CN112608314A - Method for purifying sitagliptin - Google Patents
Method for purifying sitagliptin Download PDFInfo
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- CN112608314A CN112608314A CN201910946335.5A CN201910946335A CN112608314A CN 112608314 A CN112608314 A CN 112608314A CN 201910946335 A CN201910946335 A CN 201910946335A CN 112608314 A CN112608314 A CN 112608314A
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- sitagliptin
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- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims abstract description 62
- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 60
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000003756 stirring Methods 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 239000000047 product Substances 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 239000012065 filter cake Substances 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 30
- 238000000746 purification Methods 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000002386 leaching Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940090473 januvia Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for purifying sitagliptin, which comprises the following specific processes: (a) dissolving a sitagliptin crude product in a first solvent, heating and stirring to dissolve the sitagliptin crude product; (b) adding a second solvent into the clear solution, stirring at a constant temperature, and slowly cooling to low temperature and stirring; (c) filtering, washing a filter cake, and drying in vacuum to obtain the pure sitagliptin product. The purification method has remarkable impurity removal effect, can reduce the total impurity level of about 3.8% to 0.25% or below, and the purified sitagliptin has the purity of more than 99.75%, the maximum single impurity content of less than 0.1% and the yield of more than 81%. Can reach the level of the bulk drug sitagliptin and can meet the quality and management standards of clinical and commercial use.
Description
Technical Field
The invention belongs to the technical field of medical industry, and particularly relates to a purification method of sitagliptin serving as a dipeptidyl peptidase-IV inhibitor.
Background
Sitagliptin, chemical name is (2R) -4-oxo-4- [ 3-trifluoromethyl-5, 6-dihydro [1,2,4 ]]Triazole [4,3-a ]]Pyrazin-7 (8H) -yl]-1- (2,4, 5-trifluorophenyl) -butan-2-amine of formula: c16H15F6N5O, CAS number 486460-32-6, structural formula as follows:
sitagliptin is a peptidylpeptidase-IV inhibitor developed by Merck, USA, and phosphate (Januvia) thereof is approved by FDA, USA, on the market at 10 months 2006 as the first DPP-IV inhibitor, and is clinically used for treating insulin resistance and insulin resistance in the process of type 2 diabetes mellitusɑ，βThe dysfunction of cells plays a role in reducing blood sugar by inhibiting DPP-IV to slow down the degradation of incretin GLP-1. The product has the advantages of good tolerance, safety and effectiveness, light side effect and the like, is concerned by a plurality of pharmaceutical chemistry workers at home and abroad, and has good market prospect.
Therefore, in order to obtain sitagliptin with a purity of a bulk pharmaceutical grade, it is necessary to develop a purification method. The purification method is simple, convenient, economical and effective; meanwhile, the implementation of the purification method can effectively reduce the side reaction impurities in the process, greatly improve the purity of the product, simplify the operation flow, and simultaneously utilize three low-toxicity solvents, reduce the risk of solvent residue and greatly improve the safety of the product.
Disclosure of Invention
The invention aims to provide a simple and effective method for purifying sitagliptin, which has a remarkable impurity removal effect, can reduce the total impurity level of about 3.8 percent to 0.25 percent or less, ensures that the purity of the purified sitagliptin is about 99.75 percent or more, has the maximum single impurity content of less than 0.1 percent, and has the yield of more than 81 percent.
The invention is realized by the following technical scheme:
(a) dissolving a sitagliptin crude product in a first solvent, heating and stirring to dissolve the sitagliptin crude product;
(b) adding a second solvent into the clear solution, stirring at a constant temperature, and slowly cooling to low temperature and stirring;
(c) filtering, washing a filter cake, and drying in vacuum to obtain the pure sitagliptin product.
The invention provides a purification method of sitagliptin, wherein the first solvent used in the step (a) is selected from one or more of acetonitrile, isopropyl acetate, ethanol, ethyl acetate, tetrahydrofuran and isopropanol, and preferably one or more of ethyl acetate, isopropyl acetate, ethanol, isopropanol or tetrahydrofuran.
The invention provides a purification method of sitagliptin, wherein the dosage of a first solvent used in step (a) is 1.3-3 times of the volume of a crude sitagliptin product, preferably 1.3-2.5 times of the volume, and more preferably 1.8 times of the volume.
The invention provides a purification method of sitagliptin, wherein the heating temperature in the step (a) is 40-60 ℃, and preferably 50 ℃.
The invention provides a purification method of sitagliptin, wherein the heating and stirring time in the step (a) is 10-60 min, preferably 10-40min, and more preferably 30 min.
The invention provides a purification method of sitagliptin, wherein the second solvent used in the step (b) is selected from one or more of n-heptane, methyl tert-butyl ether, isopropyl ether, n-hexane and diethyl ether, and is preferably isopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
The present invention provides a purification process of sitagliptin, wherein the amount of the second preferred solvent isopropyl ether used in step (b) is 3-10 times volume, preferably 4-8 times volume, more preferably 6 times volume of the weight of crude sitagliptin.
The present invention provides a method for purifying sitagliptin, wherein the temperature of the second solvent used in the step (b) is 40-60 ℃, preferably 50 ℃.
The invention provides a purification method of sitagliptin, wherein the heat preservation stirring temperature in the step (b) is 40-60 ℃, and preferably 50 ℃.
The invention provides a sitagliptin purification method, wherein the heat preservation stirring time in the step (b) is 10min-60min, preferably 20-50min, and more preferably 15 min.
The invention provides a purification method of sitagliptin, wherein the low temperature in the step (b) means that the temperature is less than or equal to 10 ℃, and is preferably-10-5 ℃.
The invention provides a purification method of sitagliptin, wherein the low-temperature cooling stirring time in the step (b) is 30min-5h, preferably 30min-3, and more preferably 1.5 h.
The invention provides a purification method of sitagliptin, wherein the washing solvent in the step (c) is isopropyl ether, and the dosage of the isopropyl ether is 0.5-3 times of the volume of the crude sitagliptin, preferably 0.5-1.5 times of the volume of the crude sitagliptin.
The invention provides a purification method of sitagliptin, wherein the vacuum drying temperature in the step (c) is 40-60 ℃, the vacuum drying time is 3-10 h, preferably 45 ℃, and the drying time is 8 h.
The method separates impurities from the finished product by utilizing the solubility difference of the impurities and the finished product in the mixed solvent, the obtained sitagliptin pure product has high yield and good purity, the cost is effectively reduced, and meanwhile, the production method is simple and easy to operate, so that the aim of large-scale industrial production is fulfilled. The purification method has remarkable impurity removal effect, can reduce the total impurity level of about 3.8% to 0.25% or below, and the purified sitagliptin has the purity of more than 99.75%, the maximum single impurity content of less than 0.1% and the yield of more than 81%. Can reach the level of the bulk drug sitagliptin and can meet the quality and management standards of clinical and commercial use.
Detailed Description
The following specific examples of the invention are provided to illustrate possible implementations, but not to limit the invention. In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
heating 40g of a self-made sitagliptin crude product (with HPLC purity of 96.2% and impurity of 3.8%) and 60mL of ethyl acetate to 55 ℃, stirring for 30min to dissolve, adding 160mL of isopropyl ether at the temperature, keeping the temperature and stirring for 30min, slowly cooling to 0 ℃, stirring for 1h, filtering, and leaching a filter cake with 20mL of isopropyl ether. Vacuum drying at 40 deg.C for 10 hr to obtain 34.2g white powdery solid with HPLC purity of 99.83%, maximum single impurity content of 0.07%, and total impurity content of 0.17%.
Example 2:
heating 40g of a self-made sitagliptin crude product (HPLC purity is 95.7%, impurity is 4.3%) and 80mL of isopropyl acetate to 50 ℃, stirring for 35min to dissolve, adding 200mL of isopropyl ether at the temperature, keeping the temperature and stirring for 20min, slowly cooling to 0 ℃, stirring for 40min, filtering, and leaching a filter cake with 25mL of isopropyl ether. Vacuum drying at 45 deg.C for 6 hr to obtain 35.6g white powdery solid with HPLC purity of 99.86%, maximum single impurity content of 0.04%, and total impurity content of 0.14%.
Example 3:
heating 40g of a self-made crude sitagliptin product (with HPLC purity of 95.9% and impurities of 4.1%) and 72mL of ethanol to 53 ℃, stirring for 20min to dissolve, adding 220mL of methyl tert-butyl ether at the temperature, keeping the temperature and stirring for 45min, slowly cooling to-5 ℃, stirring for 1.5h, filtering, and leaching a filter cake with 40mL of isopropyl ether. Vacuum drying at 55 deg.C for 8 hr to obtain 33.8g white powdery solid with HPLC purity of 99.75%, maximum single impurity content of 0.08%, and total impurity content of 0.25%.
Example 4:
heating 40g of a self-made crude sitagliptin product (with HPLC purity of 95.9% and impurity content of 4.1%) and 90mL of isopropanol to 60 ℃, stirring for 25min to dissolve, adding 240mL of methyl tert-butyl ether at the temperature, keeping the temperature and stirring for 30min, slowly cooling to-0 ℃, stirring for 0.5h, filtering, and leaching a filter cake with 50mL of isopropyl ether. Vacuum drying at 45 deg.C for 8 hr to obtain 32.5g white powdery solid with HPLC purity of 99.78%, maximum single impurity content of 0.07%, and total impurity content of 0.22%.
Example 5:
heating 40g of a self-made crude sitagliptin (HPLC purity is 96.3%, impurity is 3.7%) and 65mL of ethyl acetate to 48 ℃, stirring for 35min to dissolve, adding 210mL of n-heptane at the temperature, keeping the temperature and stirring for 40min, slowly cooling to-8 ℃, stirring for 2h, filtering, and leaching a filter cake with 55mL of isopropyl ether. Vacuum drying at 45 deg.C for 10 hr to obtain 34.2g white powdery solid with HPLC purity of 99.76%, maximum single impurity content of 0.09%, and total impurity content of 0.24%.
Example 6:
heating 40g of a self-made sitagliptin crude product (with HPLC purity of 96.0 percent and impurity of 4.0 percent) and 55mL of tetrahydrofuran to 40 ℃, stirring for 15min to dissolve, adding 320mL of n-hexane at the temperature, keeping the temperature and stirring for 50min, slowly cooling to-2 ℃, stirring for 2.5h, filtering, and leaching a filter cake with 40mL of isopropyl ether. Vacuum drying at 50 deg.C for 6 hr to obtain 32.8g white powdery solid with HPLC purity of 99.77%, maximum single impurity content of 0.06%, and total impurity content of 0.23%.
Claims (10)
1. A method for purifying sitagliptin, characterized by comprising the following steps:
(a) dissolving a sitagliptin crude product in a first solvent, heating and stirring to dissolve the sitagliptin crude product;
(b) adding a second solvent into the clear solution, stirring at a constant temperature, and slowly cooling to low temperature and stirring;
(c) filtering, washing a filter cake, and drying in vacuum to obtain the pure sitagliptin product.
2. The method of purifying sitagliptin according to claim 1, characterized in that: the first solvent used in step (a) is selected from one or more of acetonitrile, isopropyl acetate, ethanol, ethyl acetate, tetrahydrofuran, isopropanol, preferably one or more of ethyl acetate, isopropyl acetate, ethanol, isopropanol or tetrahydrofuran.
3. The method of purifying sitagliptin according to claim 1 or 2, characterized in that: the amount of the first solvent used in the step (a) is 1.3-3 times by volume, preferably 1.3-2.5 times by volume of the weight of the crude sitagliptin.
4. The method of purifying sitagliptin according to claim 1, characterized in that: the heating temperature in the step (a) is 40-60 ℃, and preferably 50 ℃; the heating and stirring time in the step (a) is 10-60 min, preferably 10-40 min.
5. The method of purifying sitagliptin according to claim 1, characterized in that: the second solvent used in step (b) is selected from one or more of n-heptane, methyl tert-butyl ether, isopropyl ether, n-hexane, diethyl ether, preferably isopropyl ether, methyl tert-butyl ether, n-heptane or n-hexane.
6. The method for purifying sitagliptin according to claim 1 or 5, characterized in that: the amount of the second solvent used in step (b) is 3 to 10 volumes, preferably 4 to 8 volumes, based on the weight of the crude sitagliptin product; the temperature at which the second solvent is dropped is 40 ℃ to 60 ℃, preferably 50 ℃.
7. The method for purifying sitagliptin according to claim 1, characterized in that: the temperature of the heat preservation and stirring in the step (b) is 40-60 ℃, and preferably 50 ℃; the stirring time is 10-60 min, preferably 20-50 min.
8. The method for purifying sitagliptin according to claim 1, characterized in that: the low temperature in the step (b) means that the temperature is less than or equal to 10 ℃, and is preferably-10-5 ℃; the low-temperature cooling stirring time is 30min-5h, preferably 30min-3 h.
9. The method for purifying sitagliptin according to claim 1, characterized in that: the washing solvent in the step (c) is isopropyl ether, and the dosage of the isopropyl ether is 0.5-3 times of the volume of the crude sitagliptin product, and preferably 0.5-1.5 times of the volume of the crude sitagliptin product.
10. The method for purifying sitagliptin according to claim 1, which is characterized in that: the vacuum drying temperature in the step (c) is 40-60 ℃, and the vacuum drying time is 3-10 h.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910946335.5A CN112608314A (en) | 2019-10-04 | 2019-10-04 | Method for purifying sitagliptin |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910946335.5A CN112608314A (en) | 2019-10-04 | 2019-10-04 | Method for purifying sitagliptin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024086263A1 (en) * | 2022-10-21 | 2024-04-25 | Merck Sharp & Dohme Llc | Compositions of a dipeptidyl peptidase-iv inhibitor and an antioxidant |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024086263A1 (en) * | 2022-10-21 | 2024-04-25 | Merck Sharp & Dohme Llc | Compositions of a dipeptidyl peptidase-iv inhibitor and an antioxidant |
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Application publication date: 20210406 |