WO2021165995A1

WO2021165995A1 - Novel salts and/or co-crystals of tenofovir alafenamide

Info

Publication number: WO2021165995A1
Application number: PCT/IN2021/050164
Authority: WO
Inventors: Srinivas Laxminarayan Pathi; Ramanaiah CHENNURU; Ramesh DEVARAPALLI
Original assignee: Cipla Limited
Priority date: 2020-02-20
Filing date: 2021-02-20
Publication date: 2021-08-26
Also published as: EP4085062A1

Abstract

The present invention relates to novel salts and/or co-crystals of tenofovir alafenamide with an acid selected from D-malic acid and adipic acid. Another aspect of the present invention relates to novel crystalline forms of the novel salts and/or co-crystals tenofovir alafenamide, process for preparation, the pharmaceutical formulations and therapeutic uses thereof for the treatment of diseases or symptoms of HIV infection and viral hepatitis B.

Description

NOVEL SALTS AND/OR CO-CRYSTALS OF TENOFOVIR

ALAFENAMIDE

TECHNICAL FIELD OF THE INVENTION:

The present invention relates to novel salts and/or co-crystals of tenofovir alafenamide, process for preparation and the pharmaceutical formulations and therapeutic uses thereof. The invention further provides novel crystalline forms of these novel salts.

BACKGROUND OF THE INVENTION:

9-[(R)-2-[[(S)-[[(S)-l- isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] adenine, an isopropylalaninyl monoamidate phenyl monoester (Tenofovir alafenamide), is a prodrug of (R)-9-(2-phosphonomethoxypropyl)adenine (tenofovir) and can be represented by the following chemical structure according to formula (I):

Formula I

Tenofovir alafenamide, is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease. The Tenofovir alafenamide fumarate (TAF) active ingredient in Vemlidy is present as tenofovir alafenamide hemifumarate. The process for preparation of the tenofovir alafenamide and Tenofovir alafenamide fumarate salt was first disclosed in the patent application W02002008241.

Pharmaceutical solids can exist in different crystal forms, such as crystalline, amorphous, or glass and also in solvated or hydrated states (Haleblian et al., 1969,1975; Kuhnert- Brandstaetter, 1973; Sohn 2004). Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystal species.

Polymorphism has been observed for Tenofovir alafenamide and salts thereof.

The US patent no. 8,754,065 B2 discloses crystalline Tenofovir alafenamide hemifumarate and process for preparation thereof.

The application WO2015040640 provides an improved process for the preparation of Tenofovir alafenamide or pharmaceutically acceptable salts namely ferulate, phosphate, succinate, citrate, tartrate, lactate, and methanesulfonate.

WO 2015/107451 Al discloses purification process of Tenofovir alafenamide suing chiral resolving agents such as (L)-(+)-tartaric acid, (D)-(-)-tartaric acid, (I S)-(+)- 10-camphor sulfonic acid, (lR)-(-)-10-camphor sulfonic acid, (15, 3R)-(-)- camphoric acid, (S)-(+)-mandelic acid, (R)-(-)-mandelic acid, benzoic acid, L- malic acid, succinic acid, oxalic acid, orthophosphoric acid, maleic acid, orotic acid,

WO2015176602 discloses Tenofovir alafenamide complex, preparation method and use thereof. Preferred salts are selected from the group consisting of tenofovir alafenamide L-tartrate (1:2), tenofovir alafenamide D-tartrate (1:1), Tenofovir alafenamide tartrate (1:1), Tenofovir alafenamide L-malate (1:2), Tenofovir alafenamide citrate (1:1), tenofovir alafenamide succinate (1:1), tenofovir alafenamide oxalate (1:1), tenofovir alafenamide phosphate (1:1) and Tenofovir alafenamide sulfate (1:1). WO2016192692A1 discloses solid forms of Tenofovir alafenamide with inorganic and organic acids and methods for preparing the same namely hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic and 4-aminobenzoic acids.

W02016205141/US 9,777,028 B2 discloses co-crystals, salts and crystalline forms of Tenofovir alafenamide and methods for preparation, use and isolation of such compounds. The claimed salts are sesquifumarate, oxalate, malonate, L-malate saccharinate, mucate, maleate hydrochloride, ethanesulfonate, benzenesulfonate and crystal forms thereof.

The application WO 2018/115046 discloses crystalline polymorphic forms of Tenofovir alafenamide maleate, tenofovir alafenamide malonate, tenofovir alafenamide protocatechuate, and methods for preparing the same.

WO 2018/144390 A1 discloses crystalline polymorphic forms of Tenofovir alafenamide hemipamoate Form I and Form II, Tenofovir alafenamide sebacate Form I, Tenofovir alafenamide napsylate Form I, Tenofovir alafenamide orotate Form I, Form II and Form III, Tenofovir alafenamide vanillate, and Tenofovir alafenamide bis-xinafoate.

WO 2019/130354A1 discloses crystalline polymorphic forms of Tenofovir alafenamide monofumarate and Tenofovir alafenamide hemifumarate and methods for preparation, use and isolation of such compounds.

US 10,479,810 B2 discloses crystalline polymorphic forms of Tenofovir alafenamide fumarate such as Form II, Form A and Form B and methods for preparation, use and isolation of such compounds.

A drug and a salt thereof may exist in a plurality of crystalline form states, and different crystal forms of the same drug and its salt may have different dissolution and absorption in the body, thereby affecting dissolution and release of the preparation.

In view of the above discussed prior art references, it is evident that Tenofovir alafenamide or salts exhibits different polymorphic forms under differential conditions that include solvent, moisture, temperature, time and drying conditions and thus the bioavailability of the same also varies with polymorphic modification.

A change in crystal structure of compound by means of change in polymorphism affects physicochemical properties like dissolution and solubility, chemical and physical stability, flowability and hygroscopicity of a compound. Therefore, there remains a need in the art for solid forms of tenofovir alafenamide acid addition salts which are having greater stability, flowability, dissolution properties; thereby increasing the bioavailability of the drug.

OBJECTIVES OF THE INVENTION:

An object of the present invention is to provide novel salts and/or co-crystals of Tenofovir alafenamide thereof.

Another object of the present invention is to provide a process for the preparation of novel salts and/or co-crystals of Tenofovir alafenamide thereof.

Yet another object of the invention is to provide pharmaceutical composition comprising a therapeutically effective amount of novel salts and/or co-crystals of Tenofovir alafenamide thereof.

Yet another object of the invention is to provide method of treatment of diseases or symptoms of HIV, wherein novel crystalline forms of salts and/or co-crystals of Tenofovir alafenamide thereof, are useful. SUMMARY OF THE INVENTION:

In some embodiments, the present invention is directed to novel crystalline forms of salts and/or co-crystals of Tenofovir alafenamide.

In some embodiments, the present invention provides acid salts selected from: Tenofovir alafenamide D-malate, and Tenofovir alafenamide adipate, or a solvate or hydrate thereof.

In some embodiments, the present invention further provides methods of preparing a salt of the invention comprising steps of combining Tenofovir alafenamide with an acid selected from D-malic acid, or adipic acid, in a suitable solvent, and thereafter optionally isolating the acid addition salt so formed.

In some embodiments, the present invention further provides one or more polymorphic forms or pseudo polymorphic forms of the salts of Tenofovir alafenamide. Accordingly, pseudo polymorphs provided include hydrates and/or solvates.

In some embodiments, the present invention is directed to crystalline Tenofovir alafenamide mono D-malate Form Cl.

In some embodiments, the present invention is directed to crystalline Tenofovir alafenamide hemi D-malate Form C2.

In some embodiments, the present invention is directed to crystalline Tenofovir alafenamide mono adipate Form Cl.

In some embodiments, the present invention is directed to the processes for the preparation of these novel crystalline salts and/or co-crystals of tenofovir alafenamide. In some embodiments, the invention further relates to a composition comprising one or more of the aforementioned novel crystalline salts and/or co-crystals of tenofovir alafenamide and processes for the preparation of the novel crystalline salts and/or co-crystals and the composition. In addition, the invention relates to the use of the novel crystalline salts and/or co-crystals of Tenofovir alafenamide of the present invention for the preparation of a pharmaceutical composition and to a pharmaceutical composition comprising an effective amount of the novel crystalline salts and/or co-crystals of Tenofovir alafenamide of the present invention and and at least one pharmaceutically acceptable excipient.

In some embodiments, the present invention is directed to methods of treating an HIV infection by administering a therapeutically effective amount of a salt and/or co-crystal of Tenofovir alafenamide provided herein.

In some embodiments, the present invention is directed to the use of a salt and/or cocrystal of Tenofovir alafenamide provided herein in the manufacture of a medicament for treating an HIV infection.

BRIEF DESCRIPTION OF DRAWINGS:

Figure 1 depicts powder X-ray diffraction (PXRD) of Tenofovir alafenamide mono D-malate Form Cl.

Figure 2 depicts a DSC thermogram of Tenofovir Alafenamide mono D-malate Form Cl.

Figure 3 depicts a TGA thermogram of Tenofovir Alafenamide mono D-malate Form Cl. Figure 4 depicts powder X-ray diffraction (PXRD) of Tenofovir alafenamide hemi D-malate Form C2

Figure 5 depicts a DSC thermogram of Tenofovir Alafenamide hemi D-malate Form C2.

Figure 6 depicts a TGA thermogram of Tenofovir Alafenamide hemi D-malate Form C2.

Figure 7 depicts powder X-ray diffraction (PXRD) of Tenofovir alafenamide mono adipate Form Cl.

Figure 8 depicts a DSC thermogram of Tenofovir Alafenamide mono adipate Form Cl.

Figure 9 depicts a TGA thermogram of Tenofovir Alafenamide mono adipate Form Cl.

Figure 10 depicts the pH - dependent solubility of the Tenofovir alafenamide hemi D-malate with Tenofovir alafenamide hemifumarate and Tenofovir alafenamide monofumarate in buffer solutions at pH 2.1

Figure 11 depicts the pH - dependent solubility of the Tenofovir alafenamide hemi D-malate with Tenofovir alafenamide hemifumarate and Tenofovir alafenamide monofumarate in buffer solutions at pH 4.5

Figure 12 depicts the pH - dependent solubility of the Tenofovir alafenamide hemi D-malate with Tenofovir alafenamide hemifumarate and Tenofovir alafenamide monofumarate in buffer solutions at pH 6.8 DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides, inter alia, novel acid salts of the hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor Tenofovir alafenamide, selected from the D-malic acid salt, and adipic acid salt or a solvate or hydrate thereof. These salts are useful, for example, in the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

Salts of the present invention also include all isotopes of atoms occurring in the salts. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The salts of the invention have numerous advantageous properties over the free base form and other salt forms. In particular, these salts were highly crystalline which would facilitate the preparation of pharmaceutical formulations and improve general handling, manipulation, and storage of the active ingredient. The salts of the invention also have superior aqueous solubility, rate of dissolution, chemical stability (with a longer shelf life), compatibility with excipients, and reproducibility compared with the free base form.

In some embodiments, the salts of the invention are substantially isolated. By "substantially isolated" is meant that the salt is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the salt of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the salt Salts of the invention can be prepared using known techniques. Conventionally, a salt form is prepared by combining in solution the free base compound and an acid containing the anion of the salt form desired, and then isolating the solid salt product from the reaction solution (e.g., by crystallization, precipitation, evaporation, etc.). Other salt-forming techniques can be employed.

The use of certain solvents during the aforementioned process has been found to produce different polymorphic forms of the acid salts of Tenofovir Alafenamide, which may exhibit one or more favourable characteristics described above. The processes for the preparation of the polymorphs described herein, and characterization of these polymorphs are described in greater detail below.

As used herein, the term "solvated" is understood to mean formation of a complex of variable stoichiometry comprising Tenofovir alafenamide salt and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Typically, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include C1-C4 alcohol solvents, acetone, acetonitrile, methyl ethyl ketone (MEK), dimethylsulfoxide (DMSO), dichloromethane (MDC) and tetrahydrofuran (THF) and solvates other than water at levels of more than 1%.

The solvate can be isolated either as an amorphous form or in a crystalline form, preferably in crystalline form.

The solvate can be further isolated either in anhydrous form or hydrated form.

As used herein, the term "hydrate" is understood as a substance that is formed by adding water molecules. The skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio. The notation for a hydrated compound may be nEbO, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on.

In certain embodiments, one or more of the polymorphic forms provided may be a channel solvate. As commonly referred to by a person skilled in the art, the term "channel solvate", or a variant thereof, refers to a crystal lattice containing tunnels that can be occupied by solvent molecules (e.g., channel solvents), and other molecules and ions.

As used herein, the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2Q values within ±0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.

As used herein, the term "DSC" refers to Differential Scanning Calorimetric.

As used herein, the term "TGA" refers to Thermo Gravimetric Analysis.

As used herein the term "crystalline purity," refers to a particular crystalline form of a compound in a sample which may contain amorphous form of the compound, one or more other crystalline forms of the compound other than the crystalline form of the compound of this invention, or a mixture thereof wherein the particular form of the compound is present in an amount of at least about 80%, preferably at least about 95%, most preferably at least about 99% crystalline.

Those skilled in the art would recognize that crystal forms or amorphism of the present invention can be further identified by a variety of technical means, including, but not limited to infrared absorption spectroscopy (IR), melting point method, Nuclear magnetic resonance, Raman spectroscopy, dynamic vapor sorption (DYS), X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate or combination thereof.

According to one embodiment of the present invention, there is provided novel acid salt of Tenofovir Alafenamide, Tenofovir Alafenamide D-malate. The Tenofovir Alafenamide D-malate may be in the form of a derivative thereof. The derivative may be a pharmaceutically acceptable solvate, hydrate, tautomer, anhydrate, complex, polymorph, prodrug or combination thereof.

The D-malate salt may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.

Because D-malic acid has two acid groups per molecule, compounds of these acids and Tenofovir alafenamide may be isolated as either mono- or di-acid addition salts and/or solvates thereof, having either one or two Tenofovir alafenamide molecules per acid molecule respectively.

The ratio of Tenofovir alafenamide to D-malic acid may range from about 1 to about 2 molecules of Tenofovir Alafenamide per 1 molecule of D-malic acid.

In one embodiment, the ratio is 1 molecule of Tenofovir alafenamide per 1 molecule of D-malic acid. The isolated salt is Tenofovir alafenamide mono D- malate.

In a further aspect, the present invention relates to a process for preparing Tenofovir alafenamide mono D-malate which comprises reacting 1 mole Tenofovir alafenamide with 0.9 to 1.1 mole of D-malic acid in a suitable solvent.

In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide mono D-malate having a purity greater than 95%, preferably at least 99%, more preferably at least 99.5% area % by HPLC. In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide mono D-malate having enantiomeric excess greater than 97%. Preferably greater than 98%, most preferably greater than 99%.

The mono D-malate salt according to the invention is characterised by good crystallinity and low amorphisation during grinding and compression. In addition, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.

The inventors have discovered a surprisingly advantageous crystalline polymorphic form of Tenofovir alafenamide mono D-malate which hereinafter referred to as Form Cl. This form is described in more detail herein.

The crystalline Tenofovir alafenamide mono D-malate Form Cl is relatively stable towards moisture and humidity, thereby representing a crystalline form of Tenofovir alafenamide, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Tenofovir alafenamide mono D-malate Form Cl, according to the present invention may be characterized by powder X-ray diffraction.

The crystalline Tenofovir alafenamide mono D-malate Form Cl, may be characterized by having an XRPD diffractogram comprising peaks at 3.05, 9.06, 15.09 and 18.14 ± 0.2°20. The XRPD diffractogram may comprise further peaks at 14.22, 20.90, 24.28 and 28.72 ± 0.2°20.

The XRPD diffractogram may be as depicted in Figure 1.

The crystalline Tenofovir alafenamide mono D-malate Form Cl may be characterized by having a DSC thermogram as shown in Figure 2. The DSC plot for the sample shows an endotherm peak melting with an onset at 95.16°C, a peak maximum at 102.74 ± 5°C, and an enthalpy change of 79.969 j/g.

The crystalline Tenofovir alafenamide mono D-malate Form Cl may be characterized by having a TGA thermogram substantially as depicted in Figure 3.

TGA data indicated a weight loss of 0.045% at temperatures up to 140°C. The TGA analysis indicates the crystalline Tenofovir alafenamide mono D-malate Form Cl is the anhydrous form.

Preferably the Tenofovir alafenamide mono D-malate Form Cl has a crystalline purity of at least 80%, more preferably at least 90%, more preferably at least 95%, most preferably at least 99% by weight.

In another embodiment, the ratio is 2 molecules of Tenofovir Alafenamide per 1 molecule of D-malic acid. The isolated salt is Tenofovir alafenamide hemi D- malate.

In a further aspect, the present invention relates to a process for preparing Tenofovir alafenamide hemi D-malate which comprises reacting 1 mole of Tenofovir alafenamide with 0.4 to 0.6 moles of D-malic acid in a suitable solvent.

In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide hemi D-malate having a purity greater than 95%, preferably at least 99%, more preferably at least 99.5% area % by HPLC.

In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide hemi D-malate having enantiomeric excess greater than 97%. Preferably greater than 98%, most preferably greater than 99%. The hemi D-malate salt according to the invention is characterised by good crystallinity and low amorphisation during grinding and compression. In addition, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.

The inventors have discovered a surprisingly advantageous crystalline polymorphic form of Tenofovir alafenamide hemi D-malate which hereinafter referred to as Form C2. This form is described in more detail herein.

The crystalline Tenofovir alafenamide hemi D-malate Form C2 is relatively stable towards moisture and humidity, thereby representing a crystalline form of Tenofovir alafenamide, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Tenofovir alafenamide hemi D-malate Form C2, according to the present invention may be characterized by powder X-ray diffraction.

The crystalline Tenofovir alafenamide hemi D-malate Form C2, may be characterized by having an XRPD diffractogram comprising peaks at 3.93, 7.82, 15.19, 9.59 and 22.90 ± 0.2°2Q. The XRPD diffractogram may comprise further peaks at 12.35, 15.67, 17.10, 18.08, 19.24 and 24.83± 0.2°20.

The XRPD diffractogram may be as depicted in Figure 4.

The crystalline Tenofovir alafenamide hemi D-malate Form C2 may be characterized by having a DSC thermogram as shown in Figure 5.

The DSC plot for the sample shows an endotherm peak melting with an onset at 114.14°C, a peak maximum at 121.95± 5°C °C, and an enthalpy change of 83.179 j/g. The crystalline Tenofovir alafenamide hemi D-malate Form C2 may be characterized by having a TGA thermogram substantially as depicted in Figure 6.

TGA data indicated a weight loss of 0.045% at temperatures up to 140°C. The TGA analysis indicates the crystalline Tenofovir alafenamide hemi D-malate Form C2 is the anhydrous form.

Preferably the Tenofovir alafenamide hemi D-malate Form C2 has a crystalline purity of at least 80%, more preferably at least 90%, more preferably at least 95%, most preferably at least 99% by weight.

According to second embodiment of the present invention, there is provided novel acid salt of Tenofovir Alafenamide, Tenofovir Alafenamide adipate. The Tenofovir Alafenamide adipate may be in the form of a derivative thereof. The derivative may be a pharmaceutically acceptable solvate, hydrate, tautomer, anhydrate, complex, polymorph, prodrug or combination thereof.

The adipate salt may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.

Because adipic acid has two acid groups per molecule, compounds of these acids and Tenofovir alafenamide may be isolated as either mono- or di-acid addition salts and/or solvates thereof having either one or two Tenofovir alafenamide molecules per acid molecule respectively. The ratio of Tenofovir alafenamide to adipic acid may range from about 1 to about 2 molecules of Tenofovir alafenamide per 1 molecule of adipic acid.

In one embodiment, the ratio is 1 molecule of Tenofovir alafenamide per 1 molecule of adipic acid. The isolated salt is Tenofovir alafenamide mono adipate.

In a further aspect, the present invention relates to a process for preparing Tenofovir alafenamide mono adipate which comprises reacting 1 mole of Tenofovir alafenamide with 0.9 to 1.1 moles of adipic acid in a suitable solvent.

In another embodiment, the ratio is 2 molecules of Tenofovir alafenamide per 1 molecule of adipic acid. The isolated salt is Tenofovir alafenamide hemi adipate.

In a further aspect, the present invention relates to a process for preparing Tenofovir alafenamide hemi adipate which comprises reacting 2 moles of Tenofovir alafenamide with 0.9 to 1.1 moles of adipic acid in a suitable solvent.

In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide mono adipate having a purity greater than 95%, preferably at least 99%, more preferably at least 99.5% area % by HPLC.

In a further aspect, the present invention relates to substantially pure Tenofovir alafenamide mono adipate having enantiomeric excess greater than 97%. Preferably greater than 98%, most preferably greater than 99%.

The mono adipate salt according to the invention is characterised by good crystallinity and low amorphisation during grinding and compression. In addition, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.

The inventors have discovered a surprisingly advantageous crystalline polymorphic form of Tenofovir alafenamide mono adipate which hereinafter referred to as Form Cl. This form is described in more detail herein. The crystalline Tenofovir alafenamide mono adipate Form Cl is relatively stable towards moisture and humidity, thereby representing a crystalline form of Tenofovir alafenamide, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Tenofovir alafenamide mono adipate Form Cl, according to the present invention may be characterized by powder X-ray diffraction.

The crystalline Tenofovir alafenamide mono adipate Form Cl, may be characterized by having an XRPD diffractogram comprising peaks at 3.91, 6.25, 6.61, 15.74, 18.17 and 21.94 ± 0.2°2Q. The XRPD diffractogram may comprise further peaks at 8.05, 11.03, 12.09, 19.77 and 23.99 ± 0.2°20.

The XRPD diffractogram may be as depicted in Figure 7.

The crystalline Tenofovir alafenamide mono adipate Form Cl may be characterized by having a DSC thermogram as shown in Figure 8.

The DSC plot for the sample shows an endotherm peak melting with an onset at 107.30°C, a peak maximum at 110.72± 5°C, and an enthalpy change of 84.289 j/g.

The crystalline Tenofovir alafenamide mono adipate Form Cl may be characterized by having a TGA thermogram substantially as depicted in Figure 9.

TGA data indicated a weight loss of 0.069% at temperatures up to 140°C. The TGA analysis indicates the crystalline Tenofovir alafenamide mono adipate Form Cl is the anhydrous form.

Preferably the Tenofovir alafenamide mono adipate Form Cl has a crystalline purity of at least 80%, more preferably at least 90%, more preferably at least 95%, most preferably at least 99% by weight. General process

According to the fourth embodiment, the present invention provides a process for the preparation of novel salts of tenofovir alafenamide comprises steps of: a) providing a solution of tenofovir alafenamide in a suitable solvent, b) treating the solution with D-malic acid, or adipic acid, c) optionally treating with an antisolvent, d) optionally cooling the solution and optionally stirring, e) isolating tenofovir alafenamide salt, and f) drying

In some embodiments, the above method further comprises: (bl) seeding the solution from step (b) with appropriate seed at room temperature and allowing the solution to stir until a slurry forms.

Providing a solution in step a) includes: i) direct use of a reaction mixture containing tenofovir alafenamide that is obtained in the course of its synthesis; or ii) dissolving tenofovir alafenamide in a suitable solvent optionally by heating. The Tenofovir alafenamide may be obtained by the processes known in the art. The tenofovir alafenamide used in preparing the salts and polymorphs may be obtained by methods described in the prior art which are herein incorporated by reference in their entirety. The tenofovir alafenamide used as a starting material can be in any form, e.g. it can be in a reaction solution, suspension, crude or in amorphous, anhydrous, hydrated or solvated form.

In one embodiment, Tenofovir alafenamide is dissolved in a suitable solvent to facilitate formation of the acid salt. Suitable solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol, isoamyl alcohol, n-butanol, 1,2-dimethoxy ethanol, 2-m ethoxy ethanol, 2-ethoxy ethanol and ethylene glycol, and like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; nitriles like acetonitrile; aprotic polar solvents such as DMF, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2- pyridone, l-methyl-2-pyrolidinone (NMP) and the like; any mixtures of two or more thereof.

In step b), the solution containing Tenofovir alafenamide is treated with D-malic acid, or adipic acid. The acid may be in the form of a solution or solid.

The reaction may be carried out at elevated temperature to facilitate the reaction.

Suitable antisolvents used in the step c), include, but are not limited to, ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane tetrahydrofuran, isopropyl ether, diisopropyl ether (DIPE), methyl t-butyl ether (MTBE), and the like; hydrocarbons such as heptane, hexane, toluene, xylene and the like; and any mixtures of two or more thereof.

In step d) prior to the isolation, the reaction material obtained in step c) of the process, is optionally cooled to a temperature range of -5°C to 30°C and stirred for about 10 minutes to about 10 hours, preferably for about 20 minutes to about 8 hours, more preferably for about 30 minutes hours to about 6 hours.

In step d), the resulting acid addition salt may be isolated as a solid by any one of the general techniques known in the art, including but not limited to, cooling, chilling, completely or partially removing solvents, and/or filtering.

Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art. The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, or any other suitable temperatures.

In step f) the solid isolated from step e), may be optionally further dried to afford novel salt forms of tenofovir alafenamide.

Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 70°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the product is not degraded in its quality. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 hours or more.

Alternatively, acid addition salts of Tenofovir alafenamide may be prepared in accordance with the present invention by a salt interconversion method. This process involves reacting an acid salt of Tenofovir alafenamide with a suitable base to form the free base of Tenofovir alafenamide and thereafter converting the free base so formed into an acid salt form (by addition of an acid from the present invention).

The obtained acid addition salts of Tenofovir alafenamide may be further purified.

According to another aspect of the present invention, there is provided Tenofovir alafenamide mono D-malate, Tenofovir alafenamide hemi D-malate and Tenofovir alafenamide mono adipate having a purity of at least 95%, preferably at least 99%, more preferably at least 99.5% area % by HPLC. Crystalline forms of the present invention may be prepared by dissolving, crystallizing, stirring, evaporating the solvent or seeding with crystal. The crystals may be isolated form the reaction mixture by any of the general techniques known in the art.

In certain aspects, the acid salts and polymorphic forms described herein may potentially exhibit improved properties. For example, in certain aspects, the acid salts and polymorphic forms described herein may potentially exhibit improved long term physical and chemical stability. Such improved stability could have a potentially beneficial impact on the manufacture of the Tenofovir alafenamide, such as for example offering the ability to store process intermediate for extended periods of time. Improved stability could also potentially benefit a composition or pharmaceutical composition of the Tenofovir alafenamide. In further aspects, the salts and polymorphic forms described herein may also potentially result in improved yield of the Tenofovir alafenamide, or potentially result in an improvement of the quality of the Tenofovir alafenamide. In certain aspects, the salts and polymorphic described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.

The acid salts and polymorphic forms of the present invention may be administered by any route appropriate to the condition to be treated. Suitable administration routes include, but are not limited to, oral, rectal, nasal, pulmonary, topical, vaginal and parenteral.

The acid salts and polymorphic forms of the present invention may be formulated as solid compositions together with a pharmaceutically acceptable carrier, glidant, diluent, or excipient, for oral administration in the form of capsules, tablets, pills, powders or granules.

The pharmaceutical compositions of the present invention comprise a Tenofovir alafenamide or a pharmaceutically acceptable acid addition salt thereof of the type disclosed herein, together with one or more pharmaceutically acceptable excipients, and optionally one or more further active pharmaceutical ingredients.

In one aspect, the pharmaceutical composition of the present invention is formulated to provide immediate release of the active pharmaceutical ingredient(s) present therein. In an alternative aspect, the pharmaceutical composition of the present invention is formulated to provide controlled release of the active pharmaceutical ingredient(s) present therein. Controlled release comprises delayed, sustained and pulsed release of the active pharmaceutical ingredient(s).

Suitable pharmaceutical excipients are known in the art and include, but are not limited to, carriers, diluents and/or vehicles. The excipients (s) must be "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not harmful to the patient. The excipient(s) may be selected to provide a desired release profile of the active pharmaceutical ingredient(s) present.

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of Tenofovir alafenamide or a pharmaceutically acceptable acid addition salt thereof. Suitable dosages include, but are not limited to, 150 mg, and 200mg.

The following examples, which include preferred aspects, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred aspects of the invention. EXAMPLES

Example 1: Process to prepare Tenofovir alafenamide mono D-malate

1.0 g of Tenofovir alafenamide and 0.28 g of D-malic acid (1.0 eqv) were dissolved in 3.0 ml isopropyl alcohol at 30 to 35°C. The resultant solution was slowly charged into the 30.0 ml of precooled n-heptane (0-5°C). Stirred the solution at 0 - 10°C for 4 hrs followed by holding the reaction mass at ambient temperature for 12 hrs. The reaction mass was dried under vacuum and then dried in an air tray drier at 40°C for 6 hrs to obtain the title product.

Product weight: 0.9 g

NMR spectrum showed a 1:1 stoichiometry ratio of Tenofovir alafenamide to D- malic acid.

XRD, DSC and TGA thermograms of Tenofovir alafenamide mono D-malate are shown in Figures 1-3.

Example 2: Process to prepare Tenofovir alafenamide mono D-malate

5.0 g of Tenofovir alafenamide and 1.4 g of D-malic acid (1.0 eqv) were dissolved in 50.0 ml acetonitrile at 70 to 75°C. The hot solution was made particle free and cooled to 25°C. Seeded the solution with 2% Tenofovir alafenamide mono D- malate and then stirred for 1 hr. Charged 100.0 ml MTBE in to the above slurry and continued stirring for 30 min. Filtered the reaction mass under vacuum and dried in air tray drier for 3 hrs at 45°C followed by 8 hr at 50°C to obtain the title product.

Product weight: 4.2 g

XRD, DSC and TGA thermograms of Tenofovir alafenamide mono D-malate are shown in Figures 1-3. Example 3: Process to prepare Tenofovir alafenamide hemi D-malate

1.0 g of Tenofovir alafenamide and 0.14 g of D-malic acid (0.5 eqv) were dissolved in 3.0 ml isopropyl alcohol at 40 to 45°C. The resultant solution was slowly charged into the 25.0 ml of precooled n-heptane (0-5°C). Stirred the solution at 0 - 10°C for 3 hr followed by stirring at 25°C for 1 hr. Filtered the reaction mass under vacuum and suck dried the material for 30 min. The resultant solid was dried in an air tray drier at 40°C for 5 hrs to obtain the title product.

Product weight: 0.7 g

Chromatographic purity (By HPLC): >99.5%

NMR spectrum showed a 2:1 stoichiometry ratio of Tenofovir alafenamide to D- malic acid.

XRD, DSC and TGA thermograms of Tenofovir alafenamide hemi D-malate are shown in Figures 4-6.

Example 4: Process to prepare Tenofovir alafenamide hemi D-malate

5.0 g of Tenofovir alafenamide and 0.7 g of D-malic acid (0.5 eqv) were dissolved in 50.0 ml acetonitrile at 70 to 75°C. The hot solution was made particle free and cooled to 25°C. Seeded the solution with 2% Tenofovir alafenamide hemi D-malate and then stirred for 1 hr. Charged 70.0 ml MTBE in to the above slurry and continued stirring for 30 min. Filtered the reaction mass under vacuum and dried in air tray drier at 40°C for 6 hrs to obtain the title product.

Product weight: 3.5 g

Chromatographic purity (By HPLC): >99.5%

XRD, DSC and TGA thermograms of Tenofovir alafenamide hemi D-malate are shown in Figures 4-6. Example 5: Determination of the Chemical Stability of Tenofovir alafenamide hemi D-malate

Within the context of the present disclosure, Tenofovir alafenamide hemi D-malate may exhibit long-term physical and chemical stability. As an example, Table 1 below shows laboratory data collected on Tenofovir alafenamide hemi D-malate, all prepared according to the processes disclosed in the present disclosure. The data demonstrate that Tenofovir alafenamide hemi D-malate show no significant degradation or change in PXRD pattern (e.g., is stable at 1, 2 and 3 months storage) when stored for 3 months at 40±2°C/75±5% relative humidity (RH). In certain particularly effective embodiments, Tenofovir alafenamide hemi D-malate displayed better long term storage stability with significantly less than 1 % degradation over three months under those conditions.

Table 1

Table 1 shows no significant degradation or change in the XRPD pattern when stored at 2 to 8C or 25±2°C/60±5%RH or 40±2°C/75±5%RH, indicates that Tenofovir alafenamide hemi D-malate has improved thermal stability. Example 6: Determination of the solubility of Tenofovir alafenamide hemi D- malate in buffered solutions (Solubility as a Function of pH )

The aqueous solubility of Tenofovir alafenamide hemi D-malate was compared with Tenofovir alafenamide hemifumarate and Tenofovir alafenamide monofumarate. The solubility of salts of the invention was determined at pH 2.1 (Gastric Buffer), pH 4.5 (Acetate Buffer) and pH 6.8 (Intestinal Buffer), by suspending 1-5 mg of each salt in 10 mL of corresponding aqueous solution. The samples were allowed to equilibrate at ambient temperature for at least 24 hours for pH 2.1, 4.5 and 6.8 Buffers. The supernatant was filtered and used for the solubility determination by UV-VIS spectroscopy. The solid residue was analyzed by XRPD.

The solubility data obtained are shown in Tables 2, 3 and 4. The data and Figures 10-12 indicated that the solubility is pH and temperature dependent.

Table 2 pH solubility data at pH 2.1

Table 3 pH solubility data at pH 4.5

Table 4 pH solubility data at pH 6.8

The above pH solubility data suggests that Tenofovir alafenamide hemi D-malate is having 1.3 to 1.8 times higher solubility in comparison to Tenofovir alafenamide hemi fumarate. On the other side mono fumarate is having 0.5 to 0.8 times less solubility in comparison to the Tenofovir alafenamide hemi fumarate. Example 5: Process to prepare Tenofovir alafenamide mono adipate

10.0 g of Tenofovir alafenamide and 3.7 g of Adipic acid (1.2 eqv) were dissolved in 20.0 ml methanol at 30 to 35°C. The resultant solution was concentrated in a Buchi rotavapor at 50°C until residue was obtained. The residue was slowly charged into the 250.0 ml of precooled MTBE (0-5°C). Stirred the solution at 0 - 10°C for 2 hr and then filtered the reaction mass under vacuum. The suck dried material was dried in an air tray drier at 50°C for 6 hrs to obtain the title product.

Product weight: 11.5 g

NMR spectrum showed a 1 : 1 stoichiometry ratio of Tenofovir alafenamide to adipic acid.

XRD, DSC and TGA thermograms of Tenofovir alafenamide mono adipate are shown in Figures 7-9.

Claims

We Claims,

1. A crystalline Tenofovir alafenamide hemi D-malate Form C2.

2. Tenofovir Alafenamide hemi D-malate of claim 1, wherein the molar ratio of Tenofovir Alafenamide to D-malic acid is 2: 1.

3. The crystalline Tenofovir alafenamide hemi D-malate Form C2 of claim 1 characterized by having an XRPD diffractogram comprising peaks at 3.93, 7.82, 15.19, 9.59 and 22.90 ± 0.2°2Q.

4. The crystalline Tenofovir alafenamide hemi D-malate Form C2 of claim 3 wherein the XRPD diffractogram comprising further peaks at 12.35, 15.67, 17.10, 18.08, 19.24 and 24.83± 0.2°20.

5. The crystalline Tenofovir alafenamide hemi D-malate Form C2 as claimed in any one of claims 1 to 4 characterized by the XRPD diffractogram as depicted in Figure 4.

6. The crystalline Tenofovir alafenamide hemi D-malate Form C2 of claim 1 characterized by the DSC isotherm comprising an endotherm peak melting with an onset at 114.14°C, a peak maximum at 121 95± 5°C, and an enthalpy change of 83.179 j/g.

7. The crystalline Tenofovir alafenamide hemi D-malate Form C2 of claim 6 characterized by having a DSC thermogram as shown in Figure 5.

8. The crystalline Tenofovir alafenamide hemi D-malate Form C2 of claim 1 characterized by having a TGA thermogram substantially as depicted in Figure 6.

9. The crystalline Tenofovir alafenamide hemi D-malate Form C2 as claimed in any one of claims 1 to 8, wherein the crystalline form is an anhydrous form.

10. A method for preparing Tenofovir Alafenamide hemi D-malate comprising the steps of: a) providing a solution of tenofovir alafenamide in a suitable solvent, b) treating the solution with 0.4 to 0.6 equivalence of D-malic acid w r t, Tenofovir Alafenamide, c) optionally treating with an antisolvent, d) optionally cooling the solution and optionally stirring, e) isolating tenofovir alafenamide salt, and f) drying.

11. The process of claim 10, further comprises: (bl) optionally seeding the solution from step (b) with appropriate seed at room temperature and allowing the solution to stir until a slurry forms.

12. The process of claim 10, wherein solvent is selected from the group comprising of alcohols, halogenated hydrocarbons, ketones, esters , nitriles, aprotic polar solvents or any mixtures of two or more thereof.

13. The process of claim 10, wherein antisolvent is selected from the group comprising of ethers, hydrocarbons and any mixtures of two or more thereof.

14. A pharmaceutical composition comprising the Tenofovir Alafenamide hemi D-malate as claimed in any one of claims 1 or 10, together with one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition of claim 14 further comprising one or more active pharmaceutical ingredients.

16. A method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of Tenofovir Alafenamide hemi D-malate as claimed in any one of claims 1 or 10.

17. A method of treating a hepatitis B virus (HBV) infection comprising administering a therapeutically effective amount of Tenofovir Alafenamide hemi D-malate as claimed in any one of claims 1 or 10.

18. A crystalline Tenofovir alafenamide mono D-malate Form Cl.

19. Tenofovir Alafenamide mono D-malate of claim 18, wherein the molar ratio of Tenofovir Alafenamide to D-malic acid is 1:1.

20. The crystalline Tenofovir alafenamide mono D-malate Form Cl of claim 18 characterized by having an XRPD diffractogram comprising peaks at 3.05, 9.06, 15.09 and 18.14 ± 0.2°20.

21. The crystalline Tenofovir alafenamide mono D-malate Form Cl of claim 20 wherein the XRPD diffractogram comprising further peaks at 14.22, 20.90, 24.28 and 28.72 ± 0.2°20.

22. The crystalline Tenofovir alafenamide mono D-malate Form Cl as claimed in any one of claims 18 to 21 characterized by the XRPD diffractogram as depicted in Figure 1.

23. The crystalline Tenofovir alafenamide mono D-malate Form Cl of claim 18 characterized by the DSC isotherm comprising an endotherm peak melting with an onset at 95.16°C, a peak maximum at 102.74±5°C, and an enthalpy change of 79.969 j/g.

24. The crystalline Tenofovir alafenamide mono D-malate Form Cl of claim 23 characterized by having a DSC thermogram as shown in Figure 2.

25. The crystalline Tenofovir alafenamide mono D-malate Form Cl of claim 18 characterized by having a TGA thermogram substantially as depicted in Figure 3.

26. The crystalline Tenofovir alafenamide mono D-malate Form Cl as claimed in any one of claims 18 to 25, wherein the crystalline form is an anhydrous form.

27. Tenofovir Alafenamide mono adipate.

28. Tenofovir Alafenamide mono adipate of claim 27, wherein the molar ratio of Tenofovir Alafenamide to adipic acid is 1:1.

29. A crystalline Tenofovir alafenamide mono adipate Form Cl.

30. The crystalline Tenofovir alafenamide mono adipate Form Cl of claim 29 characterized by having an XRPD diffractogram comprising peaks at 3.91, 6.25, 6.61, 15.74, 18.17 and 21.94 ± 0.2°2Q.

31. The crystalline Tenofovir alafenamide mono adipate Form Cl of claim 30 wherein the XRPD diffractogram comprising further peaks at 8.05, 11.03, 12.09, 19.77 and 23.99 ± 0.2°20.

32. The crystalline Tenofovir alafenamide mono adipate Form Cl as claimed in any one of claims 29, 30 or 31 characterized by the XRPD diffractogram as depicted in Figure 7.

33. The crystalline Tenofovir alafenamide mono adipate Form Cl of claim 29 characterized by the DSC isotherm comprising an endotherm peak melting with an onset at 107.30°C, a peak maximum at 110.72± 5°C, and an enthalpy change of 84.289 j/g.

34. The crystalline Tenofovir alafenamide mono adipate Form Cl of claim 33 characterized by having a DSC thermogram as shown in Figure 8.

35. The crystalline Tenofovir alafenamide mono adipate Form Cl of claim 29 characterized by having a TGA thermogram substantially as depicted in Figure 9.

36. The crystalline Tenofovir alafenamide mono adipate Form Cl as claimed in any one of claims 29 to 35, wherein the crystalline form is an anhydrous form.

37. A substantially pure Tenofovir Alafenamide hemi D-malate having a purity of greater than 99.5% by HPLC and enantiomeric excess greater than 99%.

38. A process for the preparation of substantially pure Tenofovir Alafenamide hemi D-malate of claim 37, which comprises reacting 1 mole of Tenofovir alafenamide with 0.4 to 0.6 moles of D-malic acid in a suitable solvent.

39. A substantially pure Tenofovir Alafenamide mono D-malate having a purity of greater than 99.5% by HPLC and enantiomeric excess greater than 99%.

40. A process for the preparation of substantially pure Tenofovir Alafenamide mono D-malate of claim 39, which comprises reacting 1 mole Tenofovir alafenamide with 0.9 to 1.1 mole of D-malic acid in a suitable solvent.

41. A substantially pure Tenofovir Alafenamide mono adipate having a purity of greater than 99.5% by HPLC and enantiomeric excess greater than 99%.

42. A process for the preparation of substantially pure Tenofovir Alafenamide mono adipate of claim 41, which comprises reacting 1 mole of Tenofovir alafenamide with 0.9 to 1.1 moles of adipic acid in a suitable solvent.