WO2022107166A1 - Novel crystalline form of tafamidis and its process thereof - Google Patents
Novel crystalline form of tafamidis and its process thereof Download PDFInfo
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- WO2022107166A1 WO2022107166A1 PCT/IN2021/051080 IN2021051080W WO2022107166A1 WO 2022107166 A1 WO2022107166 A1 WO 2022107166A1 IN 2021051080 W IN2021051080 W IN 2021051080W WO 2022107166 A1 WO2022107166 A1 WO 2022107166A1
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- tafamidis
- acid
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- TXEIIPDJKFWEEC-UHFFFAOYSA-N tafamidis Chemical compound O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 TXEIIPDJKFWEEC-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960001353 tafamidis Drugs 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 title claims abstract description 34
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- RGISOLFSSBPMSO-UHFFFAOYSA-N 4-[(3,5-dichlorobenzoyl)amino]-3-hydroxybenzoic acid Chemical compound OC1=CC(C(=O)O)=CC=C1NC(=O)C1=CC(Cl)=CC(Cl)=C1 RGISOLFSSBPMSO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 14
- 229940081715 tafamidis meglumine Drugs 0.000 claims description 13
- DQJDBUPLRMRBAB-WZTVWXICSA-N tafamidis meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 DQJDBUPLRMRBAB-WZTVWXICSA-N 0.000 claims description 13
- 238000004566 IR spectroscopy Methods 0.000 claims description 11
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims 2
- 238000001816 cooling Methods 0.000 claims 1
- 238000002411 thermogravimetry Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 239000002002 slurry Substances 0.000 description 4
- 208000034846 Familial Amyloid Neuropathies Diseases 0.000 description 2
- 206010019889 Hereditary neuropathic amyloidosis Diseases 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JRUHAIBYXWRVJA-UHFFFAOYSA-N 2-phenyl-1,3-benzoxazole-4-carboxylic acid Chemical class N=1C=2C(C(=O)O)=CC=CC=2OC=1C1=CC=CC=C1 JRUHAIBYXWRVJA-UHFFFAOYSA-N 0.000 description 1
- 206010007509 Cardiac amyloidosis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 108010071690 Prealbumin Proteins 0.000 description 1
- 102000009190 Transthyretin Human genes 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 208000022256 primary systemic amyloidosis Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 208000027121 wild type ATTR amyloidosis Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
Definitions
- the present invention relates to a process for the preparation of stable crystalline form of Tafamidis free acid and its pharmaceutically acceptable salts.
- This invention relates to solid forms of 6-carboxy-2-(3.5-dichlorophenyl)- benzoxazole (Tafamidis) that are useful in the treatment of transthyretin amyloid diseases, such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC), in mammals.
- transthyretin amyloid diseases such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC)
- SSA senile systemic amyloidosis
- FAP familial amyloid polyneuropathy
- FAC familial amyloid cardiomyopathy
- the present invention relates to a stable crystalline form of Tafamidis and a process for its preparation.
- a novel crystalline form of Tafamidis we surprisingly found a novel crystalline form of Tafamidis.
- Second aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (26) of 5.4 ⁇ 0.2 and 16.3 ⁇ 0.2, 11.8 ⁇ 0.2 9.
- Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2 9) essentially the same as shown in FIG. 1.
- Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 ⁇ 2 0 C and second onset peak temperature at about 286 to 288 ⁇ 2 0 C (DSC, Fig. 2).
- Another aspect of the present invention provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram same as shown in FIG. 2.
- Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by Infrared spectroscopy (IR) spectrum comprising wave numbers (cm 1 ) selected from at 3434 + 2, 3081+ 2, 2984+ 2, 2631+ 2, 2490+ 2, 1921+ 2, 1706+ 2, 1571+ 2, 1546+ 2, 1387+ 2, 1101+ 2, 781+ 2 (cm’ 1 ) (IR, Fig. 3).
- IR Infrared spectroscopy
- Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by an Infrared spectroscopy (IR) spectrum same as shown in FIG. 3.
- IR Infrared spectroscopy
- Yet another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by significant weight loss by thermo gravimetric analysis (TGA) same as show in FIG.
- TGA thermo gravimetric analysis
- third aspect of the present invention provides a method for preparing crystalline Form-N2 of Tafamidis, wherein said method comprising:
- step 2) adding acid solution to step 1) at ambient temperature,
- crystalline Form-N2 of Tafamidis wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (26) of 9.8+0.2,11.5+0.2 and 19.3+0.2 9.
- crystalline Form-N2 of Tafamidis wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising peaks at diffraction angles (29) essentially the same as shown in FIG. 5.
- Yet another aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by an DSC thermogram comprising an endotherm onset peak temperature with a maximum at about 288 + 2 °C (DSC, Fig. 6). Yet another aspect of the present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by significant weight loss by Thermo Gravimetric Analysis (TGA) same as show in FIG. 7.
- TGA Thermo Gravimetric Analysis
- a method for preparing Tafamidis meglumine without isolating Tafamidis free acid comprises:
- Fig. 1 XRPD diffractogram of crystalline polymorph, Form-Nl of Tafamidis
- Fig. 2 DSC thermogram of crystalline polymorph, Form-Nl of Tafamidis.
- Fig. 3 Infrared spectrum of crystalline polymorph, Form-Nl of Tafamidis.
- Fig. 4 Thermogravimetric analysis of crystalline polymorph, Form-Nl of Tafamidis.
- Fig. 5 XRPD diffractogram of crystalline polymorph, Form-N2 of Tafamidis
- Fig. 6 DSC thermogram of crystalline polymorph, Form-N2 of Tafamidis.
- Fig. 7 Thermogravimetric analysis of crystalline polymorph, Form-N2 of Tafamidis.
- the present invention provides a method for preparing crystalline Form-Nl of Tafamidis said method comprising: 1) adding the acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
- the acid used in step 1) is selected from the group Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or a mixture thereof preferably Methanesulphonic acid.
- the acid can be added to the compound 4-[(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid or to slurry of the compound 4- [(3, 5-dichlorobenzoyl) amino] -3 -hydroxybenzoic acid.
- the slurry of the compound 4- [(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding the co- solvent or solvent selected form 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
- step 2 The temperature of step 2) at which cyclization reaction proceeds in the range of 90-130 °C.
- the base solution of Step 3 is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
- Yet another embodiment of present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 5.4+0.2, 16.3+0.2 and 11.8+0.2 ⁇ 2 (29).
- crystalline Form-N 1 of Tafamidis wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 + 2 C and second onset peak temperature at between about 286 to 288 + 2 C (DSC, Fig. 2).
- Form-Nl of Tafamidis is characterized by Infrared spectroscopy (IR) spectrum wave numbers (cm -1 ) comprising at 3434+ 2, 3081+ 2, 2984+ 2, 2631+ 2, 2490+ 2, 1921+ 2, 1706+ 2, 1571+ 2, 1546+ 2, 1387+ 2, 1101+ 2, 781+ 2 (IR, Fig. 3).
- IR Infrared spectroscopy
- Form-Nl of Tafamidis is characterized by significant weight loss by Thermogravimetric analysis (TGA) as shown in Fig.4.
- crystalline Form-N2 of Tafamidis is prepared from Tafamidis meglumine by adding solvent at ambient temperature, followed by addition of acid solution and stir to obtain the compound.
- the solvent adding to Tafamidis meglumine is water at 20 to 25 °C.
- the acid used in process of crystalline Form -N2 Tafamidis is hydrochloric acid.
- Yet another embodiment of present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 9.8+0.2,11.5+0.2 and 19.3+0.2 (29).
- crystalline Form-N2 of Tafamidis is characterized by a DSC thermogram comprising an endotherm onset peak temperature maximum at about 288 °C + 2°C.
- Yet another embodiment of the invention to provides the process of Tafamidis meglumine without isolating the Tafamidis comprises: 1) adding acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid;
- the acid used at step 1) is selected from group of Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or mixture of acid or thereof preferably Methanesulphonic acid.
- the acid can be added to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid or to the slurry of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid.
- the slurry of the compound 4- [(3, 5 -dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding co-solvent or solvent selected from group of 1,4- dioxane, Tetrahydrofuran , Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
- step 2 The temperature of step 2) at which cyclization reaction proceed in the range of 90- 130°C preferably 105-110°C.
- the base solution of Step 3 is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
- the process of the present invention is feasible to produce novel crystalline polymorph, Form-Nl and N2 of Tafamidis on commercial scale.
- the crystalline Tafamidis Form-Nl and N2 are stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients. 3.
- the crystalline Tafamidis Form-Nl and N2 are stable at ambient temperature and at elevated temperatures (60°C).
- Crystalline Tafamidis Form-Nl and N2 are non-hygroscopic and are compatible for further converting to Tafamidis meglumine pharma.
- Example 1 Process for the preparation of crystalline Form-Nl of Tafamidis ⁇
- DSC DSC thermogram with endotherm having an onset peak temperature at about 165°C, and second endotherm having an onset peak temperature at about 287°C. (see Fig:2)
- IR k, cm 1
- TGA Weight loss of 13.93% w/w was observed due to loss of Tnethylamine (see Fig. 4)
- Example 2 Process for the preparation of crystalline Form-Nl of Tafamidis.
- Example 3 Process of Tafamidis meglumine without isolation of Tafamidis free acid (direct preparation of crystalline polymorph of Tafamidis Meglumine from 4- [(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid):
- Example 4 Process for the preparation of crystalline Form-N2 of Tafamidis.
- Tafamidis meglumine (100.0 gm) was suspended in water (4.0 L) at 20-25°C. After that, added Cone. HC1 (25.0 gm 1.2 mole) drop-wise to the above suspension at 20- 25 C for about 30 mins. After l.Oh maintenance, the obtained solid was filtered, and dried to yield Tafamidis Form-N2.
- DSC DSC thermogram with endotherm having an onset peak temperature at 288 °C. (see Fig.6)
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Abstract
The present invention relates to novel crystalline Forms of Tafamidis and process to prepare thereof. The present invention also relates to process of Tafamidis N-methyl-D-glucamine.
Description
NOVEL CRYSTALLINE FORM OF TAFAMIDIS AND ITS PROCESS THEREOF
Field of invention:
The present invention relates to a process for the preparation of stable crystalline form of Tafamidis free acid and its pharmaceutically acceptable salts.
Background of the invention:
This invention relates to solid forms of 6-carboxy-2-(3.5-dichlorophenyl)- benzoxazole (Tafamidis) that are useful in the treatment of transthyretin amyloid diseases, such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC), in mammals. The compound 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole having the structure
The solid states of Tafamidis are described in U.S. patent Nos. 9770441 name as crystalline forms 1, 2, 4, 6 and methods of making carboxy-2-phenyl-benzoxazoles, as well as pharmaceutical compositions comprising the same, are also described therein.
Although significant strides have been made in the development of polymorphic form of Tafamidis still there is a need in the art to develop a stable and commercially viable polymorphic forms.
Summary of the Invention
The present invention relates to a stable crystalline form of Tafamidis and a process for its preparation. In course of our investigations on industrially feasible procedures for Tafamidis, we surprisingly found a novel crystalline form of Tafamidis. During our continuous efforts in research and development of novel polymorphic forms, we have come across a novel crystalline form of Tafamidis
which is consistently reproducible and found to be more stable under standard pharmaceutical operation conditions such as drying, milling, compression, granulation and blending.
In one aspect of the present invention provides a method for preparing crystalline Form-Nl of Tafamidis said method comprising:
1) adding the acid to the compound of 4- [(3, 5 -dichlorobenzoyl) amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) distil the solvent to obtain the compound,
5) optionally, adding the solvent and cool to obtain the compound.
Second aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (26) of 5.4±0.2 and 16.3±0.2, 11.8±0.2 9.
Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2 9) essentially the same as shown in FIG. 1.
Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 ± 2 0 C and second onset peak temperature at about 286 to 288 ± 2 0 C (DSC, Fig. 2).
Another aspect of the present invention provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram same as shown in FIG. 2.
Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by
Infrared spectroscopy (IR) spectrum comprising wave numbers (cm 1) selected from at 3434 + 2, 3081+ 2, 2984+ 2, 2631+ 2, 2490+ 2, 1921+ 2, 1706+ 2, 1571+ 2, 1546+ 2, 1387+ 2, 1101+ 2, 781+ 2 (cm’1) (IR, Fig. 3).
Another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by an Infrared spectroscopy (IR) spectrum same as shown in FIG. 3.
Yet another aspect of the present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by significant weight loss by thermo gravimetric analysis (TGA) same as show in FIG.
4.
In third aspect of the present invention provides a method for preparing crystalline Form-N2 of Tafamidis, wherein said method comprising:
1) adding solvent to Tafamidis Meglumine,
2) adding acid solution to step 1) at ambient temperature,
3) after completion of reaction filter to obtain crystalline Tafamidis Form-N2.
In forth aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (26) of 9.8+0.2,11.5+0.2 and 19.3+0.2 9.
In another aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising peaks at diffraction angles (29) essentially the same as shown in FIG. 5.
Yet another aspect of the present invention provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by an DSC thermogram comprising an endotherm onset peak temperature with a maximum at about 288 + 2 °C (DSC, Fig. 6).
Yet another aspect of the present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline Form-N2 of Tafamidis is characterized by significant weight loss by Thermo Gravimetric Analysis (TGA) same as show in FIG. 7.
In fifth aspect of the present invention provides a method for preparing Tafamidis meglumine without isolating Tafamidis free acid comprises:
1) adding the acid to the compound of 4- [(3, 5 -dichlorobenzoyl) amino] -3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) stir the reaction mixture to get clear solution,
5) adding the N-methyl-glucamine and stir to obtain the compound.
Brief description of the Drawings:
Fig. 1 : XRPD diffractogram of crystalline polymorph, Form-Nl of Tafamidis
Fig. 2: DSC thermogram of crystalline polymorph, Form-Nl of Tafamidis.
Fig. 3 : Infrared spectrum of crystalline polymorph, Form-Nl of Tafamidis.
Fig. 4: Thermogravimetric analysis of crystalline polymorph, Form-Nl of Tafamidis.
Fig. 5 : XRPD diffractogram of crystalline polymorph, Form-N2 of Tafamidis
Fig. 6: DSC thermogram of crystalline polymorph, Form-N2 of Tafamidis.
Fig. 7: Thermogravimetric analysis of crystalline polymorph, Form-N2 of Tafamidis.
Detailed description of the Invention:
In one embodiment, the present invention provides a method for preparing crystalline Form-Nl of Tafamidis said method comprising:
1) adding the acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding base solution,
4) distil the solvent to obtain the compound,
5) optionally add the solvent and cool to obtain the compound.
The acid used in step 1) is selected from the group Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or a mixture thereof preferably Methanesulphonic acid.
The acid can be added to the compound 4-[(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid or to slurry of the compound 4- [(3, 5-dichlorobenzoyl) amino] -3 -hydroxybenzoic acid.
The slurry of the compound 4- [(3, 5-dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding the co- solvent or solvent selected form 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
The temperature of step 2) at which cyclization reaction proceeds in the range of 90-130 °C.
The base solution of Step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
Yet another embodiment of present invention to provides a crystalline Form-Nl of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 5.4+0.2, 16.3+0.2 and 11.8+0.2 ±2 (29).
In another embodiment of the present invention to provides a crystalline Form-N 1 of Tafamidis, wherein said crystalline Form-Nl of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 +
2 C and second onset peak temperature at between about 286 to 288 + 2 C (DSC, Fig. 2).
In another embodiments of the present invention to provides crystalline polymorph, Form-Nl of Tafamidis is characterized by Infrared spectroscopy (IR) spectrum wave numbers (cm-1) comprising at 3434+ 2, 3081+ 2, 2984+ 2, 2631+ 2, 2490+ 2, 1921+ 2, 1706+ 2, 1571+ 2, 1546+ 2, 1387+ 2, 1101+ 2, 781+ 2 (IR, Fig. 3).
In another embodiments of the present invention to provides crystalline polymorph, Form-Nl of Tafamidis is characterized by significant weight loss by Thermogravimetric analysis (TGA) as shown in Fig.4.
In one embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is prepared from Tafamidis meglumine by adding solvent at ambient temperature, followed by addition of acid solution and stir to obtain the compound.
The solvent adding to Tafamidis meglumine is water at 20 to 25 °C.
The acid used in process of crystalline Form -N2 Tafamidis is hydrochloric acid.
Yet another embodiment of present invention to provides a crystalline Form-N2 of Tafamidis, wherein said crystalline form is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 9.8+0.2,11.5+0.2 and 19.3+0.2 (29).
In another embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is characterized by a DSC thermogram comprising an endotherm onset peak temperature maximum at about 288 °C + 2°C.
In another embodiment of the present invention to provides crystalline Form-N2 of Tafamidis is characterized by weight loss by Thermo Gravimetric Analysis (TGA) same as show in FIG. 7.
Yet another embodiment of the invention to provides the process of Tafamidis meglumine without isolating the Tafamidis comprises:
1) adding acid to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid;
2) heating the reaction mixture;
3) after completion of reaction, adding base solution;
4) stir the reaction mixture up to get clear solution;
5) adding the N-methyl-glucamine and stir to obtain the compound.
The acid used at step 1) is selected from group of Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid or mixture of acid or thereof preferably Methanesulphonic acid.
The acid can be added to the compound of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid or to the slurry of 4-[(3, 5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid.
The slurry of the compound 4- [(3, 5 -dichlorobenzoyl) amino]-3-hydroxybenzoic acid is prepared by adding co-solvent or solvent selected from group of 1,4- dioxane, Tetrahydrofuran , Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
The temperature of step 2) at which cyclization reaction proceed in the range of 90- 130°C preferably 105-110°C.
The base solution of Step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
Advantages of the present invention:
1. The process of the present invention is feasible to produce novel crystalline polymorph, Form-Nl and N2 of Tafamidis on commercial scale.
2. The crystalline Tafamidis Form-Nl and N2 are stable during standard pharmaceutical operations such as drying, milling, compression, granulation and blending with excipients.
3. The crystalline Tafamidis Form-Nl and N2 are stable at ambient temperature and at elevated temperatures (60°C).
4. Crystalline Tafamidis Form-Nl and N2 are non-hygroscopic and are compatible for further converting to Tafamidis meglumine pharma.
The following examples are provided for illustration purpose only and are not intended to limit the scope of the invention.
Experimental procedure:
Example 1: Process for the preparation of crystalline Form-Nl of Tafamidis^
Into the round bottom flask containing 4-[(3,5-Dichlorobenzoyl)amino]-3- hydroxybenzoic acid (25g) was added Methanesulfonic acid (37.5 mL). The reaction mass was heated to 105-110°C and maintained under stirring up to reaction completion by monitoring HPLC. After completion of reaction, Cyclohexane (75 mL) was added to the homogeneous reaction mass at higher temperature. A mixture of Tetrahydrofuran (107 ml) and Trimethylamine (107 mL) was slowly added at the reflux temperature followed by addition of Tetrahydrofuran (143 mL). Volatile solvents were distilled from the reaction mass at atmospheric pressure keeping the vapour temperature up to 85 °C. Later 375 mL of water was added at 80-85°C allowing volatiles to collect in receiver and maintained for 2 to 3 hours at same temperature. Obtained solid was cooled, filtered, and dried to afford Tafamidis crystalline polymorph Form-Nl with 13.93 % w/w TEA content.
Yield: 25g; 92% by theory; HPLC purity: >99%
XRPD (29): The XPRD pattern with characteristic peaks are observed at 5.4+0.2 and 16.3+0.2. (see Fig.l).
DSC: DSC thermogram with endotherm having an onset peak temperature at about 165°C, and second endotherm having an onset peak temperature at about 287°C. (see Fig:2)
IR (k, cm 1): The IR spectrum comprising IR shift peaks observed at about 3434, 3081, 2984, 2631, 2490, 1921, 1706, 1571, 1546, 1387, 1101, and 781 + 4. (see Fig. 3)
TGA: Weight loss of 13.93% w/w was observed due to loss of Tnethylamine (see Fig. 4)
Example 2: Process for the preparation of crystalline Form-Nl of Tafamidis.
Into the round bottom flask 4- [(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid (100g) was added Methanesulphonic acid (150 mL). The reaction mixture was heated to 110-115°C and maintained under stirring up to reaction completion (monitored by HPLC). After completion of reaction, reaction mass was cooled to 85-90°C. In another flask, mixture of Tetrahydrofuran (430 ml) and Triethylamine (430 mL) is taken and cooled to 0-5°C. The above reaction was slowly added to the Tetrahydrofuran and Triethylamine mixture at below 25 °C followed by addition of Tetrahydrofuran (1070 mL) and Triethylamine (82 mL). After completion of the maintenance at 35-40°C for 1 hour, solvent was completely distilled under vacuum at below 40°C. After that, 1500 mL of water was added to the reaction mass at 30- 35°C and maintained for 2.5-3.0 hours at 30-35°C. Obtained solid was filtered and dried to afford Tafamidis crystalline Form-Nl with 14.5 % TEA content.
Example 3: Process of Tafamidis meglumine without isolation of Tafamidis free acid (direct preparation of crystalline polymorph of Tafamidis Meglumine from 4- [(3, 5-dichlorobenzoyl) amino]-3- hydroxybenzoic acid):
Into the round bottom flask added 4-[(3, 5-Dichlorobenzoyl) amino]-3- hydroxybenzoic acid (0.015 mole) and 1,4-dioxane (50 mL), Triflic acid (0.030 moles). The reaction mass was heated to 105-110°C and progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was cooled to 60-80°C and Triethylamine (0.046 moles) was added. To the above clear solution, N-methyl-D-glucamine (0.017 moles) was added. Obtained solid was cooled, filtered and dried to afford crystalline Tafamidis meglumine.
Yield: 4.6g; 64.7% by theory; HPLC Purity: >99%.
Example 4: Process for the preparation of crystalline Form-N2 of Tafamidis.
Tafamidis meglumine (100.0 gm) was suspended in water (4.0 L) at 20-25°C. After that, added Cone. HC1 (25.0 gm 1.2 mole) drop-wise to the above suspension at 20-
25 C for about 30 mins. After l.Oh maintenance, the obtained solid was filtered, and dried to yield Tafamidis Form-N2.
Yield: 56.5g; HPLC purity: 99.9%
XRPD (29): The XPRD pattern with characteristic peaks are observed at 9.8±0.2,11.5±0.2 and 19.3±0.2 (29). (see Fig.5)
DSC: DSC thermogram with endotherm having an onset peak temperature at 288 °C. (see Fig.6)
TGA: No significant weight loss was observed.
Claims
1. A process for preparation of novel crystalline Form-Nl of Tafamidis characterized by powder X-ray diffraction pattern comprising two or more characteristic peaks selected from peaks at (29) values 5.4+0.2, 16.3+0.2 and 11.8+0.2 9 comprising:
1) adding acid to the compound of 4-[(3,5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
2) heating the reaction mass,
3) after completion of reaction, adding base solution,
4) distil of the solvent to obtain Form-Nl crystals of Tafamidis,
5) optionally adding the solvent and cooling to obtain Form-N 1 crystals of Tafamidis.
2. The process as claimed in claim-1, wherein said acid used in step 1) is selected from Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid.
3. The process as claimed in claim- 1, wherein said reaction temperature in step 2) is in the range of 90-130°C.
4. The process as claimed in claim- 1, wherein said base solution in step 3) is prepared by adding Triethylamine to solvents selected from 1,4-Dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
5. A novel crystalline Form-Nl of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 5.4+0.2, 11.8+0.2 and 16.3+0.2 9.
6. A novel crystalline Form-Nl of Tafamidis is characterized by DSC thermogram comprising an endotherm onset peak temperature at about 163 + 2 0 C and second onset peak temperature at about 286 to 288 + 2 0 C.
7. A novel crystalline Form-Nl of Tafamidis is characterized by Infrared spectroscopy (on 1) spectrum comprising of characteristic wave numbers at 3434+2, 3081+2, 2984+2, 2631+2, 2490+2, 1921+2, 1706+2, 1571+2, 1546+2, 1387+2, 1101+2 and 781+2 cm’1.
8. A process for preparation of novel crystalline Form-N2 of Tafamidis characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (29) of 9.8±0.2,11.5±0.2 and 19.3+0.2 comprising, adding a solvent to Tafamidis meglumine at ambient temperature, followed by addition of acid solution to obtain the crystalline Form-N2.
9. The process as claimed in claim- 8, wherein said solvent is water.
10. The process as claimed in claim-8, wherein said ambient temperature is at 20 to 30 °C, preferably 20-25°C.
11. The process as claimed in claim-8, wherein said acid is hydrochloric acid.
12. A novel crystalline Form-N2 of Tafamidis is characterized by powder X-ray diffraction pattern comprising characteristic peaks at diffraction angles (2 9) of 9.8+0.2, 11.5+0.2, and 19.3+0.2 9.
13. A novel crystalline form-N2 is characterized by DSC thermogram comprising an endotherm onset peak temperature maximum at 288+2 °C.
14. A process to prepare the Tafamidis Meglumine without isolating the Tafamidis free acid comprising:
1) adding acid to the compound of 4-[(3,5-dichlorobenzoyl)amino]-3- hydroxybenzoic acid,
2) heating the reaction mixture,
3) after completion of reaction, adding the base solution,
4) stir the reaction mixture up to get clear solution,
5) adding N-methyl-glucamine and stir to obtain Tafamidis meglumine.
15. The process as claimed in claim-14, wherein said acid used in step 1) is selected from Methanesulphonic acid, Ethanesulphonic acid, Trifluromethanesulphonic acid (Triflic acid), Sulphuric acid.
16. The process as claimed in claim-14, wherein said reaction temperature of step 2) is about 90 to 130° ± 2 °C.
17. The process as claimed in claim- 14, wherein said base solution at step 3) is prepared by adding Triethylamine to solvents selected from 1,4-dioxane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, Acetonitrile, Toluene, Xylene and Water or a mixture thereof.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016038500A1 (en) * | 2014-09-08 | 2016-03-17 | Pfizer Inc. | Crystalline solid forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole |
| GB2571950A (en) * | 2018-03-13 | 2019-09-18 | Azad Pharma Ag | New polymorph and new path to synthesize tafamidis |
| IN202041038234A (en) * | 2020-09-04 | 2020-09-25 | Neuland Laboratories Limited |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016038500A1 (en) * | 2014-09-08 | 2016-03-17 | Pfizer Inc. | Crystalline solid forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole |
| GB2571950A (en) * | 2018-03-13 | 2019-09-18 | Azad Pharma Ag | New polymorph and new path to synthesize tafamidis |
| IN202041038234A (en) * | 2020-09-04 | 2020-09-25 | Neuland Laboratories Limited |
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