WO2015186139A2 - Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same - Google Patents
Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same Download PDFInfo
- Publication number
- WO2015186139A2 WO2015186139A2 PCT/IN2015/000225 IN2015000225W WO2015186139A2 WO 2015186139 A2 WO2015186139 A2 WO 2015186139A2 IN 2015000225 W IN2015000225 W IN 2015000225W WO 2015186139 A2 WO2015186139 A2 WO 2015186139A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tenofovir disoproxil
- suitable solvent
- disoproxil oxalate
- oxalate form
- isopropanol
- Prior art date
Links
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 title claims abstract description 174
- 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 title claims abstract description 147
- 229960001355 tenofovir disoproxil Drugs 0.000 title claims abstract description 146
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 62
- 239000002904 solvent Substances 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 23
- 235000006408 oxalic acid Nutrition 0.000 claims description 21
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 19
- 150000001298 alcohols Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 238000002411 thermogravimetry Methods 0.000 claims description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 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 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 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 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229960004556 tenofovir Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 description 10
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 238000004313 potentiometry Methods 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- -1 organic acid salts Chemical class 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- PHDAZHGCTGTQAS-UHFFFAOYSA-M dimethyl-tetradecyl-(3-trimethoxysilylpropyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CCC[Si](OC)(OC)OC PHDAZHGCTGTQAS-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- GZMYLSJUNSCMTD-MOPGFXCFSA-N OC[C@@H](C)NC1=NC(=CC(=C1)C=1C=C(C=CC=1C)NC(=O)N1C[C@@H](CC1)CC(F)(F)F)N1CCOCC1 Chemical compound OC[C@@H](C)NC1=NC(=CC(=C1)C=1C=C(C=CC=1C)NC(=O)N1C[C@@H](CC1)CC(F)(F)F)N1CCOCC1 GZMYLSJUNSCMTD-MOPGFXCFSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 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
- 239000013557 residual solvent Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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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
Definitions
- the present invention relates to novel polymorphs of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical composition comprising the same.
- Tenofovir disoproxil is a highly potent antiviral agent, particularly for the prophylaxis or therapy of retroviral infections and belongs to a class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase an enzyme crucial to viral production in HIV-infected people.
- NRTI Nucleoside Reverse Transcriptase Inhibitors
- Tenofovir disoproxil is chemically known as 9- [(R)-2 [ [bis [ [(isopropoxycarbonyl)oxy] methoxy] phosphinyl]methoxy]propyl] adenine and represented by the following structural formula-I.
- Tenofovir disoproxil is approved as its fumarate salt and is available in the market under the brand name VIREAD® in the form of 300 mg of oral tablets and in combination with other antiviral agents.
- U.S. Patent No. 5,922,695 discloses phosphonomethoxy nucleotide analogs such as tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof.
- the '695 paten further discloses a process for the preparation of tenofovir disoproxil as its fumarate salt.
- PCT publication number WO 2009074351 discloses solid forms of weak organic acid salts of tenofovir disoproxil such as succinic acid (TDSU ULT-1, TDSU ULT-2, TDSU ULT-3 & TDSU ULT-4), tartaric acid (TDTA ULT-1, TDTA ULT-2 & TDTA ULT-3), saccharic acid (TDSA ULT-1, TDSA ULT-2 & TDSA ULT-3), citric acid (TDCI ULT-1), oxalic acid (TDOX ULT-1, TDOX ULT-2, TDOX ULT-3 & TDOX ULT-4), salicylic acid (TDSY ULT-1) and processes for their preparation.
- succinic acid TDSU ULT-1, TDSU ULT-2, TDSU ULT-3 & TDSU ULT-4
- tartaric acid TDTA ULT-1, TDTA ULT-2 & TDTA ULT-3
- saccharic acid TDSA ULT-1
- Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.
- Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
- New polymorphic forms or solvates of a pharmaceutically useful compound may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
- New polymorphic forms of the tenofovir disoproxil oxalate have now been discovered and have been designated as tenofovir disoproxil oxalate Form-Ll and Form-L2.
- the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical compositions comprising one or more of the novel polymorphic forms of tenofovir disoproxil oxalate.
- the present invention provides tenofovir disoproxil oxalate Form-Ll.
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
- PXRD powder X-Ray diffraction
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.86, 7.54, 7.95, 9.00, 10.02, 11.69, 12.96, 14.88, 15.66, 16.01, 16.31, 16.61, 16.95, 17.22, 17.58, 18.17, 18.40, 18.74, 19.60, 20.39, 20.60, 21.18, 22.07, 22.84, 23.08, 23.60, 24.17, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09, 30.48, 30.83, 31.62, 32.52, 33.74, 34.40 and 35.00 ⁇ 0.2° 2 ⁇ .
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 9.00, 10.02, 12.96, 14.88, 18.17, 18.40, 21.18, 22.84, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09 and 31.62 ⁇ 0.2° 2 ⁇ .
- the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-Ll, comprising:
- step b) adding oxalic acid to step a) solution at a suitable temperature
- the present invention provides a process for purification of tenofovir disoproxil oxalate, comprising:
- the present invention provides tenofovir disoproxil oxalate Form-L2.
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
- PXRD powder X-Ray diffraction
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.90, 7.46, 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 15.89, 16.3, 16.66, 17.00, 17.62, 18.02, 18.50, 19.44, 19.96, 20.37, 21.17, 21.95, 22.61, 23.51, 24.02, 24.59, 25.15, 25.63, 25.95, 26.71, 27.35, 28.14, 29.13, 30.27, 30.68, 31.11, 32.23, 32.79, 33.89, 34.52 and 35.15 ⁇ 0.2° 2 ⁇ .
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 19.96, 22.61, 25.15, 27.35, 28.14, 30.68, 31.11 and 32.23 ⁇ 0.2° 2 ⁇ .
- the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-L2, comprising:
- step ii) adding oxalic acid to step i) solution at a suitable temperature
- step iv) slurrying the obtained wet solid in a suitable solvent and isolating tenofovir disoproxil oxalate Form-L2; wherein the suitable solvent in step i) is selected from the group consisting of C 1-4 alcohols, water and mixtures thereof and the suitable solvent in step iv) is selected from the group consisting of C alcohols, esters, ketones, water and mixture thereof.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the novel polymorphic forms of tenofovir disoproxil oxalate described above and at least one pharmaceutically acceptable excipient.
- Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of tenofovir disoproxil oxalate Form-L 1.
- Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of tenofovir disoproxil oxalate Form-L 1.
- Figure 3 is the characteristic thermo gravimetric analysis (TGA) of tenofovir disoproxil oxalate Form-L 1.
- Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of tenofovir disoproxil oxalate Form-L2.
- Figure 5 is the characteristic differential scanning calorimetric (DSC) thermogram of tenofovir disoproxil oxalate Form-L2.
- the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical compositions comprising one or more of such polymorphic forms.
- polymorphic forms of tenofovir disoproxil oxalate of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
- the polymorphic forms of tenofovir disoproxil oxalate of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, Differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA).
- XRPD X-ray powder diffraction
- DSC Differential scanning calorimetry
- TGA thermo gravimetric analysis
- the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate; which are designated as tenofovir disoproxil oxalate Form-Ll and tenofovir disoproxil oxalate Form-L2.
- the present invention provides tenofovir disoproxil oxalate Form-Ll. In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
- PXRD powder X-Ray diffraction
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.86, 7.54, 7.95, 9.00, 10.02, 11.69, 12.96, 14.88, 15.66, 16.01, 16.31, 16.61, 16.95, 17.22, 17.58, 18.17, 18.40, 18.74, 19.60, 20.39, 20.60, 21.18, 22.07, 22.84,
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 9.00, 10.02, 12.96, 14.88, 18.17, 18.40, 21.18, 22.84, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09 and 31.62 ⁇ 0.2° 2 ⁇ .
- the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.
- DSC differential scanning calorimetry
- TGA thermo gravimetric analysis
- the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-Ll , comprising:
- providing a solution of tenofovir disoproxil first includes dissolving tenofovir disoproxil in a suitable solvent at a suitable temperature ranging from about 25°C to reflux temperature of the solvent, preferably at about 35°C to about 50°C.
- the suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and the like; water and mixtures thereof; preferably mixture of alcohol and water; more preferably mixture of isopropanol and water.
- the oxalic acid can be added either as a solution in a suitable solvent such as alcohol solvent selected from methanol, ethanol, isopropanol and the like and mixtures thereof or it may be added directly to the solution of step a) at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent, preferably at about 40°C to about 45°C.
- a suitable temperature ranging from about 25 °C to reflux temperature of the solvent, preferably at about 40°C to about 45°C.
- the oxalic acid used may be in anhydrous or hydrated form.
- the solution of oxalic acid in isopropanol is added to a solution of tenofovir disoproxil at a temperature of about 40°C to about 45°C.
- the isolation of tenofovir disoproxil oxalate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature from about 30°C or less and filtering the tenofovir disoproxil oxalate Form-Ll.
- the present invention provides a process for purification of tenofovir disoproxil oxalate, comprising:
- the starting tenofovir disoproxil oxalate can be prepared by the processes known in the art or it can be prepared according to the process described just as above; preferably, tenofovir disoproxil oxalate Form-Ll .
- the aforementioned process involves slurrying the tenofovir disoproxil oxalate in a suitable solvent for a sufficient period of time of about 30 minutes to about 48 hours at a temperature ranging from about 25°C to about 35°C.
- the suitable solvent used herein for slurrying is selected from the group consisting of alcohols, ethers, ketones and esters; preferably selected from ethanol, isopropanol, tetrahydrofuran, methyl isobutyl ketone, acetone, methyl tertiary butyl ether, dioxane, n-butyl acetate, ethyl acetate and the like and mixtures thereof; more preferably ethyl acetate.
- the resultant pure tenofovir disoproxil oxalate can be isolated by known techniques such as filtration followed by drying under vacuum to obtain tenofovir disoproxil oxalate Form-Ll .
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
- PXRD powder X-Ray diffraction
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.90, 7.46, 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 15.89, 16.3, 16.66, 17.00, 17.62, 18.02, 18.50, 19.44, 19.96, 20.37; 21.17, 21.95, 22.61, 23.51, 24.02, 24.59, 25.15, 25.63, 25.95, 26.71, 27.35, 28.14, 29.13, 30.27, 30.68, 31.11, 32.23, 32.79, 33.89, 34.52 and 35.15 ⁇ 0.2° 2 ⁇ .
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 19.96, 22.61, 25.15, 27.35, 28.14, 30.68, 31.11 and 32.23 ⁇ 0.2° 2 ⁇ .
- the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 5.
- DSC differential scanning calorimetry
- the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-L2, comprising:
- step ii) adding oxalic acid to step i) solution at a suitable temperature
- step iv) slurrying the obtained wet solid in a suitable solvent and isolating tenofovir disoproxil oxalate Form-L2; wherein the suitable solvent in step i) is selected from the group consisting of C 1-4 alcohols, water and mixtures thereof and the suitable solvent in step iv) is selected from the group consisting of C 1-4 alcohols, esters, ketones, water and mixture thereof.
- providing a solution of tenofovir disoproxil includes dissolving tenofovir disoproxil in a suitable solvent at a suitable temperature ranging from about 25°C to reflux temperature of the solvent, preferably at about 35°C to about 50°C.
- the suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol and the like; water and mixtures thereof; preferably mixture alcohol and water; more preferably isopropanol and water.
- the oxalic acid can be added either as a solution in a suitable solvent such as alcohol solvent as defined above or it may be added directly to the solution of step i) at a suitable temperature ranging from 25°C to reflux temperature of the solvent, preferably at about 40°C to about 45°C.
- the oxalic acid used may be in anhydrous or hydrated form.
- the solution of oxalic acid in isopropanol was added to a solution of tenofovir disoproxil at a temperature of about 40°C to about 45°C.
- step iii) of the forgoing process cooling the reaction mass at a temperature from about 30°C or less and filtering the precipitated solid.
- step iv) of the forgoing process the wet solid obtained in step iii) was slurried in a suitable solvent selected from alcohols, esters, ketones, water and mixtures thereof; preferably ethyl acetate or methyl ethyl ketone for a sufficient period of time at a temperature ranges from about 25°C to about 35°C and isolating the tenofovir disoproxil oxalate Form-L2 by filtration.
- the tenofovir disoproxil. which is used as a starting material is known in the art and can be prepared by any known method.
- the starting tenofovir disoproxil may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of tenofovir disoproxil, including various solvates and hydrates known in the art.
- the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more and more preferably 99.5% or more.
- novel polymorphs of tenofovir disoproxil oxalate described above are stable under ambient conditions; further novel polymorphs of tenofovir disoproxil oxalate described above having higher dissolution rate compared to known solid forms of tenofovir disoproxil and its salts.
- compositions containing one or more polymorphic forms of tenofovir disoproxil oxalate described above such as pharmaceutical dosage forms.
- Such pharmaceutical dosage forms may include one or more excipients, including, without limitation, binders, fillers, lubricants, emulsiflers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other conventional excipients and additives.
- compositions of the invention can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art.
- additional formulation additives and agents will often be biologically inactive and can be administered to humans without causing deleterious side effects or interactions.
- novel polymorphs of tenofovir disoproxil oxalate of the present invention have an increased solubility as compared to the commercially available tenofovir disoproxil fumarate and tenofovir disoproxil.
- Table I shows comparison study for solubility of tenofovir disoproxil oxalate of the invention and tenofovir disoproxil fumarate as well as tenofovir disoproxil.
- the present invention provides tenofovir disoproxil oxalate, obtained by the process described herein, as analyzed using the high performance liquid chromatography ("HPLC") with the conditions described below:
- reaction mass was then washed with cyclohexane (400 mL x 2) and cooled to 12 ⁇ 3°C.
- Methylene chloride 500 ml was added to the reaction mass and stirred for 1 hr.
- the precipitated material was filtered off and the filtrate washed with water (1000 mL).
- Organic and aqueous layer from the filtrate was separated.
- Water (1000 ml) was added to the organic layer and pH was adjusted to 6.5-7.5 with 10% ammonia solution. The layers were separated and the organic layer was concentrated under vacuum at below 35°C, to afford Tenofovir disoproxil as residue.
- Tenofovir disoproxil 200 g; obtained as per Reference example was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 mins. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 mins. Ethyl acetate (1000 mL) was added to the dried solid and slurried for an hour at 30 ⁇ 5°C. The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll.
- Oxalic acid content 15.3 %w/w (by potentiometry method)
- Tenofovir disoproxil 200 g; obtained as per Reference example was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered. Ethyl acetate (1000 mL) was added to the obtained wet solid and slurried for an hour at 30 ⁇ 5°C to get tenofovir disoproxil oxalate Form-L2.
- Oxalic acid content 15.2 %w/w (by potentiometry method)
- Tenofovir disoproxil 200 g; obtained as per Reference example was dissolved in a mixture of isopropanol (1000 mL) and cyclohexane (1000 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min.
- Tenofovir disoproxil 50 g; obtained as per Reference example was dissolved in isopropanol (500 mL) and water (25 mL) and heated to 43 ⁇ 3°C. A solution of anhydrous oxalic acid (6.2 g) in isopropanol (125 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min.
- the solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll .
- Oxalic acid content 15.1 %w/w (by potentiometry method)
- EXAMPLE 5-12 Preparation and purification of Tenofovir disoproxil oxalate: Tenofovir disoproxil (10 g; obtained as per Reference example) was dissolved in isopropanol (100 mL) and water (5 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (1.76 g) in isopropanol (25 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min.
- Tenofovir disoproxil (10 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (100 mL) and water (5 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (1.76 gm) isopropanol (25 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Methyl ethyl ketone (25 mL) was added to the obtained solid and slurried for 48 hr at 30 ⁇ 5°C to get Tenofovir disoproxil oxalate Form-L2.
- Tenofovir disoproxil 200 g; obtained as per Reference example was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (35.1 gm) in isopropanol (500 mL) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 min. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under vacuum at 40 ⁇ 3°C to get the titled compound.
- the tenofovir disoproxil oxalate crystalline Form LI obtained as per example-14 was purified by slurrying in ethyl acetate (10 volumes, with 20%, 40% isopropanol) and in ethyl acetate (10V) as described in the following table, at 30 ⁇ 5°C for lhr to afford the pure Form-Ll .
- Tenofovir disoproxil (5 kg; obtained as per Reference example) was dissolved in a mixture of isopropanol (50 lit) and water (2.5 lit) and heated to 43 ⁇ 3°C. A solution of oxalic acid dihydrate (0.88 kg) in isopropanol (12.5 lit) was added to the reaction mass at 43 ⁇ 3°C and stirred for 60 mins. The reaction mass was then cooled to 30 ⁇ 5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Ethyl acetate (25 lit) was added to the dried solid and slurried for an hour at 30 ⁇ 5°C for 60 min. The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll.
- Oxalic acid content 15.3 %w/w (by potentiometry method)
- Example-20 Comparison of physical properties of Tenofovir disoproxil oxalate and Tenofovir disoproxil fumarate:
- Table-2 and Table-3 respectively shows indicative and accelerated thermodynamic stability study details of Tenofovir disoproxil oxalate Form-Ll (all impurities are listed in US monograph and measured by %w/w by HPLC).
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Abstract
The present invention relates to novel polzmorphs of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical composition comprising the same.
Description
"NOVEL POLYMORPHS OF TENOFOVIR DISOPROXIL OXALATE AND PROCESS FOR PREPARATION OF THE SAME"
PRIORITY: This application claims the benefit under Indian Provisional Application No. 2687/CHE/2014 filed on June 2, 2014 entitled "Novel polymorphs of tenofovir disoproxil oxalate and process for preparation of the same", the content of which is incorporated by reference herein. FIELD OF THE INVENTION:
The present invention relates to novel polymorphs of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical composition comprising the same. BACKGROUND OF THE INVENTION:
Tenofovir disoproxil is a highly potent antiviral agent, particularly for the prophylaxis or therapy of retroviral infections and belongs to a class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTI) which blocks reverse transcriptase an enzyme crucial to viral production in HIV-infected people. Tenofovir disoproxil is chemically known as 9- [(R)-2 [ [bis [ [(isopropoxycarbonyl)oxy] methoxy] phosphinyl]methoxy]propyl] adenine and represented by the following structural formula-I.
Formula-I
Tenofovir disoproxil is approved as its fumarate salt and is available in the market under the brand name VIREAD® in the form of 300 mg of oral tablets and in combination with other antiviral agents.
U.S. Patent No. 5,922,695 ("the '695 patent") discloses phosphonomethoxy nucleotide analogs such as tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof. The '695 paten further discloses a process for the preparation of tenofovir disoproxil as its fumarate salt.
PCT publication number WO 2009074351 ("the '351 publication") discloses solid forms of weak organic acid salts of tenofovir disoproxil such as succinic acid (TDSU ULT-1, TDSU ULT-2, TDSU ULT-3 & TDSU ULT-4), tartaric acid (TDTA ULT-1, TDTA ULT-2 & TDTA ULT-3), saccharic acid (TDSA ULT-1, TDSA ULT-2 & TDSA ULT-3), citric acid (TDCI ULT-1), oxalic acid (TDOX ULT-1, TDOX ULT-2, TDOX ULT-3 & TDOX ULT-4), salicylic acid (TDSY ULT-1) and processes for their preparation. All the above solid forms of tenofovir disoproxil salts were characterized by PXRD, DSC and TGA analytic techniques. PCT publication number WO2015051874 ("the '874 publication") discloses a process for the preparation of tenofovir disoproxil oxalate by treating the solution of tenofovir disoproxil in toluene with oxalic acid.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
The discovery of new polymorphic forms or solvates of a pharmaceutically useful compound, like tenofovir, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms of the tenofovir disoproxil oxalate have now been discovered and have been designated as tenofovir disoproxil oxalate Form-Ll and Form-L2.
SUMMARY OF THE INVENTION:
The present invention provides novel polymorphic forms of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical compositions comprising one or more of the novel polymorphic forms of tenofovir disoproxil oxalate.
Accordingly in one embodiment the present invention provides tenofovir disoproxil oxalate Form-Ll. In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.86, 7.54, 7.95, 9.00, 10.02, 11.69, 12.96, 14.88, 15.66, 16.01, 16.31, 16.61, 16.95, 17.22, 17.58, 18.17, 18.40, 18.74, 19.60, 20.39, 20.60, 21.18, 22.07, 22.84, 23.08, 23.60, 24.17, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09, 30.48, 30.83, 31.62, 32.52, 33.74, 34.40 and 35.00 ± 0.2° 2Θ.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 9.00, 10.02, 12.96, 14.88, 18.17, 18.40, 21.18, 22.84, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09 and 31.62 ± 0.2° 2Θ.
In another embodiment, the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-Ll, comprising:
a) providing a solution of tenofovir disoproxil in a suitable solvent,
b) adding oxalic acid to step a) solution at a suitable temperature, and
c) isolating tenofovir disoproxil oxalate Form-Ll; wherein the suitable solvent is selected from the group consisting of alcohols, hydrocarbons, water and mixtures thereof.
In another embodiment, the present invention provides a process for purification of tenofovir disoproxil oxalate, comprising:
1) providing a suspension of tenofovir disoproxil oxalate in a suitable solvent and slurrying the suspension at a suitable temperature; and
2) isolating the pure tenofovir disoproxil oxalate; wherein the suitable solvent is selected from the group consisting of C1-4 alcohols, esters, ethers, ketones and mixtures thereof.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.90, 7.46, 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 15.89, 16.3, 16.66, 17.00, 17.62, 18.02, 18.50, 19.44, 19.96, 20.37, 21.17, 21.95, 22.61, 23.51, 24.02, 24.59, 25.15, 25.63, 25.95, 26.71, 27.35, 28.14, 29.13, 30.27, 30.68, 31.11, 32.23, 32.79, 33.89, 34.52 and 35.15 ± 0.2° 2Θ. In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 19.96, 22.61, 25.15, 27.35, 28.14, 30.68, 31.11 and 32.23 ± 0.2° 2Θ. In another embodiment, the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-L2, comprising:
i) providing a solution of tenofovir disoproxil in a suitable solvent ,
ii) adding oxalic acid to step i) solution at a suitable temperature,
iii) cooling the reaction mass and filtering the solid; and
iv) slurrying the obtained wet solid in a suitable solvent and isolating tenofovir disoproxil oxalate Form-L2; wherein the suitable solvent in step i) is selected from the group consisting of C1-4 alcohols, water and mixtures thereof and the suitable solvent in step iv) is selected from the group consisting of C alcohols, esters, ketones, water and mixture thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising the novel polymorphic forms of tenofovir disoproxil oxalate described above and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of tenofovir disoproxil oxalate Form-L 1.
Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of tenofovir disoproxil oxalate Form-L 1.
Figure 3 is the characteristic thermo gravimetric analysis (TGA) of tenofovir disoproxil oxalate Form-L 1. Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of tenofovir disoproxil oxalate Form-L2.
Figure 5 is the characteristic differential scanning calorimetric (DSC) thermogram of tenofovir disoproxil oxalate Form-L2.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides novel polymorphic forms of tenofovir disoproxil oxalate, process for its preparation and pharmaceutical compositions comprising one or more of such polymorphic forms.
The polymorphic forms of tenofovir disoproxil oxalate of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
The polymorphic forms of tenofovir disoproxil oxalate of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, Differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA).
The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer equipped with a Cu-anode ([λ] = 1.54 Angstrom), X-ray source operated at 40kV, 30 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range = 3-50°2θ; step width = 0.020°; and scan speed = 2 minute.
All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using
DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
All TGA data reported herein were analyzed using TGA Q500 V 20.2 build 27 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C.
In one embodiment, the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate; which are designated as tenofovir disoproxil oxalate Form-Ll and tenofovir disoproxil oxalate Form-L2.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll. In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.86, 7.54, 7.95, 9.00, 10.02, 11.69, 12.96, 14.88, 15.66, 16.01, 16.31, 16.61, 16.95, 17.22, 17.58, 18.17, 18.40, 18.74, 19.60, 20.39, 20.60, 21.18, 22.07, 22.84,
23.08, 23.60, 24.17, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79,
30.09, 30.48, 30.83, 31.62, 32.52, 33.74, 34.40 and 35.00 ± 0.2° 20.
-
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 9.00, 10.02, 12.96, 14.88, 18.17, 18.40, 21.18, 22.84, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09 and 31.62 ± 0.2° 2Θ.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2. In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-Ll characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.
In another embodiment, the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-Ll , comprising:
a) providing a solution of tenofovir disoproxil in a suitable solvent ,
b) adding oxalic acid to step a) solution at a suitable temperature, and c) isolating tenofovir disoproxil oxalate Form-Ll; wherein the suitable solvent is selected from the group consisting of alcohols, hydrocarbons, water and mixtures thereof.
In step a) of the forgoing process, providing a solution of tenofovir disoproxil first includes dissolving tenofovir disoproxil in a suitable solvent at a suitable temperature ranging from about 25°C to reflux temperature of the solvent, preferably at about 35°C to about 50°C. The suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane and the like; water and mixtures thereof; preferably mixture of alcohol and water; more preferably mixture of isopropanol and water.
In step b) of the forgoing process, the oxalic acid can be added either as a solution in a suitable solvent such as alcohol solvent selected from methanol, ethanol, isopropanol and the like and mixtures thereof or it may be added directly to the solution of step a) at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent, preferably at about 40°C to about 45°C. Further the oxalic acid used may be in anhydrous or hydrated form. Preferably, the solution of oxalic acid in isopropanol is added to a solution of tenofovir disoproxil at a temperature of about 40°C to about 45°C.
In step c) of the forgoing process, the isolation of tenofovir disoproxil oxalate may be carried out by the methods known in the art, for example, cooling the reaction mass at a temperature from about 30°C or less and filtering the tenofovir disoproxil oxalate Form-Ll.
In another embodiment, the present invention provides a process for purification of tenofovir disoproxil oxalate, comprising:
1) providing a suspension of tenofovir disoproxil oxalate in a suitable solvent and slurrying the suspension at a suitable temperature; and
2) isolating the pure tenofovir disoproxil oxalate; wherein the suitable solvent is selected from the group consisting of C alcohols, esters, ethers, ketones and mixtures thereof. The starting tenofovir disoproxil oxalate can be prepared by the processes known in the art or it can be prepared according to the process described just as above; preferably, tenofovir disoproxil oxalate Form-Ll .
The aforementioned process involves slurrying the tenofovir disoproxil oxalate in a suitable solvent for a sufficient period of time of about 30 minutes to about 48 hours at a temperature ranging from about 25°C to about 35°C. The suitable solvent used herein for
slurrying is selected from the group consisting of alcohols, ethers, ketones and esters; preferably selected from ethanol, isopropanol, tetrahydrofuran, methyl isobutyl ketone, acetone, methyl tertiary butyl ether, dioxane, n-butyl acetate, ethyl acetate and the like and mixtures thereof; more preferably ethyl acetate. The resultant pure tenofovir disoproxil oxalate can be isolated by known techniques such as filtration followed by drying under vacuum to obtain tenofovir disoproxil oxalate Form-Ll .
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 3.90, 7.46, 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 15.89, 16.3, 16.66, 17.00, 17.62, 18.02, 18.50, 19.44, 19.96, 20.37; 21.17, 21.95, 22.61, 23.51, 24.02, 24.59, 25.15, 25.63, 25.95, 26.71, 27.35, 28.14, 29.13, 30.27, 30.68, 31.11, 32.23, 32.79, 33.89, 34.52 and 35.15 ± 0.2° 2Θ.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 19.96, 22.61, 25.15, 27.35, 28.14, 30.68, 31.11 and 32.23 ± 0.2° 2Θ.
In another embodiment, the present invention provides tenofovir disoproxil oxalate Form-L2 characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 5.
In another embodiment, the present invention provides a process for preparation of tenofovir disoproxil oxalate Form-L2, comprising:
i) providing a solution of tenofovir disoproxil in a suitable solvent,
ii) adding oxalic acid to step i) solution at a suitable temperature,
iii) cooling the reaction mass and filtering the solid; and
iv) slurrying the obtained wet solid in a suitable solvent and isolating tenofovir disoproxil oxalate Form-L2; wherein the suitable solvent in step i) is selected from the group consisting of C1-4 alcohols, water and mixtures thereof and the suitable solvent in step iv) is selected from the group consisting of C 1-4 alcohols, esters, ketones, water and mixture thereof.
In step i) of the forgoing process, providing a solution of tenofovir disoproxil includes dissolving tenofovir disoproxil in a suitable solvent at a suitable temperature ranging from about 25°C to reflux temperature of the solvent, preferably at about 35°C to about
50°C. The suitable solvent used is selected from alcohols such as methanol, ethanol, isopropanol and the like; water and mixtures thereof; preferably mixture alcohol and water; more preferably isopropanol and water. In step ii) of the forgoing process, the oxalic acid can be added either as a solution in a suitable solvent such as alcohol solvent as defined above or it may be added directly to the solution of step i) at a suitable temperature ranging from 25°C to reflux temperature of the solvent, preferably at about 40°C to about 45°C. The oxalic acid used may be in anhydrous or hydrated form. Preferably, the solution of oxalic acid in isopropanol was added to a solution of tenofovir disoproxil at a temperature of about 40°C to about 45°C.
In step iii) of the forgoing process, cooling the reaction mass at a temperature from about 30°C or less and filtering the precipitated solid. In step iv) of the forgoing process, the wet solid obtained in step iii) was slurried in a suitable solvent selected from alcohols, esters, ketones, water and mixtures thereof; preferably ethyl acetate or methyl ethyl ketone for a sufficient period of time at a temperature ranges from about 25°C to about 35°C and isolating the tenofovir disoproxil oxalate Form-L2 by filtration.
As used herein above, the tenofovir disoproxil. which is used as a starting material is known in the art and can be prepared by any known method. The starting tenofovir disoproxil may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of tenofovir disoproxil, including various solvates and hydrates known in the art.
In another embodiment, the present invention provides novel polymorphic forms of tenofovir disoproxil oxalate having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more and more preferably 99.5% or more.
The novel polymorphs of tenofovir disoproxil oxalate described above are stable under ambient conditions; further novel polymorphs of tenofovir disoproxil oxalate described above having higher dissolution rate compared to known solid forms of tenofovir disoproxil and its salts.
Other embodiments of the invention include composition containing one or more polymorphic forms of tenofovir disoproxil oxalate described above, such as pharmaceutical dosage forms. Such pharmaceutical dosage forms may include one or more excipients, including, without limitation, binders, fillers, lubricants, emulsiflers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other conventional excipients and additives. The
compositions of the invention can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art. These additional formulation additives and agents will often be biologically inactive and can be administered to humans without causing deleterious side effects or interactions.
The novel polymorphs of tenofovir disoproxil oxalate of the present invention have an increased solubility as compared to the commercially available tenofovir disoproxil fumarate and tenofovir disoproxil. Table I shows comparison study for solubility of tenofovir disoproxil oxalate of the invention and tenofovir disoproxil fumarate as well as tenofovir disoproxil.
The present invention provides tenofovir disoproxil oxalate, obtained by the process described herein, as analyzed using the high performance liquid chromatography ("HPLC") with the conditions described below:
The following examples are provided by way of illustration only, and are not intended to be limiting of the present invention. Further, the present invention covers all the possible combinations of particular and preferred embodiments indicated herein.
EXAMPLES:
Reference Example: Preparation of Tenofovir Disoproxil:
A mixture of tenofovir (100 g) in cyclohexane (800 mL) was heated to 83±3°C in a Dean-Stark apparatus under azeotropic condition. The reaction mass was cooled to 65°C and then concentrated under vacuum at below 65°C. The obtained residue was cooled to ambient temperature then N-methylpyrrolidone (300 mL), triethylamine (64 g) and tetrabutylammonium bromide (53 g) were added to it. The reaction mass was heated to 52±3°C, chloromethyl isopropyl carbonate (250 g) was added to it at same temperature and stirred for 2 hrs. After the reaction completion, the reaction mass was cooled to
22±3°C. The reaction mass was then washed with cyclohexane (400 mL x 2) and cooled to 12±3°C. Methylene chloride (500 ml) was added to the reaction mass and stirred for 1 hr. The precipitated material was filtered off and the filtrate washed with water (1000 mL). Organic and aqueous layer from the filtrate was separated. Water (1000 ml) was added to the organic layer and pH was adjusted to 6.5-7.5 with 10% ammonia solution. The layers were separated and the organic layer was concentrated under vacuum at below 35°C, to afford Tenofovir disoproxil as residue.
Yield: 210 g EXAMPLE-1: Preparation of Tenofovir disoproxil oxalate Form-Ll:
Tenofovir disoproxil (200 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43±3°C and stirred for 60 mins. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 mins. Ethyl acetate (1000 mL) was added to the dried solid and slurried for an hour at 30±5°C. The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll.
Yield: 110 g
HPLC purity: 99.6%
Oxalic acid content: 15.3 %w/w (by potentiometry method)
The XRPD is set forth in Figure 1 EXAMPLE-2: Preparation of Tenofovir disoproxil oxalate Form-L2:
Tenofovir disoproxil (200 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered. Ethyl acetate (1000 mL) was added to the obtained wet solid and slurried for an hour at 30±5°C to get tenofovir disoproxil oxalate Form-L2.
Yield: 106 g
HPLC purity: 99.65%
Oxalic acid content: 15.2 %w/w (by potentiometry method)
The XRPD is set forth in Figure 4.
EXAMPLE-3: Preparation of Tenofovir disoproxil oxalate Form-Ll:
Tenofovir disoproxil (200 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (1000 mL) and cyclohexane (1000 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (35.1 g) in isopropanol (500 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Isopropanol (1500 mL) and cyclohexane (1000 mL) was added to the dried solid and slurried at 30±5°C for 60 min. The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll .
Yield: 114g
HPLC purity: 99.4%
Oxalic acid content: 14.9 %w/w (by potentiometry method) EXAMPLE-4: Preparation of Tenofovir disoproxil oxalate Form-Ll :
Tenofovir disoproxil (50 g; obtained as per Reference example) was dissolved in isopropanol (500 mL) and water (25 mL) and heated to 43±3°C. A solution of anhydrous oxalic acid (6.2 g) in isopropanol (125 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min.
Ethyl acetate (250 mL) was added to the dried solid and slurried for an hour at 30±5°C.
The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll .
Yield: 22 g
HPLC purity: 99.6%
Oxalic acid content: 15.1 %w/w (by potentiometry method)
EXAMPLE 5-12: Preparation and purification of Tenofovir disoproxil oxalate: Tenofovir disoproxil (10 g; obtained as per Reference example) was dissolved in isopropanol (100 mL) and water (5 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (1.76 g) in isopropanol (25 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Thus obtained tenofovir disoproxil oxalate was purified by slurrying in different solvents (5 volumes) described in the following table, at 30±5°C for 48 hrs to afford the pure Tenofovir disoproxil oxalate.
7 5 g Methyl isobutyl ketone 3.0g Form-Ll
8 5 g Acetone 3.7g Form-Ll
9 5 g Methyl tertiary butyl ether 2.9g Form-Ll
10 5 g . Ethanol 3.5g Form-Ll
11 5 g Dioxane 1.8 g Form-Ll
12 5 g n-Butyl acetate 3.8g Form-Ll
Example-13: Preparation of Tenofovir disoproxil oxalate Foi
Tenofovir disoproxil (10 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (100 mL) and water (5 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (1.76 gm) isopropanol (25 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Methyl ethyl ketone (25 mL) was added to the obtained solid and slurried for 48 hr at 30±5°C to get Tenofovir disoproxil oxalate Form-L2.
Yield: 3.1 g
Oxalic acid content: 15.1 %w/w (by potentiometry method) Example-14: Preparation of Tenofovir disoproxil oxalate Form-Ll:
Tenofovir disoproxil (200 g; obtained as per Reference example) was dissolved in a mixture of isopropanol (2000 mL) and water (100 mL) and heated to 43±3°C. A solution of oxalic acid dihydrate (35.1 gm) in isopropanol (500 mL) was added to the reaction mass at 43±3°C and stirred for 60 min. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under vacuum at 40±3°C to get the titled compound.
Yield: 115 g
Oxalic acid content: 14.9% Example-15-17: Purification of Tenofovir disoproxil oxalate Form-Ll:
The tenofovir disoproxil oxalate crystalline Form LI obtained as per example-14 was purified by slurrying in ethyl acetate (10 volumes, with 20%, 40% isopropanol) and in ethyl acetate (10V) as described in the following table, at 30±5°C for lhr to afford the pure Form-Ll .
Tenofovir disoproxil (5 kg; obtained as per Reference example) was dissolved in a mixture of isopropanol (50 lit) and water (2.5 lit) and heated to 43±3°C. A solution of oxalic acid dihydrate (0.88 kg) in isopropanol (12.5 lit) was added to the reaction mass at 43±3°C and stirred for 60 mins. The reaction mass was then cooled to 30±5°C and stirred for another 3 hrs. The precipitated material was filtered and dried under suction for 30 min. Ethyl acetate (25 lit) was added to the dried solid and slurried for an hour at 30±5°C for 60 min. The solid obtained was filtered and dried to get Tenofovir disoproxil oxalate Form-Ll.
Yield: 1.09 w/w
HPLC purity: 99.7%
Oxalic acid content: 15.3 %w/w (by potentiometry method)
The XRPD is set forth in Figure 1
Example-1 : Solubility Comparison:
The solubility of tenofovir disoproxil oxalate of the present invention, tenofovir disoproxil (TD) and tenofovir disoproxil fumarate was tested in different media. The result shows that the solubility of tenofovir disoproxil oxalate of the present invention is greater. The solubility results are tabulated as follows:
Table-1: solubility comparison table
Example-20: Comparison of physical properties of Tenofovir disoproxil oxalate and Tenofovir disoproxil fumarate:
Table-2 and Table-3 respectively shows indicative and accelerated thermodynamic stability study details of Tenofovir disoproxil oxalate Form-Ll (all impurities are listed in US monograph and measured by %w/w by HPLC).
Table-2: Indicative stability (at 2-8°C)
ND: Not detected
Table-3: Accelerated stability (at 25±2°C/60±5%RH)
ND: Not detected
Claims
WE CLAIM:
Claim 1 : Tenofovir disoproxil oxalate Form-Ll characterized by a powder X-Ray diffraction pattern having one or more peaks at about 9.00, 10.02, 12.96, 14.88, 18.17, 18.40, 21.18, 22.84, 24.46, 24.73, 25.01, 25.63, 25.89, 26.70, 27.60, 28.51, 29.09, 29.79, 30.09 and 31.62 ± 0.2° 20..
Claim 2: Tenofovir disoproxil oxalate Form-Ll of claim 1 is further characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
Claim 3: Tenofovir disoproxil oxalate Form-Ll of claim 1 is further characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2. Claim 4: Tenofovir disoproxil oxalate Form-Ll of claim 1 is further characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.
Claim 5: A process for preparation of tenofovir disoproxil oxalate Form-Ll of claim 1, comprising:
a) providing a solution of tenofovir disoproxil in a suitable solvent,
b) adding oxalic acid to step a) solution at a suitable temperature, and
c) isolating tenofovir disoproxil oxalate Form-Ll; wherein the suitable solvent is selected from the group consisting of alcohols, hydrocarbons, water and mixtures thereof.
Claim 6: The process of claim 5, wherein the suitable solvent is selected from the group consisting of methanol, ethanol, isopropanol, hexane, heptane, cyclohexane, cycloheptane; water and mixtures thereof. Claim 7: The process of claim 5, wherein the suitable solvent is a mixture of isopropanol and water.
Claim 8: The process of claim 5, wherein the suitable temperature is at about 25 °C to about reflux temperature.
Claim 9: A process for purification of tenofovir disoproxil oxalate, comprising: 1) providing a suspension of tenofovir disoproxil oxalate in a suitable solvent and slurrying the suspension at a suitable temperature; and
2) isolating the pure tenofovir disoproxil oxalate; wherein the suitable solvent is selected from the group consisting of C alcohols, esters, ethers, ketones and mixtures thereof. Claim 10: The process of claim 9, wherein the tenofovir disoproxil oxalate is a tenofovir disoproxil oxalate Form-Ll.
Claim 11 : The process of claim 9, wherein the suitable solvent is selected from the group consisting of ethanol, isopropanol, tetrahydrofuran, methyl isobutyl ketone, " acetone, methyl tertiary butyl ether, dioxane, n-butyl acetate, ethyl acetate and mixtures thereof.
Claim 12: The process of claim 11, wherein the suitable solvent is ethyl acetate. Claim 13: The process of claim 9, wherein the step of slurrying is carried out at a temperature of about 25°C to about 35°C.
Claim 14: The process of claim 9, wherein the step of slurrying is carried out for a period of about 30 minutes to 48 hours.
Claim 15: Tenofovir disoproxil oxalate Form-L2 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 7.71, 8.43, 9.52, 11.89, 12.42, 14.08, 15.12, 19.96, 22.61, 25.15, 27.35, 28.14, 30.68, 31.1 1 and 32.23 ± 0.2° 2Θ. Claim 16: Tenofovir disoproxil oxalate Form-L2 of claim 15 is further characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.
Claim 17: Tenofovir disoproxil oxalate Form-L2 of claim 15 is further characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 5.
Claim 18: A process for preparation of tenofovir disoproxil oxalate Form-L2 of claim 15, comprising:
i) providing a solution of tenofovir disoproxil in a suitable solvent,
ii) adding oxalic acid to step i) solution at a suitable temperature,
iii) cooling the reaction mass and filtering the solid; and
iv) slurrying the obtained wet solid in a suitable solvent and isolating tenofovir disoproxil oxalate Form-L2; wherein the suitable solvent in step i) is selected from the group consisting of C1-4 alcohols, water and mixtures thereof and the suitable
solvent in step iv) is selected from the group consisting of C alcohols, esters, ketones, water and mixture thereof.
Claim 19: The process of claim 18, wherein the suitable solvent in step i) is selected from the group consisting of methanol, ethanol, isopropanol; water and mixtures thereof.
Claim 20: The process of claim 18, wherein the suitable solvent in step i) is a mixture of isopropanol and water. Claim 21 : The process of claim 18, wherein the suitable temperature is at about 25°C to about reflux temperature.
Claim 22: The process of claim 18, wherein the suitable solvent in step iv) is selected from ethyl acetate, methyl ethyl ketone and mixtures thereof.
Claim 23: The process of claim 18, wherein the step of slurrying is carried out at a temperature of about 25°C to about 35°C.
Claim 24: The process claim 1 to claim 23, wherein the tenofovir disoproxil oxalate obtained having a chemical purity of 99% or more as measured by HPLC.
Claim 25: A pharmaceutical composition comprising one or more polymorphic forms of tenofovir oxalate according to claim 1 to 24, and at least one pharmaceutically acceptable excipient.
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