KR20230062916A - Fimasartan Anhydride Form A Crystal Polymorph and Method for the preparation thereof - Google Patents
Fimasartan Anhydride Form A Crystal Polymorph and Method for the preparation thereof Download PDFInfo
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- 229960003489 fimasartan Drugs 0.000 title claims abstract description 64
- 239000005475 Fimasartan Substances 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 title claims abstract description 9
- 239000013078 crystal Substances 0.000 title description 10
- 238000002360 preparation method Methods 0.000 title description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- -1 Fimasartan anhydride Chemical class 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000004458 analytical method Methods 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 238000000646 scanning calorimetry Methods 0.000 claims 1
- AMEROGPZOLAFBN-UHFFFAOYSA-N fimasartan Chemical compound CCCCC1=NC(C)=C(CC(=S)N(C)C)C(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 AMEROGPZOLAFBN-UHFFFAOYSA-N 0.000 description 18
- 238000002441 X-ray diffraction Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000004095 fimasartan derivatives Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
본 발명은 본 발명은 피마살탄 무수물 A형 결정다형 및 그 제조방법에 관한 것이다.The present invention relates to fimasartan anhydride Form A polymorph and a method for preparing the same.
Description
본 발명은 피마살탄 무수물 A형 결정다형 및 그 제조방법에 관한 것이다.The present invention relates to fimasartan anhydride form A polymorph and a method for preparing the same.
피마살탄(Fimarsartan)은 고혈압 및 심부전 치료에 사용되는 비 펩타이드 안지오텐신 II 수용체 길항제 (ARB)로 하기 화학식 1의 구조를 갖는다. Fimarsartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure and has the structure of Formula 1 below.
<화학식 1><Formula 1>
피마살탄은 기존의 안지오텐신 Ⅱ 수용체 길항제로 사용되는 약물과는 다른 구조의 피리미디논 화합물로써 국내 공개특허 제10-2004-0032639호에 기재되어 있으며, 대한민국 등록특허 10-0521980호에 개시된 피마살탄 포타슘염 삼수화물 형태는 카나브정이라는 이름으로 시판되고 있다.Fimasartan is a pyrimidinone compound with a different structure from drugs used as existing angiotensin II receptor antagonists, and is described in Korean Patent Publication No. 10-2004-0032639 and Fimasartan Potassium disclosed in Korean Patent Registration No. 10-0521980. The salt trihydrate form is marketed under the name Kanarb tablets.
상기의 피마살탄 포타슘염 삼수화물은 수분 안정성이 떨어지는 문제점이 있어, 이를 개선하기 위한 새로운 형태로서 대한민국 등록특허 10-1490329호에서는 피마살탄 포타슘염 일수화물을 개시하고 있다. 그러나 피마살탄 포타슘염 일수화물 또한 보관 온도 및 건조 조건에 따라 수분 안정성이 떨어지는 문제가 있다.The fimasartan potassium salt trihydrate has a problem of poor water stability, and as a new form for improving this problem, Korean Patent Registration No. 10-1490329 discloses fimasartan potassium salt monohydrate. However, fimasartan potassium salt monohydrate also has a problem of poor moisture stability depending on storage temperature and drying conditions.
또 다른 피마살탄 염으로서 대한민국 공개특허 제10-2017-0061616호에는 피마살탄 메글루민염, 암모늄염 또는 아르기닌염에 대하여 개시하고 있고, 대한민국 공개특허 제10-2018-0105450호에서는 피마살탄 콜린염을 개시하고 있으며, 대한민국 공개특허 제10-2019-0123607호에는 피마살탄 트로메타민염에 대하여 개시하고 있다.As another fimasartan salt, Korean Patent Publication No. 10-2017-0061616 discloses fimasartan meglumine salt, ammonium salt or arginine salt, and Korean Patent Publication No. 10-2018-0105450 discloses fimasartan choline salt. and Korean Patent Publication No. 10-2019-0123607 discloses fimasartan tromethamine salt.
상기의 피마살탄 염은 무기물 또는 유기물염의 형태를 나타내는 것들이다. The above fimasartan salts are in the form of inorganic or organic salts.
대한민국특허 등록특허 제10-2221856호에는 상기의 무기물 또는 유기물염 형태의 피마살탄염과 다른 피마살탄 신규 결정다형으로서 피마살탄 무수물 결정2형, 및 피마살탄 일수화물 결정1형에 대하여 개시하고 있다. Korean Patent Registration No. 10-2221856 discloses fimasartan anhydride
한편, 다형성(polymorphism)은 어떤 하나의 물질 결정다형에서 분자의 공간적 배열, 배위 등에 의하여 서로 다른 다양한 결정다형형이 나타내는 것을 말하며, 이 서로 다른 결정다형은 융점 및 용해도 등과 같은 물리적 성질, X선 회절 패턴 등에 차이가 있게 된다. 이러한 물질적 성질, X선 회절 패턴 등의 차이로 서로 상이한 결정다형을 구별할 수 있다. On the other hand, polymorphism refers to a variety of crystal polymorphs that differ from each other due to the spatial arrangement and coordination of molecules in a single crystal polymorph, and these different crystal polymorphs have physical properties such as melting point and solubility, X-ray diffraction There are differences in patterns, etc. Different polymorphs can be distinguished from each other by differences in material properties, X-ray diffraction patterns, and the like.
또한, 약학적 측면에서 결정다형에 따라 약제로 사용될 때에 안정성, 생물학적 이용가능성, 용해성과 같은 특성이 달라지기 때문에 다른 결정다형의 필요성이 존재한다. In addition, since properties such as stability, bioavailability, and solubility vary when used as a drug depending on the polymorph form in the pharmaceutical aspect, there is a need for another polymorph form.
그러나 어떤 물질에 대한 결정다형체(crystalline polymorphic form)가 얼마나 존재하는지는 알 수 없으며, 이들 결정다형체 각각을 제조하는 방법도 알려져 있지 아니하다. However, it is not known how many crystalline polymorphic forms exist for a certain substance, and methods for preparing each of these crystalline polymorphic forms are also unknown.
이에 본 발명에서는 상기와 같은 종래의 알려진 결정다형체와는 다른 신규한 결정다형체로서 1 wt% 미만의 수분을 함유하며, 특정의 X선 회절 패턴을 갖는 신규한 피마살탄 무수물 A형 결정다형 및 이 신규한 결정다형을 고수율 및 고순도로 쉽게 제조할 수 있는 제조방법을 제공하고자 하는 것이다. Therefore, in the present invention, a novel polymorph of fimasartan anhydride Form A containing less than 1 wt% of water and having a specific X-ray diffraction pattern as a novel polymorph different from the conventionally known polymorph as described above, and It is an object of the present invention to provide a manufacturing method capable of easily producing this novel polymorph in high yield and high purity.
본 발명이 해결하고자 하는 과제는 본원 발명이 해결하고자 하는 과제는 기존에 알려진 피마살탄의 결정다형과는 다른 열역학적으로 안정하며 흡습성이 낮아, 고온에서도 수분 함량이 변화되지 않을 뿐 아니라 습한 조건에서도 수분 함량이 변화되지 않는 안정성이 높은 신규한 피마살탄 결정다형인 피마살탄 무수물 A형 결정다형을 제공하는 것이다. The problem to be solved by the present invention is thermodynamically stable and low in hygroscopicity, which is different from the previously known polymorphs of fimasartan, so that the water content does not change even at high temperatures and the water content is not changed even under humid conditions. To provide a fimasartan anhydride Form A polymorph, which is a novel polymorph of fimasartan with high stability that does not change.
또한, 제조가 용이하며 수율과 순도가 높은 피마살탄 무수물 A형 결정다형의 제조방법을 제공하는 것이다.In addition, it is to provide a method for preparing fimasartan anhydride form A polymorph, which is easy to manufacture and has high yield and purity.
상기 과제를 해결하기 위하여 본 발명은, 분말 X선 회절(PXRD) 분석에서 2θ 회절각(세기%) 6.85±0.2°(100%), 9.46±0.2°(56.5%), 10.04±0.2° (22.1%), 10.46±0.2°(29.5%) 12.66±0.2°(30.1%) 18.31±0.2°(52.9%), 19.88±0.2°(38.7%), 및 22.02±0.2°(31.2%)에서 특징적인 피크를 나타내는 분말 X선 회절 패턴을 갖는 것을 특징으로 하는, 신규한 피마살탄 결정다형인 피마살탄 무수물 A형 결정다형을 제공한다.In order to solve the above problems, the present invention, in powder X-ray diffraction (PXRD) analysis, 2θ diffraction angle (intensity%) 6.85 ± 0.2 ° (100%), 9.46 ± 0.2 ° (56.5%), 10.04 ± 0.2 ° (22.1 %), 10.46±0.2° (29.5%) 12.66±0.2° (30.1%) 18.31±0.2° (52.9%), 19.88±0.2° (38.7%), and characteristic peaks at 22.02±0.2° (31.2%) Fimasartan anhydride Form A polymorph, which is a novel polymorph of fimasartan, characterized by having a powder X-ray diffraction pattern showing
본 발명에 따른 피마살탄 무수물 A형 결정다형의 분말 X선 회절의 강도 및 피크 위치는 하기 [표 1]의 '피마살탄 무수물 A형 결정다형의 PXRD의 강도 및 피크 위치'와 같다.The intensity and peak position of powder X-ray diffraction of the form A polymorph form of fimasartan anhydride according to the present invention are the same as 'PXRD intensity and peak position of form A polymorph form of fimasartan anhydride' in [Table 1].
또한, 본 발명에 따른 신규한 피마살탄 무수물 A형 결정다형은, 시차주사열량(DSC) 분석에서 124.54℃의 개시온도(onset) 및 133.95℃의 흡열 피크를 가지는 것을 특징으로 한다.In addition, the novel fimasartan anhydride Form A polymorph according to the present invention is characterized by having an onset of 124.54°C and an endothermic peak of 133.95°C in differential scanning calorimetry (DSC) analysis.
또한, 본 발명에 따른, 신규한 피마살탄 무수물 A형 결정다형은 수분 칼피셔 분석에서 1 wt% 미만의 수분을 함유하는 것을 특징으로 한다.In addition, the novel fimasartan anhydride Form A polymorph according to the present invention is characterized by containing less than 1 wt% of water in a water Karl Fischer analysis.
또한, 본 발명은, 본 발명에 따른 신규한 피마살탄 무수물 A형 결정다형을 제조하는 신규한 제조방법을 제공한다. In addition, the present invention provides a novel preparation method for preparing the novel fimasartan anhydride Form A polymorph according to the present invention.
상기 본 발명의 신규한 제조방법은 또 다른 신규한 결정다형인 피마살탄 일수화물 B형을 사용하는 단계를 포함하는 것을 특징으로 한다. The novel manufacturing method of the present invention is characterized in that it includes the step of using fimasartan monohydrate form B, which is another novel polymorph.
또한, 상기 본 발명의 신규한 제조방법은 결정다형화 용매를 사용하는 단계를 포함하는 것을 특징으로 한다. In addition, the novel manufacturing method of the present invention is characterized in that it includes the step of using a crystal polymorphization solvent.
구체적인 제조방법은 A) 신규한 피마살탄 일수화물 B형을 유기용매에 용해하고, 탈수물질을 투입하여 탈수 후 농축하는 단계와; B) 결정다형화 용매를 이용한 결정다형화 및 건조하는 단계;를 포함한다. The specific manufacturing method includes the steps of A) dissolving the novel fimasartan monohydrate type B in an organic solvent, adding a dehydrating material, dehydrating, and then concentrating; B) polymorphism using a polymorphism solvent and drying.
구체적으로 A) 단계 중 상기 유기용매의 사용량(ml)은 상기 피마살탄 일수화물 B형(1g)에 대하여 1 내지 20 ml이고, 바람직하게는 5 내지 15 ml로 사용한다. 유기용매의 사용량이 1 ml 미만이면 피마살탄 일수화물 B형의 용해가 충분히 이루어지지 않아 무수화로의 변환이 충분하지 않으며, 20 ml 초과하는 경우는 유기용매의 많은 사용량에 따른 공정상 어려움 및 경제적인 면이 발생할 수 있는 단점이 있다.Specifically, in step A), the organic solvent used (ml) is 1 to 20 ml, preferably 5 to 15 ml, based on the fimasartan type B monohydrate (1 g). If the amount of the organic solvent used is less than 1 ml, fimasartan monohydrate form B is not sufficiently dissolved and the conversion to anhydrous is not sufficient. There are downsides that can occur.
상기 유기용매는 메틸렌클로라이드, 클로로포름, 메탄올, 에탄올 또는 이들의 혼합물이고, 바람직하게 메틸렌클로라이드를 사용한다. The organic solvent is methylene chloride, chloroform, methanol, ethanol or a mixture thereof, preferably methylene chloride.
상기 B) 단계의 결정다형화의 용매는 메틸-t-부틸에테르, 아세톤, 에틸아세테이트, 이소프로필 아세테이트, 헥산, 헵탄 또는 이들의 혼합물이고, 바람직하게는 에틸아세테이트이다. 상기 결정다형화 용매의 사용량은 상기 피마살탄 수화물 B형(1g)에 대하여 5 내지 20ml 사용한다. 바람직하게는 7 내지 15ml을 사용한다. The solvent for polymorphism in step B) is methyl-t-butyl ether, acetone, ethyl acetate, isopropyl acetate, hexane, heptane or a mixture thereof, preferably ethyl acetate. The amount of the polymorphization solvent used is 5 to 20 ml based on the fimasartan hydrate type B (1 g). Preferably, 7 to 15 ml is used.
상기 B) 단계의 건조는 상기 결정다형화 용매를 이용하여 얻은 결정다형을 건조하는 것이고, 약 30℃ 내지 50℃에서 10 시간 이상, 바람직하게는 50℃에서 12시간 건조한다. 이때 건조는 -0.1 mPa이하에서 이루어진다. The drying in step B) is to dry the polymorph obtained using the polymorphism solvent, and is dried at about 30°C to 50°C for 10 hours or more, preferably at 50°C for 12 hours. At this time, drying is performed below -0.1 mPa.
상기와 같은 본 발명의 제조방법으로부터 얻어지는 본 발명의 상기 피마살탄 무수물 A형 결정다형은 1 wt% 미만의 수분 함량을 함유한다. The fimasartan anhydride Form A polymorph of the present invention obtained from the preparation method of the present invention as described above contains less than 1 wt% of water content.
본 발명에 따른 신규한 피마살탄 무수물 A형 결정다형은 제조가 용이하며 순도가 높고, 높은 안정성 및 낮은 흡습성 등의 물성으로 약제로 사용하기에 우수한 형태 및 물성을 보유하고 있다. 특히 약으로 시판 중인 종래기술의 피마살탄 포타슘염 삼수화물의 문제점인 보관 과정에서의 수분 함량 변화를 개선한 것으로서, 보관 및 저장 과정에서도 수분 함량의 변화가 없고 열역학적으로 안정하며 높은 결정다형성을 나타낸다.The novel fimasartan anhydride Form A polymorph according to the present invention is easy to manufacture, has high purity, high stability and low hygroscopicity, and has excellent form and physical properties for use as a drug. In particular, it is improved in the water content change during the storage process, which is a problem of the prior art fimasartan potassium salt trihydrate commercially available as a drug, and has no change in the water content during the storage and storage process, is thermodynamically stable, and exhibits high crystal polymorphism.
또한, 본 발명의 제조방법은 제조의 단계 및 조작방법이 간단하고, 수율이 높아 제조생산단가를 낮출 수 있는 효과를 나타낸다. In addition, the manufacturing method of the present invention shows the effect of lowering the manufacturing production cost due to the simple manufacturing steps and operation method and high yield.
도 1은 실시예 1에서 얻어진 피마살탄 무수물 A형 결정다형에 대한 수소핵자기공명 스펙트럼이다.
도 2는 실시예 1에서 얻어진 피마살탄 무수물 A형 결정다형에 대한 X선 회절 스펙트럼이다.
도 3은 실시예 1에서 얻어진 피마살탄 무수물 A형 결정다형에 대한 시차주사 열량 스펙트럼이다.1 is a hydrogen nuclear magnetic resonance spectrum of the form A polymorph of fimasartan anhydride obtained in Example 1.
2 is an X-ray diffraction spectrum of the form A polymorph of fimasartan anhydride obtained in Example 1.
3 is a differential scanning calorimetry spectrum of the polymorph form of fimasartan anhydride Form A obtained in Example 1.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예 등을 설명한다. 그러나 본 발명에 따른 실시예는 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예로 인해서 본 발명의 권리범위가 제한되는 것은 아니다.Hereinafter, preferred embodiments and the like will be described to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention is not limited due to the following examples.
<피마살탄 무수물 A형 결정다형의 제조><Preparation of Fimasartan Anhydride Form A Polymorph Form>
제조예 1. 피마살탄 수화물 B형 결정의 제조 Preparation Example 1. Preparation of Fimasartan Hydrate Form B Crystals
상온에서 2-n-Butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-2- ((N-triphenyl-methyl)tetrazol-5-yl)biphenyl-4-yl-methyl-pyrimidin-4(3H)-one 3g을 톨루엔 15 ml에 투입하여 용해하였다. 여기에 Lawesson’s 시약 1.6g을 넣고 90℃에서 4시간 교반하였다. 반응이 완료되면 톨루엔을 농축하고 여기에 메탄올 30 ml을 투입하고 환류교반하였다. 반응이 완료되면 메탄올을 농축하고 EA와 정제수로 결정다형화를 하고 40도에서 12시간 동안 -0.1mPa하에서 감압건조하여 피마살탄 수화물 B형 결정 1.65g을 수득하였다(수율: 77.1%, 순도: 99.89%).2-n-Butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-2- ((N-triphenyl-methyl)tetrazol-5-yl)biphenyl-4-yl-methyl-pyrimidin-4(3H)-one at room temperature 3 g was added to 15 ml of toluene and dissolved. 1.6 g of Lawesson's reagent was added thereto and stirred at 90°C for 4 hours. When the reaction was completed, toluene was concentrated, 30 ml of methanol was added thereto, and the mixture was stirred under reflux. After the reaction was completed, methanol was concentrated, polymorphized with EA and purified water, and dried under reduced pressure at -0.1 mPa at 40 degrees for 12 hours to obtain 1.65 g of fimasartan hydrate form B crystals (yield: 77.1%, purity: 99.89%). ).
실시예 1. 피마살탄 무수물 A형 결정다형의 제조Example 1. Preparation of Fimasartan Anhydride Form A Polymorph
상온에서 상기 제조예 1에서 제조한 피마살탄 수화물 B형 결정 1g을 메틸렌클로라이드 10 ml에 투입하여 용해하였다. 여기에 MgSO4로 탈수를 하고 여과 후 농축하였다. EA로 결정다형화를 하고 40도에서 12시간 동안 -0.1mPa하에서 감압건조하여 건조하여 피마살탄 무수물 A형 결정다형 0.91g을 수득하였다(수율: 94.8%, 순도: 99.96%).At room temperature, 1 g of fimasartan hydrate type B crystal prepared in Preparation Example 1 was added to 10 ml of methylene chloride and dissolved. Here, dehydrated with MgSO4 and concentrated after filtration. After polymorphization with EA, the mixture was dried at 40 degrees for 12 hours under reduced pressure of -0.1 mPa to obtain 0.91 g of fimasartan anhydride Form A polymorph (yield: 94.8%, purity: 99.96%).
상기 실시예 1에서 수득한 피마살탄 무수물 A형 결정다형에 대하여 수소 핵자기공명(NMR) 스펙트럼 분석을 실시하고, 그 결과를 도 1에 첨부하였다. 상기 피마살탄 무수물 A형 결정다형의 NMR (400mhz)은 7.90(d, 1H), 7.55(m, 1H), 7.48(m, 1H), 7.36(d, 1H), 7.05(m, 4H), 5.21(s, 2H), 3.79(s, 2H), 3.44(d, 6H), 2.66(m, 2H), 2.28(s, 3H), 1.66(m, 2H), 1.35(m, 2H), 0.88(t, 3H)에서 각각 피크를 보였다. Fimasartan anhydride Form A polymorph obtained in Example 1 was subjected to hydrogen nuclear magnetic resonance (NMR) spectral analysis, and the results are attached in FIG. 1. NMR (400 mhz) of the fimasartan anhydride Form A polymorph was 7.90 (d, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.36 (d, 1H), 7.05 (m, 4H), 5.21 (s, 2H), 3.79(s, 2H), 3.44(d, 6H), 2.66(m, 2H), 2.28(s, 3H), 1.66(m, 2H), 1.35(m, 2H), 0.88( t, 3H) showed peaks, respectively.
또한, 상기에서 얻은 피마살탄 무수물 A형 결정다형의 XRD 패턴은 도 2에 나타내었고, 이의 온도 시차주사 열량 스펙트럼은 도 3에 나타내었다.In addition, the XRD pattern of the fimasartan anhydride Form A polymorph obtained above is shown in FIG. 2, and the temperature differential scanning calorimetry spectrum thereof is shown in FIG. 3.
<결정다형형 분석><Polymorphic analysis>
가. 분말 X선 회절(XRD) 분석go. Powder X-ray diffraction (XRD) analysis
상기 실시예 1에서 얻어진 피마살탄 무수물 A형 결정다형에 대하여 분말 X선 회절 분석을 실시한 결과, 도 1에서 보는 바와 같이 6.85±0.2°(100%), 9.46±0.2°(56.5%), 10.04±0.2°(22.1%), 10.46±0.2°(29.5%) 12.66±0.2° (30.1%) 18.31±0.2°(52.9%), 19.88±0.2°(38.7%), 및 22.02±0.2°(31.2%)에서 각각 피크를 보였다. 이때, 분말 X선 회절(XRD) 스펙트럼의 측정조건은 다음과 같다.As a result of powder X-ray diffraction analysis on the Fimasartan anhydride Form A polymorph obtained in Example 1, as shown in FIG. 0.2° (22.1%), 10.46±0.2° (29.5%) 12.66±0.2° (30.1%) 18.31±0.2° (52.9%), 19.88±0.2° (38.7%), and 22.02±0.2° (31.2%) showed peaks in each. At this time, the measurement conditions of the powder X-ray diffraction (XRD) spectrum are as follows.
1) 장치 : Rigaku사의 MiniFlex 600/X선원 : Cu1) Device: Rigaku's MiniFlex 600/X-ray source: Cu
2) 관 전압 : 40 kV/관 전류 : 15mA2) Tube voltage: 40 kV/tube current: 15 mA
3) 발산 슬릿 : 1°/산란 슬릿 : 1°/수광 슬릿 : 0.15mm3) Divergence slit : 1° / Scattering slit : 1° / Light receiving slit : 0.15mm
4) 주사 범위 : 3 내지 40° 2θ/샘플링 간격 0.04℃4) Scan range: 3 to 40° 2θ/sampling interval 0.04°C
5) 스캔 속도 : 10°/min5) Scan speed: 10°/min
반면, 대한민국 등록특허공보 제10-2221856호에 따르면, 피마살탄 무수물 결정2형의 2θ 회절각은 6.84°(24.6%), 8.84°(52.6%), 11.37°(99.6%), 11.65°(76.9%), 13.59°(84.9%), 16.85°(100%), 21.69°(69.0%), 24.14°(74.6%) 등인 것으로 보고되어 있다(특허문헌 7 참조). On the other hand, according to Korean Patent Registration No. 10-2221856, the 2θ diffraction angles of
위에서 본 바와 같이 본 발명의 피마살탄 무수물 A형 결정다형은 종래기술의 피마살탄 무수화물 결정2형과 대비할 때 확실히 상이한 2θ 회절각을 나타내고 있다. As seen above, the crystalline polymorph form of fimasartan anhydride of the present invention exhibits a distinctly different 2θ diffraction angle when compared to the
따라서 본 발명의 피마살탄 무수물 A형 결정다형은 종래의 피마살탄 무수화물 결정2형의 결정다형과는 다른 신규한 결정다형임을 알 수 있다. Therefore, it can be seen that the polymorph form of fimasartan anhydride Form A of the present invention is a novel polymorph form different from the conventional polymorph form of
나. 시차주사 열량(DSC) 분석 me. Differential Scanning Calorimetry (DSC) Analysis
상기 실시예 1에서 수득한 피마살탄 무수물 A형 결정다형에 대하여 시차주사 열량(DSC) 분석을 실시하고, 그 결과를 도 2에 첨부하였다. 도 2에서 보는 바와 같이, 상기 본 발명의 결정다형은, 124.54℃의 개시온도(onset) 및 133.95℃의 흡열 피크를 보였다. 상기 시차주사 열량계 스펙트럼의 측정조건은 다음과 같다.Differential scanning calorimetry (DSC) analysis was performed on the fimasartan anhydride form A polymorph obtained in Example 1, and the results are attached in FIG. 2. As shown in FIG. 2, the polymorph of the present invention showed an onset of 124.54°C and an endothermic peak of 133.95°C. The measurement conditions of the differential scanning calorimetry spectrum are as follows.
1) 장치: Q20(TA instrument)1) Device: Q20 (TA instrument)
2) 측정 범위: 10 내지 200 ℃/승온 간격: 10℃/min2) Measurement range: 10 to 200 ° C / temperature increase interval: 10 ° C / min
다. 함수량의 변화 분석all. Analysis of changes in water content
약품의 제제학적으로 바람직한 화합물의 형태는 초기 형태를 유지하면서 어떠한 환경에서도 수분의 변화가 일어나지 않는 형태인 것이 바람직하다. 따라서, 상기 실시예 1에서 수득한 본 발명의 피마살탄 무수물 A형 결정다형의 함수량 변화를 확인하기 위하여, 25℃에서 상대습도 50% 조건하에 본 발명의 피마살탄 무수물 A형 결정다형 화합물의 시간에 따른 함수량(K.F. 수분 %)을 측정하였다. 그 결과를 하기 표 2에 나타내었다.It is preferable that the form of the pharmaceutically desirable compound of the drug is a form in which moisture does not change in any environment while maintaining the initial form. Therefore, in order to confirm the change in water content of the Fimasartan Anhydride Form A polymorph of the present invention obtained in Example 1, the Fimasartan Anhydride Form A polymorph of the present invention was measured for a period of time under the condition of 25° C. and 50% relative humidity. The water content (K.F. moisture %) was measured according to. The results are shown in Table 2 below.
A형 결정다형Fimasartan Anhydrous
Form A polymorphism
상기 표 2에 나타난 바와 같이, 본 발명에 따른 피마살탄 무수물 A형 결정다형은 시간의 변화에 따른 수분의 변화가 일어나지 않았다. 즉, 초기 함수량과 비교하여 시간이 경과 하여도 함수량은 거의 동일한 수준으로 유지되었다. 더욱이 본 발명의 피마살탄 무수물 A형 결정다형은 수분 함량이 1% 미만, 즉 0.21%로서 종래기술의 피마살탄 포타슘 삼수화물 결정다형의 수분 함량 9.45%(특허문헌 2 참조), 및 피마살탄 일수화물 결정I형의 수분 함량 3.42%(특허문헌 7 참조)에 비하여 현저히 낮은 수준임을 알 수 있다.As shown in Table 2, the fimasartan anhydride Form A polymorph according to the present invention did not show a change in moisture over time. That is, compared to the initial water content, the water content was maintained at almost the same level over time. Furthermore, the fimasartan anhydride Form A polymorph of the present invention has a water content of less than 1%, that is, 0.21%, which is 9.45% of the prior art fimasartan potassium trihydrate polymorph (refer to Patent Document 2) and fimasartan monohydrate. It can be seen that the water content of crystalline form I is significantly lower than that of 3.42% (see Patent Document 7).
따라서 본 발명의 피마살탄 무수물 A형 결정다형은 위에서 본 바와 같이 환경변화에서도 수분의 변화가 거의 일어나지 않는 형태이고, 또한, 수분 함량이 낮은 결정다형이어서 약품의 제제학적으로 바람직한 신규한 결정다형의 화합물이다. Therefore, as seen above, the fimasartan anhydride form A polymorph of the present invention is a form in which moisture hardly changes even when the environment changes, and also has a low moisture content, so it is a novel polymorphic compound suitable for pharmaceutical pharmaceuticals. am.
Claims (5)
상기 결정다형은, 전체 결정다형 중 1 wt% 미만의 수분을 함유하는 것을 특징으로 하는, 피마살탄 무수물 A형 결정다형According to claim 1,
The polymorph form of fimasartan anhydride Form A polymorph, characterized in that it contains less than 1 wt% of water in the total polymorph form.
상기 결정다형은, 온도시차주사 열량(DSC)분석에서 탈수화 피크가 존재하지 않고, 흡열 개시 온도 124.54℃의 개시온도(onset) 및 133.95℃의 흡열곡선을 보이는 것을 특징으로 하는, 피마살탄 무수물 A형 결정다형According to claim 1,
Fimasartan anhydride A, characterized in that the polymorph does not have a dehydration peak and shows an endothermic onset temperature of 124.54 ° C and an endothermic curve of 133.95 ° C in differential temperature scanning calorimetry (DSC) analysis. form polymorphism
상기 유기용매는 상기 유기용매는 메틸렌클로라이드, 클로로포름, 메탄올, 에탄올 또는 이들의 혼합물이며,
상기 결정다형화 용매는 메틸-t-부틸에테르, 아세톤, 에틸아세테이트, 이소프로필 아세테이트, 헥산, 헵탄 또는 이들의 혼합물인 것을 특징으로 하는 피마살탄 무수물 A형 결정다형의 제조방법A method for preparing the fimasartan anhydride form A polymorph according to any one of claims 1 to 3; ; B) polymorphism using a polymorphism solvent and drying;
The organic solvent is methylene chloride, chloroform, methanol, ethanol or a mixture thereof,
Method for producing fimasartan anhydride type A polymorph, characterized in that the polymorphization solvent is methyl-t-butyl ether, acetone, ethyl acetate, isopropyl acetate, hexane, heptane or a mixture thereof
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| KR20040032639A (en) | 2002-10-10 | 2004-04-17 | 보령제약 주식회사 | The preparation method for pyrimidinone compound and trihydrate of the salt of the pyrimidinone compound |
| KR101490329B1 (en) | 2012-10-12 | 2015-02-04 | 보령제약 주식회사 | Fimasartan Potassium Monohydrate Crystal, Preparation Thereof And Pharmaceutical Composition Comprising Them |
| KR20170061616A (en) | 2015-11-26 | 2017-06-05 | 보령제약 주식회사 | New salt of fimasartan |
| KR20180105450A (en) | 2017-03-15 | 2018-09-28 | 보령제약 주식회사 | A Method of preparing Fimarsartan choline salt and hydrate thereof |
| KR20190123607A (en) | 2018-04-24 | 2019-11-01 | (주)국전약품 | Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same |
| KR102221856B1 (en) | 2020-10-12 | 2021-03-02 | 유니셀랩 주식회사 | Novel crystalline polymorph of fimasartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20040032639A (en) | 2002-10-10 | 2004-04-17 | 보령제약 주식회사 | The preparation method for pyrimidinone compound and trihydrate of the salt of the pyrimidinone compound |
| KR100521980B1 (en) | 2002-10-10 | 2005-10-17 | 보령제약 주식회사 | The preparation method for pyrimidinone compound and trihydrate of the salt of the pyrimidinone compound |
| KR101490329B1 (en) | 2012-10-12 | 2015-02-04 | 보령제약 주식회사 | Fimasartan Potassium Monohydrate Crystal, Preparation Thereof And Pharmaceutical Composition Comprising Them |
| KR20170061616A (en) | 2015-11-26 | 2017-06-05 | 보령제약 주식회사 | New salt of fimasartan |
| KR20180105450A (en) | 2017-03-15 | 2018-09-28 | 보령제약 주식회사 | A Method of preparing Fimarsartan choline salt and hydrate thereof |
| KR20190123607A (en) | 2018-04-24 | 2019-11-01 | (주)국전약품 | Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same |
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