WO2022239020A1 - Solid forms of tafamidis and preparative processes thereof - Google Patents
Solid forms of tafamidis and preparative processes thereof Download PDFInfo
- Publication number
- WO2022239020A1 WO2022239020A1 PCT/IN2022/050422 IN2022050422W WO2022239020A1 WO 2022239020 A1 WO2022239020 A1 WO 2022239020A1 IN 2022050422 W IN2022050422 W IN 2022050422W WO 2022239020 A1 WO2022239020 A1 WO 2022239020A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tafamidis
- crystalline form
- tlp
- present application
- mixture
- Prior art date
Links
- 229960001353 tafamidis Drugs 0.000 title claims abstract description 48
- 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 47
- 238000000034 method Methods 0.000 title claims abstract description 18
- 239000007787 solid Substances 0.000 title description 10
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 6
- 229930182821 L-proline Natural products 0.000 claims abstract description 6
- 229960002429 proline Drugs 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 108010071690 Prealbumin Proteins 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 102000009190 Transthyretin Human genes 0.000 claims description 4
- 206010002022 amyloidosis Diseases 0.000 claims description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 description 2
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940081715 tafamidis meglumine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- 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
-
- 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
Definitions
- aspects of the present application relate to solid forms of Tafamidis and preparative processes thereof. Specific aspects relate to crystalline form TLP of Tafamidis and processes for their preparation.
- the drug compound having the adopted name “Tafamidis” has chemical name: 2-(3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid as below.
- Tafamidis is a selective stabilizer of transthyretin developed by The Scripps Research Institute and marketed by Pfizer as VYNDAQEL® (Tafamidis meglumine) and VYNDAMAXTM (Tafamidis) oral capsule for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.
- US 7214695 B2 patent first disclosed Tafamidis and its use thereof for the treatment of transthyretin amyloid disease. It further discloses a general procedure for the preparation of benzoxazoles, particularly Tafamidis.
- US 9249112 B2 patent discloses the meglumine salt of Tafamidis along with its amorphous and crystalline forms.
- the US 9770441 B2 patent discloses amorphous and crystalline forms (Form 1, 2, 4 and 6) of Tafamidis.
- the present application provides a crystalline Form TFP of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 7.1, 10.7, 11.6 and 12.8° ⁇ 0.2° 2Q.
- the present application provides a process for the preparation of crystalline Form TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s).
- the present application provides a pharmaceutical composition comprising crystalline Form TLP of Tafamidis and atleast one pharmaceutically acceptable excipient.
- Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form-TLP of Tafamidis, prepared by the method of Example 1.
- Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis, prepared by the method of Example 2.
- aspects of the present application relates to solid form of Tafamidis and the pharmaceutical compositions thereof.
- Specific aspect of present application relate to crystalline Form TLP of Tafamidis and their preparative processes.
- the present application provides a crystalline Form TLP of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 7.1, and 10.7 ⁇ 0.2° 2Q.
- the crystalline Form TLP is characterized by one or more additional peaks at about 11.6 and 12.8° ⁇ 0.2° 2Q.
- the present application provides crystalline Form-TLP of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.
- the present application provides a process for the preparation of crystalline Form-TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s).
- Tafamidis used in this aspect may be obtained by any methods known in the art or a reaction mixture comprising Tafamidis may be used directly.
- the crystalline Form TLP may be isolated by separating the solids from the solvent through suitable techniques known in the art such as evaporation, filtration, decantation and the like.
- the isolated solid may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25 °C or above.
- the crystalline forms of Tafamidis of the present application are stable under thermal, humid and stress conditions. Further, the crystalline forms of present application exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Tafamidis.
- the present application provides a crystalline Form TLP Tafamidis, and its the pharmaceutical compositions thereof, comprising Tafamidis with a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
- Example-1 Preparation of crystalline Form TLP of Tafamidis.
- Tafamidis 500 mg was dissolved in 20mLTetrahydrofuran (THF) at ⁇ 75°C. The said mixture was added to a precooled 1: 1 (v/v) mixture of ethanol and propylene glycol (50ml :50ml) at 0°C followed by stirring at the same temperature for about an hour. The mixture was cooled and the solid obtained was isolated followed by drying to afford the title crystalline Form of Tafamidis, having ethanol -4.5% and THF -0.9%.
- THF 20mLTetrahydrofuran
- Example-3 Preparation of crystalline Form TLP of Tafamidis.
- a mixture of Tafamidis (20 mg) was dissolved in Tetrahydrofuran (600mL) at -45- 50°C. Then a solution of L-Proline (14.93 g) in methanol (lOOmL) was prepared at room temperature. Then, these two solutions were simultaneously charged to acetonitrile (400mL) at room temperature. The mixture was stirred for 5-6 hours at 20-25°C. The obtained solid was filtered under vacuum and dried in VTD at 60-65°C about 6-8 hours to afford the title compound.
Abstract
Aspects of the present application relates to crystalline Form TLP of Tafamidis. The present application provides a process for the preparation of crystalline Form TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s). The present application further relates to its pharmaceutical composition.
Description
SOLID FORMS OF TAFAMIDIS AND PREPARATIVE PROCESSES
THEREOF
INTRODUCTION
Aspects of the present application relate to solid forms of Tafamidis and preparative processes thereof. Specific aspects relate to crystalline form TLP of Tafamidis and processes for their preparation.
The drug compound having the adopted name “Tafamidis” has chemical name: 2-(3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid as below.
Tafamidis is a selective stabilizer of transthyretin developed by The Scripps Research Institute and marketed by Pfizer as VYNDAQEL® (Tafamidis meglumine) and VYNDAMAX™ (Tafamidis) oral capsule for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.
US 7214695 B2 patent first disclosed Tafamidis and its use thereof for the treatment of transthyretin amyloid disease. It further discloses a general procedure for the preparation of benzoxazoles, particularly Tafamidis. US 9249112 B2 patent discloses the meglumine salt of Tafamidis along with its amorphous and crystalline forms. The US 9770441 B2 patent discloses amorphous and crystalline forms (Form 1, 2, 4 and 6) of Tafamidis.
The reported solid forms of Tafamidis are not viable at industrial scale and there remains a need for alternate solid forms of Tafamidis and their preparative processes.
SUMMARY
In an aspect, the present application provides a crystalline Form TFP of
Tafamidis, characterized by a PXRD pattern comprising the peaks at about 7.1, 10.7, 11.6 and 12.8° ± 0.2° 2Q.
In another aspect, the present application provides a process for the preparation of crystalline Form TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s).
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form TLP of Tafamidis and atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form-TLP of Tafamidis, prepared by the method of Example 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Tafamidis, prepared by the method of Example 2.
DETAILED DESCRIPTION
Aspects of the present application relates to solid form of Tafamidis and the pharmaceutical compositions thereof. Specific aspect of present application relate to crystalline Form TLP of Tafamidis and their preparative processes.
In an aspect, the present application provides a crystalline Form TLP of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 7.1, and 10.7 ± 0.2° 2Q. In an embodiment, the crystalline Form TLP is characterized by one or more additional peaks at about 11.6 and 12.8° ± 0.2° 2Q. In an embodiment, the present application provides crystalline Form-TLP of Tafamidis, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.
In another aspect, the present application provides a process for the preparation of crystalline Form-TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s).
In embodiments, Tafamidis used in this aspect may be obtained by any methods known in the art or a reaction mixture comprising Tafamidis may be used directly.
In embodiments, the crystalline Form TLP may be isolated by separating the
solids from the solvent through suitable techniques known in the art such as evaporation, filtration, decantation and the like.
In embodiments, the isolated solid may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25 °C or above.
In embodiments, the crystalline forms of Tafamidis of the present application are stable under thermal, humid and stress conditions. Further, the crystalline forms of present application exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Tafamidis.
In another aspect, the present application provides a crystalline Form TLP Tafamidis, and its the pharmaceutical compositions thereof, comprising Tafamidis with a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Examples
Example-1: Preparation of crystalline Form TLP of Tafamidis.
A mixture of Tafamidis (100 mg) and L-Proline (75mg) was dissolved in l: lv/v mixture isopropanol and acetonitrile (100 mL) followed by sonication. The mixture was subjected to evaporation at ~85°C followed by drying to afford the title crystalline Form TLP of Tafamidis.
Example-2: Preparation of crystalline Form of Tafamidis.
A mixture of Tafamidis (500 mg) was dissolved in 20mLTetrahydrofuran (THF) at ~75°C. The said mixture was added to a precooled 1: 1 (v/v) mixture of ethanol and propylene glycol (50ml :50ml) at 0°C followed by stirring at the same temperature for about an hour. The mixture was cooled and the solid obtained was isolated followed by drying to afford the title crystalline Form of Tafamidis, having ethanol -4.5% and THF -0.9%.
Example-3: Preparation of crystalline Form TLP of Tafamidis.
A mixture of Tafamidis (20 mg) was dissolved in Tetrahydrofuran (600mL) at -45- 50°C. Then a solution of L-Proline (14.93 g) in methanol (lOOmL) was prepared at room temperature. Then, these two solutions were simultaneously charged to acetonitrile (400mL) at room temperature. The mixture was stirred for 5-6 hours at 20-25°C. The obtained solid was filtered under vacuum and dried in VTD at 60-65°C about 6-8 hours to afford the title compound.
Claims
Claims:
Claim 1: A crystalline Form TLP of Tafamidis, characterized by a PXRD pattern comprising the peaks at about 7.1, 10.7, 11.6 and 12.8° ± 0.2° 2Q.
Claim 2: A process for the preparation of crystalline Form TLP of Tafamidis, comprising the step of crystallizing from a mixture comprising Tafamidis free acid and L-Proline in suitable solvent(s).
Claim 3: The process of claim 2, wherein solvents are selected from alcohols, ethers, esters, ketones, aromatic hydrocarbons, polar aprotic solvents and mixtures thereof.
Claim 4: The process of claim 3 wherein solvents are selected from methanol, ethanol, propylene glycol, Tetrahydrofuran, acetonitrile and mixtures thereof.
Claim 5: A pharmaceutical composition comprising crystalline Form TLP of Tafamidis and at least one pharmaceutically acceptable excipient.
Claim 6: Use of crystalline Form TLP of Tafamidis of claim 1 for manufacture of medicament for treatment of transthyretin amyloid disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202141021191 | 2021-05-11 | ||
| IN202141021191 | 2021-05-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022239020A1 true WO2022239020A1 (en) | 2022-11-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2022/050422 WO2022239020A1 (en) | 2021-05-11 | 2022-05-04 | Solid forms of tafamidis and preparative processes thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022239020A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019175263A1 (en) * | 2018-03-13 | 2019-09-19 | Azad Pharma Ag | New polymorphs and new path to synthesize tafamidis |
| WO2020232325A1 (en) * | 2019-05-16 | 2020-11-19 | Teva Pharmaceuticals International Gmbh | Solid state forms of tafamidis and salts thereof |
| WO2021019448A1 (en) * | 2019-08-01 | 2021-02-04 | Honour (R&D) | Process for the preparation of transthyretin dissociation inhibitor |
-
2022
- 2022-05-04 WO PCT/IN2022/050422 patent/WO2022239020A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019175263A1 (en) * | 2018-03-13 | 2019-09-19 | Azad Pharma Ag | New polymorphs and new path to synthesize tafamidis |
| WO2020232325A1 (en) * | 2019-05-16 | 2020-11-19 | Teva Pharmaceuticals International Gmbh | Solid state forms of tafamidis and salts thereof |
| WO2021019448A1 (en) * | 2019-08-01 | 2021-02-04 | Honour (R&D) | Process for the preparation of transthyretin dissociation inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| CAIRA M R ET AL.: "Crystalline polymorphism of organic compounds", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, DOI: 10.1007/3-540-69178-2_5 * |
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