WO2018115046A1

WO2018115046A1 - Crystalline solid forms of tenofovir alafenamide

Info

Publication number: WO2018115046A1
Application number: PCT/EP2017/083690
Authority: WO
Inventors: Hannes Lengauer; Arthur Pichler; Erwin Schreiner
Original assignee: Sandoz Ag
Priority date: 2016-12-23
Filing date: 2017-12-20
Publication date: 2018-06-28

Abstract

The present invention relates to crystalline solid forms of tenofovir alafenamide and methods for their preparation. Furthermore, the invention relates to the use of one or more of the crystalline solid forms of tenofovir alafenamide of the present invention for the preparation of pharmaceutical compositions as well as to pharmaceutical compositions comprising an 5 effective amount of one or more of said forms. The pharmaceutical compositions of the present invention can be used as medicaments, in particular for the treatment and/or prophylaxis of viral infections such as HIV infections.

Description

CRYSTALLINE SOLID FORMS OF TENOFOVIR ALAFENAMIDE FIELD OF THE INVENTION

The present invention relates to crystalline solid forms of tenofovir alafenamide and methods for their preparation. Furthermore, the invention relates to the use of one or more of the crystalline solid forms of tenofovir alafenamide of the present invention for the preparation of pharmaceutical compositions as well as to pharmaceutical compositions comprising an effective amount of one or more of said forms. The pharmaceutical compositions of the present invention can be used as medicaments, in particular for the treatment and/or prophylaxis of viral infections such as HIV infections. BACKGROUND OF THE INVENTION

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

formula (I)

Tenofovir alafenamide is an antiviral compound useful for the treatment and/or prophylaxis of viral infections including infections caused by DNA viruses, R A viruses, herpesviruses (e.g. CMV, HSV 1 , HSV 2, VZV), retroviruses, hepadnaviruses (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV. Tenofovir alafenamide may be administered alone or in combination with other antiviral agents to patients in need.

WO 02/008241 A2 discloses tenofovir alafenamide and a tenofovir alafenamide monofumarate form as well as processes for their preparations. WO 2013/025788 Al describes a crystalline hemifumarate form of tenofovir alafenamide. WO 2015/040640 discloses acid addition salts of tenofovir alafenamide (from ferulic acid, phosphoric acid, succinic acid, citric acid, tartaric acid, lactic acid or methane sulfonic acid). WO 2015/176602 discloses a synthesis for preparing tenofovir alafenamide forms of phosphoric acid, succinic acid, citric acid, L-tartaric acid, D- tartaric acid, D,L-tartaric acid, L-malic acid, oxalic acid and sulfuric acid. WO 2016/192692 discloses solid forms of tenofovir alafenamide with hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic, 4-aminobenzoic acids.

Different solid state forms of an active pharmaceutical ingredient often possess different properties. Different properties of solid state forms can allow for improved formulations, for example, formulations with improved dissolution profile, or with improved stability and shelf- life. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. Thus, new solid state forms of an active pharmaceutical ingredient can have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid state forms. Different properties of different salts and solid state forms and solvates in turn can allow improved formulations, for example, formulations with improved dissolution profile, or with improved stability and shelf-life. Also processing or handling of the active pharmaceutical ingredient during the formulation process may also be improved. Even bioavailability of the drug in the pharmaceutical dosage form may be improved. Thus, there is still a strong need for the provision of further solid forms of tenofovir alafenamide. In particular, there is the need for the provision of new salts of tenofovir alafenamide. There is also the need for the provision of new cocrystals of tenofovir alafenamide.

SUMMARY OF THE INVENTION

It was an objective of the current invention to provide new means of improving the properties of tenofovir alafenamide, especially in regard to the treatment and/or prophylaxis of viral infections such as HIV infections, by providing new drugable forms of tenofovir alafenamide.

Especially desirable improvements/advantages of the new drugable form include:

• improvement of physicochemical properties in order to facilitate the formulation, the manufacture, or to enhance the absorption and/or the bioavailability: • thus being more active when compared to the hemifumarate or monofumarate forms of tenofovir alafenamide; or

• being easily obtainable, easy to manufacture or

• allowing more flexibility in formulating, or facilitating its formulation,

• being highly soluble, thus allowing better dissolution rates, especially if dissolving in an aqueous physiological surrounding, or

• reducing hygroscipicity;

• improving stability;

• allowing new routes of administration;

• allowing to combine tenofovir alafenamide with a chemically usually non-compatible active agent in the same formulation or even in immediate contact, without having to isolate tenofovir alafenamide;

• or minimizing/reducing the side effects, especially the severe side effects, assigned to tenofovir alafenamide.

Most desirably the new drugable forms should combine more than one, or even most of these advantages.

The present invention provides a crystalline form (salt/co crystal) of tenofovir alafenamide with maleic acid, herein also designated "tenofovir alafenamide maleate".

In addition, the present invention provides a crystalline form (salt/co crystal) of tenofovir alafenamide with malonic acid, herein also designated "tenofovir alafenamide malonate".

Furthermore, the present invention provides a crystalline form (salt/co crystal) of tenofovir alafenamide with 3,4-dihydroxybenzoic acid, herein also designated "tenofovir alafenamide protocatechuate".

The invention further relates to a composition comprising one or more of the aforementioned crystalline form(s) of tenofovir alafenamide and processes for the preparation of the crystalline form(s) and the composition. In addition, the invention relates to the use of the crystalline form(s) 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 crystalline form(s) of tenofovir alafenamide of the present invention. Abbreviations

PXRD powder X-ray diffractogram

XRPD X-ray powder diffraction

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption

THF tetrahydrofuran

MTBE methyl tert-butyl ether

RH relative humidity

MF monofumarate

HF hemifumarate

Mp melting point

Definitions

The term "tenofovir alafenamide" as used herein refers to 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl] adenine according to formula (I) disclosed herein above. A process for the preparation is disclosed in WO 02/008241 A2. Tenofovir alafenamide (INN/USAN, formerly GS-7340) is a nucleotide reverse transcriptase inhibitor and a prodrug of tenofovir. Developed by Gilead Sciences for use in the treatment of HIV infection and chronic hepatitis B, it is applied in the form of tenofovir alafenamide fumarate (TAF).

The term "tenofovir alafenamide hemifumarate" as used herein refers to the hemifumarate form of tenofovir alafenamide, having a chemical structure, wherein about two molecules of tenofovir alafenamide are associated with one molecule of fumaric acid. In one embodiment, the tenofovir alafenamide hemifumarate can be a crystalline salt, wherein protons have been transferred from at least some of the fumaric acid molecules to tenofovir alafenamide molecules. Since fumaric acid is a dicarboxylic acid, either one proton (i.e. hydrogen fumarate) or two protons (i.e. fumarate) can be transferred, dependent on the environment. In another embodiment, the tenofovir alafenamide hemifumarate can be a cocrystal, wherein substantially no protons have been transferred from fumaric acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide hemifumarate" as used herein refers to a cocrystal. The transfer of protons from one molecule to another in a crystal is dependent on the environment. Crystalline salts and cocrystals may be thought of as two ends of a proton transfer spectrum, where the salt has completed the proton transfer at one end and an absence of proton transfer exists for cocrystals at the other end. The term "crystalline tenofovir alafenamide hemifumarate" as used herein refers to the crystalline form of tenofovir alafenamide hemifumarate disclosed in WO 2013/025788 Al . This form can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (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)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm.

The term "tenofovir alafenamide monofumarate" as used herein refers to the monofumarate form of 9-[(i?)-2-[[(5)-[[(5)-l-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine having a chemical structure comprising about one molecule of tenofovir alafenamide per molecule fumaric acid. Tenofovir alafenamide monofumarate has a molar ratio of tenofovir alafenamide and fumaric acid typically and preferably in a range of from about 1.0: 0.7 to 1.3, more preferably in a range of from about 1.0: 0.8 to 1.2, most preferably in a range of from about 1.0: 0.9 to 1.1 and in particular the molar ratio is about 1.0:

1.0.

The term "crystalline form (salt/cocrystal) of tenofovir alafenamide with maleic acid" as used herein refers to the maleate form of 9-[(i?)-2-[[(5)-[[(5)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine according to formula (II) disclosed herein having a chemical structure comprising about one molecule of tenofovir alafenamide per molecule maleic acid:

Formula (II) In one embodiment, the tenofovir alafenamide maleate can be a crystalline salt, wherein protons have been transferred from at least some of the maleic acid molecules to tenofovir alafenamide molecules. Since maleic acid is a dicarboxylic acid, either one proton (i.e. hydrogen maleate) or two protons (i.e. maleate) can be transferred, dependent on the environment. In another embodiment, the tenofovir alafenamide maleate can be a cocrystal, wherein substantially no protons have been transferred from maleic acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide maleate" as used herein refers to a cocrystal.

The term "crystalline form (salt/cocrystal) of tenofovir alafenamide with malonic acid" as used herein refers to the malonate form of 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine according to formula (III) disclosed herein having a chemical structure comprising about one molecule of tenofovir alafenamide per molecule malonic acid:

Formula (III)

In one embodiment, the tenofovir alafenamide malonate can be a crystalline salt, wherein protons have been transferred from at least some of the malonic acid molecules to tenofovir alafenamide molecules. Since malonic acid is a dicarboxylic acid, either one proton (i.e. hydrogen malonate) or two protons (i.e. malonate) can be transferred, dependent on the environment. In another embodiment, the tenofovir alafenamide malonate can be a cocrystal, wherein substantially no protons have been transferred from malonic acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide malonate" as used herein refers to a cocrystal.

The term "crystalline form (salt/cocrystal) of tenofovir alafenamide with 3,4-dihydroxybenzoic acid" as used herein refers to the protocatechuate form of 9-[(R)-2-[[(S)-[[(S)-l- (isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl] methoxy]propyl] adenine according to formula (IV) disclosed herein having a chemical structure comprising about one molecule of tenofovir alafenamide per molecule 3,4-dihydroxybenzoic acid:

Formula (IV)

In one embodiment, the tenofovir alafenamide protocatechuate can be a crystalline salt, wherein protons have been transferred from at least some of the 3,4-dihydroxybenzoic acid molecules to tenofovir alafenamide molecules. In another embodiment, the tenofovir alafenamide protocatechuate can be a cocrystal, wherein substantially no protons have been transferred from 3,4-dihydroxybenzoic acid molecules to tenofovir alafenamide molecules. Preferably, the term "tenofovir alafenamide protocatechuate" as used herein refers to a cocrystal.

The term "drugable form (of tenofovir alafenamide)" as used herein is defined as any form (salt, amorphous, crystal, solution, dispersion, mixture etc.) that tenofovir alafenamide might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom.

As used herein, the term "measured at a temperature in the range of from 20 to 30 °C" refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30 °C, i.e. at room temperature. Standard conditions can mean a temperature of about 22 °C. Standard conditions can also mean a temperature of about 25 °C. Typically, standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity.

As used herein the term "room temperature" refers to a temperature in the range of from 20 to 30 °C.

The term "reflection" with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials " by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term "essentially the same" with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-theta. Thus, a reflection that usually appears at 7.3° 2-Theta for example can appear between 7.1° and 7.5° 2-theta, preferably between 7.2 and 7.4° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only. As used herein, the term "substantially pure" with reference to a particular physical form means that the physical form includes at most 20%, preferably at most 10%, more preferably at most 5%, even more preferably at most 3% and most preferably at most 1% by weight of any other physical form of the compound.

The terms "physical form" and "solid form" are used interchangeably herein and refer to any crystalline and/or amorphous phase of a compound.

A crystalline solid form of tenofovir alafenamide may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, PXRDs, DSCs, TGAs and GMS isotherms. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art. The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,^'" Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOP AS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).

As used herein, the term "mother liquor" refers to the solution remaining after crystallization of a solid.

The term "non-hygroscopic" as used herein refers to a compound which shows a water uptake of at most 0.5 weight%, based on the weight of the compound, when measured with gravimetric moisture sorption at a relative humidity in the range of from 0 to 95% and a temperature of 25.0 ± 0.1 °C. The term "anhydrous" as used herein, refers to a solid, where no water is coordinated in or accommodated by the crystal structure. However, an anhydrate may still comprise residual water due to surface adsorption, solvent inclusions and/or absorption in disordered regions.

The term "solvate" as used herein, refers to a solid, where one or more organic solvent(s) is/are coordinated in or accommodated by the crystal structure. The term "isostructural solvate" as used herein, refers to solvates having the same space group with only small distortions of the unit cell dimensions and the same type of molecular network of the host molecule. Isostructural solvates as defined herein, only differ in the type of organic solvent present as guest molecule.

The term "desolvating" as used herein, means the at least partial removal of organic solvent from the crystal structure of the host molecule.

"Reduced pressure" as used herein means a pressure in the range of from 10 mbar to 900 mbar.

As used herein, the term "about" means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: illustrates a representative PXRD of the crystalline form of tenofovir alafenamide maleate of the present invention. The x-axis shows the scattering angle in °2-theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 2: illustrates a representative DSC curve of the crystalline form of tenofovir alafenamide maleate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 3: illustrates a representative TGA curve of the crystalline form of tenofovir alafenamide maleate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in percent (%).

Figure 4: illustrates a representative FTIR spectrum of the crystalline form of tenofovir alafenamide maleate.

Figure 5: illustrates a representative gravimetric moisture sorption of the crystalline form of tenofovir alafenamide maleate of the present invention.

Figure 6: illustrates a representative PXRD of the crystalline form of tenofovir alafenamide malonate of the present invention. The x-axis shows the scattering angle in °2-theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 7: illustrates a representative DSC curve of the crystalline form of tenofovir alafenamide malonate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up. Figure 8: illustrates a representative TGA curve of the crystalline form of tenofovir alafenamide malonate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in percent (%).

Figure 9: illustrates a representative FTIR spectrum of the crystalline form of tenofovir alafenamide malonate.

Figure 10: illustrates a representative gravimetric moisture sorption of the crystalline form of tenofovir alafenamide malonate of the present invention. Figure 11: illustrates a representative PXRD of the crystalline form of tenofovir alafenamide protocatechuate of the present invention. The x-axis shows the scattering angle in °2-theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 12: illustrates a representative DSC curve of the crystalline form of tenofovir alafenamide protocatechuate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 13: illustrates a representative TGA curve of the crystalline form of tenofovir alafenamide protocatechuate of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in percent (%).

Figure 14: illustrates a representative FTIR spectrum of the crystalline form of tenofovir alafenamide protocatechuate.

Figure 15: illustrates a representative gravimetric moisture sorption of the crystalline form of tenofovir alafenamide protocatechuate of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline form (salt/cocrystal) of tenofovir alafenamide with maleic acid, herein also designated "tenofovir alafenamide maleate".

In addition, the present invention provides a crystalline form (salt/cocrystal) of tenofovir alafenamide with malonic acid, herein also designated "tenofovir alafenamide malonate".

Furthermore, the present invention provides a crystalline form (salt/cocrystal) of tenofovir alafenamide with 3,4-dihydroxybenzoic acid, herein also designated "tenofovir alafenamide protocatechuate".

A process for the preparation of tenofovir alafenamide is described WO 02/08241 A2. The crystalline forms of tenofovir alafenamide of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to PXRD, Raman, DSC, TGA and GMS. The crystalline forms of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, they may be characterized by any one of the following embodiments or by combining two or more of the following embodiments. Tenofovir alafenamide maleate

In a first aspect the present invention relates to a crystalline form of tenofovir alafenamide maleate. Surprisingly it has been found that tenofovir alafenamide can form a crystalline salt or cocrystal with maleic acid, which salt/cocrystal has properties that makes it useful for use in pharmaceutical formulations.

In an embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by having a PXRD comprising reflections at 2-Theta angles of:

(4.6 ± 0.2)°, (7.8 ± 0.2)° and (12.6 ± 0.2)°; or

(4.6 ± 0.2)°, (7.8 ± 0.2)°, (12.6 ± 0.2)° and (6.7 ± 0.2)°; or

(4.6 ± 0.2)°, (7.8 ± 0.2)°, (12.6 ± 0.2)° and (16.9 ± 0.2)°; or

(4.6 ± 0.2)°, (7.8 ± 0.2)°, (12.6 ± 0.2)° and (18.0 ± 0.2)°; or

(4.6 ± 0.2)°, (6.7 ± 0.2)°; (7.8 ± 0.2)°, (12.6 ± 0.2)° and (18.0 ± 0.2)°; or

(4.6 ± 0.2)°, (6.7 ± 0.2)°; (7.8 ± 0.2)°, (12.6 ± 0.2)°, (16.9 ± 0.2)° and (18.0 ± 0.2)°; when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm.

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by having a PXRD comprising at least 4, more preferably at least 5, even more preferably at least 6 or most preferably at least 7 reflections at 2-Theta angles selected from Table 1 (± 0.2° 2-Theta), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalpha ir radiation having a wavelength of 0.15419 nm:

Table 1

Tenofovir alafenamide maleate

Pos. [°2Θ] Rel. Int. [%]

4,6 28

6,7 16

7,8 65

1 1 , 1 9

12,6 63

13,4 8

15,2 3

15,6 9

16,7 1 1 16,9 21

17,3 12

18,0 100

18,5 52

19,2 8

19,5 18

20,2 4

20,5 4

21 , 1 44

21 ,5 6

22, 1 7

22,9 4

24,0 13

25,4 9

25,7 23

26,3 4

27,0 3

27,4 8

27,9 4

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by having a PXRD essentially the same as shown in figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a further preferred embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by showing an endotherm with an onset temperature in the range of from 121.0 to 121.5 °C, preferably of about 121 °C, more preferably of 121.1°, when measured with DSC at a heating rate of 10 K/min.

More preferably, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by having a heat of fusion of at least 102.0 J/g, preferably of at least 103.0 J/g, even more preferably of at least 104.0 J/g, such as of at least 104.4 J/g, when measured with DSC at a heating rate of 10 K/min. Most preferably, a crystalline form of tenofovir alafenamide maleate is characterized by a heat of fusion of 104.5 J/g, when measured with DSC at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min.

Preferably, the crystalline form of tenofovir alafenamide maleate of the present invention is anhydrous, more preferably it is non-hygroscopic. In a further embodiment, the present invention relates to a crystalline form of tenofovir alafenamide maleate characterized by having a FTIR essentially the same as shown in figure 4 of the present invention, when measured at a temperature in the range of from 20 to 30 °C.

Also preferably, the crystalline form of tenofovir alafenamide maleate of the present invention is a cocrystal. In one embodiment of the disclosure, the crystalline form of tenofovir alafenamide maleate is provided in substantially pure form. The crystalline form of tenofovir alafenamide maleate in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.

Preferably, the crystalline form of tenofovir alafenamide maleate has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.

In one embodiment, a composition is provided consisting essentially of the crystalline form of tenofovir alafenamide maleate of the present invention. The composition of this embodiment may comprise at least 90 weight % of the crystalline form of tenofovir alafenamide maleate of the present invention, based on the weight of tenofovir alafenamide maleate in the composition.

Embodiments:

Some aspects, advantageous features and preferred embodiments of the present invention are summarized in the following items: 1. Crystalline tenofovir alafenamide maleate.

2. The crystalline tenofovir alafenamide maleate according to item 1, which is a cocrystal.

3. The crystalline tenofovir alafenamide maleate according to any one of items 1 or 2 in substantially pure form. 4. The crystalline tenofovir alafenamide maleate according to any one of aspects 1 to 3 having a molar ratio of tenofovir alafenamide : maleic acid in a range of from 1.0 : 0.7 to 1.0 : 1.3.

5. The crystalline tenofovir alafenamide maleate according to item 4, having a molar ratio of tenofovir alafenamide : maleic acid in a range of from 1.0 : 0.8 to 1.0 : 1.2.

6. The crystalline tenofovir alafenamide maleate according to item 5 having a molar ratio of tenofovir alafenamide : maleic acid of about 1.0 : 1.0.

7. The crystalline tenofovir alafenamide maleate according to any one of items 1 to 6, characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of the values listed in Table 1 (± 0.2° 2-Theta) when measured at a temperature of about 22° C using Cu Ka radiation. 8. The crystalline tenofovir alafenamide maleate according to item 7, characterized by a XRPD comprising characteristic peaks at 2-Theta angles of (4.6 ± 0.2)°, (6.7 ± 0.2)°, (7.8 ± 0.2)° and (12.6 ± 0.2)°.

9. The crystalline tenofovir alafenamide maleate according to any one of items 7 or 8, wherein the XRPD further comprises at least one additional peak at 2-Theta angles of (16.9 ± 0.2)° or (18.0 ± 0.2)°.

10. The crystalline tenofovir alafenamide maleate according to any one of items 7 or 8, wherein the XRPD comprises peaks at all positions identified in Table 1 (± 0.2° 2-Theta).

11. The crystalline tenofovir alafenamide maleate according to item 10, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.

12. The crystalline tenofovir alafenamide maleate according to any one of items 1 to 11 further characterized by showing an endotherm with an onset temperature in the range of from 121.0 to 121.5 °C, preferably of about 121 °C, more preferably of 121.1°, when measured with DSC at a heating rate of 10 K/min.

13. The crystalline tenofovir alafenamide maleate according to any one of items 1 to 11 further characterized by having a heat of fusion of at least 102.0 J/g, preferably of at least 103.0 J/g, even more preferably of at least 104.0 J/g, such as of at least 104.4 J/g, when measured with DSC at a heating rate of 10 K/min.

14. The crystalline tenofovir alafenamide maleate according to any one of items 1 to 13 further characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min.

15. The crystalline tenofovir alafenamide maleate according to any one of items 1 to 14 further characterized by having a FTIR essentially the same as shown in figure 4 of the present invention, when measured at a temperature in the range of from 20 to 30 °C.

16. A composition comprising at least 90 weight % of crystalline tenofovir alafenamide maleate according to any one of items 1 to 15, based the weight of the composition.

17. The composition of item 16 consisting essentially of the crystalline form of any one of items 4 to 15. 18. Use of the crystalline tenofovir alafenamide maleate according to any one of items 1 to 5 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition.

19. Use of the crystalline tenofovir alafenamide maleate according to any one of items 1 to 15 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of viral infections such as HIV or HBV infections.

20. A pharmaceutical composition comprising crystalline tenofovir alafenamide maleate according to any one of claims 1 to 15 or a composition according to any one of claims 16 or 17, and a pharmaceutically acceptable carrier or diluent. 21. The pharmaceutical composition of item 20 which is an oral solid dosage form.

22. The pharmaceutical composition of item 21 which is a tablet.

23. The pharmaceutical composition according to any one of items 21 or 22, further comprising at least one water-soluble filler; at least one water-insoluble filler; at least one binder; and at least one lubricant.

24. A method of treating and/or preventing viral infections in a human comprising administering to the human a therapeutically-effective amount of crystalline tenofovir alafenamide maleate according to any one of items 1 to 15.

25. A process of making crystalline tenofovir alafenamide maleate accoding to any one of items 1 to 15 comprising the step of

- allowing tenofovir alafenamide maleate to crystallize from a solvent comprising a nitrile.

26. The process of claim 25, wherein the nitrile has a solubility in water at 20°C of at least lOOg/1.

27. The process of any one of items 25 or 26, wherein the nitrile is acetonitrile. 28. The process of any one of items 25 to 27, wherein tenofovir alafenamide maleate is allowed to crystallize at a temperature of from 0°C to 40°C.

Tenofovir alafenamide malonate

In a second aspect the present invention relates to a crystalline form of tenofovir alafenamide malonate. Surprisingly it has been found that tenofovir alafenamide can form a crystalline salt or cocrystal with malonic acid, which salt/cocrystal has properties that makes it useful for use in pharmaceutical formulations.

In an embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by having a PXRD comprising reflections at 2-Theta angles of: (4.0 ± 0.2)°, (6.8 ± 0.2)° and (8.7 ± 0.2)°; or

(4.0 ± 0.2)°, (6.8 ± 0.2)°, (8.7 ± 0.2)° and (9.0 ± 0.2)°; or

(4.0 ± 0.2)°, (6.8 ± 0.2)°, (8.7 ± 0.2)°, (9.0 ± 0.2)° and (18.4 ± 0.2)°; when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm.

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by having a PXRD comprising at least 4, more preferably at least 5, even more preferably at least 6 or most preferably at least 7 reflections at 2-Theta angles selected from Table 2 (± 0.2° 2-Theta), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm:

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by having a PXRD essentially the same as shown in figure 6 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm. In a further preferred embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by showing an endotherm with an onset temperature in the range of from 132.0 to 132.5 °C, preferably of about 132 °C, more preferably of 132.2°, when measured with DSC at a heating rate of 10 K/min. More preferably, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by having a heat of fusion of at least 83.0 J/g, preferably of at least 84.0 J/g, even more preferably of at least 85.0 J/g, such as of at least 85.6 J/g, when measured with DSC at a heating rate of 10 K/min. Most preferably, a crystalline form of tenofovir alafenamide maleate is characterized by a heat of fusion of 85.7 J/g, when measured with DSC at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min.

Preferably, the crystalline form of tenofovir alafenamide malonate of the present invention is anhydrous, more preferably it is non-hygroscopic.

In a further embodiment, the present invention relates to a crystalline form of tenofovir alafenamide malonate characterized by having a FTIR essentially the same as shown in figure 9 of the present invention, when measured at a temperature in the range of from 20 to 30 °C.

Also preferably, the crystalline form of tenofovir alafenamide malonate of the present invention is a cocrystal.

In one embodiment of the disclosure, the crystalline form of tenofovir alafenamide malonate is provided in substantially pure form. The crystalline form of tenofovir alafenamide malonate in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure. Preferably, the crystalline form of tenofovir alafenamide malonate has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.

In one embodiment, a composition is provided consisting essentially of the crystalline form of tenofovir alafenamide malonate of the present invention. The composition of this embodiment may comprise at least 90 weight % of the crystalline form of tenofovir alafenamide malonate of the present invention, based on the weight of tenofovir alafenamide malonate in the composition.

Embodiments:

Some aspects, advantageous features and preferred embodiments of the present invention are summarized in the following items:

1. Crystalline tenofovir alafenamide malonate.

2. The crystalline tenofovir alafenamide malonate according to item 1, which is a cocrystal.

3. The crystalline tenofovir alafenamide malonate according to any one of items 1 or 2 in substantially pure form. 4. The crystalline tenofovir alafenamide malonate according to any one of aspects 1 to 3 having a molar ratio of tenofovir alafenamide : malonic acid in a range of from 1.0 : 0.7 to 1.0 : 1.3.

5. The crystalline tenofovir alafenamide malonate according to item 4, having a molar ratio of tenofovir alafenamide : malonic acid in a range of from 1.0 : 0.8 to 1.0 : 1.2.

6. The crystalline tenofovir alafenamide malonate according to item 5 having a molar ratio of tenofovir alafenamide : malonic acid of about 1.0 : 1.0.

7. The crystalline tenofovir alafenamide malonate according to any one of items 1 to 6, characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of the values listed in Table 2 (± 0.2° 2-Theta) when measured at a temperature of about 22° C using Cu Ka radiation.

8. The crystalline tenofovir alafenamide malonate according to item 7, characterized by a XRPD comprising characteristic peaks at 2-Theta angles of (4.0 ± 0.2)°, (6.8 ± 0.2)°, (8.7 ± 0.2)° and (9.0 ± 0.2)°.

9. The crystalline tenofovir alafenamide malonate according to any one of items 7 or 8, wherein the XRPD further comprises at least one additional peak at the 2-Theta angle of (18.4 ± 0.2)°.

10. The crystalline tenofovir alafenamide malonate according to any one of items 7 or 8, wherein the XRPD comprises peaks at all positions identified in Table 2 (± 0.2° 2-Theta).

11. The crystalline tenofovir alafenamide malonate according to item 10, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 6.

12. The crystalline tenofovir alafenamide malonate according to any one of items 1 to 11 further characterized by showing an endotherm with an onset temperature in the range of from 132.0 to 132.5 °C, preferably of about 132 °C, more preferably of 132.2°, when measured with DSC at a heating rate of 10 K/min.

13. The crystalline tenofovir alafenamide malonate according to any one of items 1 to 11 further characterized by having a heat of fusion of at least 83.0 J/g, preferably of at least 84.0 J/g, even more preferably of at least 85.0 J/g, such as of at least 85.6 J/g, when measured with DSC at a heating rate of 10 K/min.

14. The crystalline tenofovir alafenamide malonate according to any one of items 1 to 13 further characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min.

15. The crystalline tenofovir alafenamide malonate according to any one of items 1 to 14 further characterized by having a FTIR essentially the same as shown in figure 9 of the present invention, when measured at a temperature in the range of from 20 to 30 °C. 16. A composition comprising at least 90 weight % of crystalline tenofovir alafenamide malonate according to any one of items 1 to 15, based the weight of the composition.

17. The composition of item 16 consisting essentially of the crystalline form of any one of items 4 to 15. 18. Use of the crystalline tenofovir alafenamide malonate according to any one of items 1 to 5 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition.

19. Use of the crystalline tenofovir alafenamide malonate according to any one of items 1 to 15 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of viral infections such as HIV or HBV infections.

20. A pharmaceutical composition comprising crystalline tenofovir alafenamide malonate according to any one of claims 1 to 15 or a composition according to any one of claims 16 or 17, and a pharmaceutically acceptable carrier or diluent. 21. The pharmaceutical composition of item 20 which is an oral solid dosage form.

22. The pharmaceutical composition of item 21 which is a tablet.

23. The pharmaceutical composition according to any one of items 21 or 22, further comprising at least one water-soluble filler; at least one water-insoluble filler; at least one binder; and at least one lubricant. 24. A method of treating and/or preventing viral infections in a human comprising administering to the human a therapeutically-effective amount of crystalline tenofovir alafenamide malonate according to any one of items 1 to 15.

25. A process of making crystalline tenofovir alafenamide malonate accoding to any one of items 1 to 15 comprising the step of - allowing tenofovir alafenamide malonate to crystallize from a solvent comprising a nitrile.

26. The process of claim 25, wherein the nitrile has a solubility in water at 20°C of at least lOOg/1. 27. The process of any one of items 25 or 26, wherein the nitrile is acetonitrile.

28. The process of any one of items 25 to 27, wherein tenofovir alafenamide malonate is allowed to crystallize at a temperature of from 0°C to 40°C.

Tenofovir alafenamide protocatechuate

In a third aspect the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate. Surprisingly it has been found that tenofovir alafenamide can form a crystalline salt or cocrystal with 3,4-dihydroxybenzoic acid, which salt/cocrystal has properties that makes it useful for use in pharmaceutical formulations. In an embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by having a PXRD comprising reflections at 2-Theta angles of:

(3.0 ± 0.2)°, (8.9 ± 0.2)° and (12.2 ± 0.2)°; or

(3.0 ± 0.2)°, (8.9 ± 0.2)°, (12.2 ± 0.2)° and (10.3 ± 0.2)°; or

(3.0 ± 0.2)°, (8.9 ± 0.2)°, (12.2 ± 0.2)°, (10.3 ± 0.2)° and (17.6 ± 0.2)°;

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

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by having a PXRD comprising at least 4, more preferably at least 5, even more preferably at least 6 or most preferably at least 7 reflections at 2-Theta angles selected from Table 3 (± 0.2° 2-Theta), when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm:

Table 3:

Tenofovir alafenamide protocatechuate

Pos. [°2Θ] Rel. Int. [%]

3,0 27

6, 1 7

8,9 51

10,3 17

12,2 100

14,7 13

17,3 32

17,6 57 18,4 1 1

19,3 50

19,6 46

20,4 18

21 ,3 10

23,2 9

24,6 80

25,3 72

26,2 12

27,5 16

29,2 1 1

31 ,0 8

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by having a PXRD essentially the same as shown in figure 11 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a further preferred embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by showing an endotherm with an onset temperature in the range of from 124.5 to 125.0 °C, preferably of about 125 °C, more preferably of 124.8°, when measured with DSC at a heating rate of 10 K/min. More preferably, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by having a heat of fusion of at least 91.0 J/g, preferably of at least 92.0 J/g, even more preferably of at least 93.0 J/g, such as of at least 93.6 J/g, when measured with DSC at a heating rate of 10 K/min. Most preferably, a crystalline form of tenofovir alafenamide protocatechuate is characterized by a heat of fusion of 93.7 J/g, when measured with DSC at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min.

Preferably, the crystalline form of tenofovir alafenamide protocatechuate of the present invention is anhydrous, more preferably it is non-hygroscopic. In a further embodiment, the present invention relates to a crystalline form of tenofovir alafenamide protocatechuate characterized by having a FTIR essentially the same as shown in figure 14 of the present invention, when measured at a temperature in the range of from 20 to 30 °C. Also preferably, the crystalline form of tenofovir alafenamide protocatechuate of the present invention is a cocrystal.

In one embodiment of the disclosure, the crystalline form of tenofovir alafenamide protocatechuate is provided in substantially pure form. The crystalline form of tenofovir alafenamide protocatechuate in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure.

Preferably, the crystalline form of tenofovir alafenamide protocatechuate has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. In one embodiment, a composition is provided consisting essentially of the crystalline form of tenofovir alafenamide protocatechuate of the present invention. The composition of this embodiment may comprise at least 90 weight % of the crystalline form of tenofovir alafenamide protocatechuate of the present invention, based on the weight of tenofovir alafenamide protocatechuate in the composition. Embodiments:

1. Crystalline tenofovir alafenamide protocatechuate. 2. The crystalline tenofovir alafenamide protocatechuate according to item 1, which is a cocrystal.

3. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 or 2 in substantially pure form. 4. The crystalline tenofovir alafenamide protocatechuate according to any one of aspects 1 to 3 having a molar ratio of tenofovir alafenamide : 3,4-dihydroxybenzoic acid in a range of from 1.0 : 0.7 to 1.0 : 1.3.

5. The crystalline tenofovir alafenamide protocatechuate according to item 4, having a molar ratio of tenofovir alafenamide : 3,4-dihydroxybenzoic acid in a range of from 1.0 : 0.8 to 1.0 : 1.2.

6. The crystalline tenofovir alafenamide protocatechuate according to item 5 having a molar ratio of tenofovir alafenamide : 3,4-dihydroxybenzoic acid of about 1.0 : 1.0.

7. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 6, characterized by a x-ray powder diffraction pattern comprising four or more 2Θ values selected from the group consisting of the values listed in Table 3 (± 0.2° 2-Theta) when measured at a temperature of about 22° C using Cu Ka radiation.

8. The crystalline tenofovir alafenamide protocatechuate according to item 7, characterized by a XRPD comprising characteristic peaks at 2-Theta angles of (3.0 ± 0.2)°, (8.9 ± 0.2)°, (10.3 ± 0.2)° and (12.2 ± 0.2)°. 9. The crystalline tenofovir alafenamide protocatechuate according to any one of items 7 or 8, wherein the XRPD further comprises at least one additional peak at the 2-Theta angle of (17.6 ± 0.2)°.

10. The crystalline tenofovir alafenamide protocatechuate according to any one of items 7 or 8, wherein the XRPD comprises peaks at all positions identified in Table 3 (± 0.2° 2-Theta). 11. The crystalline tenofovir alafenamide protocatechuate according to item 10, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 11. 12. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 11 further characterized by showing an endotherm with an onset temperature in the range of from 124.5 to 125.0 °C, preferably of about 125 °C, more preferably of 124.8°, when measured with DSC at a heating rate of 10 K/min. 13. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 11 further characterized by having a heat of fusion of at least 91.0 J/g, preferably of at least 92.0 J/g, even more preferably of at least 93.0 J/g, such as of at least 93.6 J/g, when measured with DSC at a heating rate of 10 K/min.

14. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 13 further characterized by showing a mass loss of not more than 2.0 weight%, preferably not more than 1.5 weight%, more preferably not more than 1.0 weight% and most preferably not more than 0.5 weight%, such as not more than 0.3 weight%, based on the weight of the crystalline form, when measured with TGA at a temperature in the range of from 25 to 130 °C and a heating rate of 10 K/min. 15. The crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 14 further characterized by having a FTIR essentially the same as shown in figure 14 of the present invention, when measured at a temperature in the range of from 20 to 30 °C.

16. A composition comprising at least 90 weight % of crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 15, based the weight of the composition. 17. The composition of item 16 consisting essentially of the crystalline form of any one of items 4 to 15.

18. Use of the crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 5 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition. 19. Use of the crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 15 or of the composition according to any one of items 16 to 17 for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of viral infections such as HIV or HBV infections. 20. A pharmaceutical composition comprising crystalline tenofovir alafenamide protocatechuate according to any one of claims 1 to 15 or a composition according to any one of claims 16 or 17, and a pharmaceutically acceptable carrier or diluent.

21. The pharmaceutical composition of item 20 which is an oral solid dosage form. 22. The pharmaceutical composition of item 21 which is a tablet.

24. A method of treating and/or preventing viral infections in a human comprising administering to the human a therapeutically-effective amount of crystalline tenofovir alafenamide protocatechuate according to any one of items 1 to 15.

25. A process of making crystalline tenofovir alafenamide protocatechuate accoding to any one of items 1 to 15 comprising the step of

- allowing tenofovir alafenamide protocatechuate to crystallize from a solvent comprising a nitrile.

27. The process of any one of items 25 or 26, wherein the nitrile is acetonitrile.

28. The process of any one of items 25 to 27, wherein tenofovir alafenamide protocatechuate is allowed to crystallize at a temperature of from 0°C to 40°C.

Preparation of Crystalline Materials

Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.

Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2^nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph). A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.

Preferred processes for the preparation of the crystalline solid forms of tenofovir alafenamide of the invention are provided in the examples and in the embodiment sections, respectively.

The crystalline solid forms of tenofovir alafenamide according to the present invention may be prepared in situ by reacting tenofovir alafenamide free base with either maleic acid, malonic acid or 3,4-dihydroxybenzoic acid in the presence of a solvent comprising a nitrile, preferably acetonitrile. Tenofovir alafenamide free base can be prepared according to the procedure disclosed in WO 02/08241 A2 (compound IV with development code GS-7340 corresponds to tenofovir alafenamide free base).

The solid starting material may be slurried in a solvent comprising acetonitrile. Most preferably acetonitrile is the only solvent present in the slurry. The tenofovir alafenamide concentration of the suspension is preferably in the range of from about 10 to 200 g/L, more preferably from about 25 to 150 g/L and most preferably from about 25 to 100 g/L, for example the concentration is about 50 g/L. Preferably, slurrying is performed at room temperature but depending on the applied concentration may also be conducted at elevated temperature. Slurrying emcompasses any kind of movement of the solid material suspended in the solvent caused by, but not limited to e.g. agitation, stirring, mixing, shaking, vibration, sonication, wet milling and the like.

Once, the crystalline solid form of tenofovir alafenamide is obtained in essentially pure form, at least a part of the crystals are separated from their mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration. Optionally, in a further step the isolated crystals are washed with a suitable solvent, for example acetonitrile. The obtained crystals may optionally be dried. Compositions and medical use

In a further aspect the present invention relates to the use of the crystalline form(s) of tenofovir alafenamide of the present invention for the preparation of a pharmaceutical composition.

The pharmaceutical composition of the present invention can be prepared by wet or dry processing methods. In certain embodiments the pharmaceutical composition is prepared by wet processing methods, such as, but not limited to, wet granulation methods. Suitable wet granulation methods comprise high-shear granulation or fluid-bed granulation. In another embodiment the pharmaceutical composition is prepared by dry processing methods, such as, but not limited to, direct compression or dry granulation methods. An example of dry granulation is roller compaction. The pharmaceutical composition obtained by dry or wet processing methods may be compressed into tablets, encapsulated or metered into sachets.

In a further aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of the crystalline form(s) of tenofovir alafenamide of the present invention, one or more pharmaceutically acceptable excipient(s) and optionally one or more additional active pharmaceutical ingredient(s). The one or more pharmaceutically acceptable excipient(s) which is comprised in the pharmaceutical composition of the present invention is/are preferably selected from the group of carriers, fillers, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavouring agents, binders, colorants, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials and combinations thereof.

In a preferred embodiment, the pharmaceutically acceptable excipient(s) is/are selected from the group consisting of croscarmellose sodium, hydroxypropyl cellulose, lactose (as monohydrate), magnesium stearate, microcrystalline cellulose, silicon dioxide and sodium lauryl sulfate. In a preferred embodiment, all these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention. In one embodiment, the pharmaceutical composition contains one or more additional active pharmaceutical ingredient(s) selected from the group consisting of elvitegravir, cobicistat, emtricitabine, darunavir and rilpivirine.

In a further aspect, the present invention relates to the pharmaceutical composition as described above for use as a medicament. In yet another aspect, the present invention relates to the pharmaceutical composition as described above for use in the treatment or prophylaxis of viral infections caused by DNA viruses, R A viruses, herpesviruses (e.g. CMV, HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV.

In a particular embodiment, the present invention relates to the crystalline form(s) of tenofovir alafenamide or pharmaceutical compositions as described above for use in the treatment or prophylaxis of HIV- 1 infections. The present invention also relates to a method of treatment and/or prophylaxis of HIV- 1 infections in humans, comprising administration of an effective amount of the crystalline form(s) of tenofovir alafenamide or pharmaceutical compositions as described above to a human in need thereof.

In a further particular embodiment, the present invention relates to the crystalline form(s) of tenofovir alafenamide or pharmaceutical compositions as described above for use in the treatment or prophylaxis of Hepatitis B (HBV) infections. The present invention also relates to a method of treatment and/or prophylaxis of HBV infections in humans, comprising administration of an effective amount of the crystalline form(s) of tenofovir alafenamide or pharmaceutical compositions as described above to a human in need thereof.

EXAMPLES

Powder X-ray diffraction: PXRD was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphal,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PlXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-theta at ambient conditions. A typical precision of the 2-theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-theta. Thus, the diffraction peak of the crystalline solid forms of tenofovir alafenamide that appears for example at 7.3° 2-Theta can appear in the range of from 7.1 to 7.5° 2-theta, preferably in the range of from 7.2 to 7.4° 2-Theta on most X-ray diffractometers under standard conditions. Differential scanning calorimetry:

Differential scanning calorimetry was performed on a Mettler Polymer DSC R instrument. The sample was heated in a 40 microL aluminum pan with pierced aluminum lid from 25 to 200 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas. Thermogravimetric analysis:

TGA was performed on a Mettler TGA/DSC 1 instrument. The sample was weighed into a 100 microL aluminum pan closed with an aluminum lid. The lid was automatically pierced at the beginning of the measurement. The sample was heated from 25 to 200 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas. Gravimetric moisture sorption:

Moisture sorption isotherms were recorded with an SPSx-Ιμ moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (r.h.) of 25%. Relative humidity was then decreased to 5% r.h. in 5% steps, followed by a further decrease to 3% r.h. and to 0% r.h.. Afterwards r.h. was increased from 0% to 95% r.h. in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally r.h. was increased to 30% r.h. in 5% steps.

The time per step was set to a minimum of 2 hours and a maximum of 6 hours. If an equilibrium condition with a constant mass of ± 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 6 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 6 hours. The temperature was 25 ± 0.1 °C.

Fourier transform infrared spectrometry:

Fourier transform infrared spectroscopy (FTIR) was performed on an MKII Golden Gate™ Single Reflection Diamond ATR (attenuated total reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4 cm-1 resolution at ambient conditions. To record a spectrum a spatula tip of a sample was applied to the surface of the diamond in powder form. Then the sample was pressed onto the diamond with a sapphire anvil and the spectrum was recorded. A spectrum of the clean diamond was used as background spectrum. A typical precision of the wavenumber values is in the range of about ± 2 cm-1. Example 1: Preparation of crystalline tenofovir alafenamide maleate

500mg tenofovir alafenamide free base were mixed at room temperature with 10ml of acetonitrile. 128mg of maleic acid (l,05eq) were added and the mixture was heated to reflux until a solution was observed. The hot solution was filtered and allowed to cool to room temperature and further stored at 2-8°C in a fridge. The precipitate was filtered and dried under vacuum to yield 250mg of tenofovir alafemamide maleic acid form.

The final product was investigated by powder X-ray diffraction (Figure 1) and the results are summarized in Table 1 disclosed herein above. The isolated crystals of tenofovir alafenamide maleate were investigated in more detail by means of DSC, TGA, GMS and FTIR. The results are below discussed in more detail.

The DSC curve of tenofovir alafenamide maleate shows a single melting endotherm with an onset temperature of 121.1 °C and a heat of fusion of 104.5 J/g. The DSC curve is displayed in Figure 2 herein. Thermogravimetric analysis revealed a mass loss of about 0.3 weight% from the beginning of the measurement up to a temperature of about 130 °C. The TGA curve is displayed in Figure 3 herein. From the thermal analysis it can be concluded that this crystalline form is an anhydrous and non-solvated form of tenofovir alafenamide maleate. The corresponding GMS isotherm is displayed in Figure 5. The final product was also investigated by fourier transform infrared spectroscopy (Figure 4) and the results are summarized in Table

Table 4

Wavenumber (cm^"1)

3201

3090

2983

2938

1741

1703

1681

1615

1557

1471

1408

1362

1258

1200

1148

1133 1110

1062

1029

993

917

904

881

864

819

802

757

719

690

654

641

Example 2: Preparation of crystalline tenofovir alafenamide malonate

500mg tenofovir alafenamide free base were mixed at room temperature with 10ml of acetonitrile. 115mg of malonic acid (l,05eq) were added and the mixture was heated to reflux until a solution was observed. The hot solution was filtered and allowed to cool to room temperature and further stored at 2-8°C in a fridge. The precipitate was filtered and dried under vacuum to yield 330mg of tenofovir alafemamide malonic acid form.

The final product was investigated by powder X-ray diffraction (Figure 6) and the results are summarized in Table 2 disclosed herein above. The isolated crystals of tenofovir alafenamide maleate were investigated in more detail by means of DSC, TGA, GMS and FTIR. The results are below discussed in more detail.

The DSC curve of tenofovir alafenamide malonate shows a single melting endotherm with an onset temperature of 132.2 °C and a heat of fusion of 85.7 J/g. The DSC curve is displayed in Figure 7 herein. Thermo gravimetric analysis revealed a mass loss of about 0.3 weight% from the beginning of the measurement up to a temperature of about 130 °C. The TGA curve is displayed in Figure 8 herein. From the thermal analysis it can be concluded that this crystalline form is an anhydrous and non-solvated form of tenofovir alafenamide malonate. The corresponding GMS isotherm is displayed in Figure 10. The final product was also investigated by fourier transform infrared spectroscopy (Figure 9) and the results are summarized in Table 5: Table 5

Wavenumber [cm ¹]

3329

3163

2979

2934

1732

1698

1595

1493

1441

1409

1372

1317

1267

1203

1152

1101

1025

998

919

894

733

647

Example 3: Preparation of crystalline tenofovir alafenamide protocatechuate

500mg tenofovir alafenamide free base were mixed at room temperature with 10ml of acetonitrile. 170mg of 3,4-dihydroxybenoic acid (l,05eq) were added and the mixture was heated to reflux until a solution was observed. The hot solution was filtered and allowed to cool to room temperature and further stored at 2-8°C in a fridge. The precipitate was filtered and dried under vacuum to yield 480mg of tenofovir alafemamide 3,4-dihydroxybenoic acid form.

The final product was investigated by powder X-ray diffraction (Figure 11) and the results are summarized in Table 3 disclosed herein above. The isolated crystals of tenofovir alafenamide protocatechuate were investigated in more detail by means of DSC, TGA, GMS and FTIR. The results are below discussed in more detail.

The DSC curve of tenofovir alafenamide protocatechuate shows a single melting endotherm with an onset temperature of 132.2 °C and a heat of fusion of 85.7 J/g. The DSC curve is displayed in Figure 12 herein. Thermogravimetric analysis revealed a mass loss of about 0.3 weight% from the beginning of the measurement up to a temperature of about 130 °C. The TGA curve is displayed in Figure 13 herein. From the thermal analysis it can be concluded that this crystalline form is an anhydrous and non-solvated form of tenofovir alafenamide protocatechuate. The corresponding GMS isotherm is displayed in Figure 15. The final product was also investigated by fourier transform infrared spectroscopy (Figure 14) and the results are summarized in Table 6:

Table 6

Wavenumber [cm ¹]

3381

3351

3201

2976

2937

2890

1720

1663

1601

1487

1434

1372

1334

1287

1254

1223

1210

1186

1091

1027

1010

979

940

919

892

874

832

814

782

755

688

Claims

1. A crystalline form of tenofovir alafenamide maleate, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (4.6 ± 0.2)°, (7.8 ± 0.2)° and (12.6 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

2. The crystalline form of claim 1, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.

3. A crystalline form of tenofovir alafenamide malonate, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (4.0 ± 0.2)°, (6.8 ± 0.2)° and (8.7 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

4. The crystalline form of claim 3, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 6.

5. A crystalline form of tenofovir alafenamide protocatechuate, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (3.0 ±

0.2)°, (8.9 ± 0.2)° and (12.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,₂ radiation having a wavelength of 0.15419 nm.

6. The crystalline form of claim 5, having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 11.

7. A pharmaceutical composition comprising an effective amount of the crystalline form as defined in any one of claims 1 to 6 and one or more pharmaceutically acceptable excipient(s).

8. The pharmaceutical composition of claim 7 for use as a medicament.

9. The pharmaceutical composition of claim 7 for use in the treatment and/or prophylaxis of viral infections, optionally viral infections caused by DNA viruses, RNA viruses, herpesviruses, retroviruses, hepadnaviruses, papillomavirus, hantavirus, adenoviruses and HIV.