"SOLID FORMS OF TENOFOVIR ALAFENAMIDE AND SALTS THEREOF, PROCESSES FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF" PRIORITY

This application claims the benefit under Indian Provisional Application No. 4540/CHE/2015 filed on 28 ^th August 2015 and entitled "Solid forms of Tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof, the content of which is incorporated by reference herein.

FIELD OF THE INVENTION

The invention generally relates to solid forms of Tenofovir alafenamide and salts thereof, processes for its preparation and pharmaceutical compositions thereof. The present invention also relates to an improved process for the preparation of Tenofovir alafenamide hemifumarate.

BACKGROUND OF THE INVENTION

9-[(i?)-2-[[(5)-[[(5)-l-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine (GS-7340) is an isopropylalaninyl phenyl ester prodrug of the nucleotide HIV reverse transcriptase inhibitor tenofovir, for use in the treatment of HIV infection and chronic hepatitis B which has enhanced ability to deliver parent tenofovir into peripheral blood mononuclear cells (PBMCs) and other lymphatic tissues in vivo. Tenofovir alafenamide is represented by the following structure:

Tenofovir Alafenamide

U.S. Patent No 7,390,791 discloses Tenofovir alafenamide or pharmaceutically acceptable salts thereof including tenofovir alafenamide monofumarate and methods for chemically synthesizing this prodrug. The disclosed process involves reaction of Tenofovir alafenamide with fumaric acid in acetonitrile solvent to obtain Tenofovir alafenamide fumarate with a melting point of 119.7°C-121.1°C.

U.S. Patent No 8,754,065 ("the Ό65 patent") discloses Tenofovir alafenamide hemifumarate characterized by the following powder X-ray diffraction (PXRD) pattern having peaks at 6.9±0.2°, 8.6±0.2°, 10.0+0.2°, 11.0+0.2°, 12.2+0.2°, 15.9+0.2°, 16.3±0.2°, 20.2±0.2° and 20.8±0.2° and Differential Scanning Calorimetry (DSC) onset endofherm at 131°C.

The Ό65 patent also disclosed a process for preparation of tenofovir alafenamide hemifumarate by reaction of tenofovir alafenamide free base with fumaric acid in acetonitrile solvent followed by seeding with tenofovir alafenamide hemifumarate seed crystals.

Further, the '065 patent disclosed another process for the preparation of tenofovir alafenamide hemifumarate by dissolving a mixtures of (R,S,S) & (R,R,S)-diastereomers of tenofovir alafenamide monofumarate salt in acetonitrile at reflux followed by cooling the solution naturally under stirring and then further cooling using ice water bath and isolating the product. The solids were analyzed by XRD and found to be mixtures of (R,S,S) & (R,R,S)-diastereomers of tenofovir alafenamide monofumarate salt and tenofovir alafenamide hemifumarate.

According to the '065 patent processes, tenofovir alafenamide hemifumarate in essentially pure form is obtained only when the process comprises the step of adding seed crystals of tenofovir alafenamide hemifumarate otherwise mixture of tenofovir alafenamide monofumarate and tenofovir alafenamide hemifumarate is obtained.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), thermal gravimetric analysis (TGA) and Infrared spectrometry (IR).

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound, like Tenofovir alafenamide, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Therefore, there is a need in the art for pharmaceutically useful solid state forms of Tenofovir alafenamide and salts thereof having good physiochemical properties, desirable bioavailability and advantageous pharmaceutical parameters.

Further, there is a need for simple and improved methods for the preparation of Tenofovir alafenamide hemifumarate, which may provide higher polymorphic purity by providing an efficient, economic and reproducible process, particularly on large scale without need for the step of addition of seed crystals.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel solid forms of tenofovir alafenamide monofumarate, processes for its preparation and pharmaceutical compositions containing the same.

The present invention also provides novel solid forms of tenofovir alafenamide hemifumarate, process for its preparation and pharmaceutical compositions containing the same.

The present invention further provides processes for the preparation of tenofovir alafenamide hemifumarate and pharmaceutical compositions containing the same.

In accordance with one embodiment, the present invention provides novel crystalline forms of tenofovir alafenamide monofumarate.

In accordance with another embodiment, the present invention provides a crystalline form of tenofovir alafenamide monofumarate, hereinafter designated as crystalline form LI.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01; a ^Χ Η NMR Spectrum substantially in accordance with Figure 02; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form LI comprising the step of drying tenofovir alafenamide monofumarate form L2 at about 70°C to about 140°C under reduced pressure.

In accordance with another embodiment, the present invention provides a crystalline form of tenofovir alafenamide monofumarate, hereinafter designated as crystalline form L2. In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L2 of the present invention is an n-butanol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05; a ¹ H NMR Spectrum substantially in accordance with Figure 06; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L2, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in n-butanol; and

b) isolating the tenofovir alafenamide monofumarate crystalline form L2. In accordance with another embodiment, the present invention provides a crystalline form of tenofovir alafenamide monofumarate, hereinafter designated as crystalline form L3.

In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L3 of the present invention is an iso-butanol solvate. In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a ^X H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12. In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L3, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in isobutanol; and

b) isolating the tenofovir alafenamide monofumarate crystalline form L3.

In accordance with another embodiment, the present invention provides a crystalline form of tenofovir alafenamide monofumarate, hereinafter designated as crystalline form L4.

In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L4 of the present invention is an isoamyl alcohol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 13.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a ^X H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L4, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in isoamyl alcohol and

b) isolating the tenofovir alafenamide monofumarate crystalline form L4.

In accordance with another embodiment, the present invention provides a crystalline form of tenofovir alafenamide hemifumarate, hereinafter designated as crystalline form- HL. In accordance with another embodiment, the tenofovir alafenamide hemifumarate Form- HL of the present invention is an 1,4-dioxane solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline Form-HL characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a ^X H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate crystalline form- HL, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in 1 ,4-dioxane and

b) isolating tenofovir alafenamide hemifumarate crystalline form- HL.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate that provides high polymorphic purity consistently without the requirement of seeding.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution comprising tenofovir alafenamide and fumaric acid in a first organic solvent;

b) optionally cooling the step a) solution to room temperature,

c) adding a second organic solvent to the step b), and

d) isolating the tenofovir alafenamide hemifumarate; wherein the first organic solvent is selected from the group comprising alcohols, ketones, ethers, aromatic hydrocarbons, halogenated hydrocarbons, nitriles and the like and mixtures thereof; and a second organic solvent is selected from the group comprising ethers, cyclic hydrocarbons, water and the like and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in an organic solvent, and

b) filtering the tenofovir alafenamide hemifumarate; wherein the organic solvent is selected from the group comprising alcohols, ketones, ethers, aromatic hydrocarbons, halogenated hydrocarbons, nitriles and the like and mixtures thereof.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the solid forms of tenofovir alafenamide and salts thereof described above and at least one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 is the characteristic powder XRD pattern of Tenofovir alafenamide crystalline form LI. Figure 2 is the characteristic ^X H NMR Spectrum of Tenofovir alafenamide crystalline form LI.

Figure 3 is the characteristic DSC thermogram of Tenofovir alafenamide crystalline form LI.

Figure 4 is the characteristic TGA curve of Tenofovir alafenamide crystalline form LI.

Figure 5 is the characteristic powder XRD pattern of Tenofovir alafenamide crystalline form L2.

Figure 6 is the characteristic ^Χ Η NMR Spectrum of Tenofovir alafenamide crystalline form L2.

Figure 7 is the characteristic DSC thermogram of Tenofovir alafenamide crystalline form L2.

Figure 8 is the characteristic TGA curve of Tenofovir alafenamide crystalline form L2.

Figure 9 is the characteristic powder XRD pattern of Tenofovir alafenamide crystalline form L3.

Figure 10 is the characteristic ¹ H NMR Spectrum of Tenofovir alafenamide crystalline form L3.

Figure 11 is the characteristic DSC thermogram of Tenofovir alafenamide crystalline form L3.

Figure 12 is the characteristic TGA curve of Tenofovir alafenamide crystalline form L3. Figure 13 is the characteristic powder XRD pattern of Tenofovir alafenamide crystalline form L4.

Figure 14 is the characteristic ¹ H NMR Spectrum of Tenofovir alafenamide crystalline form L4.

Figure 15 is the characteristic DSC thermogram of Tenofovir alafenamide crystalline form L4.

Figure 16 is the characteristic TGA curve of Tenofovir alafenamide crystalline form L4.

Figure 17 is the characteristic powder XRD pattern of Tenofovir alafenamide crystalline form HL.

Figure 18 is the characteristic ¹ H NMR Spectrum of Tenofovir alafenamide crystalline form HL. Figure 19 is the characteristic DSC thermogram of Tenofovir alafenamide crystalline form HL.

Figure 20 is the characteristic TGA curve of Tenofovir alafenamide crystalline form HL.

Figure 21 is the characteristic powder XRD pattern of Tenofovir alafenamide hemifumarate obtained according to examples 1 - 8 of the present invention.

Figure 22 is the characteristic DSC thermogram of Tenofovir alafenamide hemifumarate obtained according to examples 1 - 8 of the present invention.

Figure 23 is the characteristic TGA curve of Tenofovir alafenamide hemifumarate obtained according to examples 1 - 8 of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides solid forms of tenofovir alafenamide and salts thereof such as tenofovir alafenamide monofumarate and tenofovir alafenamide hemifumarate, processes for its preparation and pharmaceutical compositions containing the same.

The present invention also provides processes for the preparation of Tenofovir alafenamide hemifumarate and pharmaceutical compositions containing the same.

Unless otherwise specified in this specification, "solid forms" herein used in this specification collectively represents a crystalline form, solvates or their polymorphic forms.

The starting tenofovir alafenamide to be used in the present invention is known in the art and can be prepared by any known method, for example starting tenofovir alafenamide may be synthesized as disclosed in U.S. Patent No. 7,390,791 or PCT Publication No. 2015/040640.

In accordance with one embodiment, the present invention provides novel crystalline forms of tenofovir alafenamide monofumarate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.66, 5.46, 9.48, 10.36, 11.04, 11.38, 11.96, 12.40, 13.12, 13.98, 14.44, 16.68, 17.42, 18.94, 19.36, 20.66, 21.12, 21.42, 22.32, 23.46, 24.58, 25.08, 25.86, 26.70, 28.06, 30.28 and 33.86 ±0.2° 2Θ.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by a ^X H NMR Spectrum substantially in accordance with Figure 02.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04. In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form LI characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01, a ^X H NMR Spectrum substantially in accordance with Figure 02, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03 and/or thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form LI comprising the step of drying tenofovir alafenamide monofumarate Form L2 at about 70°C to about 140°C under reduced pressure; wherein the tenofovir alafenamide monofumarate Form L2 is characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 05.

Drying may typically be carried out at about 90°C to about 120°C, preferably at about 100°C. The drying process is carried out for a period of about 1 hour to about 24 hours, preferably for about 5 hours.

The drying may be carried out using drying techniques known in the art for removal of solvent from the solvent containing products, for example solvates. Exemplary drying techniques include, but are not limited to tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2.

In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L2 of the present invention is an n-butanol solvate. In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate n-butanol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate n-butanol solvate characterized by a ¹ H NMR Spectrum substantially in accordance with Figure 06.

In accordance with another embodiment, the present invention provides Tenofovir alafenamide monofumarate crystalline form L2 characterized by ¹ H NMR Spectrum having peaks at about 0.8, 1.2-1.4, 3.2-3.5 and 4.3-4.4 ppm.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05.

In accordance with another embodiment, the present invention provides Tenofovir alafenamide monofumarate crystalline form L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.58, 4.94, 5.40, 8.38, 9.42, 10.36, 11.04, 12.30, 13.02, 13.98, 14.38, 15.02, 15.58, 16.70, 17.08, 17.40, 18.88, 19.30, 20.52, 21.08, 21.38, 22.26, 23.16, 23.68, 24.20, 25.10, 25.78, 26.46, 28.02, 28.56, 30.16 and 33.66 ±0.2° 2Θ.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L2 characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05, a ^X H NMR Spectrum substantially in accordance with Figure 06, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L2, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in n-butanol; and

b) isolating the tenofovir alafenamide monofumarate crystalline form L2. The step of providing a solution or suspension comprising tenofovir alafenamide and fumaric acid may include stirring tenofovir alafenamide and fumaric acid in n-butanol in suspension state or by heating to dissolve tenofovir alafenamide and fumaric acid in n- butanol. The temperature suitable for dissolving the tenofovir alafenamide and fumaric acid in n-butanol depends on the amount of solvent used and the amount of tenofovir alafenamide and fumaric acid used.

The step a) may be stirred at a temperature of about 10°C to about 50°C, preferably at 25 °C to about 35 °C. The reaction is allowed to stir for a period of time from about 2 hrs to until completion of the salt formation, preferably about 4 - 20 hrs.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 20°C to about 90°C, preferably from about 20°C to about 65°C.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3.

In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L3 of the present invention is an iso-butanol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate iso-butanol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by a ^Χ Η NMR Spectrum substantially in accordance with Figure 10. In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by ¹ H NMR Spectrum having peaks at about 0.8, 1.5-1.7, 3.1-3.4 and 4.3-4.5 ppm.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.66, 8.48, 9.68, 10.48, 11.20, 12.50, 13.34, 14.08, 14.98, 15.64, 16.16, 16.90, 17.58, 19.06, 19.52, 21.18, 21.68, 22.38, 23.24, 23.88, 24.36, 25.20, 26.72, 27.14, 28.16, 28.76, 29.18 and 30.32 ±0.2° 2Θ.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.

In accordance with another embodiment, the present invention provides Tenofovir alafenamide monofumarate crystalline form L3 characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a ^X H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L3, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in iso-butanol; and

b) isolating the tenofovir alafenamide monofumarate crystalline form L3.

The step of providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in isobutanol may include stirring tenofovir alafenamide and fumaric acid in isobutanol in suspension state or by heating to dissolve tenofovir alafenamide and fumaric acid in isobutanol. The temperature suitable for dissolving the tenofovir alafenamide and fumaric acid in isobutanol depends on the amount of solvent used and the amount of tenofovir alafenamide and fumaric acid used.

The temperature suitable for step a) may be of about 10°C to about 50°C, preferably at 25 °C to about 35 °C. The reaction is allowed to stir for a period of time from about 2 hrs to until completion of the salt formation, preferably 4 - 20 hrs.

Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 20°C to about 90°C, preferably from about 20°C to about 65°C. In another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4.

In accordance with another embodiment, the tenofovir alafenamide monofumarate Form- L4 of the present invention is an isoamyl alcohol solvate.

In another embodiment, the present invention provides tenofovir alafenamide monofumarate isoamyl alcohol solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by ¹ H NMR Spectrum substantially in accordance with Figure 14.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by ¹ H NMR Spectrum having peaks at about 0.8, 1.2-1.4, 1.5-1.7, 3.1-3.5 and 4.2-4.4 ppm.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 13.

In another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 an X-Ray diffraction (XRD) pattern having one or more peaks at about 4.46, 8.22, 9.52, 10.06, 10.28, 11.04, 12.30, 13.08, 13.86, 14.84, 15.44, 16.00, 16.60, 17.34, 18.64, 19.18, 20.90, 22.08, 22.88, 23.44, 24.90, 25.56, 26.30, 26.70, 28.28 and 29.90±0.2° 2Θ.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.

In another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form L4 characterized by one or more of the following: an X- Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a ¹ H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.

In another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide monofumarate crystalline form L4, comprising the steps of: a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in isoamyl alcohol and

b) isolating the tenofovir alafenamide monofumarate crystalline form L4. The step of providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in isoamyl alcohol may include heating to dissolve or suspend the tenofovir alafenamide and fumaric acid in isoamyl alcohol. The temperature suitable for dissolving or suspending the tenofovir alafenamide and fumaric acid in isoamyl alcohol depends on the solvent used and the amount of tenofovir alafenamide and fumaric acid in the solution.

Typically, the step a) reaction mass may be stirred at a temperature of about 10°C to about 50°C, preferably at 25 °C to about 35 °C. The reaction is allowed to stir for a period of time from about 2 hrs to until completion of the salt formation, preferably 4 - 20 hrs. Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 20°C to about 90°C, preferably from about 20°C to about 65°C.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL.

In accordance with another embodiment, the tenofovir alafenamide hemifumarate Form- HL of the present invention is an 1,4-dioxane solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate 1,4-dioxane solvate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by a ^X H NMR Spectrum substantially in accordance with Figure 18.

In accordance with another embodiment, the present invention provides tenofovir alafenamide monofumarate crystalline form HL characterized by ^X H NMR Spectrum having peaks at about 3.3-3.6 ppm.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17.

In another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.64, 8.24, 9.48, 10.64, 11.78, 13.60, 14.42, 15.38, 15.90, 16.68, 17.28, 17.94, 18.82, 19.84, 20.40, 20.98, 21.56, 22.08, 22.70, 23.74, 24.30, 24.62, 25.12, 26.10, 26.50, 27.38, 27.86, 28.28, 28.64, 29.18, 29.96 and 31.06 ±0.2° 2Θ.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate crystalline form HL characterized by one or more of the following: an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a ^X H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate crystalline form HL, comprising the steps of:

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in 1 ,4-dioxane and

b) isolating tenofovir alafenamide hemifumarate crystalline form HL.

A solution or suspension comprising tenofovir alafenamide and fumaric acid in 1,4- dioxane of step a) can be provided by mixing tenofovir alafenamide and fumaric acid in 1,4-dioxane. The temperature suitable for dissolving or suspending the tenofovir alafenamide and fumaric acid in 1,4-dioxane depends on the solvent used and the amount of tenofovir alafenamide and fumaric acid in the solution which is typically from ambient temperature to about reflux temperature of the solvent; preferably at a temperature of about 20°C to about 50°C.

The step a) reaction mass is stirred for appropriate period of time to allow for salt formation completion, typically the reaction mass is allowed to stir for a period of time from about 2 hrs to until completion of the reaction, preferably 4 - 20 hrs. Isolation of the product may be carried out by any of the conventional techniques such as filtration, centrifugation and the like. The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 20°C to about 90°C, preferably from about 20°C to about 65°C.

The solid forms of tenofovir alafenamide as described above may have greater stability, bioavailability and having desired pharmacological, pharmacokinetic and pharmacodynamic effects as compared to the known forms of tenofovir alafenamide monofumarate or tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate that provides high polymorphic purity consistently without the requirement of seeding.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution comprising tenofovir alafenamide and fumaric acid in a first organic solvent;

b) optionally cooling the step a) solution to room temperature,

c) adding a second organic solvent to the step b), and

d) isolating the tenofovir alafenamide hemifumarate; wherein the first organic solvent is selected from the group comprising alcohols, ketones, ethers, aromatic hydrocarbons, halogenated hydrocarbons, nitriles and the like and mixtures thereof; and a second organic solvent is selected from the group comprising ethers, cyclic hydrocarbons, water and the like and mixtures thereof.

Examples of first organic solvent for use in step a) of the foregoing process includes but are not limited to alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, iso-butanol and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like and mixtures thereof.

The step of dissolving tenofovir alafenamide and fumaric acid in first organic solvent may include heating to dissolve the tenofovir alafenamide and fumaric acid in the first organic solvent. The temperature suitable for dissolving the tenofovir alafenamide and fumaric acid in the first organic solvent depends on the solvent used and the amount of tenofovir alafenamide and fumaric acid in the solution. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, the solution is heated at about 30°C to about 85 °C. Optional step b) of the foregoing process may include allowing the clear solution obtained in step a) to cool to a temperature of less than about 40°C. Preferably, the solution is cooled to about 20°C to about 40°C, more preferably to about 20°C to about 30°C. To the resulting reaction mass, a second organic solvent is added to precipitate out the product. Examples of second organic solvent includes but are not limited to ethers such as diethyl ether, methyl tertiary butyl ether and the like; cyclic hydrocarbons such as n- hexane, n-heptane, cyclohexane, methyl cyclohexane and the like and mixtures thereof. Isolation of the tenofovir alafenamide hemifumarate obtained may be carried out by optionally allowing the reaction mass to gradually cool to a temperature of less than 10°C and the tenofovir alafenamide hemifumarate can be isolated by conventional techniques, for example by filtration. The resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 75°C, preferably from about 40°C to about 65°C, for a period ranging from about 1 hour to about 10 hours.

In accordance with another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate, comprising;

a) providing a solution or suspension comprising tenofovir alafenamide and fumaric acid in an organic solvent, and

b) filtering the tenofovir alafenamide hemifumarate; wherein the organic solvent is selected from the group comprising alcohols, ketones, ethers, aromatic hydrocarbons, halogenated hydrocarbons, nitriles and the like and mixtures thereof.

Examples of organic solvent for use in step a) of the foregoing process includes but are not limited to alcohols such as methanol, ethanol, isopropanol, n- propanol, n-butanol, isobutanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, 1,4-dioxane and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile, benzonitrile and the like; and mixtures thereof.

The reaction is typically carried out at a suitable temperature such as 20°C to reflux temperature of the solvent employed. Preferably, the reaction temperature is about 20°C to about 80°C. The reaction is allowed to stir for a period of time from about 2 hours to until completion of the salt formation, preferably about 20 hours. Then, optionally the reaction mass may be allowed to cool to less than 20°C to complete precipitation of the product and followed by filtering the product. The resultant tenofovir alafenamide hemifumarate may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 80 °C for a time period ranging from about 1 hour to about 10 hours.

Tenofovir alafenamide hemifumarate recovered using the process described just as above is substantially pure tenofovir alafenamide hemifumarate and free of corresponding monofumarate salt.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate, obtained by the process described herein is substantially pure tenofovir alafenamide hemifumarate.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate, obtained by the process described herein is having less than 10% of corresponding monofumarate salt, preferably less than 5%, more preferably less than 2% by weight.

In accordance with another embodiment, the present invention provides tenofovir alafenamide hemifumarate, obtained by the process described herein with a chemical purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC.

It has been observed that in the reported processes, tenofovir alafenamide hemifumarate is obtained in pure form due to the presence of tenofovir alafenamide hemifumarate seed crystals. It is believed that seeding plays an important role for the selective formation of tenofovir alafenamide hemifumarate and is a prerequisite to obtain tenofovir alafenamide hemifumarate with high polymorphic purity.

In contrast, the present invention involves preparation of tenofovir alafenamide hemifumarate in high polymorphic purity even without requiring the addition of seed crystals as its use require undue monitoring of reaction conditions to induce crystallization, i.e. addition of seed crystals prior to or after the start of crystallization of product, optimization of temperature, solvent quantity. Moreover, seeding requires special care as they influence the quality of the crystals to be grown thereon and the current process does not require preparation of seed crystals of high purity in advance. In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising at least one of the solid forms of tenofovir alafenamide and salts thereof described above and at least one or more pharmaceutically acceptable excipients. Solid forms of Tenofovir alafenamide were characterized by one or more of the techniques such as PXRD, ^X H NMR, Thermogravimetric analysis (TGA) and DSC techniques.

The X-Ray powder diffraction can be measured by X-ray powder diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=5° 2#/minute. All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.

1H-NMR spectra in solution for different forms in DMSO-d ₆ were recorded on a Bruker Avance-II 300 MHz spectrometer at a ¹ H Larmor frequency of 300.131 MHz. The spectrum was acquired using a ¹ H pulse width of 10.50 μ 8, a 3.64 s acquisition time, a 5 s delay between scans, spectral width of 15 ppm and 32 co-added scans. The free induction decay (FID) was processed using TOPSPIN version 2.0 software and an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio.

EXAMPLES

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

COMPARATIVE EXAMPLE:

PREPARATION OF TENOFOVIR ALAFENAMIDE HEMIFUM ARATE :

Tenofovir alafenamide monofumarate solids (5.0 gms) and GS-7339 monofumarate solids (0.75 gms) were charged into MTBE (35 gms) at 22°C and the mixture was stirred for 1 hour. The formed slurry was dried in a rotary evaporator and acetonitrile (58 gms) was charged into the solids and the mixture was heated to reflux to dissolve the solids. The resulting solution was allowed to cool naturally while agitated. The slurry formed was further allowed to cool by ice- water-bath. The solid was isolated by filtration and washed with 5 gms acetonitrile and dried in a vacuum oven at 40° C overnight. 5.52 gms off-white solids were obtained. The solid was analyzed by XRPD and found to contain tenofovir alafenamide monofumarate, GS-7339 monofumarate, and tenofovir alafenamide hemifumarate.

EXAMPLE 1 : Preparation of tenofovir alafenamide hemifumarate (acetone + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in acetone (13 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30°C and stirred for 30 mins. MTBE (13 ml) was added and stirred the resulting mixture for 30 mins at same temperature, filtered and washed with MTBE. The obtained solid was dried at 50°C under vacuum for 5 hrs to yield of tenofovir alafenamide hemifumarate (830 mg).

The XRPD is set forth in Figure 21;

The DSC thermogram is set forth in Figure 22;

The TGA is set forth in Figure 23.

EXAMPLE 2: Preparation of tenofovir alafenamide hemifumarate (acetone)

Tenofovir alafenamide (500 mg) and fumaric acid (60 mg) was suspended in acetone (2 mL) at 25°C to 35°C. Stirred the suspension for 19 hrs at same temperature, filtered, washed with MTBE and dried the solids at 45°C under vacuum for 2 hrs to yield tenofovir alafenamide hemifumarate (488 mg).

EXAMPLE 3 : Preparation of tenofovir alafenamide hemifumarate (acetone + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in acetone (13 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30°C and stirred at same temperature for 30 mins. MTBE (13 ml) was added and allowed to further cool to 0-5°C and stirred at 0-5°C for 30 min. Filtered the solids and washed with chilled MTBE and dried the solids at 55°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (930 mg).

EXAMPLE 4: Preparation of tenofovir alafenamide hemifumarate (2-methyl Tetrahydrofuran + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in 2-methyl tetrahydrofuran (20 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30°C and stirred the suspension at same temperature for 30 mins. MTBE (20 mL) was added and stirred for another 30 mins, filtered the solids and washed with MTBE. The resulting solid was dried at 50°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (930 mg).

EXAMPLE 5: Preparation of tenofovir alafenamide hemifumarate (Tetrahydrofuran + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in tetrahydrofuran (10 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30°C and stirred for 30 mins. MTBE (10 ml) was added at same temperature and allowed to cool to 0-5°C and stirred for 30 min at 0-5°C. The solid was filtered, washed with chilled MTBE and dried the solids at 55°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (900 mg).

EXAMPLE 6: Preparation of tenofovir alafenamide hemifumarate (Methyl ethyl ketone + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in methyl ethyl ketone (10 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30° and stirred for 30 mins. MTBE (lOmL) was added at same temperature and allowed to further cool to 0- 5°C and stirred for 30 min. The solid was filtered and washed with chilled MTBE and dried the solids at 55°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (920 mg).

EXAMPLE 7: Preparation of tenofovir alafenamide hemifumarate (Isopropanol + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in isopropanol (10 mL) at 55-60°C. The solution was allowed to cool to 25°C to 30°C and stirred at RT for 30 mins. MTBE (10 mL) was added at same temperature and further allowed to cool to 0-5°C and stirred for 30 min. The solid was filtered, washed with chilled MTBE and dried the solids at 55°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (750 mg).

EXAMPLE 8: Preparation of tenofovir alafenamide hemifumarate (Acetonitrile + MTBE)

Tenofovir alafenamide (1 gm) and fumaric acid (122 mg) was dissolved in acetonitrile (15 mL) at 70-75°C. The solution was allowed to cool to 25°C to 30°C and stirred for 30 mins. MTBE (15 mL) was added at same temperature and allowed to cool to 0-5°C and stirred the mixture for 30 min at 0-5°C. The solid was filtered, washed with chilled MTBE and dried the solids at 55°C under vacuum for 5 hrs to yield tenofovir alafenamide hemifumarate (920 mg).

EXAMPLE 9: Preparation of Tenofovir alafenamide monofumarate form LI

Tenofovir alafenamide Form L2 (350 mg; from Example 12) was dried in a tray drier at 100°C under vacuum for 5 hrs to yield tenofovir alafenamide Form LI (340 mg).

The XRPD is set forth in Figure 01 ;

The DSC thermogram is set forth in Figure 03 ;

The TGA is set forth in Figure 04.

EXAMPLE 10: Preparation of Tenofovir alafenamide monofumarate form LI

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was dissolved in n-butanol (10 mL) at 60-65°C. The solution was allowed to cool to 20-26°C, seeded with Tenofovir alafenamide Form L2 (20 mg; from Example 12) at 20-26°C and stirred for 4 hrs. The solid was filtered, washed with MTBE and dried the solids at 20-26°C under vacuum for 6 hrs. The drying was further continued at 47-53°C for 2 hrs, at 97-103°C for 5 hrs and then at 97-103 °C for additional 7 hrs to yield tenofovir alafenamide monofumarate Form LI (565 mg).

EXAMPLE 11 : Preparation of Tenofovir alafenamide monofumarate Form L2

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in n-butanol (2 mL) at 25°C to 30°C. The resulting mixture was stirred for 17 hrs, filtered, washed with MTBE and dried the solids at 55°C under vacuum for 4 hrs to yield tenofovir alafenamide monofumarate Form L2 (910 mg).

The XRPD is set forth in Figure 05;

The DSC thermogram is set forth in Figure 07;

The TGA is set forth in Figure 08.

EXAMPLE 12: Preparation of Tenofovir alafenamide monofumarate Form L2

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in n-butanol (10 mL) at 25°C to 30°C. The resulting mixture was stirred for 4 hrs, filtered, washed with MTBE and dried the solids at 25°C to 35°C under vacuum for 20 hrs to yield tenofovir alafenamide monofumarate Form L2 (688 mg).

EXAMPLE 13: Preparation of Tenofovir alafenamide monofumarate Form L3

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in isobutanol (2 mL) at 25°C to 30°C. The resulting mixture was stirred for 17 hrs, filtered, washed with MTBE and dried the solids at 55°C under vacuum for 4 hrs to yield tenofovir alafenamide monofumarate Form L3 (1150 mg).

The XRPD is set forth in Figure 09;

The DSC thermogram is set forth in Figure 11 ;

The TGA is set forth in Figure 12.

EXAMPLE 14: Preparation of Tenofovir alafenamide monofumarate Form L3

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in isobutanol (10 mL) at 25°C to 30°. The resulting mixture was stirred for 4 hrs, filtered, washed with MTBE and dried the solids at RT under vacuum for 20 hrs to yield tenofovir alafenamide monofumarate Form L3 (938 mg).

EXAMPLE 15: Preparation of Tenofovir alafenamide monofumarate Form L4

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in isoamyl alcohol (2 mL) at 25°C to 30°. The resulting mixture was stirred for 17 hrs, filtered, washed with MTBE and dried the solids at 55°C under vacuum for 4 hrs to yield tenofovir alafenamide monofumarate Form L4 (1150 mg).

The XRPD is set forth in Figure 13;

The DSC thermogram is set forth in Figure 15;

The TGA is set forth in Figure 16.

EXAMPLE 16: Preparation of Tenofovir alafenamide monofumarate Form L4

Tenofovir alafenamide (1 gm) and fumaric acid (242 mg) was suspended in isoamyl alcohol (10 mL) at 25°C to 30°C. The resulting mixture was stirred for 4 hrs, filtered the reaction mass, washed with MTBE and dried the solids at 25°C to 30°C under vacuum for 20 hrs to yield tenofovir alafenamide monofumarate Form L4 (987 mg).

EXAMPLE 17: Preparation of Tenofovir alafenamide hemifumarate Form HL

Tenofovir alafenamide (1 gm) and fumaric acid (122 gms) was suspended in 1,4-dioxane (2 mL) at 25°C to 30°C. The resulting mixture was stirred for 17 hrs, filtered and washed with MTBE. The obtained solids were dried at 55°C under vacuum for 4 hrs to yield tenofovir alafenamide hemifumarate Form FfL (1020 mg).

The XRPD is set forth in Figure 17;

The DSC thermogram is set forth in Figure 19;

The TGA is set forth in Figure 20.

EXAMPLE 18: Preparation of Tenofovir alafenamide hemifumarate Form HL

Tenofovir alafenamide (500 mg) and fumaric acid (60 mg) was suspended in 1,4-dioxane (2 mL) at 25°C to 30°C. The resulting mixture was stirred for 19 hrs, filtered, washed with MTBE and dried the solids at 45°C for 2 hrs to yield tenofovir alafenamide hemifumarate Form HL (488 mg).

EXAMPLE 19: Preparation of Tenofovir alafenamide hemifumarate Form HL

Tenofovir alafenamide (1 gm) and fumaric acid (122 gms) was suspended in 1,4-dioxane (10 mL) at 25°C to 30°C. The resulting mixture was stirred for 4 hrs, filtered, washed with MTBE and dried the solids at RT under vacuum for 20 hrs to yield tenofovir alafenamide hemifumarate Form HL (827 mg).