WO2007013086A1 - Novel polymorphs of tenofovir disoproxil fumarate - Google Patents
Novel polymorphs of tenofovir disoproxil fumarate Download PDFInfo
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- WO2007013086A1 WO2007013086A1 PCT/IN2005/000248 IN2005000248W WO2007013086A1 WO 2007013086 A1 WO2007013086 A1 WO 2007013086A1 IN 2005000248 W IN2005000248 W IN 2005000248W WO 2007013086 A1 WO2007013086 A1 WO 2007013086A1
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- Prior art keywords
- tenofovir disoproxil
- disoproxil fumarate
- solution
- solvent
- pharmaceutical composition
- Prior art date
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 76
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 9
- 238000001228 spectrum Methods 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000006186 oral dosage form Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012296 anti-solvent Substances 0.000 claims description 4
- 238000007796 conventional method Methods 0.000 claims description 4
- 238000010899 nucleation Methods 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 2
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- -1 isopropyloxycarbonyloxymethyl Chemical group 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Definitions
- the present invention relates to novel polymorphs of tenofovir disoproxil fumarate, to processes for their preparation and to pharmaceutical compositions comprising them.
- Tenofovir disoproxil chemically (R)-9-(2-phosphonomethoxypropyl) 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:
- 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 2 ⁇ 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).
- Form A 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.
- tenofovir disoproxil fumarate form A 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 2 ⁇ 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.
- 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 0 C and more preferably to about 20 - 30 0 C.
- tenofovir disoproxil fumarate form B 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 disoproxil fumarate form B is characterized by peaks in the powder X-ray diffraction pattern having 2 ⁇ angle positions at about 5.2, 15.4, 20.6, 25.8 and 31.0 + 0.2 degrees.
- 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 0 C and more preferably to about 20 - 30 0 C.
- a novel amorphous form of tenofovir disoproxil fumarate is provided.
- the amorphous tenofovir disoproxil fumarate is characterized by having broad x-ray diffraction spectrum as in figure 3.
- 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.
- 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
- 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.
- 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.
- 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.
- 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-K ⁇ 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.
- Tenofovir disoproxil fumarate crude (2 gm) is added to methanol (20 ml) at 25 - 30 0 C and then heated to 50 - 55 0 C to form a clear solution. The solution is cooled to 25 - 30 0 C and stirred for 1 hour at 25 - 30 0 C. Filtered the solid and dried at 50 - 60 0 C to give 1.6 gm of crystalline tenofovir disoproxil fumarate form
- 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 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.
- 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 6 is repeated using tenofovir disoproxil fumarate form A instead of tenofovir disoproxil fumarate to give 4.7 gm of amorphous tenofovir disoproxil fumarate.
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to novel polymorphs of tenofovir disoproxil fumarate, to processes for their preparation and to pharmaceutical compositions comprising them.
Description
NOVEL POLYMORPHS OF TENOFOVlR DISOPROXIL FUMARATE
FIELD OF THE INVENTION
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-phosphonomethoxypropyl) 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 2Θ 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 2Θ 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 400C and more preferably to about 20 - 300C.
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 disoproxil fumarate form B is characterized by peaks in the powder X-ray diffraction pattern having 2Θ 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 400C and more preferably to about 20 - 300C.
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 - 300C and then heated to 45 - 500C to form a clear solution. The solution is cooled to 25 - 300C and stirred for 1 hour at 25 - 300C. Filtered the solid and dried at 45 - 550C 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 - 300C and then heated to 50 - 550C to form a clear solution. The solution is cooled to 25 - 300C and stirred for 1 hour at 25 - 300C. Filtered the solid and dried at 50 - 600C 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 -
300C and then heated to 55 - 600C to form a clear solution. The solution is cooled to 25 - 300C and stirred for 1 hour 30 minutes at 25 - 300C. Filtered the solid and dried at 45 - 550C 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.
Claims
1. A crystalline tenofovir disoproxil fumarate form A, characterized by an X-ray powder diffraction spectrum having peaks expressed as 2Θ 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.
2. A process for preparation of crystalline tenofovir disoproxil fumarate form A as defined in claim 1 , which comprises: a) dissolving tenofovir disoproxil fumarate in isopropyl alcohol; and b) crystallizing tenofovir disoproxil fumarate form A from the solution.
3. The process as claimed in claim 2, 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.
4. The process as claimed in claim 3, wherein the crystallization is initiated by cooling the solution.
5. The process as claimed in claim 4, wherein the solution is cooled to below about 400C.
6. The process as claimed in claim 5, wherein the solution is cooling to about 20 - 300C.
7. A crystalline tenofovir disoproxil fumarate form B, characterized by an X-ray powder diffraction spectrum having peaks expressed as 2Θ angle positions at about 5.2, 15.4, 20.6, 25.8 and 31.0 + 0.2 degrees.
8. A process for preparation of crystalline tenofovir disoproxil fumarate form B as defined in claim 7, which comprises: a) dissolving tenofovir disoproxil fumarate in methanol or ethanol; and c) crystallizing tenofovir disoproxil fumarate form B from the solution.
9. The process as claimed in claim 8, 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.
10. The process as claimed in claim 9, wherein the crystallization is initiated by cooling the solution.
11. The process as claimed in claim 10, wherein the solution is cooling to below about 400C.
12. The process as claimed in claim 11 , wherein the solution is cooling to about 20 - 300C.
13. Amorphous form of tenofovir disoproxil fumarate.
14. A process for preparation of amorphous tenofovir disoproxil fumarate as defined in claim 13, which comprises: a) dissolving tenofovir disoproxil fumarate in a suitable solvent; and b) removing the solvent from the solution formed in step (a) by freeze drying.
15. The process as claimed in claim 14, wherein solvent is 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.
16. The process as claimed in claim 15, wherein solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol.
17. The process as claimed in claim 15, wherein solvent is ethanol.
18. A pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form A of claim 1 and a pharmaceutically acceptable excipient.
19. The pharmaceutical composition as claimed in claim 18, wherein the pharmaceutical composition of tenofovir disoproxil fumarate form A is a solid oral dosage form.
20. A pharmaceutical composition comprising crystalline tenofovir disoproxil fumarate form B of claim 7 and a pharmaceutically acceptable excipient.
21. The pharmaceutical composition as claimed in claim 20, wherein the pharmaceutical composition of tenofovir disoproxil fumarate form B is a solid oral dosage form.
22. A pharmaceutical composition comprising amorphous tenofovir disoproxil fumarate of claim 13 and a pharmaceutically acceptable excipient.
23. The pharmaceutical composition as claimed in claim 22, wherein the pharmaceutical composition of amorphous tenofovir disoproxil fumarate is a solid oral dosage form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2005/000248 WO2007013086A1 (en) | 2005-07-26 | 2005-07-26 | Novel polymorphs of tenofovir disoproxil fumarate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2005/000248 WO2007013086A1 (en) | 2005-07-26 | 2005-07-26 | Novel polymorphs of tenofovir disoproxil fumarate |
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| Publication Number | Publication Date |
|---|---|
| WO2007013086A1 true WO2007013086A1 (en) | 2007-02-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2005/000248 WO2007013086A1 (en) | 2005-07-26 | 2005-07-26 | Novel polymorphs of tenofovir disoproxil fumarate |
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| Country | Link |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008140302A1 (en) * | 2007-05-14 | 2008-11-20 | Ultimorphix Technologies B.V. | Polymorphic forms of tenofovir disoproxil fumarate |
| WO2008143500A1 (en) * | 2007-05-22 | 2008-11-27 | Ultimorphix Technologies B.V. | Tenofovir disoproxil hemi-fumaric acid co-crystal |
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| WO2009074351A3 (en) * | 2007-12-12 | 2009-11-12 | Ultimorphix Technologies B.V. | Solid forms of tenofovir disoproxil |
| CN101781335A (en) * | 2010-03-04 | 2010-07-21 | 福建广生堂药业有限公司 | New tenofovir disoproxil fumarate crystal and preparation method thereof |
| WO2010142761A1 (en) * | 2009-06-10 | 2010-12-16 | Ultimorphix Technologies B.V. | The succinate of tenofovir disoproxil |
| JP2011518815A (en) * | 2008-04-25 | 2011-06-30 | シプラ・リミテッド | Crystalline form of tenofovir disoproxil and process for producing the same |
| WO2012027972A1 (en) * | 2010-08-30 | 2012-03-08 | 杭州和素化学技术有限公司 | TENOFOVIR DISOPROXIL FUMARATE α-CRYSTAL FORM, PREPARATION METHOD AND APPLICATION THEREOF |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2015051875A1 (en) | 2013-10-09 | 2015-04-16 | Zentiva, K.S. | Dihydrogenphosphate salt of tenofovir disoproxil |
| US9296769B2 (en) | 2011-08-16 | 2016-03-29 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN109867696A (en) * | 2017-12-04 | 2019-06-11 | 国药集团国瑞药业有限公司 | A kind of tenofovir dipivoxil tripolymer compound, preparation method and application |
| CN110372748A (en) * | 2018-04-12 | 2019-10-25 | 湖南千金湘江药业股份有限公司 | Amorphous half tenofovir disoproxil fumarate of one kind and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
-
2005
- 2005-07-26 WO PCT/IN2005/000248 patent/WO2007013086A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008140302A1 (en) * | 2007-05-14 | 2008-11-20 | Ultimorphix Technologies B.V. | Polymorphic forms of tenofovir disoproxil fumarate |
| WO2008143500A1 (en) * | 2007-05-22 | 2008-11-27 | Ultimorphix Technologies B.V. | Tenofovir disoproxil hemi-fumaric acid co-crystal |
| JP2010527996A (en) * | 2007-05-22 | 2010-08-19 | ウルティモルフィクス・テクノロジーズ・ベー・フェー | Tenofovir disoproxil-hemifumarate co-crystal |
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| WO2009074351A3 (en) * | 2007-12-12 | 2009-11-12 | Ultimorphix Technologies B.V. | Solid forms of tenofovir disoproxil |
| CN101918418A (en) * | 2007-12-12 | 2010-12-15 | 阿尔迪默菲克斯技术有限责任公司 | Solid forms of tenofovir disoproxil |
| JP2011518815A (en) * | 2008-04-25 | 2011-06-30 | シプラ・リミテッド | Crystalline form of tenofovir disoproxil and process for producing the same |
| WO2010142761A1 (en) * | 2009-06-10 | 2010-12-16 | Ultimorphix Technologies B.V. | The succinate of tenofovir disoproxil |
| CN101781335A (en) * | 2010-03-04 | 2010-07-21 | 福建广生堂药业有限公司 | New tenofovir disoproxil fumarate crystal and preparation method thereof |
| WO2012027972A1 (en) * | 2010-08-30 | 2012-03-08 | 杭州和素化学技术有限公司 | TENOFOVIR DISOPROXIL FUMARATE α-CRYSTAL FORM, PREPARATION METHOD AND APPLICATION THEREOF |
| US9296769B2 (en) | 2011-08-16 | 2016-03-29 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
| EP2744810B1 (en) | 2011-08-16 | 2016-10-05 | Gilead Sciences, Inc. | Tenofovir alafenamide hemifumarate |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| WO2015051875A1 (en) | 2013-10-09 | 2015-04-16 | Zentiva, K.S. | Dihydrogenphosphate salt of tenofovir disoproxil |
| CN109867696A (en) * | 2017-12-04 | 2019-06-11 | 国药集团国瑞药业有限公司 | A kind of tenofovir dipivoxil tripolymer compound, preparation method and application |
| CN110372748A (en) * | 2018-04-12 | 2019-10-25 | 湖南千金湘江药业股份有限公司 | Amorphous half tenofovir disoproxil fumarate of one kind and preparation method thereof |
| CN110372748B (en) * | 2018-04-12 | 2023-04-07 | 湖南千金湘江药业股份有限公司 | Amorphous tenofovir disoproxil hemifumarate and preparation method thereof |
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