Field of the Invention

The present invention relates to novel polymorphic form of tenofovir disoproxil succinate and to pharmaceutical composition of novel form.

Background of the Invention

Tenofovir is a highly potent antiviral agent, particularly for the therapy or prophylaxis of retroviral infections and belongs to a class of drugs called Nucleotide Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase, an enzyme crucial to viral production in HIV-infected people.

Tenofovir disoproxil is a prodrug of Tenofovir and is marketed in the form of fumarate salt under the trade name Viread®. The chemical name of Tenofovir disoproxil fumarate is 9-[(R)-2-[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl- Jadenine fumarate. Tenofovir Disoproxil and its pharmaceutically acceptable salts were first disclosed in U.S. Pat. Nos. 5,935,946; 5,922,695; 5,977,089; 6,043,230 and 6,069,249.

WO 2010/142761 disclose succinate salt of Tenofovir disoproxil characterised by X-ray powder diffraction peaks having two-theta values at 5.0, 9.9, 11.7, 12.7, 14.1, 15.7, 17 3, 18.2, 18.9, 19.9, 20 8, 25.0, 30.1 and FTIR having characterising peaks at 634, 950, 1027, 1255, 1623, 1669, 1744, 1759 cm"1.

WO 2009/074351 disclose novel solid forms of Tenofovir Disoproxil selected from the group consisting of Tenofovir disoproxil succinate, Tenofovir disoproxil L-tartrate, Tenofovir disoproxil oxalate, Tenofovir disoproxil saccharate, Tenofovir disoproxil citrate, Tenofovir disoproxil salicylate. WO '351 further discloses various crystalline form of Tenofovir disoproxil succinate such as TDSU ULT-1, TDSU ULT-2, TDSU ULT-3 and TDSU ULT-4 characterized by XRD pattern.

Despite, many attempts by the prior art, there is a need to obtain stable crystalline form of Tenofovir disoproxil succinate.

Summary of the Invention
Accordingly, the present invention provides crystalline Form A of Tenofovir disoproxil
succinate having the following characteristics : X-ray diffraction pattern having 20 angle at 4.76, 9.30, 10.16, 10.77, 11.32, 13.86, 14.57, 17.689, 18.134, 18.93, 19.32, 20.08, 21.14, 21.94, 22.29, 23.34, 24.52, 26.40, 27.84, 28.25,29.54,; FTIR having characteristic peaks at 535.07, 597.64, 620.02, 637.81, 757.67, 790.06, 823.37, 856.35, 887.66, 958.41, 986.05, 1031.47, 1104.46, 1160.68, 1195.72, 1267.76, 1320.84, 1377.66, 1389.99, 1421.98, 1469.21, 1579.53, 1621.87, 1668.29, 1762.5, 2933.49, 2987.74, 3339.36 cm4; DSC endotherm between 110 -114 °C.

Another embodiment of the invention provides a pharmaceutical composition comprising more than 35% by weight of crystalline Form A of Tenofovir disoproxil succinate and one or more pharmaceutically acceptable excipients.

Detailed Description of the Invention The present invention provides a novel crystalline Form A of Tenofovir disoproxil succinate having the following characteristics : X-ray diffraction pattern having 20 angle at 4.76, 9.30, 10.16, 10.77, 11.32, 13.86, 14.57, 17.689, 18.134, 18.93, 19.32, 20.08, 21.14, 21.94, 22.29, 23.34, 24.52, 26.40, 27.84, 28.25,29.54,; FTIR having characteristic peaks at 535.07, 597.64, 620.02, 637.81, 757.67, 790.06, 823.37, 856.35, 887.66, 958.41, 986.05, 1031.47, 1104.46, 1160.68, 1195.72, 1267.76, 1320.84, 1377.66, 1389.99, 1421.98, 1469.21, 1579.53, 1621.87, 1668.29, 1762.5, 2933.49, 2987.74, 3339.36 cm"1; DSC endotherm between 110 -114 °C.

Figures of the invention
Figure 1 : X-ray diffractogram of crystalline Form A of Tenofovir disoproxil succinate,

Figure 2 : FTIR of crystalline Form A of Tenofovir disoproxil succinate,

Figure 3 : DSC thermogram of crystalline Form A of Tenofovir disoproxil succinate.

Yet another embodiment of the invention provides a process for the preparation of Tenofovir disoproxil succinate salt which comprises treating Tenofovir disoproxil ester with succinic acid in a solvent selected from methanol, ethanol, isopropanol at a temperature of 20 to 80 °C.

Yet another embodiment of the invention provides a pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate and one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, binder, lubricant and glidant.
Suitable diluents according to the present invention are selected from microcrystalline cellulose (e.g. Avicel®), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, potassium chloride, powdered cellulose, sodium chloride, sorbitol, mannitol and the like.

Suitable disintegrants according to the present invention are selected from carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium available under the brand names Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX; crosslinked polyvinylpyrrolidones (PVP), (Polyplasdone® XL and Kollidon® CL); modified starches especially sodium starch glycolate (Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P) and the like.

Suitable binders according to the present invention are selected from polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolyzed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. The binding agent is present in the composition in an amount of from about 1% to about 25%, preferably from about 1%, to about 15%, more preferably from about 1% to about 10%.

Suitable lubricants according to the present invention are selected from stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate, 10-40% of diluent, 1-10% of a disintegrant and 1-15% of a binder and 0.1-10% of a lubricant by weight of the composition.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate, 10-40% of diluent selected from microcrystalline cellulose, lactose, starch, or dibasic calcium phosphate; 1-10% of disintegrant selected from crospovidone or croscarmellose sodium; 1-15% of pregelatinized starch, polyvinyl pyrollidone or hydroxypropyl methylcellulose, 0.1-10% of a lubricant by weight of the composition.

A more preferred embodiment of the present invention provides a pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate, 1 to 15% of pregelatinized starch, 1 to 20%) of lactose, 1 to 20% croscarmellose sodium, 1 to 10 % of magnesium stearate and 0 to 5 % of colloidal anhydrous silica.

The composition of the present invention are prepared by direct compression or by granulation such as dry granulation or wet granulation using solvent such as water, methanol, isopropanol, ethanol, dichloromethane or mixture thereof. The composition may also be prepared using hot melt including extrusion and granulation.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate, 10-40% of diluent, 1-10% of a disintegrant and 1-15% of a binder and 0.1-10% of a lubricant by weight of the composition.

In one embodiment, the pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate of the invention has a comparable bioavailability to the commercial tablets of Tenofovir disoproxil fumarate marketed under the brand name Viread®.

In one embodiment, the present invention relates to a process for producing a pharmaceutical composition, comprising:

(a) mixing comprising crystalline Form A of Tenofovir disoproxil succinate and one or
more excipients;

(b) granulating the mixture obtained in the step (a); and

(c) mixing the granules from step (n) with one or more extragrnular expcients and

(d) finally compressing the blend into tablets.

In another embodiment the present invention provides a method of treating HIV or Hepatitis B viral infections comprises administering an effective amount of crystalline Form A of Tenofovir disoproxil succinate and pharmaceutical composition comprising same to a patient in need thereof.
In one embodiment, the pharmaceutical composition comprises from about 100 to about 300 mg of crystalline Form A of Tenofovir disoproxil succinate.

The pharmaceutical compositions of the present invention are in the form of capsules, tablets, powder for suspension, granules and the like, more preferably, tablets which may be coated or uncoated.

Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.

Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.

The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, and triacetin), and oils/glycerides (castor oil, acetylated monoglycerides, and fractionated coconut oil).

Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials form each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.

Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

A composition of coating suspension (calculated on dry material) is particularly preferred which comprises: 1-99% by weight of polymer, preferably 1- 95% of polymer; 1-50% by weight of plasticizer, preferably 1-40% of plasticizer; 0.1-20% of colourant/opacifier, preferably 0.1- 10% of colourant/opacifier, all the percentage are based on the total weight of coating material.

In yet another embodiment, the pharmaceutical composition comprises, one or more additional active ingredients selected from abacavir, zidovudine, lamivudine, efavirenz, emitrictabine, rilpivirine, cobicistat, elvitegravir and/or gemcitabine.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Example 1:

Preparation of Crystalline Form A of Tenofovir disoproxil succinate

Tenofovir disoproxil ester (500mg) was mixed with succinic acid (137.5mg) and isopropyl alchohol (3.2ml). The reaction temperature was slowly raised from room temperature to 55 °C for 30 minutes. Filtered and washed the product obtained with hot isopropyl alcohol and cooled to 30-35 °C and stirred at 55 °C for 2 hours to yield Tenofovir disoproxil succinate salt.

Example 2 :
Preparation of Tenofovir disoproxil succinate tablets by Wet Granulation method Preparation:
1. Weighed required quantities of Tenofovir disoproxil succinate crystalline Form A, lactose monohydrate, microcrystalline Cellulose pHlOl, croscarmellose sodium and Pregelatinized starch,

2. loaded ingredients of step 1 into Rapid Mixer Granulator (RMG) and mixed for 10 minutes,

3. granulated step 2 materials in Rapid Mixer Granulator (RMG) using water as granulating fluid,

4. dried the wet mass of step 3 in Rapid drier at 55°C ± 5°C,

5. weighed the extragranular croscarmellose sodium, microcrystalline cellulose pH 101 and magnesium stearate,

6. the granules obtained step 4 were blended with extragranular materials of step 5,

7. the blend of step 6 was compressed by using almond shaped punches,

8. coating solution was prepared using 15 gm of Opadry blue was added to 85 gm of purified water under continuous stirring for 45 minutes and

9. the tablets of step 7 were coating solution of step 8 upto 2.5 % weight buildup.
Examples 3-5: Preparation of Tenofovir disoproxil succinate tablets by Direct Compression
Method Preparation:

1. Sifted Tenofovir disoproxil succinate crystalline Form A, microcrystalline cellulose, lactose monohydrate fast flow, crospovidone, HPC and Aerosil 200 through sieve # ASTM 40.

2. Loaded the ingredients of step 1 into blender and mixed for 10 min.,

3. sifted Magnesium Stearate through sieve # ASTM 60,

4. added step 3 material to the step 2 and blended in blender for 5 min and

5. Compressed the lubricated blend of step 4 using almond shaped punches.
Example 6-11:

Preparation of combination tablet of Tenofovir disoproxil succinate with other antiretroviral drugs Preparation:

1. Weighed the required quantities of Tenofovir disoproxil succinate crystalline Form A, lactose monohydrate, microcrystalline Cellulose pHlOl, croscarmellose sodium and Pregelatinized starch,.

2. Loaded the ingredients of step 1 into Rapid Mixer Granulator (RMG) and mied for 10 minutes,

3. Granulated the step 2 materials in Rapid Mixer Granulator (RMG) using water as granulating fluid,

4. dried the wet mass of step 3 in Rapid drier at 55°C ± 5°C, to obtain granules

5. weighed the extragranular materials such as Croscarmellose sodium, microcrystalline cellulose pH 101 and magnesium stearate,

6. add step 4 materials to the step 5 material and blended for 5 minutes,

7. the blend of step 6 was compressed using almond shaped punches,

8. coating solution was prepared using 15 gm of Opadry blue was added to 85 gm of purified water under continuous stirring for 45 minutes,

9. the tablets of step 7 were coating solution of step 8 upto 2.5 % weight buildup.

The dissolution of the tablets of Tenofovir disoproxil succinate manufactured according to the present invention and commercially available tablets of Tenofovir disoproxil fumarate (Viread®) was carried out in various dissolution media using USP Type II apparatus, 900ml and 50RPM.

The comparative dissolution data of Tenofovir disoproxil salts tablets is shown in the tables given below :
Tablets prepared according to the present invention were tested for stability. Comparative stability data of Tenofovir disoproxil salts tablets shown in the tables given below :

From the above table it is evident that the tablets of novel crystalline Form A of Tenofovir disoproxil succinate prepared according to the present invention are more stable than fumarate salt.

We claim :

1. Novel crystalline Form A of Tenofovir disoproxil succinate having the following
characteristics : X-ray diffraction pattern having 26 angle at 4.76, 9.30, 10.16, 10.77, 11.32, 13.86, 14.57, 17.689, 18.134, 18.93, 19.32, 20.08, 21.14, 21.94, 22.29, 23.34, 24.52, 26.40, 27.84, 28.25,29.54,; FTIR having characteristic peaks at 535.07, 597.64, 620.02, 637.81, 757.67, 790.06, 823.37, 856.35, 887.66, 958.41, 986.05, 1031.47, 1104.46, 1160.68, 1195.72, 1267.76, 1320.84, 1377.66, 1389.99, 1421.98, 1469.21, 1579.53, 1621.87, 1668.29, 1762.5, 2933.49, 2987.74, 3339.36 cm-1;
2. A stable pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate as claimed in claim 1 and one or more pharmaceutically acceptable excipients.

3. The composition as claimed in claim 2, wherein the pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder, lubricant and glidant.

4. The composition as claimed in claim 3, wherein the diluent is selected from microcrystalline cellulose, micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, potassium chloride, powdered cellulose, sodium chloride, sorbitol or mannitol.

5. The composition as claimed in claim 3, wherein the disintegrant is selected from carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium; crosslinked polyvinylpyrrolidones (PVP) and sodium starch glycolate.

6. The composition as claimed in claim 3, wherein the binder is selected from polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolyzed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.

7. A composition comprising crystalline Form A of Tenofovir disoproxil succinate, 10-40% of diluent, 1-10% of a disintegrant and 1-15% of a binder and 0.1-10% of a lubricant by weight of the composition.

8. A pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate, 10-40% of diluent selected from microcrystalline cellulose, lactose, starch, or dibasic calcium phosphate; 1-10% of disintegrant selected from crospovidone or croscarmellose sodium; 1-15% of pregelatinized starch, polyvinyl pyrollidone or hydroxypropyl methylcellulose, 0.1-10% of a lubricant by weight of the composition.

9. The composition according to claim 3, prepared by wet granulation.

10. The composition according to claim 3, prepared by dry granulation.

11. The composition according to claim 3, prepared by direct compression.

12. The pharmaceutical composition according to claim 3, prepared by hot melt process.

13. A stable pharmaceutical composition comprising crystalline Form A of Tenofovir disoproxil succinate with less % of monoester impurity compared to Viread tablets.