DESC:FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of crystalline Form A of Tenofovir alafenamide hemifumarate, pharmaceutical composition containing them and method of treatment using the same.

Formula-I

BACKGROUND OF THE INVENTION

Tenofovir alafenamide hemifumarate is an amino phosphate derivative which is a prodrug of Tenofovir and may be useful alone or in combination with one or more anti-retroviral drug for treatment of HIV infection as well as chronic hepatitis B.

Tenofovir alafenamide hemifumarate is chemically known as hemifumarate form of “9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine” which is disclosed as a crystalline form in US 8754065 B2 characterized by the following powder X-ray diffraction (PXRD) pattern having characteristic degree 2 theta peaks at 6.9, 8.6, 10.0, 11.0, 12.2, 15.9, 16.3, 20.2 and 20.8+ 0.2 and Differential Scanning Calorimetry (DSC) onset endotherm at 131 + 2°C.

WO 2016108205 discloses amorphous form of Tenofovir alafenamide hemifumarate. The patent also disclosed a process for preparation of Tenofovir Alafenamide hemifumarate by reaction of Tenofovir Alafenamide free base with fumaric acid in acetonitrile solvent followed by seeding with Tenofovir alafenamide hemifumarate seed crystals.

WO 2016205141 discloses Sesquifumarate form of Tenofovir Alafenamide. CN 104558036 A discloses preparation of Tenofovir Alafenamide hemifumarate. Another application WO 2017037608 (IN 2015CH04540) discloses preparation of Tenofovir Alafenamide hemifumarate form HL.

WO 2017203395 (IN 201641017576) and IN 201641001993 disclose crystalline polymorphic form of Tenofovir Alafenamide hemifumarate. All these process involves the isolation of the new form from organic solvents only such as amyl alcohol, methanol, acetonitrile, ethyl acetate, and acetone and doesn’t involve use of water.

Considering the importance of Tenofovir Alafenamide hemifumarate in the pharmaceutical field, there is a need for simple and improved methods for the preparation of Tenofovir alafenamide hemifumarate, which provides higher polymorphic purity by providing an efficient, economic and reproducible process, particularly on large scale manufacturing.

SUMMARY OF THE INVENTION

In another aspect, the present invention relates to process for the preparation of crystalline Form A of Tenofovir alafenamide hemifumarate comprising steps of:
i) providing solution of Tenofovir alafenamide hemifumarate in water or mixture of water and an organic solvent(s);
ii) heating the reaction mixture obtained in step (i) at a temperature range of 20-90°C;
iii) optionally distilling the reaction mixture obtained in step (ii) partially;
iv) optionally cooling the reaction mixture obtained in step (ii) or step (iii) at a temperature range of 1-30°C; and
v) isolating crystalline Form A of Tenofovir alafenamide hemifumarate.

In another aspect of the present invention crystalline Form A of Tenofovir alafenamide hemifumarate obtained according to the present invention is characterized by X-ray diffraction pattern having characteristic degree 2 theta peaks at about 5.3, 7.4, 11.2, 12.9, 14.3 and 19.5 + 0.2.

In another general aspect, there is provided a pharmaceutical composition that includes a therapeutically effective amount of crystalline form A of Tenofovir alafenamide hemifumarate and one or more pharmaceutically acceptable carriers, excipients or diluents.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a powder X-ray diffractogram (PXRD) pattern of crystalline Form A of Tenofovir alafenamide hemifumarate prepared according to the present invention.
Figure 2 is an illustration of a Differential scanning calorimetry (DSC) pattern of crystalline Form A of Tenofovir alafenamide hemifumarate prepared according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention relates to process for the preparation of crystalline Form A of Tenofovir alafenamide hemifumarate comprising steps of:
i) providing solution of Tenofovir alafenamide hemifumarate in water or mixture of water and an organic solvent(s);
ii) heating the reaction mixture obtained in step (i) at a temperature range of 20-90°C;
iii) optionally distilling the reaction mixture obtained in step (ii) partially;
iv) optionally cooling the reaction mixture obtained in step (ii) or step (iii) at a temperature range of 1-30°C; and
v) isolating crystalline Form A of Tenofovir alafenamide hemifumarate.

In another embodiment, the present invention crystalline Form A of Tenofovir alafenamide hemifumarate obtained according to the present invention is characterized by X-ray diffraction pattern having characteristic degree two theta peaks at about 5.3, 7.4, 11.2, 12.9, 14.3 and 19.5 + 0.2. Crystalline Form A of Tenofovir alafenamide hemifumarate is further characterized by X-ray diffraction pattern having characteristic degree 2 theta peaks at about 5.3, 7.4, 9.7, 10.4, 11.2, 12.9, 14.3, 15.4, 19.5, 21.2, 22.4, 24.4 and 26.6 + 0.2.

In another embodiment, the present invention relates to crystalline Form A of Tenofovir alafenamide hemifumarate characterized by Differential scanning calorimetry (DSC) having endotherm within the range of about 109°C to 114°C.

In another embodiment of the present invention, the step of providing solution of Tenofovir alafenamide hemifumarate in water or mixture of water and organic solvent(s) can be generally referred as either dissolving Tenofovir alafenamide hemifumarate in water or water and organic solvent or preparing Tenofovir alafenamide hemifumarate by mixing Tenofovir alafenamide and fumaric acid in water or water and organic solvent medium. The dissolution is affected either at ambient temperature or at elevated temperature. The amount of fumaric acid used is 0.4 to 0.6 (or 0.5 + 0.1) moles per mole of Tenofovir alafenamide.

In another embodiment the suitable organic solvent(s) used in step (i) is selected from any solvent that doesn’t affect the nature of the polymorphism that includes but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-hexanol, n-pentanol, propylene glycol, benzyl alcohol, ethyl acetate, methyl acetate, isopropyl acetate, n-Butyl acetate, Isobutyl acetate, amyl acetate, iso-amyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclo pentyl methyl ether, diisopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, tetra methyl urea, dichloromethane, chlorobenzene, ethylene dichloride, chloroform, benzo trifluoride carbon tetrachloride, hexane, pentane, heptane, benzene, cyclohexane, toluene, xylene and like.

In another embodiment, the suitable solvent(s) is particularly selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, diiso butyl ketone, methyl isobutyl ketone or mixture of such ketone and water. The ratio of ketone and water is 1:2 or 2:1, preferably 1:1.5 or 1.5:1 or 1.25:1 or 1:1.25, more preferably 1:1.

In another embodiment, reaction mixture of step i) is optionally heated at 20-90 °C, preferably at 50-70°C. Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflo) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or to remove impurities absorb on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under vacuum. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In another embodiment, the solvent(s) from reaction mixture of either step i) or step ii) is optionally distilled out under vacuum partially to reduce the volume of solvent(s) and to precipitate/obtain product. Preferably the solvent is distilled out at a temperature in the range of 5 to 30°C, more preferably 10 to 15°C. The partial distillation as denoted in step (iii) is carried out with an aim to reduce the solvent medium approximately 30-70% of reaction solvent is distilled 50% of total volume of the solvent distilled.

In another embodiment, the reaction mixture of step iv) is optionally cooled within the temperature range of 1-30°C. The precipitated product was optionally stirred at the same temperature for about 1 to 20 hours and the product is filtered and dried at 30 to 60°C under vacuum for 5 to 20 hours.

The inventors have found that crystalline Form A of Tenofovir alafenamide hemifumarate prepared according to the present invention is stable and substantially free from any other known impurities or polymorphic forms even after storage for 6 months or more and at a relative humidity of 60 or 70% or at room temperature or at 25°C. As used herein, the term “substantially pure” with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% by weight of any other physical forms of the compound.

In another embodiment, the starting material either of Tenofovir alafenamide or its salt can be obtained by conventional method or adopting the general process as disclosed in US 7390791 or US 8754065.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermal gravimetric analyzers thermogram, melting point information, polarized light microscopy, hot stage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few may be used.

In one embodiment, the present invention provides pharmaceutical composition comprising crystalline Form A of Tenofovir alafenamide hemifumarate prepared according to the invention or in combination with other drugs. Generally it will be administered as composition in association with one or more pharmaceutically acceptable excipients. The choice of excipient(s) will to a large extent depend on factors such as the particular mode of administration, the effect of excipient on solubility and stability and the nature of dosage form.

In another embodiment, the pharmaceutical composition prepared is substantially free of one or more of its corresponding impurities.

In one embodiment, the present invention provides a process of preparing a pharmaceutical composition comprising crystalline Form A of Tenofovir alafenamide hemifumarate alone or in combination with other drugs along with a pharmaceutically acceptable carrier and/or excipients.

Pharmaceutically acceptable carrier and/or excipients include but not limited to suitable binder, filler, disintegrating agent, lubricating agent, sweetening and flavoring agent etc. Pharmaceutical compositions suitable for delivery of compound(s) described herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s pharmaceutical sciences, 19th Edition (Mack Publishing Company, 1995)

In one embodiment, the present invention provides a method for treating or preventing a viral infection in a human, comprising administering to the human crystalline Form A of Tenofovir alafenamide hemifumarate as described herein alone or in combination with other drugs. More particularly, the viral infection is human immunodeficiency virus (HIV). Alternatively, the viral infection is hepatitis B virus (HBV).

Wherever applicable the characterization of compounds given in the specification is being performed by adopting following general analytical instrumental technique:
The melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give the melting point as onset value. About 2 mg of sample is heated 10°/min in a loosely closed pan under nitrogen flow.
X-Ray powder diffractograms were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKa1 radiation. The samples were measured in reflection mode in the 2?-range 2.5-40° using an X' celerator detector.

The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

Example-1: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
Tenofovir Alafenamide hemifumarate (5 g) was dissolved in water (250 ml) to obtain clear reaction mixture. The solvent was distilled off under vacuum to obtain product which was further dried to obtain desired Form A of Tenofovir alafenamide hemifumarate (Yield 3.18 g).

Example-2: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To water (100 ml) Tenofovir alafenamide (2 g) followed by fumaric acid (0.26 g) was added at room temperature. The reaction temperature was raised to about 80°C and stirred for about 30 min. The above mixture was filtered through hyflo bed and hyflow bed was washed with pre heated water (5 ml). The filtrate was cooled down at 10 + 5°C. Approximately 25 ml of filtrate was distilled at 10 + 5°C under vacuum. The solid obtained was stirred at the same temperature. The product was filtered, washed with water and dried at 30 + 5°C for 12 h under vacuum to obtain titled compound. (Yield 1.82 g).

Example-3: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To a mixture of acetone (10 ml) and water (10 ml) Tenofovir alafenamide (1 g) followed by fumaric acid (0.14 g) was added at room temperature. The reaction mixture temperature was raised to about 60ºC and stirred for about 30 min. The above mixture was filtered through hyflo bed and hyflow bed was washed with pre heated water (2 ml). The filtrate was cooled down at 10 + 5°C. Approximately 10 ml of filtrate was distilled at 10 + 5ºC under vacuum. The product was filtered, washed with water and dried at 40 + 5ºC for 10 h under vacuum to obtain titled compound. (Yield 0.68 g)

Example-4: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To a mixture of ethyl acetate (30 ml) and water (30 ml) Tenofovir alafenamide (2 g) followed by fumaric acid (0.26 g) was added at room temperature. The reaction temperature was raised to about 70ºC and stirred for about 30 min. Reaction mixture was cooled down at 10 + 5ºC. Approximately 30 ml of filtrate was distilled at 10 + 5ºC under vacuum. The product was filtered, washed with water and dried at 30 + 5ºC for 10 h under vacuum to obtain titled compound. (Yield 1.12 g)

Example-5: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To a mixture of methyl ethyl ketone (10 ml) and water (10 ml) Tenofovir alafenamide (1 g) followed by fumaric acid (0.14 g) was added at room temperature. The reaction temperature was raised to about 70ºC and stirred for about 30 min. The above mixture was filtered through hyflo bed and hyflow bed was washed with pre heated water (2 ml). The filtrate was cooled down at 10 + 5°C. Approximately 10 ml of filtrate was distilled at 10 + 5ºC under vacuum. The product was filtered, washed with water and dried at 30 + 5ºC for 10 h under vacuum to obtain titled compound. (Yield 0.72 g)

Example-6: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To a mixture of acetonitrile (10 ml) and water (10 ml) Tenofovir alafenamide (1 g) followed by fumaric acid (0.14 g) was added at room temperature. The reaction temperature was raised to about 70ºC and stirred for about 30 min. The above mixture was filtered through hyflo bed and hyflow bed was washed with pre heated water (2ml). The filtrate was cooled down at 10 + 5°C. Approximately 10 ml of filtrate was distilled at 10 + 5ºC under vacuum. The product was filtered, washed with water and dried at 50 + 5ºC for 10 h under vacuum to obtain titled compound. (Yield 0.66 g).

Example-7: Preparation of crystalline Form A of Tenofovir alafenamide hemifumarate
To mixture of acetone (250 ml) and water (250 ml) Tenofovir Alafenamide (25 g) followed by fumaric acid (3.3 g) was added at room temperature. The reaction temperature was raised to about 60ºC and stirred for about 30 min. The above mixture was filtered through hyflo bed and hyflow bed was washed with pre heated water (25ml). The filtrate was cooled down at 10 + 5°C. Approximately 250 ml of filtrate was distilled at 10 + 5ºC under vacuum. The product was filtered, washed with water and dried at 30 + 5ºC for 10 h under vacuum to obtain titled compound. (Yield 16.8 g).

Date this 22nd day of December 2017

,CLAIMS:WE CLAIM:

1. A process for preparation of crystalline form A of Tenofovir alafenamide hemifumarate comprising the steps of:
(i) providing solution a Tenofovir alafenamide hemifumarate in water or mixture of water and an organic solvent(s);
(ii) heating the reaction mixture obtained in step (i) at a temperature range of 20-90ºC;
(iii) optionally distilling the reaction mixture obtained in step (ii) partially;
(iv) optionally cooling the reaction mixture obtained in step (ii) or step (iii) at a temperature range of 1-30ºC; and
(v) isolating crystalline Form A of Tenofovir alafenamide hemifumarate.

2. The process according to claim 1 where in crystalline form A of Tenofovir alafenamide hemifumarate characterized by having a powder X-ray diffractogram (XRD) pattern comprising of degree 2 theta peaks at about 5.2, 7.4, 10.3 and 11.2 + 0.2.

3. The process according to claim 1 where in crystalline form A of Tenofovir Alafenamide Hemifumarate further characterized by an X-ray diffraction pattern substantially in accordance with Figure-1 and differential scanning calorimetry (DSC) substantially in accordance with Figure-2.

4. The process as claimed in claim 1, wherein the solution of Tenofovir alafenamide hemifumarate is provided by either by dissolving Tenofovir alafenamide hemifumarate or mixing Tenofovir alafenamide and Fumaric acid in the solvent system as given in step (i).

5. The process as claimed in claim 4, wherein the ratio of Tenofovir alafenamide to fumaric acid is 1: 0.5 + 0.1.

6. The process according to claim 1 step (i), wherein suitable organic solvent(s) are selected from selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl acetate, methyl acetate, n-propyl acetate, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-hexanol, n-pentanol, propylene glycol, benzyl alcohol, acetonitrile, benzonitrile; acetamide, formamide, hexane, pentane, heptane, benzene, cyclohexane, toluene, xylene; dichloromethane, chlorobenzene, ethylene dichloride, chloroform, benzo trifluoride, carbon tetrachloride, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclo pentyl methyl ether, diisopropyl ether, methyl tert-butyl ether, DMF, DMAc, DMSO or their mixtures.

7. The process according to claim 1 wherein organic solvent is selected from acetone, acetonitrile, methyl ethyl ketone, or ethyl acetate.

8. The process as claimed in claim 1, wherein the partial distillation in step (ii) is carried out at a temperature in the range of 5-30°C.

9. The process as claimed in claim 1, wherein isolation of crystalline Form A of Tenofovir alafenamide hemifumarate is carried out by filtration followed by drying 30 – 60°C under vacuum.

10. The pharmaceutical composition comprising crystalline Form A of Tenofovir alafenamide hemifumarate obtained according to process of claim 1 and at least one or more pharmaceutically acceptable excipients.

Date this 22nd day of December 2017