DESC: FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

“NOVEL POLYMORPH OF TENOFOVIR ALAFENAMIDE HEMIFUMARATE AND PROCESSES THEREOF”

GRANULES INDIA LIMITED,
a company incorporated under the companies act, 1956 having address at
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad; Telangana; 500 081- India

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to novel polymorph of tenofovir alafenamide hemifumarate and processes thereof. More, particularly the present invention relates to a novel crystalline form of tenofovir alafenamide hemifumarate. The present invention also relates to a process for the purification of tenofovir alafenamide.

BACKGROUND OF THE INVENTION
Tenofovir alafenamide hemifumarate is methoxyphosphonate nucleotide analog which is useful to treat or prevent diseases or disorders such as antiretroviral infections particularly for chronic HBV in adults.

It is approved as a combination with elvitegravir, cobicistat, emtricitabine in US under the brand name Genvoya as single tablet regimen for the treatment of HIV-1.

It is chemically known as L-alanine N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethylester,(2E)-2-butenedioate(2:1) (here after referred as tenofovir alafenamide fumarate) and is represented by structural formula I.

(I)
Becker et al in U.S. Pat. Nos. 7,390,791 and 7,803,788 describes certain prodrugs of phosphonate nucleotide analogs that are useful in therapy including tenofovir alafenamide.

It also discloses a monofumarate form of tenofovir alafenamide and a preparation method.

Becker et al in U.S. Patent No 7,390,791 further discloses synthesis of tenofovir alafenamide which is purified by simulated moving bed chromatography (SMB) over Chiralpak AS column by eluting with 30% methanol in acetonitrile provided 98.7% diastereomeric purity.

Liu et al in U.S. Patent No 8,754,065 B2 discloses tenofovir alafenamide hemifumarate salt and preparation thereof. It also describes the crystalline polymorph of tenofovir alafenamde hemifumarate having X-ray powder diffraction pattern 2 theta peaks at 6.9, 8.6, 11.0, 15.9 and 20.2±0.2° and a differential scanning calorimetry (DSC) onset endotherm of 131±2° C., or 131±1° C.

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 behaviours (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, compactibility, 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 tendancy to convert under certain conditions to another crystal form with possibly less favorable characteristics.

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

In view of the pharmaceutical value of this compound, a polymorph form of tenofovir alafenamide hemifumarate for use in a medicament should have excellent properties, such as crystallinity, polymorphic stability, chemical stability and process ability to pharmaceutical compositions.

Therefore, there exists a need in the art to provide novel polymorphs having better solubility, reproducibility and chemical, polymorphic stabilities and purification process to provide pure tenofovir alafenamide substantially free from diastereomeric impurities.

The novel polymorph of present invention has better solubility, reproducibility and chemical, polymorphic stabilities.

SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a novel crystalline Form of tenofovir alafenamide hemifumarate which is designated as crystalline Form G, characterized by X –ray diffraction pattern having characteristic 2-theta peaks at about 5.3, 7.4, 10.4, 11.2, 12.9, 14.4, 17.7, 19.5, 21.2, 22.4 and 26.6 ± 0.20.

In another aspect, the present invention relates to a novel crystalline Form G of tenofovir alafenamide hemfumarate further characterized by differential scanning calorimetry (DSC) with an endotherm curve at about 109.78°C with an onset at about 101.3°C and with another endotherm curve at about 197.05°C with an onset at about 169°C measured at 5°C/min. ramp.

In another aspect, the present invention relates to a process for the preparation of tenofovir alafenamide hemifumarate novel crystalline Form G comprising:
a. providing a solution of tenofovir alafenamide or a salt thereof and fumaric acid in an organic solvents or mixture of solvents thereof;
b. heating the solution of step (a) to get clear solution;
c. filtering the solution in the hot condition;
d. cooling the solution of step (c) to a temperature ranging between 20 - 40°C;
e. optionally seeding the reaction mixture of steps (a) to (c) independently;
f. recovering the crystalline Tenofovir alafenamide hemifumarate.

In yet another aspect, the present invention relates to a process for the purification of tenofovir alafenamide, comprising:
i) providing a solution of tenofovir alafenamide in an organic solvent or a mixture of solvents;
ii) isolating the pure tenofovir alafenamide substantially free from diastereomeric impurities.

In yet another aspect, the present invention relates to a process for the preparation of Tenofovir alafenamide free base comprising the steps of:

i. Providing a mixture of Mono phenoxy ester of PMPA and thionyl chloride in ethyl acetate;
ii. Heating the reaction mass to 60-65°C and stir for 4-8 hours under argon atmosphere;
iii. Concentrate the reaction mass under argon atmosphere at below 65°C;
iv. To above residue charge chloroform and add the Alanine isopropyl ester dissolved in chloroform at -35 to -30°C;
v. Maintain for 30 minutes and add triethylamine at -20 to -25°C;
vi. Raise reaction mass to room temperature and filter if any salts. Wash the Organic layer with Sodium dihydrogen phosphate solution;
vii. Concentrate the organic layer under vacuum;
viii. Charge acetonitrile and stir at Room temperature for 10-15 minutes, then charge seed material and stir for 10-12 hours and
ix. Cool the reaction mass to 0-5°C. Stir and filter the solid under vacuum followed by acetonitrile washing and dry the pure tenofovir alafenamide.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: illustrates characteristic X-ray powder diffraction pattern of tenofovir alafenamide hemifumarate novel crystalline Form- G.
Fig. 2: illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of tenofovir alafenamide hemifumarate novel crystalline Form-G.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a novel crystalline Form of tenofovir alafenamide hemfumarate which is designated as crystalline Form G, characterized by X –ray diffraction pattern having characteristic 2-theta peaks at about 5.3, 7.4, 10.4, 11.2, 12.9, 14.4, 17.7, 19.5, 21.2, 22.4 and 26.6 ± 0.20, which is as depicted in accordance with Fig.1.

In another embodiment, the present invention provides a novel crystalline Form G of tenofovir alafenamide hemfumarate further characterized by differential scanning calorimetry (DSC) with an endotherm curve at about 109.78°C with an onset at about 101.3°C and with another endotherm curve at about 197.05°C with an onset at about 169°C measured at 5°C/min. ramp, and which is as depicted in accordance with Fig. 2.

In yet another embodiment, the present invention provides a process for the preparation of tenofovir alafenamide hemifumarate novel crystalline Form G comprising:

a. providing a solution of tenofovir alafenamide or a salt thereof and fumaric acid in an organic solvents or mixture of solvents thereof;
b. heating the solution of step (a) to get clear solution;
c. filtering the solution in the hot condition;
d. cooling the solution of step (c) to a temperature ranging between 20 - 40°C;
e. optionally seeding the reaction mixture of steps (a) to (c) independently;
f. recovering the crystalline Form G of Tenofovir alafenamide hemifumarate.

The solvents that can be used in step (a) include but are not limited to water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate and the like; nitriles such acetonitrile and the like; or a mixture thereof. Preferably, acetonitrile, ethyl acetate.

As used herein a mixture of solvents refers to a composition comprising more than one solvent.

The volume of the solvent(s) can be from about 5 to about 75 volumes. The volume of the suitable organic solvent may be preferably from about 10 to about 50 volumes.

The temperature required for obtaining homogenous solution in step (a) can range from about 40°C to about 75°C or the boiling point of the solvents used, preferably from about 50°C to about boiling point of the solvents used.

The solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.

Optionally the solvents are evaporated and is carried out at a temperature from about 35°C to about boiling point of the solvents used in the presence or absence of vacuum, preferably from 45°C to about 75°C.

In one embodiment, optionally evaporation or removal of solvent(s) in the process described above is accomplished by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain crystalline form and filtering the solid under inert atmosphere. Alternatively, the solvent may also be removed by evaporation. Preferably, the method for evaporation or removal of solvent(s) is distillation under reduced pressure.

Crystal growth may be promoted by cooling the solution of step (a) or (b) to a temperature from about - 20°C to about 40°C. Crystal growth may be promoted by cooling the solution to a temperature between about -15°C to about 35ºC. Crystal growth may be promoted by cooling the solution to a temperature between about -10°C to about 35ºC.

Optionally seeding of the desired crystalline Form is being used to obtain the desired crystalline form with purity and consistently by adding to the solution of tenofovir alafenamide hemifumarate.

Recovery or isolation of tenofovir alafenamide hemifumarate novel crystalline Form G obtained by the process described above can be achieved by any conventional methods known in the art, for example filtration.

The tenofovir alafenamide hemifumarate novel crystalline Form G of the present invention obtained by the above process may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents. When implemented, the preferred instrument is a vacuum tray dryer. The tenofovir alafenamide hemifumarate novel crystalline Form G obtained by the process of present invention are further dried at a temperature range from about 30°C to about 75°C in the presence or absence of vacuum, preferably from about 35°C to about 55°C.

The novel crystalline Form G of tenofovir alafenamide hemifumarate of the present invention was characterized by powder X-ray diffractography using Powder XRD make: Bruker model 10 D2 Phaser Goniometer type theta – 2 theta; X-ray source: Copper Ka; Detector: Lynx Eye Detector.

Tenofovir alafenamide hemifumarate samples data was collected using PMMA holder with the scan parameter details as follows:

2?range: 3-40°; Step size: 0.012; Time for step: 72.6 S; Generator kV: 30; Generator mA: 10.0; Spinner: 15 rpm;

Method of analysis:
Sample preparation: If required sample is finely grind using a mortar and pestle, then pack the sample in a suitable sample holders. Selection of the sample holder depends on the sample quantity.
The novel crystalline Form G of tenofovir alafenamide hemifumarate of the present invention was further characterized by differential scanning calorimetry (DSC) using instrument make: TA instruments, software: Universal analysis, Model: Q100.

Method of analysis:
Sample preparation: Weigh accurately about 2.0-5.0 mg of test sample and transfer into aluminium hermetic pan, close with lid and seal with a crimper. Hold it in the sample compartment with furnace temperature programme: 30°C to 300°C and at ramp of 5°C / min.

In one embodiment, tenofovir alafenamide or a salt thereof particularly hemifumarate salt used herein as starting material can be of any polymorph reported in the art or mixture thereof or may be crude tenofovir alafenamide or a salt thereof resulting from synthetic processes known in the art. Illustratively, U.S.Pat.No.7,390,791 and US 7,803,788 incorporated herein for reference.

Advantageously, the novel crystalline Form G of tenofovir alafenamide hemifumarate of present invention is thermodynamically stable and does not have tendency to transform into any other polymorph at any given temperature and pressure.

The present invention is based in part on the unexpected findings that the novel crystalline Form G of tenofovir alafenamide hemifumarate described herein possesses advantageous physicochemical properties which render its processing as a medicament beneficial. The novel crystalline Form G of tenofovir alafenamide hemifumarate of the present invention has better solubility thus would have bioavailability as well as desirable stability characteristics enabling their incorporation into a variety of different formulations particularly suitable for pharmaceutical utility. For example, the novel crystalline form of the present invention is more soluble than the known polymorphs in aqueous vehicles.

In another embodiment, the present invention provided a process for the purification of tenofovir alafenamide, comprising:

i) providing a solution of tenofovir alafenamide in an organic solvent or a mixture of solvents;
ii) isolating the pure tenofovir alafenamide substantially free from diastereomeric impurities.

The solvent that can be used is selected from the group consisting of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate; amides such as dimethyl formamide, dimethyl acetamide and the like; or mixtures thereof or their aqueous mixtures in any proportion without limitation. Preferably acetonitrile.

As used herein a mixture of solvents refers to a composition comprising more than one solvent.

The volume of the solvent or mixture of solvents or aqueous mixtures used can be from about 2 to about 25 volumes on the starting material taken. preferably, the volume of the solvents used can be from about 3 to about 20 volumes.

The temperature for dissolution can range from about 25°C to about or reflux temperatures of the solvents used, preferably about 300C. The time period required for dissolution can range from about 30 minutes to about 15 hours. preferably for about 5 hours.

The precipitation of solid is achieved but not limited to evaporation, cooling, drying, by adding antisolvent and the like. preferably by cooling below about 50C.

The suitable antisolvent optionally used is selected from the group consisting of ethers such as diethyl ether, diisopropyl ether, 1,4-dioxane and the like; hydrocarbons such as methyl cyclohexane, cyclohexane, n-hexane, n-heptane and the like;

Then, the resultant pure tenofovir alafenamide can be isolated by known techniques, for example, cooling the reaction solution to below about 50C, the solvents from solution may be concentrated under vacuum to get residue by any method known in the art, such as distillation, evaporation, rotational drying (such as with the Buchi Rotavapor), preferably by cooling the reaction solution at below room temperature. After isolation of tenofovir alafenamide, additional purification may be carried out by process such as crystallization, solvent slurry techniques or any chromatography techniques.

Advantageously, the tenofovir alafenamide obtained by the process of present invention described herein, has individual diastereomeric purity of at least about 98% as measured by chiral HPLC, preferably at least about 99% as measured by chiral HPLC, more preferably at least about 99.5% as measured by chiral HPLC.

In yet another embodimet, the present invention relates to a process for the preparation of tenofovir alafenamide free base comprising the steps of:

i. Providing a mixture of Mono phenoxy ester of PMPA and thionyl chloride in ethyl acetate;
ii. Heating the reaction mass to 60-65°C and stir for 4-8 hours under argon atmosphere;
iii. Concentrate the reaction mass under argon atmosphere at below 65°C;
iv. To above residue charge chloroform and add the Alanine isopropyl ester dissolved in chloroform at -35 to -30°C;
v. Maintain for 30 minutes and add triethylamine at -20 to -25°C;
vi. Raise reaction mass to room temperature and filter if any salts. Wash the Organic layer with Sodium dihydrogen phosphate solution;
vii. Concentrate the organic layer under vacuum;
viii. Charge acetonitrile and stir at Room temperature for 10-15 minutes, then charge seed material and stir for 10-12 hours and
ix. Cool the reaction mass to 0-5°C. Stir and filter the solid under vacuum followed by acetonitrile washing and dry the pure tenofovir alafenamide.

In yet further embodiment, the present invention encompasses a pharmaceutical composition comprising tenofovir alafenamide hemifumarate novel crystalline Form G and atleast a pharmaceutically acceptable carrier.

Such pharmaceutical compositions may be administered to a mammalian patient for the treatment or prevention of HIV-1 and HBV in adults in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings containing at least phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

The compound of formula I of a defined particle size may be produced by various methods using recrystallization from different solvents. Particle size plays of the active pharmaceutical ingredient (API) plays a vital role in the solubility properties. The reduction in particle size results in an increase in surface area of the solid phase that is in contact with the liquid phase, thus leading to increased solubility. The bioavailability depends vastly on the rate of dissolution of the poorly soluble drug. As dissolution of drug limit its rate of absorption. Thus, particle size reduction may enhance the absorption thereby improving the bioavailability. Further, particle size can also affect how freely crystals or a powdered form of a drug will flow past each other, which in turn, has consequences in the production process of pharmaceutical products containing the drug.

Various techniques are known in the art to get a defined particle size. These methods include pH adjustment, cooling, evaporation of solvent, addition of antisolvent to a solution or by co-precipitation to obtain a precipitate with a defined particle size. Particle size of the compound of formula I may be further adjusted by employing known methods of particle size reduction like compaction, milling or micronizing and sorting the milled product according to particle size. Malvern PSD method is generally being used for analysis.

In one embodiment, the present invention provides tenofovir alafenamide or a pharmaceutically acceptable salt hemifumarate with 90% of the particles have a particle size less than about 500µ.

In another embodiment, the present invention provides tenofovir alafenamide or a pharmaceutically acceptable salt hemifumarate with 90% of the particles have a particle size less than about 400 µ.

In yet another embodiment, the present invention provides tenofovir alafenamide or a pharmaceutically acceptable salt hemifumarate with 50% of the particles have a particle size less than 200 µ.

In yet further embodiment, the present invention provides tenofovir alafenamide or a pharmaceutically acceptable salt hemifumarate with 50% of the particles have a particle size less than about 100 µ.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Form G of tenofovir alafenamide hemifumarate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of Crystalline Form G of tenofovir alafenamide hemifumarate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

EXAMPLES
Example 1: Experimental Example for preparing Tenofovir alafenamide Free base:
Charge Ethyl acetate, Mono phenoxy ester of PMPA and thionyl chloride. Heat the reaction mass to 60-65°C and stir for 4-8 hours under argon atmosphere. Concentrate the reaction mass under argon atmosphere at below 65°C. To above residue charge chloroform and add the Alanine isopropyl ester dissolved in chloroform at -35 to -30°C. Maintain for 30 minutes and add triethylamine at -20 to -25°C. Raise reaction mass to room temperature and filter if any salts. Wash the Organic layer with Sodium dihydrogen phosphate solution. Concentrate the organic layer under vacuum. Charge acetonitrile and stir at Room temperature for 10-15 minutes, then charge seed material and stir for 10-12 hours. Cool the reaction mass to 0-5°C. Stir and filter the solid under vacuum followed by acetonitrile washing and dry the material.
Yield: 31%
Purity: 99.71 (By HPLC)

Example 2: Preparation of Tenofovir alafenamide hemifumarate crystalline Form-G
using acetonitrile
To a mixture of Tenofovir alafenamide (0.0188 mol) and acetonitrile (10.0 volumes), (0.0081 mol) of Fumaric acid was charged and heated the reaction mixture to get clear solution. Filtered the unwanted mass at higher temperature and cooled the filtrate mother liquid to 25-35°C and further cooled to 0-5°C. Stirred at same temperature and the solid obtained was filtered and washed with acetonitrile (4.0 volumes). The solid compound at was dried at 40-50°C to afford the title compound.

Example 3: Preparation of Tenofovir alafenamide hemifumarate crystalline Form-G using ethyl acetate
To a mixture of Tenofovir alafenamide (0.0188 mol) and ethyl acetate (10.0 volumes), (0.0081 mol) of Fumaric acid was charged and heated the reaction mixture to get clear solution. Filtered the unwanted mass at higher temperature and cooled the filtrate mother liquid to 25-35°C and further cooled to 0-5°C. Stirred at same temperature and the solid obtained was filtered and washed with ethyl acetate (4.0 volumes). The solid compound at was dried at 40-50°C to afford the title compound.

Example 4: Preparation of Tenofovir alafenamide hemifumarate crystalline Form-G
using acetone
To a mixture of Tenofovir alafenamide (0.0188 mol) and acetone (10.0 volumes), (0.0081 mol) of Fumaric acid was charged and heated the reaction mixture to get clear solution. Filtered the unwanted mass at higher temperature and cooled the filtrate mother liquid to 25-35°C and further cooled to 0-5°C. Stirred at same temperature and the solid obtained was filtered and washed with acetone (4.0 volumes). The solid compound at was dried at 40-50°C to afford the title compound.

Example 5: Preparation of Tenofovir alafenamide hemifumarate crystalline Form-G
using methanol
To a mixture of Tenofovir alafenamide (0.0188 mol) and methanol (10.0 volumes), (0.0081 mol) of Fumaric acid was charged and heated the reaction mixture to get clear solution. Filtered the unwanted mass at higher temperature and cooled the filtrate mother liquid to 25-35°C and further cooled to 0-5°C. Stirred at same temperature and the solid obtained was filtered and washed with methanol (4.0 volumes). The solid compound at was dried at 40-50°C to afford the title compound.

Example 6: Purification of Tenofovir alafenamide

To the tenofovir alafenamide (0.221 mol) having diastereomeric purity of 87.31 %, charged acetonitrile (3.8 volumes) and stirred for 2-3 hours at room temperature. Further cooled the mass to 5-10°C and stirred for 5-6 hours. Filtered the solid obtained and washed with acetonitrile (1.9 volumes) and dried aerially if this wet compound gives the diastereomeric pure compound (98.73%) with the % yield 50.47%.
Repetitive recrystallization in acetonitrile affords greater than 99.0 % diastereomeric purity. ,CLAIMS:We Claim:
1) A process for the preparation of crystalline Form G of Tenofovir alafenamide hemifumarate of Formula (I) characterized by X-ray powder diffraction angle peaks at 5.3, 7.4, 10.4, 11.2, 12.9, 14.4, 17.7, 19.5, 21.2, 22.4 and 26.6 ± 0.2° comprising the steps of:

(I)

a. providing a solution of tenofovir alafenamide or a salt thereof and fumaric
acid in an organic solvents or mixture of solvents thereof;
b. heating the solution of step (a) to get clear solution;
c. filtering the solution in the hot condition;
d. cooling the solution of step (c) to a temperature ranging between 20 - 40°C;
e. optionally seeding the reaction mixture of steps (a) to (c) independently and
f. recovering the crystalline Tenofovir alafenamide hemifumarate.

2) Process for the preparation of crystalline Form G of Tenofovir alafenamide hemifumarate, according to claim 1, wherein an organic solvent selected from alcohols as methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, tertiary butyl alcohol or esters as ethyl acetate, isopropyl acetate, isobutyl acetate or nitriles as acetonitrile or a mixture thereof.

3) Process for the preparation of crystalline Form G of Tenofovir alafenamide hemifumarate, according to claim 2, wherein organic solvents selected from acetonitrile or ethyl acetate.

4) Process for the preparation of crystalline Form G of Tenofovir alafenamide hemifumarate, according to claim 1, wherein Step f of recovering the pure crystalline material comprises the steps of:

i) providing a solution of tenofovir alafenamide in an organic solvent or a mixture of solvents;
ii) isolating the pure tenofovir alafenamide substantially free from diastereomeric impurities.

5) Crystalline Form G of Tenofovir alafenamide hemifumarate characterized by

a. X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 5.3, 7.4, 10.4, 11.2, 12.9, 14.4, 17.7, 19.5, 21.2, 22.4 and 26.6 ± 0.2° and
b. DSC isothermal peaks ranging 100 - 110°C & 150 - 200°C.

6) A process for preparing pure Tenofovir alafenamide free base comprising the steps of:

i. Providing a mixture of Mono phenoxy ester of PMPA and thionyl chloride in ethyl acetate;
ii. Heating the reaction mass to 60-65°C and stir for 4-8 hours under argon atmosphere;
iii. Concentrate the reaction mass under argon atmosphere at below 65°C;
iv. To above residue charge chloroform and add the Alanine isopropyl ester dissolved in chloroform at -35 to -30°C;
v. Maintain for 30 minutes and add triethylamine at -20 to -25°C;
vi. Raise reaction mass to room temperature and filter if any salts, wash the Organic layer with Sodium dihydrogen phosphate solution;
vii. Concentrate the organic layer under vacuum;
viii. Charge acetonitrile and stir at Room temperature for 10-15 minutes, then charge seed material and stir for 10-12 hours and
ix. Cool the reaction mass to 0-5°C, stir and filter the solid under vacuum followed by acetonitrile washing and dry the pure tenofovir alafenamide.
7) A pharmaceutical composition comprising crystalline form G of Tenofovir alafenamide hemifumarate and atleast one or more pharmaceutically acceptable excipients.
Dated this Nineteenth (19th) day of January 2017.

_______________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883