The present invention relates to novel polymorphs of tenofovir disoproxil fumarate, to processes for their preparation and to pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION
U.S. Patent No. 5,922,695, which is herein incorporated by reference, disclosed phosphonomethoxy nucleotide analogs, in particular compounds suitable for use in the efficient oral delivery of such analogs and their pharmaceutically acceptable salts. This class of nucleoside analogues possesses broad-spectrum antiviral activity, together with a high level of selectivity in vitro and in vivo. An especially important compound among those disclosed is tenofovir disoproxil, chemically (R)-9-(2-phosphonomethoxypropyi) adenine bis(isopropyloxycarbonyloxymethyl) ester is a highly potent antiviral agent having particular potential for the therapy or prophylaxis of retroviral infections. Tenofovir disoproxil is represented by the following structure:

As per the processes described for preparation of tenofovir disoproxil fumarate in U.S. Patent No. 5,922,695 and U.S. Patent No. 5,935,946, tenofovir disoproxil fumarate is obtained as a crystalline form and may be designated as form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 20 at about 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4 degrees).
We have discovered two stable novel crystalline forms (designated as Form A, Form B) of tenofovir disoproxil fumarate. The novel forms are at least as stable as the reported form (Form I). The novel crystalline forms are stable over the time and has good flow properties and so, the novel crystalline forms are suitable for formulating tenofovir disoproxil fumarate.

Amorphous form of tenofovir disoproxil fumarate has not been reported in the prior art. So, there is a need for stable amorphous form of tenofovir disoproxil fumarate for better pharmaceutical preparations.
One object of the present invention is to provide stable novel crystalline forms of tenofovir disoproxil fumarate, process for preparing them and pharmaceutical, compositions containing them.
Another object of the present invention is to provide a novel stable amorphous form of tenofovir disoproxil fumarate, process for preparing it and a pharmaceutical composition containing it.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a novel crystalline form of tenofovir disoproxil fumarate, designated as tenofovir disoproxil fumarate form A and typical X-ray powder diffraction spectrum of tenofovir disoproxil fumarate form A is shown in figure 1.
Tenofovir disoproxil fumarate form A is characterized by peaks in the powder X-ray diffraction pattern having 20 angle positions at about 7.7, 8.0, 11.8, 13.6, 14.2, 16.0, 16.6, 17.9, 19.1, 20.3, 21.1, 21.5, 22.4, 22.7, 24.2, 24.6 and 25.2+ 0.2 degrees.
According to another aspect of the present invention, a process is provided for preparation of crystalline tenofovir disoproxil fumarate form A. Crystalline tenofovir disoproxil fumarate form A is prepared by dissolving tenofovir disoproxil fumarate in isopropyl alcohol and then crystallizing tenofovir disoproxil fumarate form A from the solution.
Crystallization may be initiated by any conventional methods usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Crystallization is preferably initiated by cooling the solution to below about 40°C and more preferably to about 20 - 30°C.
According to another aspect of the present invention, there is provided a novel crystalline form of tenofovir disoproxil fumarate, designated as tenofovir disoproxil fumarate form B and typical X-ray powder diffraction spectrum of tenofovir disoproxil fumarate form B is shown in figure 2.

Tenofovir clisoproxil fumarate form B is characterized by peaks in the powder X-ray diffraction pattern having 28 angle positions at about 5.2, 15.4, 20.6, 25.8 and 31.0 + 0.2 degrees.
According to another aspect of the present invention, a process is provided for preparation of crystalline tenofovir disoproxil fumarate form B. Crystalline tenofovir disoproxil fumarate form B is prepared by dissolving tenofovir disoproxil fumarate in methanol or ethanol and then crystallizing tenofovir disoproxil fumarate form B from the solution.
Crystallization may be initiated by any conventional methods usually known in the art such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Crystallization is preferably initiated by cooling the solution to below about 40°C and more preferably to about 20 - 30°C.
According to another aspect of the present invention, there is provided a novel amorphous form of tenofovir disoproxil fumarate. The amorphous tenofovir disoproxil fumarate is characterized by having broad x-ray diffraction spectrum as in figure 3.
According to another aspect of the present invention, a process is provided for preparation of amorphous tenofovir disoproxil fumarate. Amorphous tenofovir disoproxil fumarate is prepared by dissolving tenofovir disoproxil fumarate in a suitable solvent and removing the solvent by freeze-drying.
Preferable solvent is selected from alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone; tetrahydrofuran; dimethylformamide, dimethylsulfoxide; and a mixture thereof. More preferable solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. Most preferable solvent is ethanol.
Tenofovir disoproxil fumarate used as starting materials may be obtained by processes described in the art, for example by the processes described in U.S. Patent No. 5,922,695, U.S. Patent No. 5,935,946.
The novel crystalline forms can be produced in a consistently reproducible manner by simple procedures. The novel crystalline forms are

obtained polymorphically pure with no or less contamination with other crystalline forms.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form A and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of tenofovir disoproxil fumarate form A is a solid oral dosage form.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form B and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of tenofovir disoproxil fumarate form B is a solid oral dosage form.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising amorphous tenofovir disoproxil fumarate and a pharmaceutically acceptable excipient.
Preferable pharmaceutical composition of amorphous tenofovir disoproxil fumarate is a solid oral dosage form.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a X-ray powder diffraction spectrum of crystalline tenofovir disoproxil fumarate form A.
Figure 2 is a X-ray powder diffraction spectrum of crystalline tenofovir disoproxil fumarate form B.
Figure 3 is a X-ray powder diffraction spectrum of amorphous tenofovir disoproxil fumarate.
X-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance X-ray powder diffractometer having a Copper-Kα radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Example 1
Tenofovir disoproxil fumarate crude (5 gm) is added to isopropyl alcohol (50 ml) at 25 - 30°C and then heated to 45 - 50°C to form a clear solution. The solution is cooled to 25 - 30°C and stirred for 1 hour at 25 - 30°C. Filtered the solid and dried at 45 - 55°C to give 4.6 gm of crystalline tenofovir disoproxil fumarate form A.
Example 2
Tenofovir disoproxil fumarate crude (2 gm) is added to methanol (20 ml) at 25 - 30°C and then heated to 50 - 55°C to form a clear solution. The solution is cooled to 25 - 30°C and stirred for 1 hour at 25 - 30°C. Filtered the solid and dried at 50 - 60°C to give 1.6 gm of crystalline tenofovir disoproxil fumarate form B.
Example 3
Tenofovir disoproxil fumarate (2 gm) is added to ethanol (20 ml) at 25 -30°C and then heated to 55 - 60°C to form a clear solution. The solution is cooled to 25 - 30°C and stirred for 1 hour 30 minutes at 25 - 30°C. Filtered the solid and dried at 45 - 55°C to give 1.8 gm of crystalline tenofovir disoproxil fumarate form B.
Example 4
Example 1 is repeated using tenofovir disoproxil fumarate form B instead of tenofovir disoproxil fumarate crude to give 4.7 gm of tenofovir disoproxil fumarate form A.
Example 5
Example 2 is repeated using tenofovir disoproxil fumarate form A instead of tenofovir disoproxil fumarate crude to give 1.6 gm of tenofovir disoproxil fumarate form B.
Example 6
Tenofovir disoproxil fumarate (5 gm) is dissolved in a mixture of ethanol (75 ml) and water (20 ml) and then filtered the solution on hi-flow bed. The

solution is subjected to freeze drying to give 4.6 gm of amorphous tenofovir disoproxil fumarate.
Example 7
Example 6 is repeated using tenofovir disoproxil fumarate form A instead of tenofovir disoproxil fumarate to give 4.7 gm of amorphous tenofovir disoproxil fumarate.

We claim:
1. A process for preparation of crystalline tenofovir disoproxil fumarate form A,
characterized by an X-ray powder diffraction spectrum having peaks
expressed as 29 angle positions at about 7.7, 8.0, 11.8, 13.6, 14.2, 16.0,
16.6, 17.9, 19.1, 20.3, 21.1, 21.5, 22,4, 22.7, 24.2, 24.6 and 25.2 + 0.2
degrees, which comprises:
a) dissolving tenofovir disoproxil fumarate in isopropyl alcohol; and
b) crystallizing tenofovir disoproxil fumarate form A from the solution.

2. The process as claimed in claim 1, wherein the crystallization is initiated by
conventional methods such as cooling, seeding, partial removal of the
solvent from the solution, by adding an anti-solvent to the solution or a
combination thereof.
3. The process as claimed in claim 2, wherein the crystallization is initiated by
cooling the solution.
4. The process as claimed in claim 3, wherein the solution is cooled to below
about 40°C.
5. The process as claimed in claim 4, wherein the solution is cooling to about
20-30°C.
6. A process for preparation of crystalline tenofovir disoproxil fumarate form B,
characterized by an X-ray powder diffraction spectrum having peaks
expressed as 26 angle positions at about 5.2, 15.4, 20.6, 25.8 and 31.0 +0.2
degrees, which comprises:
a) dissolving tenofovir disoproxil fumarate in methanol or ethanol; and
c) crystallizing tenofovir disoproxil fumarate form B from the solution.
7. The process as claimed in claim 6, wherein the crystallization is initiated by
conventional methods such as cooling, seeding, partial removal of the
solvent from the solution, by adding an anti-solvent to the solution or a
combination thereof.
8. The process as claimed in claim 7, wherein the crystallization is initiated by
cooling the solution.
9. The process as claimed in claim 8, wherein the solution is cooling to below
about 40°C.
10. The process as claimed in claim 9, wherein the solution is cooling to about
20 - 30°C.

11. A process for preparation of amorphous tenofovir disoproxii fumarate as
shown in figure 3, which comprises:
a) dissolving tenofovir disoproxii fumarate in a suitable solvent; and
b) removing the solvent from the solution formed in step (a) by freeze
drying.
12. The process as claimed in claim 11, wherein the solvent is selected from
alcoholic solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl
alcohol, n-butyl alcohol; ketonic solvents such as acetone, diethyl ketone,
methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone;
tetrahydrofuran; dimethylformamide, dimethylsulfoxide; and a mixture
thereof.
13. The process as claimed in claim 12, wherein the solvent is selected from
methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
14. The process as claimed in claim 13, wherein the solvent is ethanol.
DATED: 19 October 2006