CZ2015384A3 - Tenofovir alafenamide solid forms - Google Patents

Abstract

Solid forms of tenofovir and alafenamide with an inorganic or organic acid selected from hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic, 4-aminobenzoic. A further object is a pharmaceutical composition comprising a solid form of Tenofovir and alafenamide with an inorganic or organic acid and at least one pharmaceutically acceptable excipient, which composition is used as a medicament for HIV infection and viral hepatitis B.

Description

Field of technology

The present invention relates to novel solid formulations of (N -isopropyl-2 - (((S) - ((((2R) -1- (6-amino-977-purin-9-yl) propan-2-yl) oxy) methyl) (pkenoxy) piosplioryl) amino) propanoate $ formula (I),

(I) known as tenofovir alafenamide, and methods for their preparation.

M-Isopropyl-2 - (((S) - ((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (4-L). enoxy)] & os] & oryl) amino) propanoic acid, known as Tenofovir alafenamide, is a nucleotide reverse transcriptase inhibitor and an innovative prodrug of the active substance tenofovir. It is suitable for the treatment of HIV infection and viral hepatitis B. Compared to the tenofovir disoproxil used so far, tenofovir alafenamide shows higher efficacy (the medicine is likely to contain less potency), better patient tolerability (fewer side effects) and better distribution to lymphoid tissues. . Tenofovir alafenamide is in phase 3 clinical trials and is expected to be present in the medicinal product as fumarate or hemifumarate salt. It is also expected that the medicinal products will contain, in addition to tenofovir alafenamide (hemi) fumarate, other active substance (s) acting as HIV protease inhibitors, HIV nucleotide / nucleoside reverse transcriptase, CCR5 inhibitors - eg emtricitabine, cobicistat, elvitegravir, darunavir.

The synthesis of tenofovir alafenamide is described in WO02 / 08241. Crystallographic data and the melting point of this substance are also given here. The patent further provides an example of the preparation of the fumarate salt of tenofovir alafenamide together with its melting point.

WO2013 / 025788 describes the preparation and characterization of tenofovir alefenamide hemifumarate. The main advantage of this salt is its ability to purify the major diastereoisomeric impurity (GS7339) of tenofovir alafenamide compared to the fumarate salt. Furthermore, the hemifumarate salt shows better chemical and thermodynamic stability, low hygroscopicity (absorbs 0.65% water at 90% relative humidity) and a higher melting point than the fumarate salt of tenofovir alafenamide. Patent application WO2013 / 025788 also describes pharmaceutical compositions containing tenofovir alafenamide in the form of hemifumarate.

Solid / polymorphic forms of tenofovir alafenamide have not yet been described, of the pharmaceutical salts only mentioned fumarate and hemifumarate.

The essence of the invention

The present invention relates to novel solid forms of tenofovir alafenamide (salts, cocrystals) with inorganic and organic acids and to processes for their preparation. These substances are prepared by reacting tenofovir alafenamide with a selected acid in a suitable solvent or solvent mixture.

The prepared new solid forms are crystalline or amorphous in nature and are prepared in a purity corresponding to the requirements for their possible pharmaceutical use in the formulation of new dosage forms.

Description of the picture

Figure 1: X-ray powder recording 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 recording 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 record of solid form of tenofovir alafenamide and sulfuric acid (1: 1) Figure 8: DSC record of solid form of tenofovir alafenamide and sulfuric acid (1: 1)

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

Figure 10: X-ray powder recording 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 43: X-ray powder recording of the solid form of tenofovir alafenamide and maleic acid (1: 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 56: X-ray powder record of 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 69: X-ray powder recording 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 recording 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 recording 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 record of 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 recording 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 recording 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 are a broad group of solid forms of active pharmaceutical ingredients, they can exist in the form of hydrates / solvates. They usually show better solubility and associated bioavailability compared to neutral forms. They are also more chemically and thermodynamically stable. Pharmaceutical salts / cocrystals are therefore widely used as active ingredients in final pharmaceutical compositions.

The present invention provides novel solid forms of tenofovir alafenamide with the following inorganic or organic acids: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulfonic, salicylic, 4-aminobenzoic and gallic in various molar ratios, moles are preferred. 1: 1 ratio. The invention provides crystalline or amorphous solid forms of tenofovir alafenamide or mixtures of amorphous and crystalline forms, with crystalline forms being preferred.

The described solid solid forms of tenofovir alafenamide with said inorganic or organic acids can be prepared in appropriate proportions and yields with high chemical purity in crystalline form, amorphous form or in a mixture of amorphous and crystal.

The prepared new solid forms of tenofovir alafenamide may have different internal configurations (polymorphisms) with different physicochemical properties depending on the conditions of their preparation. Therefore, the invention relates to the individual crystalline or amorphous forms or mixtures thereof in any ratio. These new solid forms can be both anhydrous and / or unsolvated, and in the form of a hydrate / solvate of the appropriate solvents.

The preparation of new solid forms of tenofovir alafenamide (formula (I)) is carried out by reacting tenofovir alafenamide with a corresponding acid selected from the group: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, DL-tartaric, benzenesulphonic, salicylic , 4-aminobenzoic and gallic. The reaction is carried out in a suitable solvent, which may be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof. Preferably acetonitrile can be used. Esters of C3 to C5 alcohol and C1 to C4 acids are preferred, preferably the ester is chosen so that the total number of carbons is 5 to 8. Thus, for example, propyl butanoic acid ester or pentyl formic acid ester is preferred. The ester may be composed of primary, secondary or tertiary alcohols. Likewise, the carbon skeleton of the acid can be linear or branched. Furthermore, it is possible to advantageously use esters of carbonic acid with C1-C3 alcohols. The esters described above can be used either neat or in a mixture with another solvent, the so-called co / solvent. Less polar solvents are chosen as cosolvent. For example, C6 to C9 aromatics or C6 to C9 alicyclic hydrocarbons or C1 to C4 chlorinated hydrocarbons substituted by one or more chlorine atoms have proved useful. Examples are cyclohexane, toluene or dichloromethane.

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

Said solid forms of Tenofovir alafenamide can be used in 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 shown in Table 1. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and hydrochloric acid of the invention are: 3.4; 8.5; 10.4; 13.4; 14.8; 18.2 and 19 ± 0.2 ° 2-theta. The X-ray powder record is shown in Figure 1.

Table 1

Pos. [° 2Th.] d [Á] Rel. Int. [%] 3.41 25,899 th most common 100.0 6.93 12,752 th most common 17.8 8.52 10,376 th most common 56.6

Pos. [° 2Th.] d [Á] Rel. Int. [%] 9.04 9,777 th most common 42.9 9.86 8,967 th most common 11.0 10.39 8,472 th most common 89.2 10.89 8,122 th most common 25.5 12.08 7,318 th most common 11.1 13.40 6,602 th most common 49.5 13.96 6,339 th most common 15.6 14.82 5,973 th most common 37.6 16.30 5,434 th most common 22.7 16.89 5,245 th most common 10.8 17.54 5,053 th most common 10.6 18.22 4,865 th most common 78.7 18.95 4,679 th most common 64.3 19.49 4,551 th most common 12.2 21.04 4,220 th most common 23.5 21.95 4,046 th most common 26.3 22.43 3,962 th most common 7.6 23.03 3,859 th most common 9.5 23.50 3,782 th most common 6.3 24.17 3,679 th most common 19.7 25.38 3,507 th most common 18.4 26.67 3,340 th most common 27.9 27.73 3,214 th most common 17.9 28.13 3,170 th most common 9.6 28.53 3,126 th most common 5.4 29.06 3,070 th most common 5.0 29.35 3,041 th most common 6.9 30.86 2,895 th most common 7.2 32.98 2,714 th most common 5.6 34.80 2,576 th most common 5.1

DSC recording of the solid form of tenofovir alafenamide and hydrochloric acid (1: 1) (Figure 2) shows an endotherm at 144 ° C, followed by recrystallization and a second endotherm at 160 ° C.

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

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

Table 2

Pos. [° 2Th.] d [Á] Rel. Int. [%] 3.42 25,842 th most common 100.0 6.94 12,723 th most common 3.8 8.31 10,637 th most common 3.8 8.90 9,926 th most common 2.8 9.69 9,117 th most common 3.8 10.46 8,451 th most common 35.9 12.00 7,371 th most common 4.8 13.34 6,634 th most common 9.7 14.01 6,316 th most common 4.1 14.77 5,993 th most common 5.3 16.38 5,408 th most common 2.8 17.48 5,070 th most common 3.6 18.43 4,810 th most common 15.2 18.73 4,735 th most common 7.5 19.17 4,627 th most common 4.5 21.09 4,208 th most common 13.6 21.73 4,086 th most common 7.0 22.14 4,011 th most common 4.7 24.28 3,663 th most common 10.4 24.67 3,605 th most common 5.8 26.85 3,318 th most common 9.2 Pos. [° 2Th.] d [Á] Rel. Int. [%]

28.20 3,161 th most common 5.9 29.56 3,019 th most common 2.8

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

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

The crystalline solid form of tenofovir alafenamide and sulfuric acid (1: 1) is characterized by the reflections shown in Table 3. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and sulfuric acid of the present invention are: 3.6; 9.2; 18.5;

22.4 and 24.5 ± 0.2 ° 2-theta. The X-ray powder record is shown in Figure 7.

Table 3

Pos. [° 2Th.] d [Á] Rel. Int. [%] 3.62 24,400 th most common 100.0 9.21 9,591 th most common 13.3 10.75 8,221 th most common 3.0 11.11 7,957 th most common 7.5 16.65 5,322 th most common 2.4 16.97 5,220 th most common 5.2 17.31 5,118 th most common 1.9 18.47 4,799 th most common 15.4 19.27 4,603 th most common 4.4 19.85 4,470 th most common 5.9 21.78 4,077 th most common 3.3 22.36 3,972 th most common 9.6 23.19 3,833 th most common 3.9 24.47 3,635 th most common 9.8 25.79 3,452 th most common 2.2 26.73 3,332 th most common 1.7 27.52 3,238 th most common 1.6 28.25 3,156 th most common 2.8 Pos. [° 2Th.] d [Á] Rel. Int. [%] 29.38 3,038 th most common 2.7

31.25 2,860 th most common 4.0 34.29 2,613 th most common 1.5

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

The infrared spectra of the solid form of tenofovir alafenamide and sulfuric acid (1: 1) are shown in Figure 9.

The crystalline solid form of tenofovir alafenamide and phosphoric acid (1: 1) is characterized by the reflections shown in Table 4. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and phosphoric acid of the invention are: 3.4; 8.1; 10.2; 13.6; 17.0 and 18.9 ± 0.2 ° 2-theta. The X-ray powder record is shown in Figure 10.

Table 4

Pos. [° 2Th.] d [Á] Rel. Int. [%] 3.44 25,691 th most common 100.0 8.13 10,865 th most common 13.1 8.92 9,910 th most common 4.1 10.19 8,675 th most common 21.4 10.59 8,347 th most common 5.6 12.50 7,074 th most common 2.0 13.64 6,489 th most common 7.9 16.26 5,445 th most common 4.6 16.98 5,217 th most common 13.1 18.85 4,704 th most common 7.2 19.55 4,537 th most common 3.1 20.31 4,369 th most common 4.9 22.31 3,982 th most common 2.7 24.20 3,675 th most common 2.1

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

The infrared spectra of the solid form of tenofovir alafenamide and phosphoric acid (1: 1) are shown in Figure 12.

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

Table 5

Pos. [° 2Th.] d [Á] Rel. Int. [%] 4.47 19,737 th most common 76.5 6.60 13,379 th most common 11.2 7.67 11,513 th most common 100.0 11.02 8,020 th most common 23.2 12.48 7,089 th most common 33.5 13.29 6,655 th most common 6.5 15.05 5,881 th most common 11.5 15.48 5,719 th most common 17.5 16.71 5,301 th most common 10.3 17.18 5,157 th most common 13.7 17.91 4,949 th most common 60.5 18.33 4,837 th most common 49.1 19.36 4,582 th most common 28.6 20.36 4,358 th most common 12.3 20.93 4,241 th most common 42.5 22.04 4,030 th most common 9.5 22.25 3,993 th most common 8.7 23.00 3,871 th most common 16.3 23.90 3,720 th most common 27.5 25.55 3,483 th most common 57.9 26.11 3,411 th most common 9.0 26.38 3,376 th most common 8.9 27.29 3,265 th most common 21.4 27.79 3,207 th most common 5.8 29.11 3,065 th most common 8.0 Pos. [° 2Th.] d Λ Rel. Int. [%] 33.01 2,712 th most common 4.7 36.09 2,487 th most common 5.2

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

The infrared spectra of the solid form of tenofovir alafenamide and maleic acid (1.1) are shown in Figure 15.

The crystalline solid form of tenofovir alafenamide and citric acid (1: 1) is characterized by the reflections shown in Table 6. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and citric acid of the 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 record is shown in Figure 16.

Table 6

Pos. [° 2Th.J d [Á] Rel. Int. [%] 5.84 15,129 th most common 58.6 8.03 11,001 th most common 100.0 8.47 10,436 th most common 18.6 10.25 8,626 th most common 21.1 10.94 8,084 th most common 12.9 11.68 7,572 th most common 24.2 12.58 7,032 th most common 44.5 14.56 6,078 th most common 40.2 15.35 5,770 th most common 40.2 15.87 5,581 th most common 96.6 16.26 5,446 th most common 17.4 16.72 5,297 th most common 10.2 17.45 5,078 th most common 35.5 17.87 4,958 th most common 84.8 20.02 4,430 th most common 36.7 20.48 4,333 th most common 52.6 21.35 4,158 th most common 56.8 21.66 4,100 th most common 47.6 Pos. [° 2Th.] d [Á] Rel. Int. [%] 22.43 3,961 th most common 19.3 23.35 3,807 th most common 29.8 24.27 3,664 th most common 8.9 25.03 3,554 th most common 7.0

25.89 3,439 th most common 13.1 26.86 3,317 th most common 38.1 29.23 3,053 th most common 19.9 31.05 2,878 th most common 8.5 31.83 2,809 th most common 18.9 32.59 2,745 th most common 12.6

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

The infrared spectra of tenofovir alafenamide and citric acid (1: 1) are shown in Figure 18.

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

Table 7

Pos. [° 2Th.] d [Á] Rel. Int. [%] 5.25 16,811 th most common 52.4 9.35 9,448 th most common 50.6 9.71 9,106 th most common 42.2 10.13 8,722 th most common 29.2 10.45 8,461 th most common 85.6 11.47 7,706 th most common 19.5 12.50 7,074 th most common 8.0 13.24 6,681 th most common 25.8 14.12 6,269 th most common 37.9 16.95 5,228 th most common 93.0 Pos. [° 2Th.] d [Á] Rel. Int. [%] 18.84 4,707 th most common 30.5 19.44 4,563 th most common 32.0 20.46 4,337 th most common 16.4 21.00 4,219 th most common 72.8 21.61 4,109 th most common 100.0 23.52 3,780 th most common 23.8

26.81 3,323 th most common 9.7 27.66 3,222 th most common 16.5

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

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

The crystalline solid form of tenofovir alafenamide and DL-tartaric acid (1: 1) is characterized by the reflections shown in Table 8. The characteristic diffraction peaks of the solid form of tenofovir alafenamide and tartaric acid of the 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 record is shown in Figure 22.

Table 8

Pos. [° 2Th.] d [Á] Rel. Int. [%] 3.67 24,061 th most common 100.0 6.73 13,132 th most common 8.5 8.04 10,995 th most common 12.5 9.58 9,225 th most common 11.7 12.59 7,024 th most common 2.2 13.66 6,477 th most common 3.6 14.91 5,937 th most common 2.2 15.96 5,549 th most common 3.4 16.83 5,264 th most common 5.4 18.23 4,862 th most common 9.3 18.94 4,681 th most common 7.3 20.51 4,326 th most common 7.6 Pos. [° 2Th.] d [Á] Rel. Int. [%] 22.72 3,911 th most common 2.7 24.46 3,636 th most common 1/4 25.27 3,521 th most common 1.1 26.65 3,342 th most common 1.4 28.63 3,116 th most common 0.9 35.76 2,509 th most common 2.3

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

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

The solid form of tenofovir alafenamide and gallic acid (1: 1) corresponds to a significantly 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.

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

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

The solid form of tenofovir alafenamide and benzenesulfonic acid (1: 1) corresponds to the 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) in this case is 22 ° C (MDSC).

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

The solid form of tenofovir alafenamide and salicylic acid (1: 1) corresponds to the 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) in this case is 24 ° C (MDSC).

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

The solid form of tenofovir alafenamide and 4-aminobenzoic acid (1: 1) corresponds to the 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 in this case 34 ° C (MDSC).

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

The invention is further elucidated in the following examples. These examples, which illustrate the preparation of the novel solid forms of tenofovir alafenamide according to the invention, are purely illustrative and do not limit the scope of the invention in any way.

Experimental part

X-ray powder diffraction (XRPD)

Diffractograms were obtained on a powder diffractometer X'PERT PRO MPD PANalytical, used CuKa radiation (λ = 1.542 Å), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 20, step size: 0.01 ° 20 while maintaining a reflection of 0.5 s, the measurement was performed on a flat sample with an area / thickness of 10 / 0.5 mm. 0.02 rad Soller diaphragm, 10 mm mask, and 1/4 ° fixed anti-scatter diaphragm were used to correct the primary beam. The irradiated area samples 10 mm, programmable divergence screens were used. 0.02 rad Soller diaphragm and 5.0 mm anti-scatter diaphragm were used to correct the secondary beam.

Infrared spectroscopy

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

Differential Scanning Calorimetry (DSC)

DSC recordings were measured on a Discovery DSC from TA Instruments. The sample weight in a standard AI crucible (40 μL) was between 1-5 mg. 5.0 N ₂ with a flow rate of 50 ml / min was used as the carrier gas.

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

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

‘HNMR

1 H NMR spectroscopy at 250 MHz from Bruker Avance 250 was used for structural characterization. Deuterated d6-dimethylsulfoxide was used as the solvent and measurements were performed at 298 K.

Examples

Example 1

Preparation of solid form of tenofovir alafenamide and hydrochloric acid (1: 1) mg (0.027 _Ί mmol) ( _β-Isopropyl -2 - (((5) - (((( _R )) - 1- (6-amino-9/7 -purin-9-yl) -propan-yl) oxy) methyl) (^ phenoxy) j ^ osphoryl) amino) propan ^ ^/ were dissolved in 0.428 m) L acetonitrile. To the solution thus prepared was added 2.4 x ^{10 3} πψ (0.027 mmol) of 35% hydrochloric acid. The resulting solution was left at room temperature. Upon gradual evaporation of the solvent, a white crystalline substance precipitated. The crystalline product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature. Melting point: 144 ° C (DSC). XRPD recording: see Figure 1. IR spectrum: see Figure 3.

Example 2

Preparation of solid form of tenofovir alafenamide and hydrobromic acid (1: 1) mg (0.027 mmol) of (4-Isopropyl-2 - (((5) - (((A) -1- (6-amino-9H-purine)) 9-yl) propan-2-yl) oxy) methyl) (penoxy) phospraoryl) amino) propanoate was dissolved in 0.428 mL of acetonitrile, and 3.05 x ^{10 3} mmol (0.027 mmol) of 48% - The resulting solution was left at room temperature, the crystalline product precipitated on gradual evaporation of the solvent, and the crystalline product was dried for 2 h in a vacuum oven (200 mBar) at room temperature, melting point: 35 ° C (DSC). : see Figure 4. IR spectrum: see Figure 6.

Example 3

Preparation of solid form of tenofovir alafenamide and sulfuric acid (1: 1) mg (0.027 mmolL of (R-Isopropyl-2 - ((( _< S) - - (((2R)) - 1- (6-amino-9H) -purine -9-yl) -propan-2-_yl) oxy) methyl) (phenoxy) phos $ Toryl) amino) propanoate £ ^/ dissolved in 0.6 m ^ of acetonitrile. to the solution was added to 1.5x10 ^'3 (0.027 mmol) 96% sulfuric acid, the solution is left at room temperature, a white crystalline substance precipitates on gradual evaporation of the solvent, the crystalline product is dried for 2 h in a vacuum oven (200 mBar) at room temperature, melting point: 115 DEG C. (DSC XRPD recording: see Figure 7. IR spectrum: see Figure 9.

Example 4

Preparation of solid form of tenofovir alafenamide and phosphoric acid (1: 1) mg (0.027 mmol) of (4-Isopropyl-2 - (((5) - (((A) -1- (6-amino-9/7-purine)) -9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) amino) propanoate E was dissolved in 0.6 ml of acetonitrile and 1.8 x 10 ³ ηψ ^ (0.027 mmol) 85 The solution was left at room temperature, the solid product (glass) precipitated on slow evaporation of the solvent, and the crystalline product was dried in a vacuum oven (200 mBar) for 2 hours at room temperature, melting point: 125 DEG C. (DSC). ). XRPD recording: see Figure 10. IR spectrum: see Figure 12.

Example 5

Preparation of solid form of tenofovir alafenamide and maleic acid (1: 1) mg (0.027 mmol) of N, N-isopropyl-2 - (((S) - (((R) -1- (6-amino-9) (1-Purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) amino) propanoate was dissolved in 0.6 m of acetonitrile, 3.3 mg (0.027 mmol) of acid. maleic acid was dissolved in 0.2 ml of acetonitrile, the two solutions were mixed and the resulting solution was left at room temperature, and white solvent precipitated on gradual evaporation of the solvent, and the crystalline product was dried in vacuum dry (200 mBar) at room temperature for 2 h. Melting point: 98 ° C (DSC).

XRPD recording: see Figure 13. IR spectrum: see Figure 15.

Example 6

Preparation of solid form of tenofovir alafenamide and citric acid (1: 1) mg (0.027, mmol) (N-Isopropyl-2 - (((5) - (((R) -1- (6-amino-9Z) Purin-9-yl) propan-2-yl) oxy) methyl) (nonenoxy) phosphoryl) amino) propanoate was dissolved in 0.428 ml of acetonitrile, 5.4 mg (0.028 mmol) of citric acid was dissolved in 0.1 ml of acetonitrile. 8 πψ acetonitrile The two solutions were combined and the resulting solution was left at room temperature, the crystalline product precipitated on gradual evaporation of the solvent, and the crystalline product was dried in a vacuum oven (200 mBar) for 2 h at room temperature. XRPD: see Figure 16. IR spectrum: see Figure 18.

Example 7

Preparation of solid form of tenofovir alafenamide and succinic acid (1: 1) mg (0.027 mmol) of (S) -Isopropyl-2 - (((5) - (((R) -1- (6-amino-9 / / -purin-9-yl) -propan-2 ^ _«> yl) oxy) methyl) (^ henoxy) ^ řlospϊíoryl) amino) propanoatp ^{l / was} dissolved in 0.428 MLJ.

acetonitrile. 3.3 mg (0.027 mmol) of succinic acid was dissolved in 0.8 ml of acetonitrile. The two solutions were mixed and the resulting solution was left at room temperature. Upon gradual evaporation of the solvent, a white crystalline substance precipitated. The crystalline product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature. Melting point: 108 ° C (DSC). XRPD: see Figure 19. IR spectrum: see Figure 21.

Example 8

Preparation of solid form of tenofovir alafenamide and DL-tartaric acid (1: 1) mg (0.027, mmol). (53-Isopropyl-2 - (((S) - ((((R) -1- (6-amino-977-purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) ppiospnoryl) 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, the two solutions were combined, and the resulting solution was allowed to stand at room temperature. The crystalline product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature Melting point: 187 ° C (DSC) XRPD record: see Figure 22. IR spectrum: see Figure 24.

Example 9

Preparation of solid form of tenofovir alafenamide and gallic acid (1: 1) mg (0.027, mmol). (α-Isopropyl-2 - (((S) - ((((R)) - 1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (f) / lenoxyphosphoryl) amino) propanoate X was dissolved in 0.6 ml of acetonitrile. 4.7 mg (0.027 mmol) of gallic acid was dissolved in 1.2 μg of acetonitrile. The two solutions were mixed and the resulting solution was left at room temperature. Upon gradual evaporation of the solvent, a white crystalline substance precipitated. The crystalline product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature. Melting point: 125 ° C (DSC). XRPD recording: see Figure 25. IR spectrum: see Figure 27.

Example 10

Preparation of solid form of tenofovir alafenamide and benzenesulfonic acid (1: 1) mg (0.02 mmol). (N-Isopropyl-2 - (((S ^r ) - ((((A) -1- (6-amino-9H-purin-9-yl) propan-2-yl) methoxy) methyl) phenoxy] phosphiosyl] amino] propanoate was dissolved in 0.428 mL of acetonitrile. 4.4 mg (0.027 mmol) of benzenesulfonic acid was dissolved in 0.2 πψ acetonitrile, the two solutions were mixed, and the resulting solution was left at room temperature.

Upon gradual evaporation of the solvent, a solid product (glass) precipitated. The solid product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature. Glass transition temperature:

° C (MDSC). XRPD recording: see Figure 28. IR spectrum: see Figure 30.

Example 11

Preparation of solid form of tenofovir alafenamide and salicylic acid (1: 1) mg (0.027 mmol) of (4-Isopropyl-2 - (((6)) - (((R) -1- (6-amino-977-purine-9 yl) propan-2 _| «yl) oxy) methyl) (pnenoxy) phosphoryl) amino) propanoate <^ ^ was dissolved in 0.6 m] L of acetonitrile. 3.8 mg (0.027 mmol) of salicylic acid were dissolved in 0.2 ml of acetonitrile, the two solutions were combined and the resulting solution was left at room temperature, the solid product (glass) precipitated on slow evaporation of the solvent, and the solid product was dried for 2 h in a vacuum oven (200 mBar) at room temperature. transition:

° C (MDSC). XRPD recording: see Figure 31. IR spectrum: see Figure 33.

Example 12

Preparation of solid form tenofovir alafenamidu and 4-aminobenzoic acid (1: 1) of Mg (0.027 - mmolýp (Isopropyl-2 - ₍₍₍₁ S) - ((((S) -l- (6-Amino-977- Purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) amino) propanoyl, dissolved in 0.6 ml of acetonitrile, 3.8 mg (0.027 mmol) of 4-aminobenzoic acid was dissolved in 0.2 πψ acetonitrile, the two solutions were mixed and the resulting solution was left at room temperature.

Upon gradual evaporation of the solvent, a solid product precipitated (glass). The solid product was dried for 2 h in a vacuum dryer (200 mBar) at room temperature. Glass transition temperature: 34 C (MDSC). XRPD recording: see Figure 34. IR spectrum: see Figure 36.

Claims (41)

Patent claims A solid form of tenofovir alafenamide with an inorganic or organic acid selected from the group: hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic, 4-minobenzoic acid. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is hydrochloric acid. Tenofovir alafenamide with hydrochloric acid according to claim 2 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 3.4; 8.5; 10.4; 13.4 and 18.2 ± 0.2 ° 2-theta. Tenofovir alafenamide with hydrochloric acid according to claim 2 in crystalline form, which shows an onset peak in the DSC record at a temperature of 144 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is hydrobromic acid. Tenofovir alafenamide with hydrobromic acid according to claim 5 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 3.4; 10.5; 18.4; 21.1 and 24.3 ± 0.2 ° 2-theta. Tenofovir alafenamide with hydrobromic acid according to claim 5 in crystalline form, which shows an onset peak in the DSC record at a temperature of 35 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the inorganic acid is sulfuric acid. Tenofovir alafenamide with sulfuric acid according to claim 8 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 3.6; 9.2; 18.5; 22.4 and 24.5 ± 0.2 ° 2-theta. Tenofovir alafenamide with sulfuric acid according to claim 8 in crystalline form, which shows an onset peak at 115 ± 2 ° C in the DSC record. The solid form of tenofovir alafenamide according to claim 1 wherein the inorganic acid is phosphoric acid. Tenofovir alafenamide with phosphoric acid according to claim 11 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 3.4; 8.1; 10.2; 13.6 and 17.0 ± 0.2 ° 2-theta. Tenofovir alafenamide with phosphoric acid according to claim 11 in crystalline form, which shows an onset peak in the DSC record at a temperature of 125 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is maleic acid. Tenofovir alafenamide with maleic acid according to claim 14 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 4.5; 7.7; 12.5; 17.9; 20.9 and 25.6 ± 0.2 ° 2-theta. Tenofovir alafenamide with maleic acid according to claim 14 in crystalline form, which shows an onset peak at 98 ± 2 ° C in the DSC record. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is citric acid. Tenofovir alafenamide with citric acid according to claim 17 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 8.0; 15.9; 17.9; 21.4 and 26.9 ± 0.2 ° 2-theta Tenofovir alafenamide with citric acid according to claim 17 in crystalline form, which shows an onset peak in the DSC record at a temperature of 148 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is antaric acid. Tenofovir alafenamide with succinic acid according to claim 20 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 5.3; 10.5; 14.1; 16.9 and 21.6 ± 0.2 ° 2-theta. Tenofovir alafenamide with succinic acid according to claim 20 in crystalline form, which shows an onset peak at 108 ± 2 ° C in the DSC record. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is tartaric acid. Tenofovir alafenamide with tartaric acid according to claim 23 in crystalline form, which shows the following characteristic reflections in the X-ray powder recording: 3.7; 8.0; 9.6; 16.8 and 18.2 ± 0.2 ° 2-theta Tenofovir alafenamide with tartaric acid according to claim 23 in crystalline form, which shows an onset peak in the DSC record at a temperature of 184 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is gallic acid. Tenofovir alafenamide with gallic acid according to claim 26 in substantially amorphous form. Tenofovir alafenamide with gallic acid according to claim 26 in a substantially amorphous form which shows an onset peak in the DSC record at a temperature of 125 ± 2 ° C. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is benzenesulfonic acid. Tenofovir alafenamide with benzenesulfonic acid according to claim 29 in amorphous form. Tenofovir alafenamide with benzenesulfonic acid according to claim 29 in amorphous form, which has a glass transition temperature of 22 ° C in a DSC record. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is salicylic acid. Tenofovir alafenamide with salicylic acid according to claim 32 in amorphous form. Tenofovir alafenamide with salicylic acid according to claim 32 in amorphous form, which has a glass transition temperature of 24 ° C in a DSC record. The solid form of tenofovir alafenamide according to claim 1, wherein the organic acid is 4-aminobenzoic acid. Tenofovir alafenamide with 4-aminobenzoic acid according to claim 35 in amorphous form. Tenofovir alafenamide with 4-aminobenzoic acid according to claim 35 in amorphous form, which has a glass transition temperature of 34 ° C in a DSC record. 38. A process for preparing solid forms of Tenofovir alafenamide according to claims 1 to 37, comprising preparing a solution of tenofovir alafenamide and a coformer in a suitable solvent selected from the group consisting of ketones, esters, ethers, alcohols, nitriles or amides, the solution being further exposed to temperature in the range of -10 to 75 ° C, preferably room temperature, and the resulting product is isolated by evaporation. Use of a solid form of tenofovir alafenamide according to claims 1 to 37 in the preparation of Tenofovir alafenamide fumarate or Tenofovir alafenamide hemifumarate. 40. A pharmaceutical composition comprising a solid form of Tenofovir alafenamide according to claims 1 to 37 and at least one pharmaceutically acceptable excipient. A pharmaceutical composition according to claim 40 for use as a medicament for the treatment of HIV infection and viral hepatitis B.