DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“NOVEL CRYSTALLINE FORMS OF TENOFOVIR ALAFENAMIDE SALTS”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA -500 081

The following specification particularly describes the invention and the manner in which it is to be performed.

“NOVEL CRYSTALLINE FORMS OF TENOFOVIR ALAFENAMIDE SALTS”

FIELD OF INVENTION:
The present invention relates to novel crystalline forms of tenofovir alafenamide salts and process for the preparation thereof. More, particularly the present invention relates to novel crystalline form of tenofovir alafenamide hemi maleate, tenofovir alafenamide hemi succinate, tenofovir alafenamide hemi malate, tenofovir alafenamide hemi citrate and tenofovir alafenamide hemi tartrate, and process for the preparation thereof.

BACKGROUND OF THE INVENTION:
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 and is chemically known as L-alanine, N- [(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy] methyl] phenoxyphosphinyl]-, 1-methylethyl ester, having the structural formula represented below:

Tenofovir alafenamide

Tenofovir alafenamide and process for its preparation was first disclosed in US7390791.

US8754065 discloses crystalline form of tenofovir alafenamide hemifumarate and its process for the preparation.

US9777028 discloses solvate of tenofovir alafenamide sesquifumarate, wherein the solvent selected from isopropanol, methyl ethyl ketone, tetrahydrofuran and acetone.

WO2015040640 discloses crystalline forms of tenofovir alafenamide fumarate, tenofovir alafenamide ferulate, tenofovir alafenamide succinate, tenofovir alafenamide citrate, tenofovir alafenamide tartarate, lactate and tenofovir alafenamide mesylate.

WO2016192692 discloses solid form of tenofovir alafenamide with an inorganic or organic acid selected from the group consisting of hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, citric, succinic, tartaric, gallic, benzenesulfonic, salicylic and 4-aminobenzoic acids.

CN105237571 discloses tenofovir alafenamide hemi succinate, hemi tartrate and its preparation.

Polymorphism is the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like tenofovir alafenamide or a pharmaceutically acceptable salt thereof particularly hemifumarate salt, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis -"TGA", or differential scanning calorimetry -"DSC"), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

A novel polymorph of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compatibility, handling, flow and blend; and filtration properties.

Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use. The reported crystal polymorph(s) are less stable and has tendency to convert under certain conditions to another crystal form with possibly less favorable characteristics.

There remains a need for novel polymorphs of tenofovir alafenamide which possess improved properties compared to the polymorphs reported, and can produce at commercial scale at ease and at low cost.

Therefore, there exists a need in the art to provide novel polymorphs having better solubility, reproducibility and chemical, polymorphic stabilities. Hence, the inventors of the present invention provide novel crystalline form of tenofovir alafenamide hemi maleate, tenofovir alafenamide hemi succinate, tenofovir alafenamide hemi malate, tenofovir alafenamide hemi citrate and tenofovir alafenamide hemi tartrate which are having greater stability, flowability, and dissolution properties.

SUMMARY OF THE INVENTION:
The main aspect of the present invention relates to novel crystalline forms of tenofovir alafenamide salts and process for the preparation thereof.

In one aspect, the present invention provides a novel crystalline form of tenofovir alafenamide hemi maleate, herein after designated as crystalline Form G1.

In another aspect, the present invention provides a process for the preparation of crystalline Form G1 of tenofovir alafenamide hemi maleate, which comprises reacting tenofovir alafenamide with maleic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi maleate.

In another aspect, the present invention provides a novel crystalline form of tenofovir alafenamide hemi succinate, herein after designated as crystalline Form G2.

In another aspect, the present invention provides a process for the preparation of crystalline Form G2 of tenofovir alafenamide hemi succinate, which comprises reacting tenofovir alafenamide with succinic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi succinate.

In another aspect, the present invention provides a novel crystalline form of tenofovir alafenamide hemi malate, herein after designated as crystalline Form G3.

In another aspect, the present invention provides a process for the preparation of crystalline Form G3 of tenofovir alafenamide hemi malate, which comprises reacting tenofovir alafenamide with malic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi malate.

In another aspect, the present invention provides a novel crystalline form of tenofovir alafenamide hemi citrate, herein after designated as crystalline Form G4.

In another aspect, the present invention provides a process for the preparation of crystalline Form G4 of tenofovir alafenamide hemi citrate, which comprises reacting tenofovir alafenamide with citric acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi citrate.

In another aspect, the present invention provides a novel crystalline form of tenofovir alafenamide hemi tartrate, herein after designated as crystalline Form G5.

In another aspect, the present invention provides a process for the preparation of crystalline Form G5 of tenofovir alafenamide hemi tartrate, which comprises reacting tenofovir alafenamide with tartaric acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi tartrate.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: Illustrates the characteristic X-ray powder diffraction (XRPD)pattern of crystalline tenofovir alafenamide hemi maleate Form G1.
Fig. 2: Illustrates the characteristic X-ray powder diffraction (XRPD) pattern of crystalline tenofovir alafenamide hemi succinate Form G2.
Fig. 3: Illustrates the characteristic X-ray powder diffraction (XRPD) pattern of crystalline tenofovir alafenamide hemi malate Form G3.
Fig. 4: Illustrates the characteristic X-ray powder diffraction (XRPD) pattern of crystalline tenofovir alafenamide hemi citrate Form G4.
Fig. 5: Illustrates the characteristic X-ray powder diffraction (XRPD) pattern of crystalline tenofovir alafenamide hemi tartrate Form G5.
Fig. 6: Illustrates the Differential Scanning Calorimetry (DSC) thermogram of crystalline tenofovir alafenamide hemi maleate Form G1.
Fig. 7: Illustrates the Differential Scanning Calorimetry (DSC) thermogram of crystalline tenofovir alafenamide hemi succinate Form G2.
Fig. 8: Illustrates the Differential Scanning Calorimetry (DSC) thermogram of crystalline tenofovir alafenamide hemi malate Form G3.
Fig. 9: Illustrates the Differential Scanning Calorimetry (DSC) thermogram of crystalline tenofovir alafenamide hemi citrate Form G4.
Fig. 10: Illustrates the Differential Scanning Calorimetry (DSC) thermogram of crystalline tenofovir alafenamide hemi tartrate Form G5.

DETAILED DESCRIPTION:
Accordingly, the present invention provides novel crystalline forms of tenofovir alafenamide salts and process for its preparation.

The term “solvent/ suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated solvents; wherein alcohol is selected from the group consisting of methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

In one embodiment, the present invention provides a novel crystalline form of tenofovir alafenamide hemi maleate, which is designated as crystalline Form G1.

In another embodiment, the present invention provides a novel crystalline Form G1 of tenofovir alafenamide hemi maleate, characterized by its X –ray diffraction pattern having one or more characteristic peaks at about 4.2, 5.9, 7.5, 11.0, 17.4, 18.9, 19.3, 21.0, 21.9, 24.3 and 26.6 ± 0.2 2?.

In another embodiment, the present invention provides a novel crystalline Form G1 of tenofovir alafenamide hemi maleate, characterized by its X –ray diffraction pattern substantially in accordance with figure1.

In another embodiment, the present invention provides a novel crystalline Form G1 of tenofovir alafenamide hemi maleate, characterized by its DSC thermogram having endotherm peak at about 118.7°C ± 5°C and illustrated in figure 6.

In another embodiment, the present invention provides a process for the preparation of crystalline Form G1 of tenofovir alafenamide hemi maleate, which comprises reacting tenofovir alafenamide with maleic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi maleate.

The aforementioned process involves the reaction of tenofovir alafenamide with maleic acid in the presence of a suitable solvent under appropriate reaction conditions to provide crystalline Form G1 of Tenofovir alafenamide hemi maleate.
Wherein the molar ratio of maleic acid to tenofovir alafenamide is about 0.4 to 0.55 mole; preferably 0.5 mole.
Wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents; preferably nitriles selected from acetonitrile, propionitrile and the like; more preferably acetonitrile.
Wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used; preferably at 50 to 60°C.
After completion of addition, the reaction mass was maintaining for a sufficient period of time till complete formation of the material; then the isolation of crystalline Form G1 of tenofovir alafenamide hemi maleate can be carried out by the methods known in the art, for example filtering the reaction mass, washing and drying the solid for a sufficient period of time under vacuum.

In another embodiment, the present invention provides a novel crystalline form of tenofovir alafenamide hemi succinate, herein after designated as crystalline Form G2.

In another embodiment, the present invention provides a novel crystalline Form G2 of tenofovir alafenamide hemi succinate, characterized by its X –ray diffraction pattern having one or more characteristic peaks at about 5.4, 7.3, 11.1, 16.8, 18.9, 19.3, 21.1, 21.5, 22.2, 26.6 and 27.7 ± 0.2 2?.

In another embodiment, the present invention provides a novel crystalline Form G2 of tenofovir alafenamide hemi succinate, characterized by its X –ray diffraction pattern substantially in accordance with figure 2.

In another embodiment, the present invention provides a novel crystalline Form G2 of tenofovir alafenamide hemi succinate, characterized by its DSC thermogram having endotherm peak at about 115.3°C ± 5°C and illustrated in figure 7.

In another embodiment, the present invention provides a process for the preparation of crystalline Form G2 of tenofovir alafenamide hemi succinate, which comprises reacting tenofovir alafenamide with succinic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi succinate.

The aforementioned process involves the reaction of tenofovir alafenamide with succinic acid in the presence of a suitable solvent under appropriate reaction conditions to provide crystalline Form G2 of Tenofovir alafenamide hemi succinate.
Wherein the molar ratio of succinic acid to tenofovir alafenamide is about 0.4 to 0.55 mole; preferably 0.5 mole.
Wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents; preferably nitriles selected from acetonitrile, propionitrile and the like; more preferably acetonitrile.
Wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used; preferably at 50 to 60°C.
After completion of addition, the reaction mass was maintaining for a sufficient period of time till complete formation of the material; then the isolation of crystalline Form G2 of tenofovir alafenamide hemi succinate can be carried out by the methods known in the art, for example filtering the reaction mass, washing and drying the solid for a sufficient period of time under vacuum.

In another embodiment, the present invention provides a novel crystalline form of tenofovir alafenamide hemi malate, herein after designated as crystalline Form G3.

In another embodiment, the present invention provides a novel crystalline Form G3 of tenofovir alafenamide hemi malate, characterized by its X –ray diffraction pattern having one or more characteristic peaks at about 5.6, 10.2, 12.1, 13.4, 14.1, 15.5, 16.7, 20.5, 21.4, 22.2 and 26.5 ± 0.2 2?.

In another embodiment, the present invention provides a novel crystalline Form G3 of tenofovir alafenamide hemi malate, characterized by its X –ray diffraction pattern substantially in accordance with figure 3.

In another embodiment, the present invention provides a novel crystalline Form G3 of tenofovir alafenamide hemi malate, characterized by its DSC thermogram having endotherm peak at about 117.3°C ± 5°C and illustrated in figure 8.

In another embodiment, the present invention provides a process for the preparation of crystalline Form G3 of tenofovir alafenamide hemi malate, which comprises reacting tenofovir alafenamide with malic acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi malate.

The aforementioned process involves the reaction of tenofovir alafenamide with malic acid in the presence of a suitable solvent under appropriate reaction conditions to provide crystalline Form G3 of Tenofovir alafenamide hemi malate.
Wherein the molar ratio of malic acid to tenofovir alafenamide is about 0.4 to 0.55 mole; preferably 0.5 mole.
Wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents; preferably nitriles selected from acetonitrile, propionitrile and the like; more preferably acetonitrile.
Wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used; preferably at 50 to 60°C.
After completion of addition, the reaction mass was maintaining for a sufficient period of time till complete formation of the material; then the isolation of crystalline Form G3 of tenofovir alafenamide hemi malate can be carried out by the methods known in the art, for example filtering the reaction mass, washing and drying the solid for a sufficient period of time under vacuum.

In another embodiment, the present invention provides a novel crystalline form of tenofovir alafenamide hemi citrate, herein after designated as crystalline Form G4.

In another embodiment, the present invention provides a novel crystalline Form G4 of tenofovir alafenamide hemi citrate, characterized by its X –ray diffraction pattern having one or more characteristic peaks at about 5.7, 7.3, 7.8, 11.1, 15.6, 17.6, 19.4, 21.1, 21.4, 22.2 and 26.6 ± 0.2 2?.

In another embodiment, the present invention provides a novel crystalline Form G4 of tenofovir alafenamide hemi citrate, characterized by its X –ray diffraction pattern substantially in accordance with figure 4.

In another embodiment, the present invention provides a novel crystalline Form G4 of tenofovir alafenamide hemi citrate, characterized by its DSC thermogram having endotherm peak at about 119.6°C ± 5°C and 140.7 ± 5°C, and illustrated in figure 9.

In another embodiment, the present invention provides a process for the preparation of crystalline Form G4 of tenofovir alafenamide hemi citrate, which comprises reacting tenofovir alafenamide with citric acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi citrate.

The aforementioned process involves the reaction of tenofovir alafenamide with citric acid in the presence of a suitable solvent under appropriate reaction conditions to provide crystalline Form G4 of Tenofovir alafenamide hemi citrate.
Wherein the molar ratio of citric acid to tenofovir alafenamide is about 0.4 to 0.55 mole; preferably 0.44 mole.
Wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents; preferably nitriles selected from acetonitrile, propionitrile and the like; more preferably acetonitrile.
Wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used; preferably at 50 to 60°C.
After completion of addition, the reaction mass was maintaining for a sufficient period of time till complete formation of the material; then the isolation of crystalline Form G4 of tenofovir alafenamide hemi citrate can be carried out by the methods known in the art, for example filtering the reaction mass, washing and drying the solid for a sufficient period of time under vacuum.

In another embodiment, the present invention provides a novel crystalline form of tenofovir alafenamide hemi tartrate, herein after designated as crystalline Form G5.

In another embodiment, the present invention provides a novel crystalline Form G5 of tenofovir alafenamide hemi tartrate, characterized by its X –ray diffraction pattern having one or more characteristic peaks at about 4.1, 7.9, 9.7, 12.6, 15.3, 15.9, 17.1, 17.7, 18.1, 19.5 and 22.9 ± 0.2 2?.

In another embodiment, the present invention provides a novel crystalline Form G5 of tenofovir alafenamide hemi tartrate, characterized by its X –ray diffraction pattern substantially in accordance with figure 5.

In another embodiment, the present invention provides a novel crystalline Form G5 of tenofovir alafenamide hemi tartrate, characterized by its DSC thermogram having endotherm peak at about 165.5°C ± 5°C and illustrated in figure 10.

In another embodiment, the present invention provides a process for the preparation of crystalline Form G5 of tenofovir alafenamide hemi tartrate, which comprises reacting tenofovir alafenamide with tartaric acid in the presence of a suitable solvent to provide Tenofovir alafenamide hemi tartrate.

The aforementioned process involves the reaction of tenofovir alafenamide with tartaric acid in the presence of a suitable solvent under appropriate reaction conditions to provide crystalline Form G5 of Tenofovir alafenamide hemi tartrate.
Wherein the molar ratio of tartaric acid to tenofovir alafenamide is about 0.4 to 0.55 mole; preferably 0.46 mole.
Wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents; preferably nitriles selected from acetonitrile, propionitrile and the like; more preferably acetonitrile.
Wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used; preferably at 50 to 60°C.
After completion of addition, the reaction mass was maintaining for a sufficient period of time till complete formation of the material; then the isolation of crystalline Form G5 of tenofovir alafenamide hemi tartrate can be carried out by the methods known in the art, for example filtering the reaction mass, washing and drying the solid for a sufficient period of time under vacuum.

As used herein above, the tenofovir alafenamide which is used as a starting material is known in the art and may be prepared by any known methods. Further the starting tenofovir alafenamide which may be purified by dissolution of tenofovir alafenamide in a suitable solvent can be carried out at a suitable temperature of about 20 °C to about 60 °C, followed by isolation in any conventional techniques known in the art, for example filtration and followed by drying. Further the starting tenofovir alafenamide may be in any form such as crude obtained directly from the reaction mass or other forms of tenofovir alafenamide or its salts including various solvates and hydrates.

EXAMPLES:
The process details of the present invention provided in examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Preparation of Tenofovir alafenamide hemi maleate crystalline Form-G1
Tenofovir alafenamide (750 g) and acetonitrile (3 L) were charged into RB Flask at 25 to 35°C, temperature rises to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. The reaction mass was filtered through 0.45µ filter at 50 to 60 °C, washed with pre-heated acetonitrile and cooled to 25 to 35 °C, stirred for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered and dried until no ML’s expels out to get wet material. Acetonitrile (1.5 L) and wet material were charged into RB Flask at 25 to 35°C, stirred for 60 to 90 min, cooled to 0-5 °C and again stirred for 60 to 90 mins at same temperature. The solid obtained was filtered, dried until no ML’s expels out, washed with pre-cooled acetonitrile and dried until no ML’s expels out, keep the material under suck dry for 3 to 4 hours. The wet material was further dried under vacuum to get pure tenofovir alafenamide. Yield: 650 g
Pure tenofovir alafenamide was taken into RBF, maleic acid (79.17 g) and acetonitrile (6.5 L) were charged into the mass at 25 to 35 °C. The mass was heated to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. Filter the reaction mass through 0.45µ filter at 50 to 60 °C, washed with pre-heated acetonitrile and cooled to 25 to 35 °C, maintained for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered, dried until no ML’s expels out, washed with pre-cooled acetonitrile and dried under vacuum for 16 to 18 hours at 50 to 60 °C, cooled to 30 to 40 °C to get the title compound.
Yield: 600 g
The PXRD and DSC thermogram of the obtained compound were shown in figure-1 and figure-6 respectively.

Example-2:
Preparation of Tenofovir alafenamide hemisuccinate crystalline Form-G2
Tenofovir alafenamide (750 g) and acetonitrile (3 L) were charged into RB Flask at 25 to 35°C, temperature rises to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. The reaction mass was filtered through 0.45µ filter at 50 to 60 °C, washed with pre-heated acetonitrile and cooled to 25 to 35 °C, stirred for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered and dried until no ML’s expels out to get wet material. Acetonitrile (1.5 L) and wet material were charged into RB Flask at 25 to 35°C, stirred for 60 to 90 min, cooled to 0-5 °C and again stirred for 60 to 90 mins at same temperature. The solid obtained was filtered, dried until no ML’s expels out, washed with pre-cooled acetonitrile and dried until no ML’s expels out, keep the material under suck dry for 3 to 4 hours. The wet material was further dried under vacuum to get pure tenofovir alafenamide.to get pure tenofovir alafenamide. Yield: 650 g
Pure tenofovir alafenamide was taken into RBF, succinic acid (80.3 g) and acetonitrile (6.5 L) were charged into the mass at 25 to 35 °C. The mass was heated to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. Filter the reaction mass through 0.45µ filter at 50 to 60 °C, washed with pre-heated acetonitrile and cooled to 25 to 35 °C, maintained for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered, dried until no ML’s expels out, washed with pre-cooled acetonitrile and dried under vacuum for 16 to 18 hours at 50 to 60 °C, cooled to 30 to 40 °C to get the title compound.
Yield: 650 g
The PXRD and DSC thermogram of the obtained compound were shown in figure-2 and figure-7 respectively.

Example-3:
Preparation of Tenofovir alafenamide hemi malate crystalline Form-G3
Tenofovir alafenamide (60 g) and acetonitrile (300 ml) were charged into RB Flask at 25 to 35°C, temperature rises to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. L-(-)-Malic acid (8.43 g) was added to the reaction mass at 50 to 60 °C, stirred for 30 to 40 mins, cool the reaction mass to 25 to 35°C, stirred for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered and dried until no ML’s expels out, washed with pre-cooled acetonitrile, suck dry until no ML’s expels out and dried under vacuum for 16 to 18 hours at 50 to 60 °C to get the title compound.
Yield: 60 g
The PXRD and DSC thermogram of the obtained compound were shown in figure-3 and figure-8 respectively.

Example-4:
Preparation of Tenofovir alafenamide hemi citrate crystalline Form-G4
Tenofovir alafenamide (200 g) and acetonitrile (2 L) were charged into RB Flask at 25 to 35°C, temperature rises to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. Citric acid (38.8g) was added to the reaction mass at 50 to 60 °C, stirred for 30 to 40 mins, cool the reaction mass to 25 to 35°C, stirred for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered and dried until no ML’s expels out, washed with pre-cooled acetonitrile, suck dry until no ML’s expels out and dried under vacuum for 16 to 18 hours at 50 to 60 °C to get the title compound.
Yield: 213 g
The PXRD and DSC thermogram of the obtained compound were shown in figure-4 and figure-9 respectively.

Example-5:
Preparation of Tenofovir alafenamide hemi tartrate crystalline Form-G5
Tenofovir alafenamide (80 g) and acetonitrile (800 ml) were charged into RB Flask at 25 to 35°C, temperature rises to 50 to 60 °C and stirred for 30 to 40 mins at same temperature. D-(-)-Tartaric acid (11.59 g) was added to the reaction mass at 50 to 60 °C, stirred for 30 to 40 mins, cool the reaction mass to 25 to 35°C, stirred for 15-18 hours, again cooled to 0 to 5 °C and stirred for 2-3 hours at same temperature. The solid obtained was filtered and dried until no ML’s expels out, washed with pre-cooled acetonitrile, suck dry until no ML’s expels out and dried under vacuum for 16 to 18 hours at 50 to 60 °C to get the title compound.
Yield: 83 g
The PXRD and DSC thermogram of the obtained compound were shown in figure-5 and figure-10 respectively.

Dated this: 02nd day of May, 2024.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA-
1268
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd
Block, Madhapur, Hyderabad,
Telangana, INDIA-500 081
,CLAIMS:We claim:
1. A novel crystalline form of tenofovir alafenamide salts, selected from:
a) Crystalline Form G1 of tenofovir alafenamide hemi maleate, characterized by:
i. its X –ray diffraction pattern having one or more characteristic peaks at about 4.2, 5.9, 7.5, 11.0, 17.4, 18.9, 19.3, 21.0, 21.9, 24.3 and 26.6 ± 0.2 2? and XRPD pattern as depicted in figure-1 or
ii. its DSC thermogram as shown in figure-6.
b) Crystalline Form G2 of tenofovir alafenamide hemi succinate, characterized by:
i. its X –ray diffraction pattern having one or more characteristic peaks at about 5.4, 7.3, 11.1, 16.8, 18.9, 19.3, 21.1, 21.5, 22.2, 26.6 and 27.7 ± 0.2 2? and XRPD pattern as depicted in figure-2 or
ii. its DSC thermogram as shown in figure-7.
c) Crystalline Form G3 of tenofovir alafenamide hemi malate, characterized by:
i. its X –ray diffraction pattern having one or more characteristic peaks at about 5.6, 10.2, 12.1, 13.4, 14.1, 15.5, 16.7, 20.5, 21.4, 22.2 and 26.5 ± 0.2 2? and XRPD pattern as depicted in figure-3 or
ii. its DSC thermogram as shown in figure-8.
d) Crystalline Form G4 of tenofovir alafenamide hemi citrate characterized by:
i. its X –ray diffraction pattern having one or more characteristic peaks at about 5.7, 7.3, 7.8, 11.1, 15.6, 17.6, 19.4, 21.1, 21.4, 22.2 and 26.6 ± 0.2 2? and XRPD pattern as depicted in figure-4 or
ii. its DSC thermogram as shown in figure-9.
e) Crystalline Form G5 of tenofovir alafenamide hemi tartrate characterized by:
i. its X –ray diffraction pattern having one or more characteristic peaks at about 4.1, 7.9, 9.7, 12.6, 15.3, 15.9, 17.1, 17.7, 18.1, 19.5 and 22.9 ± 0.2 2? and XRPD pattern as depicted in figure-5 or
ii. its DSC thermogram as shown in figure-10.

2. A process for the preparation of crystalline Form G1 of tenofovir alafenamide hemi maleate as claimed in claim 1, which comprises reacting tenofovir alafenamide with maleic acid in the presence of a suitable solvent to provide tenofovir alafenamide hemi maleate.

3. A process for the preparation of crystalline Form G2 of tenofovir alafenamide hemi succinate as claimed in claim 1, which comprises reacting tenofovir alafenamide with succinic acid in the presence of a suitable solvent to provide tenofovir alafenamide hemi succinate.

4. A process for the preparation of crystalline Form G3 of tenofovir alafenamide hemi malate as claimed in claim 1, which comprises reacting tenofovir alafenamide with malic acid in the presence of a suitable solvent to provide tenofovir alafenamide hemi malate.

5. A process for the preparation of crystalline Form G4 of tenofovir alafenamide hemi citrate as claimed in claim 1, which comprises reacting tenofovir alafenamide with citric acid in the presence of a suitable solvent to provide tenofovir alafenamide hemi citrate.

6. A process for the preparation of crystalline Form G5 of tenofovir alafenamide hemi tartrate as claimed in claim 1, which comprises reacting tenofovir alafenamide with tartaric acid in the presence of a suitable solvent to provide tenofovir alafenamide hemi tartrate.

7. The process as claimed in claim 5, wherein the molar ratio of citric acid to tenofovir alafenamide is about 0.44 mole.

8. The process as claimed in claim 6, wherein the molar ratio of tartaric acid to tenofovir alafenamide is about 0.46 mole.

9. The process as claimed in claim 2 to 6, wherein the suitable solvent used is selected from alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons or halogenated solvents.

10. The process as claimed in claim 2 to 6, wherein the reaction can be carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used.

Dated this: 02nd day of May, 2024.

Signature:
Name: Mr. Srinivasa Reddy Madduri
Patent Agent Reg. No.: IN/PA-
1268
GRANULES INDIA LIMITED
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