WO2016192692A1

WO2016192692A1 - Solid forms of tenofovir alafenamide

Info

Publication number: WO2016192692A1
Application number: PCT/CZ2016/000059
Authority: WO
Inventors: Ondrej Dammer; Tereza SKALICKA; Lukas KREJCIK; Tomas Pekarek; Ludek Ridvan
Original assignee: Zentiva K.S.
Priority date: 2015-06-05
Filing date: 2016-05-30
Publication date: 2016-12-08
Also published as: CZ2015384A3

Abstract

The invention relates to a solid form of tenofovir alafenamide with an inorganic or organic acid selected from the following group: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic, 4- aminobenzoic acid. Another aspect of the present invention provides a pharmaceutical composition, which comprises the solid form of tenofovir alafenamide and at least one pharmaceutically acceptable excipient, the composition being used as a medicament for the treatment of HIV infection and viral hepatitis B. (I)

Description

Solid forms of Tenofovir alafenamide

Technical Field

The invention relates to novel solid forms of (S)-isopropyl-2-(((5)-((((i-)-l-(6-amino- purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)arnino)propanoate formula (I),

known as tenofovir alafenamide and methods of its preparation. Background Art

(iSHsopropyl-2-(((£ ((((i-)- 1 -(6-an^

phosphoryl) amino) propanoate, known as Tenofovir alafenamide, is a nucleotide reverse transcriptase inhibitor and an innovative prodrug of the pharmaceutical substance tenofovir. It is suitable for the treatment of HIV infection and viral hepatitis B. Compared to the currently used tenofovir tenofovir disoproxil, tenofovir alafenamide exhibits higher efficiency (the pharmaceutical composition will probably require a lower strength of the active ingredient), better patient tolerance (fewer side effects) and better distribution to lymphoid tissues. Tenofovir alafenamide is in Phase 3 clinical trials and it is expected to be present in the pharmaceutical composition in the form of a salt - fumarate or hemifumarate. The pharmaceutical compositions are further expected to include, besides tenofovir alafenamide (hemi)iumarate, another active ingredient(s) acting as HTV protease inhibitors, HIV nucleotide/nucleotide reverse transcriptase inhibitors, CCR5 inhibitors - e.g. emtricitabine, cobicistat, elvitegravir, darunavir.

Synthesis of tenofovir alafenamide is described in WO02/08241. The document also contains crystallographic data and the melting point of this substance. The patent further mentions an example of preparing the fumarate salt of tenofovir alafenamide, along with its melting point.

The patent application WO2013/025788 describes preparation and characterization of tenofovir alafenamide hemifumarate. The main advantage of this salt is its ability to eliminate the principal diastereoisomeric impurity (GS7339) of tenofovir alafenamide as compared to the fumarate salt. Additionally, the hemifumarate salt exhibits better chemical and thermodynamical stability, low hygroscopicity (it absorbs 0.65% of water at 90% rel. humidity) and a higher melting point than the fumarate salt of tenofovir alafenamide. The patent application WO2013/025788 also describes pharmaceutical compositions containing tenofovir alafenamide in the hemifumarate form.

Solid/polymorphic forms of tenofovir alafenamide have not been described yet; it is only the above mentioned fumarate and hemifumarate that have been described out of its pharmaceutical salts. Disclosure of Invention

The invention provides new solid forms of tenofovir alafenamide (salts, cocrystals) with inorganic and organic acids and methods for preparing the same. These substances are prepared by a reaction of tenofovir alafenamide with a selected acid in a suitable solvent or a mixture of solvents.

The prepared novel solid forms are of a crystalline or amorphous character and are prepared in a purity corresponding to the demands for their possible pharmaceutical use in formulation of new dosage forms. Brief Description of Drawings

Figure 1 : X-ray powder pattern of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)

Figure 2: DSC record of the solid form of tenofovir alafenamide and hydrochloric acid (1:1) Figure 3: Infrared spectrum of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)

Figure 4: X-ray powder pattern of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)

Figure 5: DSC record of the solid form of tenofovir alafenamide and hydrobromic acid (1:1) Figure 6: Infrared spectrum of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)

Figure 7: X-ray powder pattern of the solid form of tenofovir alafenamide and sulphuric acid (1:1)

Figure 8: DSC record of the solid form of tenofovir alafenamide and sulphuric acid (1: 1)

Figure 9: Infrared spectrum of the solid form of tenofovir alafenamide and sulphuric acid (1:1)

Figure 10: X-ray powder pattern of the solid form of tenofovir alafenamide and phosphoric acid (1: 1)

Figure 11: DSC record of the solid form of tenofovir alafenamide and phosphoric acid (1:1) Figure 12: Infrared spectrum of the solid form of tenofovir alafenamide and phosphoric acid (1:1)

Figure 13: X-ray powder pattern of the solid form of tenofovir alafenamide and maleic acid 0:1)

Figure 14: DSC record of the solid form of tenofovir alafenamide and maleic acid (1:1)

Figure 15: Infrared spectrum of the solid form of tenofovir alafenamide and maleic acid (1:1) Figure 16: X-ray powder pattern of the solid form of tenofovir alafenamide and citric acid (1:1)

Figure 17: DSC record of the solid form of tenofovir alafenamide and citric acid (1:1) Figure 18: Infrared spectrum of the solid form of tenofovir alafenamide and citric acid (1:1) Figure 19: X-ray powder pattern of the solid form of tenofovir alafenamide and succinic acid (1 :1)

Figure 20: DSC record of the solid form of tenofovir alafenamide and succinic acid (1:1) Figure 21: Infrared spectrum of the solid form of tenofovir alafenamide and succinic acid (1:1)

Figure 22: X-ray powder pattern of the solid form of tenofovir alafenamide and tartaric acid (1 :1)

Figure 23: DSC record of the solid form of tenofovir alafenamide and tartaric acid (1 :1) Figure 24: Infrared spectrum of the solid form of tenofovir alafenamide and tartaric acid (1:1) Figure 25: X-ray powder pattern of the solid form of tenofovir alafenamide and gallic acid (1:1)

Figure 26: DSC record of the solid form of tenofovir alafenamide and gallic acid (1:1) Figure 27: Infrared spectrum of the solid form of tenofovir alafenamide and gallic acid (1:1) Figure 28: X-ray powder pattern of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)

Figure 29: DSC record of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)

Figure 30: Infrared spectrum of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)

Figure 31 : X-ray powder pattern of the solid form of tenofovir alafenamide and salicylic acid (1:1)

Figure 32: DSC record of the solid form of tenofovir alafenamide and salicylic acid (1:1) Figure 33: Infrared spectrum of the solid form of tenofovir alafenamide and salicylic acid (1:1)

Figure 34: X-ray powder pattern of the solid form of tenofovir alafenamide and 4- aminobenzoic acid (1:1)

Figure 35: DSC record of the solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1)

Figure 36: Infrared spectrum of the solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1)

Detailed description of the invention

Pharmaceutical salts and cocrystals represent a wide group of solid forms of active pharmaceutical ingredients, they can exist in the form of hydrates/solvates. They usually exhibit better solubility and the related biological availability as compared to the neutral forms. They also tend to be chemically and thermodynamically more stable. Therefore, pharmaceutical salts/cocrystals are frequently used as active ingredients in the final pharmaceutical compositions.

The invention provides novel solid forms of tenofovir alafenamide with the following inorganic or organic acid: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulfonic, salicylic, 4-aminobenzoic and gallic acid in various molar ratios, the molar ratio of 1:1 being preferred. The invention provides crystalline or amorphous solid forms of tenofovir alafenamide or mixtures of amorphous and crystalline forms; crystalline forms are preferred. The described novel solid forms of tenofovir alafenamide with the said inorganic or organic acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline form, amorphous form, or in a mixture of amorphous and crystalline forms.

The prepared new solid forms of tenofovir alafenamide may exhibit various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystalline or amorphous forms or their mixtures in any ratio. These novel solid forms can be both anhydrous or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.

Preparation of the novel solid forms of tenofovir alafenamide (formula (I)) is carried out by reaction of tenofovir alafenamide with the corresponding acid, which is selected from the following group: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulfonic, salicylic, 4-aminobenzoic and gallic acid. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Acetonitrile can be preferably used. Esters of a C3 to C5 alcohol and CI to C4 acids are preferred; the ester is preferably selected such that the total number of carbon atoms is 5 to 8. Thus, propyl ester of butanoic acid or pentyl ester of formic acid appears to be advantageous. The ester may be composed of primary, secondary or tertiary alcohols. Similarly, the carbon skeleton of the acid may be linear or branched. Further, esters of carbonic acid with C1-C3 alcohols can be used. The above mentioned esters may be used either pure or in a mixture with another solvent, referred to as a co-solvent. Less polar solvents are selected as the co-solvents. C6 to C9 aromatics, or C6 to C9 alicyclic hydrocarbons, or CI to C4 chlorinated hydrocarbons, substituted with one or more chlorine atoms have proved to be suitable. Examples may include cyclohexane, toluene or dichloromethane.

The resulting product is typically crystallized or precipitated at temperatures in the range of -10 to 75°C.

The above mentioned solid forms of tenofovir alafenamide can be used for the preparation of tenofovir alafenamide fumarate or hemifumarate.

The crystalline solid form of tenofovir alafenamide and hydrochloric acid (1:1) is characterized by the reflections presented in Table 1. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and hydrochloric acid in accordance with this invention are: 3.4; 8.5; 10.4; 13.4; 14.8; 18.2 and 19 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 1.

Table 1

30.86 2.895 7.2

32.98 2.714 5.6

34.80 2.576 5.1

The DSC record of the solid form of tenofovir alafenamide and hydrochloric acid (1:1) (Figure 2) shows an endo therm at 144 °C, subsequent recrystallization and the second endotherm at 160 °C.

The infrared spectrum of the solid form of tenofovir alafenamide and hydrochloric acid (1 :1) is shown in Figure 3.

The crystalline solid form of tenofovir alafenamide and hydrobromic acid (1:1) is characterized by the reflections presented in Table 2. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and hydrobromic acid in accordance with this invention are: 3.4; 10.5; 18.4; 21.1 and 24.3; ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 4.

Table 2

In this case, the melting point of the solid form of tenofovir alafenamide and hydrobromic acid (1:1) (Figure 5) is 35°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and hydrobromic acid (1:1) is shown in Figure 6.

The crystalline solid form of tenofovir alafenamide and sulphuric acid (1:1) is characterized by the reflections presented in Table 3. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and sulphuric acid in accordance with this invention are: 3.6; 9.2; 18.5; 22.4 and 24.5 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 7.

Table 3

28.25 3.156 2.8

29.38 3.038 2.7

31.25 2.860 4.0

34.29 2.613 1.5

In this case, the melting point of the solid form of tenofovir alafenamide and sulphuric acid (1 :1) (Figure 8) is 115°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and sulphuric acid (1:1) is shown in Figure 9.

The crystalline solid form of tenofovir alafenamide and phosphoric acid (1:1) is characterized by the reflections presented in Table 4. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and phosphoric acid in accordance with this invention are: 3.4; 8.1; 10.2; 13.6; 17.0 and 18,9 ± 0.2° 2-theta. The X-ray powder pattern is shown in Figure 10.

Table 4

In this case, the melting point of the solid form of tenofovir alafenamide and phosphoric acid (1:1) (Figure 11) is 125°C (DSC). The infrared spectrum of the solid form of tenofovir alafenamide and phosphoric acid (1:1) is shown in Figure 12.

The crystalline solid form of tenofovir alafenamide and maleic acid (1 :1) is characterized by the reflections presented in Table 5. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and maleic acid in accordance with this invention are: 4.5; 7.7; 12.5; 17.9; 20.9 and 25.6 ± 0.2° 2-theta. The X-ray powder pattern is shown in Figure 13.

Table 5

In this case, the melting point of the solid form of tenofovir alafenamide and maleic acid (1:1) (Figure 14) is 98°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and maleic acid (1:1) is shown in Figure 15.

The crystalline solid form of tenofovir alafenamide and citric acid (1:1) is characterized by the reflections presented in Table 6. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and citric acid in accordance with this invention are: 5.8; 8.0; 12.6; 15.9; 17.9; 20.5 and 26.9 ± 0.2° 2-theta. The X-ray powder pattern is shown in Figure 16.

Table 6

24.27 3.664 8.9

25.03 3.554 7.0

25.89 3.439 13.1

26.86 3.317 38.1

29.23 3.053 19.9

31.05 2.878 8.5

31.83 2.809 18.9

32.59 2.745 12.6

In this case, the melting point of the solid form of tenofovir alafenamide and citric acid (1:1) (Figure 17) is 148°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and citric acid (1: 1) is shown in Figure 18.

The crystalline solid form of tenofovir alafenamide and succinic acid (1:1) is characterized by the reflections presented in Table 7. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and succinic acid in accordance with this invention are: 5.3; 9.4; 10.5; 14.1 ; 16.9 and 21.6 ± 0.2° 2-theta. The X-ray powder pattern is shown in Fig. 19.

Table 7

21.61 4.109 100.0

23.52 3,780 23.8

26.81 3.323 9.7

27.66 3.222 16.5

In this case, the melting point of the solid form of tenofovir alafenamide and succinic acid (1:1) (Figure 20) is 108°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and succinic acid (1:1) is shown in Figure 21.

The crystalline solid form of tenofovir alafenamide and DL-tartaric acid (1:1) is characterized by the reflections presented in Table 8. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and tartaric acid in accordance with this invention are: 3.7; 8.0; 9.6; 16.8; 18.2; 18.9 and 20.5 ± 0.2° 2-theta. The X-ray powder pattern is shown in Figure 22.

Table 8

In this case, the melting point of the solid form of tenofovir alafenamide and DL-tartaric acid (1:1) (Figure 23) is 184°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and DL-tartaric acid ( 1 : 1 ) is shown in Figure 24.

The solid form of tenofovir alafenamide and gallic acid (1 :1) corresponds to a prominently amorphous form and is characterized by the diffractogram shown in Figure 25. The diffractogram may contain reflections at 12.4; 19 and 26.1 ± 0.2° 2-theta.

In this case, the melting point of the solid form of tenofovir alafenamide and gallic acid (1:1) (Figure 26) is 125°C (DSC).

The infrared spectrum of the solid form of tenofovir alafenamide and gallic acid (1:1) is shown in Figure 27.

The solid form of tenofovir alafenamide and benzenesulfonic acid (1 :1) corresponds to an amorphous form. The diffractogram of this form is shown in Figure 28.

The glass transition temperature of the amorphous solid form of tenofovir alafenamide and benzenesulfonic acid (1:1) (Figure 29) is 22°C (MDSC).

The infrared spectrum of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1) is shown in Figure 30.

The solid form of tenofovir alafenamide and salicylic acid (1:1) corresponds to an amorphous form. The diffractogram of this form is shown in Figure 31.

The glass transition temperature of the amorphous solid form of tenofovir alafenamide and salicylic acid (1:1) (Figure 32) is 24°C (MDSC).

The infrared spectrum of the solid form of tenofovir alafenamide and salicylic acid (1:1) is shown in Figure 33.

The solid form of tenofovir alafenamide and 4-aminobenzoic acid (1 :1) corresponds to an amorphous form. The diffractogram of this form is shown in Figure 34.

The glass transition temperature of the amorphous solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1) (Figure 35) is 34°C (MDSC).

The infrared spectrum of the solid form of tenofovir alafenamide and 4-aminobenzoic acid (1 : 1) is shown in Figure 36.

The invention is elucidated in a more detailed way using the embodiment examples below. These examples, which illustrate the preparation of the novel solid forms of tenofovir alafenamide in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect. Experimental part X-ray powder diffraction (XRPD)

The diffracto grams were obtained using an X'PERT PRO MPD PANalytical powder diffracto eter, used radiation Cu a (λ=1.542 A), excitation voltage: 45 kV₅ anode current: 40 mA₉ measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti- dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used. Infrared spectroscopy

ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS detector, in the measurement range of 600-4000 cm^"1 and the spectral resolution of 4.0 cm^"1. The data were obtained at 12 spectrum accumulations. The OMNIC 8.3 software was used to process the spectra.

Differential Scanning Calorimetry (DSC)

The DSC records were measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 iL was 1-5 mg. As the carrier gas 5.0 N₂ was used at the flow of 50 ml/min.

The DSC method was used for the crystalline sample: The temperature program that was used consists of 1 minute of stabilization at the temperature of -10°C and then of heating up to 300°C at the rate of 10°C/min.

For the amorphous samples (solid forms of tenofovir alafenamide with benzenesulfonic, salicylic and 4-aminobenzoic acid) the MSDC method was used: The temperature program that was used consists of 5 minutes of stabilization at the temperature of 0°C and then of heating up to 250°C at the heating rate of 5°C/min (amplitude = 0.8°C and period = 60s). 'HNMR

For the structural characterization 1H NMR spectroscopy at 250 MHz by Bruker Avance 250 was used. As the solvent deuterated d6-dimethyl sulfoxide was used and the measurements were carried out at the temperature of 298 K.

Examples

Example 1

Preparation of the solid form of tenofovir alafenamide and hydrochloric acid (1:1)

10 mg (0.027 mmol) of (^-isopropyl^-t^-i^t^-l-te-amino-gH-purin-g-ylipro an^- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. 2.4x10^"3 mL (0.027 mmol) of 35% hydrochloric acid was added to the solution prepared this way. The obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) for 2h at the room temperature. Melting point: 144 °C (DSC). XRPD pattern: see Figure 1. IR spectrum: see Figure 3.

Example 2

Preparation of the solid form of tenofovir alafenamide and hydrobromic acid (1:1)

10 mg (0.027 mmol) of (5)-Isopropyl-2-(((5)-((((Ji)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)memyl)( henoxy)phosphoryl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. The amount of 3.05xl0^"3 mL (0.027 mmol) of 48% hydrobromic acid was added to the solution prepared this way. The obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 35°C (DSC). XRPD pattern: see Figure 4. IR spectrum: see Figure 6.

Example 3

Preparation of the solid form of tenofovir alafenamide and sulphuric acid (1:1)

10 mg (0.027 mmol) of (S)-isopropyl-2-(((5)-((((^) l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 1.5xl0^"3 mL (0.027 mmol) of 96% sulfuric acid was added to the solution prepared this way. The obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum, drier (200 mBar) at the room temperature for 2h. Melting point: 115°C (DSC). XRPD pattern: see Figure 7. IR spectrum: see Figure 9. Example 4

Preparation of the solid form of tenofovir alafenamide and phosphoric acid (1 :1)

10 mg (0.027 mmol) of (5)-isopropyl-2-(((S)-((((i-)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)memyl)^henoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 1.8xl0^~3 mL (0.027 mmol) of 85% phosphoric acid was added to the solution prepared this way. The obtained solution was left at the room temperature. During slow evaporation of the solvent a solid product (glass) was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 125°C (DSC). XRPD pattern: see Figure 10. IR spectrum: see Figure 12. Example 5

Preparation of the solid form of tenofovir alafenamide and maleic acid (1:1)

10 mg (0.027 mmol) of (5)-isopropyl-2 ((S)-((((ii)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)memyl)( henoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 3.3 mg (0.027 mmol) of maleic acid was dissolved in 0.2 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 98°C (DSC). XRPD pattern: see Figure 13. IR spectrum: see Figure 15.

Example 6

Preparation of the solid form of tenofovir alafenamide and citric acid (1 :1)

10 mg (0.027 mmol) of (5)-isopropyl-2 ((S) (((^) -(6-amino-9H-purin-9-yI)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. 5.4 mg (0.028 mmol) of citric acid was dissolved in 0.8 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 148°C (DSC). XRPD: see Figure 16. IR spectrum: see Figure 18. Example 7

Preparation of the solid form of tenofovir alafenamide and succinic acid (1:1)

10 mg (0.027 mmol) of (5)-isopropyl-2-(((5 -((((i-)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. 3.3 mg (0.027 mmol) of succinic acid was dissolved in 0.8 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 108°C (DSC). XRPD: see Figure 19. I spectrum: see Figure 21.

Example 8

Preparation of the solid form of tenofovir alafenamide and DL-tartaric acid (1:1)

10 mg (0.027 mmol) of (5)-isopropyl-2-(((¾-((((J-)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)memyl)(phenoxy)phosphoiyl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. 4.2 mg (0.027 mmol) of tartaric acid was dissolved in 6.1 mL of acetonitrile.

Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 187°C (DSC). XRPD pattern: see Figure 22. IR spectrum: see Figure 24.

Example 9

Preparation of the solid form of tenofovir alafenamide and gallic acid (1:1)

10 mg (0.027 mmol) of (5)-isopropyl-2-(((5)-((((i?)-l 6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 4.7 mg (0.027 mmol) of gallic acid was dissolved in 1.2 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Melting point: 125°C (DSC). XRPD pattern: see Figure 25. IR spectrum: see Figure 27. Example 10

Preparation of the solid form of tenofovir alafenamide and benzenesulfonic acid (1:1)

10 mg (0.027 mmol) of (S)-isopropyl-2-(((5 ((((^) -(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.428 mL of acetonitrile. 4.4 mg (0.027 mmol) of benzenesulfonic acid was dissolved in 0.2 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a solid product (glass) was separated. The solid product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Glass transition temperature: 22°C (MDSC). XRPD pattern: see Figure 28. IR spectrum: see Figure 30.

Example 11

Preparation of the solid form of tenofovir alafenamide and salicylic acid (1:1)

10 mg (0.027 mmol) of (5)-isopropyl-2-(((5)-((((i?)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)memyl)( henoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 3.8 mg (0.027 mmol) of salicylic acid was dissolved in 0.2 mL of acetonitrile.

Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a solid product (glass) was separated.

The solid product was dried in a vacuum drier (200 mBar) at the room temperature for 2h. Glass transition temperature: 24°C (MDSC). XRPD pattern: see Figure 31. IR spectrum: see

Figure 33.

Example 12

Preparation of the solid form of tenofovir alafenamide and 4-aminobenzoic acid (1:1) 10 mg (0.027 mmol) of (S -Isopropyl-2-(((S -((((J?)-l-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.6 mL of acetonitrile. 3.8 mg (0.027 mmol) of 4-aminobenzoic acid was dissolved in 0.2 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a solid product (glass) was separated. The solid product was dried in a vacuum drier (200 mBar) for 2h at the room temperature. Glass transition temperature: 34°C (MDSC). XRPD pattern: see Figure 34. IR spectrum: see Figure 36.

Claims

1. A solid form of tenofovir alafenamide with an inorganic or organic acid selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic and 4-aminobenzoic acids.

2. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is hydrochloric acid.

3. Tenofovir alafenamide with hydrochloric acid according to claim 2 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 3.4; 8.5; 10.4; 13.4 and 18.2 ± 0.2° 2-theta.

4. Tenofovir alafenamide with hydrochloric acid according to claim 2 in a crystalline form, which exhibits a peak with the onset at the temperature of 144 + 2°C in the DSC record.

5. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is hydrobromic acid.

6. Tenofovir alafenamide with hydrobromic acid according to claim 5 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 3.4; 10.5; 18.4; 21.1 and 24.3 + 0.2° 2-theta.

7. Tenofovir alafenamide with hydrobromic acid according to claim 5 in a crystalline form, which exhibits a peak with the onset at the temperature of 35 ± 2°C in the DSC record.

8. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is sulfuric acid.

9. Tenofovir alafenamide with sulfuric acid according to claim 8 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 3.6; 9.2; 18.5; 22.4 and 24.5 ± 0.2° 2-theta.

10. Tenofovir alafenaraide with sulfuric acid according to claim 8 in a crystalline form, which exhibits a peak with the onset at the temperature of 115 ± 2°C in the DSC record.

11. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is phosphoric acid.

12. Tenofovir alafenamide with phosphoric acid according to claim 11 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 3.4; 8.1; 10.2; 13.6 and 17.0 ± 0.2° 2-theta.

13. Tenofovir alafenamide with phosphoric acid according to claim 11 in a crystalline form, which exhibits a peak with the onset at the temperature of 125 ± 2°C in the DSC record.

14. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is maleic acid.

15. Tenofovir alafenamide with maleic acid according to claim 14 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 4.5; 7.7; 12.5; 17.9; 20.9 and 25.6 ± 0.2 ⁰ 2-theta.

16. Tenofovir alafenamide with maleic acid according to claim 14 in a crystalline form, which exhibits a peak with the onset at the temperature of 98 ± 2°C in the DSC record.

17. The solid form of tenofovir alafenamide according to claim 1, wherein the orgamc acid is citric acid.

18. Tenofovir alafenamide with citric acid according to claim 17 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 8.0; 15.9; 17.9; 21.4 and 26.9 ± 0.2° 2-theta

19. Tenofovir alafenamide with citric acid according to claim 17 in a crystalline form, which exhibits a peak with the onset at the temperature of 148 ± 2°C in the DSC record.

20. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is succinic acid.

21. Tenofovir alafenamide with succinic acid according to claim 20 in a crystallme form, which exhibits the following characteristic reflections in the X-ray powder pattern: 5.3; 10.5; 14.1; 16.9 and 21.6 ± 0.2° 2-theta. which exhibits a peak with the onset at the temperature of 108 ± 2°C in the DSC record.

23. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is tartaric acid.

24. Tenofovir alafenamide with tartaric acid according to claim 23 in a crystalline form, which exhibits the following characteristic reflections in the X-ray powder pattern: 3.7; 8.0; 9.6; 16.8 and 18.2 ± 0.2° 2-theta

25. Tenofovir alafenamide with tartaric acid according to claim 23 in a crystalline form, which exhibits a peak with the onset at the temperature of 184 ± 2°C in the DSC record.

26. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is gallic acid.

27. Tenofovir alafenamide with gallic acid according to claim 26 in a substantially amorphous form,

28. Tenofovir alafenamide with gallic acid according to claim 26 in a substantially amorphous form, which exhibits a peak with the onset at the temperature of 125 + 2°C in the DSC record.

29. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is benzenesulfonic acid.

30. Tenofovir alafenamide with benzenesulfonic acid according to claim 29 in an amorphous form.

31. Tenofovir alafenamide with benzenesulfonic acid according to claim 29 in an amorphous form, which exhibits the glass transition temperature of 22°C in the DSC record.

32. The solid form of tenofovir alafenamide according to claim 1 , wherein the organic acid is salicylic acid.

33. Tenofovir alafenamide with salicylic acid according to claim 32 in an amorphous form.

34. Tenofovir alafenamide with salicylic acid according to claim 32 in an amorphous form, which exhibits the glass transition temperature of 24°C in the DSC record.

35. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is 4-aminobenzoic acid.

36. Tenofovir alafenamide with 4-aminobenzoic acid according to claim 35 in an amorphous form.

37. Tenofovir alafenamide with 4-aminobenzooic acid according to claim 35 in an amorphous form, which exhibits the glass transition temperature of 34°C in the DSC record.

38. A process for preparing the solid forms of tenofovir alafenamide according to any one of claims 1 to 37, characterized in that a solution of tenofovir alafenamide and a coformer is prepared in a suitable solvent selected from the group comprising ketones, esters, ethers, alcohols, nitriles or amides, the solution is further exposed to a temperature in the range of -10 to 75 °C, preferably the room temperature, and the final product is isolated by evaporation.

39. Use of the solid form of tenofovir alafenamide according to any one of claims ί to 37 for the preparation of tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate.

40. A pharmaceutical composition, characterized in that it comprises the solid form of tenofovir alafenamide according to any one of claims 1 to 37 and at least one pharmaceutically acceptable excipient.

41. The pharmaceutical composition according to claim 40 for use as a medicament for the treatment of HIV infection and viral hepatitis B.