50 ml/min).

The TGA curve shows a weight loss of about 15.8 wt.% up to a temperature of about 160°C, which corresponds to about 0.9 mol of 2,2,2-trifluoroethanol per 1 mol of bitegravir sodium (see Fig. 12 in the present invention) .

Example 3: Bilayer tablet containing form II bitegravir sodium/emtricitabine/tenofovir alafenamide hemifumarate.

Ingredient mg/tablet first layer second layer Form II bitegravir Na 52.5* Emtricitabine 200 Tenofovir hemifumarate alafenamide 28** Microcrystalline cellulose 246.3 113.2 sodium salt croscarmellose 19.4 30.2 magnesium stearate 4.9 5.7 Layer weight 323 377 Tablet core weight 700 Opadry II 21 film-coated tablet coated 721.2

* Equivalent to 50 mg bitegravir.

**Equivalent to tenofovir alafenamide 25 mg.

- 16 042594

The manufacturing/packaging procedure for the bitegravir sodium/emtricitabine/tenofovir alafenamide form II tablet is divided into 5 generic processes:

1) mixing form II bitegravir sodium with intragranular excipients, roller compaction or aggregation, grinding and mixing with extragranular excipients and the resulting final powder mixture for form II bitegravir sodium;

2) blending emtricitabine and tenofovir alafenamide hemifumarate with intragranular excipients, dry granulating, milling and mixing with extragranular excipients and obtaining a powder mixture of emtricitabine/tenofovir alafenamide hemifumarate;

3) compressing tablets to obtain bilayer tablet cores;

4) to obtain film-coated tablets and

5) packaging.

The steps in the procedure for obtaining the final medicinal product are described in detail below.

Bitegravir Sodium Form II Powder Blend:

1) Form II bitegravir sodium and excipients (microcrystalline cellulose and croscarmellose sodium) are weighed. The weight of form II bitegravir sodium is adjusted based on the drug content ratio while reducing the weight of microcrystalline cellulose;

2) intragranular part of magnesium stearate is placed in a drum mixer and mixed;

3) carry out dry granulation of the resulting mixture using a roller compactor or aggregation of the resulting mixture and grinding;

4) add extragranular microcrystalline cellulose and magnesium stearate and rush.

Tenofovir Alafenamide Emtricitabine/Hemifumarate Final Powder Blend:

5) emtricitabine and tenofovir alafenamide hemifumarate and excipients (microcrystalline cellulose and croscarmellose sodium) are weighed. The weight of emtricitabine and tenofovir alafenamide hemifumarate is adjusted based on the content ratios of the respective drugs while reducing the weight of microcrystalline cellulose;

6) emtricitabine and tenofovir alafenamide hemifumarate, microcrystalline cellulose and croscarmellose sodium are placed in a drum mixer and mixed;

7) intragranular part of magnesium stearate is placed in a drum mixer and mixed;

8) carry out dry granulation of the resulting mixture using a roller compactor or aggregation of the resulting mixture and grinding;

9) admix the extragranular portion of magnesium stearate.

Tableting:

10) The final bitegravir-sodium form II powder mixture is compressed as the first layer and the final emtricitabine/tenofovir alafenamide hemifumarate powder mixture is compressed as the second layer using an appropriate base pressing force to achieve a target hardness of 17 kPa (range: 14 to 20 kPa). The final powder mixture is compressed to achieve a target layer weight of 323 mg based on a target total tablet weight of 700 mg.

Film coating:

11) prepare a suspension of Opadry® II. The tablet cores are film coated to achieve a target weight gain of 3% (range 2-4%). The film-coated tablets are dried and then cooled and discharged.

Example 4 Film-coated tablet containing form II bitegravir sodium.

Ingredient mg/tablet Form II bitegravir Na 52.5* Microcrystalline cellulose 246.3 Croscarmellose sodium salt 19.4 magnesium stearate 4.9 Tablet core weight 323 Opadry II 10 Film-coated tablet 333

* Equivalent to 50 mg bitegravir.

The procedure for obtaining/packaging a Form II bitegravir sodium tablet is divided into 4 typical processes:

1) mixing form II bitegravir sodium with intragranular excipients, roller compaction or aggregation, grinding and mixing with extragranular excipients and the resulting final powder mixture for form II bitegravir sodium;

2) compressing tablets to obtain tablet cores;

3) applying a film to the tablets to obtain film-coated tablets and

4) packaging.

-

Claims (9)

The steps in the procedure for obtaining the final medicinal product are described in detail below. Bitegravir Sodium Form II Powder Blend: 1. Crystalline form of bitegravir sodium (form II), characterized in that it has a powder X-ray pattern containing reflections at 2-theta angles equal to (6.5±0.2), (7.5±0.2) and ( 18.8±0.2)°, when measured at a temperature in the range from 20 to 30°C using radiation Cu-K-alpha ₁ , ₂ having a wavelength equal to 0.15419 nm. 1) Form II bitegravir sodium and excipients (microcrystalline cellulose and croscarmellose sodium) are weighed. The weight of form II bitegravir sodium is adjusted based on the drug content ratio while reducing the weight of microcrystalline cellulose; 2. A crystalline form according to claim 1, characterized in that it has a powder X-ray pattern containing additional reflections at 2-theta angles equal to (19.4 ± 0.2) and (20.9 ± 0.2) °, when measured at a temperature in the range from 20 to 30°C using radiation Cu-K-alpha ₁ , ₂ with a wavelength equal to 0.15419 nm. 2) intragranular part of magnesium stearate is placed in a drum mixer and mixed; 3. A crystalline form according to claim 1 or 2, characterized in that it has a powder X-ray pattern containing no reflection at 2-theta angles in the range of (5.5±0.2)°, when measured at a temperature in the range of 20 to 30 °C using Cu-K-alpha radiation ₁ , ₂ having a wavelength of 0.15419 nm. 3) carry out dry granulation of the resulting mixture using a roller compactor or aggregation of the resulting mixture and grinding; 4. The crystalline form according to any of the preceding claims, characterized in that it has an infrared Fourier spectrum, including peaks at wave numbers equal to (3055±2), (2964±2) and (1614±2) cm ^-1 when measured at a temperature in the range from 20 to 30°C using a diamond cell of frustrated total reflection. 4) add extragranular microcrystalline cellulose and magnesium stearate and mix. Tableting: 5. A crystalline form according to any of the preceding claims, characterized in that it has a Raman spectrum including peaks at wave numbers equal to (1641±4), (1436±4) and (680±4) cm ^-1 when measured at temperature in the range from 20 to 30°C and at a wavelength of 785 nm. 5) The final bitegravir-sodium Form II powder mixture is compressed using an appropriate base pressing force to achieve a target hardness of 17 kPa (range: 14 to 20 kPa). The final powder mixture is compressed to provide a target total tablet weight of 323 mg. Film coating: 6. A composition containing a crystalline form according to any of the preceding paragraphs and not more than 5 wt.% of any other physical form of bitegravir sodium, based on the weight of the composition. 6) prepare a suspension of Opadry® II. The tablet cores are film coated to achieve a target weight gain of 3% (range 2-4%). The film-coated tablets are dried and then cooled and discharged. Reference example. Obtaining form I bitegravir sodium from WO 2015/196116 A1. Bitegravir (100 mg, for example prepared according to example 42 in WO 2014/100323 A1) was dissolved in ethanol (3.9 ml) by heating to 70°C. NaOH (1 M, 220 μl) was added to the aqueous solution and the solution was allowed to cool to room temperature, after which crystallization occurred. The resulting suspension was further stirred at room temperature for 2 hours. The suspension was then kept at 2-8° C. overnight and then the crystals were collected by filtration. The wet product was washed with ethanol and dried in vacuo at room temperature for 2 h to give bitegravir sodium (98 mg, Form I). CLAIM 7. Composition according to claim 6, in which the other physical form of bitegravir sodium is form I, characterized in that it has a powder X-ray pattern containing reflections at 2-theta angles equal to (5.5 ± 0.3), (16, 1±0.3), (22.1±0.3), (23.3±0.3) and (28.5±0.3)°, when measured at a temperature in the range from 20 to 30°С using radiation Cu-K-alpha ₁ , ₂ having a wavelength equal to 0.15419 nm. 8. The composition according to claim 6 or 7, characterized in that it has a powder X-ray pattern that does not contain reflections at angles of 2-theta in the range of (5.5 ± 0.2) °, when measured at a temperature in the range of 20 to 30 °C using Cu-K-alpha radiation ₁ , ₂ having a wavelength of 0.15419 nm. 9. Use of a crystalline form according to any one of claims 1 to 5 or a composition according to any one of claims 6 to 8 -