WO2014058268A1 - 피마살탄 포타슘염의 일수화물 결정, 그 제조방법, 및 그를 포함하는 약제학적 조성물 - Google Patents

피마살탄 포타슘염의 일수화물 결정, 그 제조방법, 및 그를 포함하는 약제학적 조성물 Download PDF

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WO2014058268A1
WO2014058268A1 PCT/KR2013/009097 KR2013009097W WO2014058268A1 WO 2014058268 A1 WO2014058268 A1 WO 2014058268A1 KR 2013009097 W KR2013009097 W KR 2013009097W WO 2014058268 A1 WO2014058268 A1 WO 2014058268A1
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WIPO (PCT)
Prior art keywords
potassium salt
fimasartan
salt monohydrate
fimasartan potassium
monohydrate
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PCT/KR2013/009097
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English (en)
French (fr)
Korean (ko)
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김제학
김지한
이준광
유병욱
한남석
남경완
김창모
이주한
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보령제약 주식회사
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Priority to IN3975DEN2015 priority Critical patent/IN2015DN03975A/en
Priority to EP13845572.0A priority patent/EP2927226A4/en
Priority to BR112015008170A priority patent/BR112015008170A2/pt
Priority to CN201380063465.5A priority patent/CN104854099B/zh
Priority to RU2015117524A priority patent/RU2613555C2/ru
Priority to AU2013330603A priority patent/AU2013330603B2/en
Priority to CA2887056A priority patent/CA2887056C/en
Priority to MX2015004573A priority patent/MX353635B/es
Publication of WO2014058268A1 publication Critical patent/WO2014058268A1/ko
Priority to PH12015500794A priority patent/PH12015500794A1/en
Priority to SA515360275A priority patent/SA515360275B1/ar

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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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention relates to a monohydrate crystal of fimasartan potassium salt, a method for preparing the same, and a pharmaceutical composition comprising the same, and more particularly, to an antagonistic action against angiotensin II receptor, and to a cardiovascular disease caused by angiotensin II receptor.
  • the present invention relates to a monohydrate crystal of fimasartan potassium salt in a form in which a fimasartan potassium salt compound useful in the present invention can be stably present in air, and to a preparation method thereof, and to a pharmaceutical composition comprising the same.
  • Fimasartan is an angiotensin II receptor antagonist and is marketed in two doses, 60 and 120 mg, under the trade name Carnab ® , with the main component being fimasartan potassium salt trihydrate.
  • Fimasaltan is described in International Application No. PCT / KR1999 / 00198 as pyrimidinone compounds other than drugs having an antagonistic action on existing angiotensin II receptors, and Fimasaltan in Korean Patent Publication No. 10-2001-0090193 A new method of preparation of is disclosed.
  • Korean Patent Publication No. 10-2004-0032639 also discloses that trihydrate form of fimasartan potassium salt is possible.
  • the trihydrate of fimasartan potassium salt is prepared in anhydrous form when dried at 60 ° C. for 24 hours as described in Example 5 and Table 1 of Korean Patent Publication No. 10-2004-0032639, and trihydrate at room temperature when left at room temperature. It gradually changes to, which can proceed to trihydrate faster under certain high humidity conditions.
  • the fimasartan potassium salt trihydrate may cause the loss of crystal water of the trihydrate depending on the drying temperature conditions, which may cause a change in water content, and further work to prepare the fimasartan potassium salt trihydrate that is more stable at room temperature. This was required.
  • the moisture content may appear in various forms depending on the temperature conditions in the drying process, and also the moisture content in the preparation process may easily vary depending on the drying conditions in the manufacturing process. .
  • the present inventors have studied to develop a new crystalline form of fimasartan potassium salt having excellent particle stability and uniform particle size, and does not require a separate milling process. It was completed.
  • Patent Document 1 Republic of Korea Patent Publication No. 10-2004-0032639
  • the present invention provides a new crystalline form of fimasartan potassium salt monohydrate having high stability against moisture and temperature while having a uniform particle size.
  • the present invention also provides a process for preparing the new crystalline form of fimasartan potassium salt monohydrate.
  • the present invention also provides a composition for preventing, alleviating, or treating hypertension, including the new crystalline form of fimasartan potassium salt monohydrate.
  • the present invention relates to a new crystalline form of fimasartan potassium salt monohydrate of a new crystalline form, which is excellent in stability to moisture and temperature, and has a uniform particle size, and is easy to form.
  • the present invention relates to fimasartan potassium salt. Provide monohydrate.
  • the change in the water content of the castor oil saltan potassium salt monohydrate the temperature according to the invention than castor oil saltan potassium salt trihydrate is used for current commercially available Kana probe ® almost not have a high stability against temperature changes, the particle size is homogeneous In addition, the crystal grain size is easy to apply in the formulation process, it is an excellent crystalline form that can significantly shorten the process time.
  • the present invention provides a novel potassium salt monohydrate of fimasartan.
  • Crystalline fimasartan potassium salt monohydrate of the present invention has an X-ray powder diffraction spectrum peak using Cu-K ⁇ radiation at 6.67 ⁇ 0.2, 7.62 ⁇ 0.2, 11.03 ⁇ 0.2, 15.32 ⁇ 0.2, 16.49 ⁇ 0.2, 20.12 ⁇ 0.2, 25.65 ⁇ 0.2, and 27.28 ⁇ 0.2.
  • the crystalline Pimasaltan potassium salt monohydrate of the present invention has an X-ray powder diffraction spectrum peak using Cu-K ⁇ radiation at 6.67 ⁇ 0.1, 7.62 ⁇ 0.1, 11.03 ⁇ 0.1, 15.32 ⁇ 0.1, 16.49 at diffraction angle 2 ⁇ . Appear at ⁇ 0.1, 20.12 ⁇ 0.1, 25.65 ⁇ 0.1, and 27.28 ⁇ 0.1.
  • the crystalline fimasartan potassium salt monohydrate of the present invention exhibits a peak of the powder X-ray diffraction spectrum of [FIG. 1].
  • the crystalline fimasartan potassium salt monohydrate of the present invention exhibits DSC (Differential Scanning Calorimetry) endothermic transition at about 267 ° C to about 268 ° C when the temperature increase rate is 10 ° C / min.
  • DSC Different Scanning Calorimetry
  • the DSC endothermic transition value may vary depending on the purity of the crystalline form of the present invention, for example, may have a value within the range of about 263 °C to about 269 °C. This value may also depend on the rate of temperature rise of the instrument for measuring the DSC endothermic transition value.
  • the crystalline fimasartan potassium salt monohydrate of the present invention exhibits a water weight change of about 3.4% when a thermogravimetric test using a Thermo Gravimetry / Differential Thermal Analyzer is performed.
  • the present invention provides a new crystalline form of fimasartan potassium salt monohydrate having high stability against moisture and temperature while having a uniform particle size.
  • the present invention relates to fimasartan potassium salt comprising crystallizing fimasartan from an organic solvent including at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane.
  • an organic solvent including at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane.
  • both the starting material fimasartan and the reaction reagent can be purchased and used in the market.
  • the suspension is preferably prepared in 2 mL to 5 mL, more preferably in 2 mL to 3 mL, based on 1 g of fimasaltan.
  • the suspension is preferably carried out at 20 ° C to 30 ° C, more preferably at 25 ° C.
  • the organic solvent used to prepare the suspension may be isopropyl alcohol.
  • the mixed solution may further include isopropyl alcohol.
  • the preparing of the reactant may include adding the mixed solution to the suspension, and heating and refluxing the reactant to prepare the reactant.
  • the heating of the reactant is preferably heated to 70 ° C to 90 ° C, more preferably to 78 ° C to 84 ° C. Fimasaltan may be dissolved by the heating.
  • the cooling is preferably cooled to 20 °C to 30 °C, more preferably to 25 °C.
  • the reflux stirring time is preferably within 30 minutes to 2 hours to obtain a high yield and high purity of the product.
  • the drying of the fourth step of the production method of the present invention may be a reduced pressure drying.
  • the drying time of the fourth step of the production method of the present invention is preferably 5 hours to 10 hours, more preferably 8 hours.
  • the drying temperature of the fourth step of the production method of the present invention is preferably 35 ° C to 45 ° C, more preferably about 40 ° C.
  • the drying pressure of the fourth step of the manufacturing method of the present invention is preferably 20mmHg to 5mmHg pressure.
  • the present invention comprises crystallizing fimasartan potassium salt trihydrate from an organic solvent comprising at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane.
  • an organic solvent comprising at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane.
  • the fimasartan potassium salt trihydrate is added to an organic solvent comprising at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane, and heated and stirred to react the reactants.
  • an organic solvent comprising at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane
  • both the starting material pimasaltan potassium salt trihydrate and the reaction reagent can be purchased and used commercially available.
  • the heating may be made at 70 °C to 80 °C.
  • the fimasartan trihydrate may be dissolved by the heating.
  • the organic solvent may be ethanol.
  • the organic solvent may be two or more mixed solvents selected from methanol, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, and dioxane.
  • the stirring time of the 1st step of the manufacturing method of this invention is 10 hours or more, It is more preferable that it is 10 hours-20 hours, It is most preferable that it is 15 hours.
  • the cooling is preferably cooled to 20 °C to 30 °C, more preferably to 25 °C.
  • the drying time of the third step of the production method of the present invention is preferably 5 hours to 10 hours, more preferably 8 hours.
  • the drying temperature of the third step of the production method of the present invention is preferably 35 ° C to 45 ° C, more preferably about 40 ° C.
  • the drying pressure of the third step of the manufacturing method of the present invention is preferably 20mmHg to 5mmHg pressure.
  • the fimasartan potassium salt trihydrate is added to an organic solvent including at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and dioxane and refluxed to prepare a reactant. step;
  • both the starting material pimasaltan potassium salt trihydrate and the reaction reagent can be purchased and used commercially available.
  • the organic solvent may be any one or more selected from the group consisting of acetonitrile, tetrahydrofuran, ethyl acetate, acetone and dioxane.
  • the reflux time of the first step of the preparation method of the present invention is preferably 10 minutes to 1 hour, more preferably 30 minutes.
  • the stirring time of the first step of the production method of the present invention is preferably 10 hours or more, more preferably 15 hours.
  • the cooling is preferably cooled to 20 °C to 30 °C, more preferably to 25 °C.
  • the drying time of the third step of the preparation method of the present invention is preferably 5 hours to 10 hours, more preferably 8 hours.
  • the drying temperature of the third step of the production method of the present invention is preferably 35 ° C to 45 ° C, more preferably about 40 ° C.
  • the drying pressure of the third step of the manufacturing method of the present invention is preferably 20mmHg to 5mmHg pressure.
  • the present invention is to be prepared by any one of the above method for preparing Pimasaltan potassium salt monohydrate, Pimasaltan potassium salt monohydrate.
  • the fimasartan potassium salt monohydrate of the present invention is not limited to this preparation method.
  • the present invention provides a composition for preventing, alleviating or treating hypertension comprising fimasartan potassium salt monohydrate and a pharmaceutically acceptable carrier thereof.
  • the term 'pharmaceutically acceptable means that when administered to a physiologically acceptable animal, preferably a human, it typically does not cause an allergic reaction such as gastrointestinal disorders, dizziness, or the like.
  • the pharmaceutically effective amount may be appropriately changed depending on the disease and its severity, the patient's age, weight, health condition, sex, route of administration and duration of treatment.
  • Examples of the pharmaceutically acceptable carrier include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose , Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, dextrin, calcium One or more selected from the group consisting of carbonate, propylene glycol, liquid paraffin, and physiological saline, but is not limited thereto, and any conventional carrier, excipient or diluent may be used.
  • composition for treating or preventing cancer is conventional fillers, extenders, binders, disintegrants, anti-coagulants, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective properties Colloids, glycerin, fragrances, emulsifiers or preservatives may be further included.
  • the components may be added independently or in combination with the composition for preventing, alleviating or treating hypertension or the fimasartan potassium salt monohydrate.
  • composition of the present invention may be administered via any general route of administration as long as it can reach the desired tissue.
  • composition of the present invention may be administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, endothelially, intranasally, intrapulmonally, rectally, or intradurally, according to the desired method. It is not limited and may be preferably administered orally.
  • the dosage of the pharmaceutical composition according to the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and severity of the patient.
  • the daily dosage or dose of the active ingredient of the pharmaceutical composition of the present invention is 0.1 to 1000 mg, preferably 50 to 500 mg, and may be administered once to several times a day.
  • the fimasartan potassium salt monohydrate according to the present invention may be contained in an amount of 20 to 80% by weight based on the total weight of the composition of the present invention, and when the composition of the present invention is prepared as a tablet, it is 30 per tablet as pimasartan potassium salt. or more, in particular 30, 60, 120, 240 mg.
  • the present invention also provides a formulation comprising fimasartan potassium salt monohydrate.
  • the preparation may be a parenteral preparation such as oral preparations such as granules, powders, solutions, tablets, capsules, or dry syrups, but is not limited to such preparations.
  • the composition of the present invention may be in the form of a tablet or capsule, or a preparation of a liquid or injectable.
  • the present invention provides a novel crystalline form of fimasartan potassium salt monohydrate that is excellent in stability against moisture and temperature but is easy to formulate and excellent in homogeneity.
  • 1 is an XRD diffraction pattern of fimasartan potassium salt monohydrate crystal form according to the present invention.
  • Fimasartan potassium salt trihydrate (Boryeong Pharmaceutical, serial number 2005), IPA (Target, serial number I0077MD), KOH (Target, serial number P0215KA), 2-ethylhexanoic acid (Samjeon, serial number 082511), MeOH ((Samjeon) , Manufacturing No. 061512), THF (Scale, Serial No. T0017MD1), EtOH (Scaled, Serial No. E1946MG), EA ((Scaled, Serial No. E0036MII1), ACN (Scaled, Serial No. A0049MG1), AC (Scaled, Serial No. A0033MJ ).
  • the vacuum drying machine mentioned below used an OV-12 (manufacturer: Jeo-Tak Korea) for Vacuum Oven and MD 4C NT (manufacturer: German Vacuumbrand) for Vacuum Pump.
  • X-ray diffraction spectrum measurement method and DSC (differential scanning calorimetry) instruments and conditions are as follows.
  • Air scatter slit 3 mm
  • LynxEye Detector (line detector)
  • Fimasartan (8.52 g, 16.4 mmol) was added to isopropyl alcohol (18.5 mL) to prepare a suspension.
  • Fimasaltan (8.91 g, 17.1 mmol) was added to isopropyl alcohol (18.5 mL) to prepare a suspension.
  • Fimasartan potassium salt trihydrate (2.50 g, 4.2 mmol) was added to ethanol (5 mL), warmed to 75 ° C, dissolved, and cooled to 25 ° C to precipitate crystals and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasartan potassium salt trihydrate (2.50 g, 4.2 mmol) was added to a mixed solvent of acetonitrile (8 mL) and methanol (1.0 mL), warmed to 75 ° C, dissolved, and cooled to 25 ° C to precipitate crystals and stirred for 15 hours. It was. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasaltan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to a mixed solvent of tetrahydrofuran (100 mL) and methanol (5 mL), warmed to 75 ° C, dissolved, cooled to 25 ° C, precipitated crystals, and stirred for 15 hours. It was. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasartan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to a mixed solvent of ethyl acetate (100 mL) and methanol (10 mL), warmed to 75 ° C, dissolved, and cooled to 25 ° C to precipitate crystals and stirred for 15 hours. .
  • the obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasaltan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to a mixed solvent of acetone (100 mL) and methanol (7.5 mL), warmed to 75 ° C, dissolved, and cooled to 25 ° C to precipitate crystals and stirred for 15 hours. .
  • the obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasartan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to a mixed solvent of acetonitrile (100 mL) and methanol (5 mL), warmed to 75 ° C, dissolved, and cooled to 25 ° C to precipitate crystals and stirred for 15 hours. .
  • the obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasartan potassium salt trihydrate (10.0 g, 16.8 mmol) was dissolved in a mixed solvent of dioxane (100 mL) and methanol (5 mL) at 75 ° C. and dissolved, cooled to 25 ° C. to precipitate crystals, and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasaltan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to tetrahydrofuran (100 mL), refluxed for 30 minutes, cooled to 25 ° C. and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasaltan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to ethyl acetate (100 mL), refluxed for 30 minutes, cooled to 25 ° C. and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasaltan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to acetone (100 mL), refluxed for 30 minutes, cooled to 25 ° C. and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • Fimasartan potassium salt trihydrate (10.0 g, 16.8 mmol) was added to acetonitrile (100 mL), refluxed for 30 minutes, cooled to 25 ° C, and stirred for 15 hours. The obtained solid was filtered at 25 ° C. and dried under reduced pressure at 10 ° C. at 40 ° C. for 8 hours to obtain fimasartan potassium salt monohydrate as a white powdery solid.
  • the obtained fimasartan potassium salt monohydrate was confirmed by X-ray powder diffraction and differential scanning calorimetry.
  • the XRD diffraction pattern of the obtained fimasartan potassium salt monohydrate by the X-ray powder diffraction method is shown in FIG. 1, and the DSC curve of the differential scanning calorimetry system is shown in FIG. 2, respectively.
  • the resulting solid product was filtered and dried to add water and tetrahydrofuran (1:10) mixed solution, and the mixture was refluxed and then cooled to 25 ° C to form crystals.
  • the resulting crystals were filtered and dried at 760 mmHg for 24 hours at 35 ° C. to obtain fimasartan potassium salt trihydrate.
  • the obtained fimasartan potassium salt trihydrate was confirmed by X-ray powder diffraction and differential scanning calorimetry.
  • the XRD diffraction pattern of the obtained fimasartan potassium salt trihydrate by the X-ray powder diffraction method is shown in FIG. 3, and the DSC curve by the differential scanning calorimetry method is shown in FIG. 4, respectively.
  • a process of preparing (granulating) granules for the purpose of improving flowability and tableting is required.
  • the granulation method commonly used is a wet granulation method, and the wet granulation method proceeds in the order of mixing, granulation using a bonding liquid, and drying.
  • the water stability of the fimasartan potassium salt monohydrate and trihydrate was compared through the manufacturing process.
  • the loss on drying after the mixing process was determined to be 1.1%.
  • binder solution 24.5 g of hydropropyl cellulose as a binder was dissolved in 165 g of purified water to prepare a binder solution. Binder was slowly added to the mixture prepared in the High Speed Mixer (SM-5C, SEJONG) and granulated for 3 minutes under the conditions of Agitator 100 rpm and Chopper 2000 rpm. The granules were then put in a tray dryer and dried at 60 ° C. for 4 hours.
  • S-5C High Speed Mixer
  • the loss on drying after the granulation drying process was measured at 0.9%.
  • the loss on drying after the mixing process was determined to be 5.7%.
  • binder solution 24.5 g of hydropropyl cellulose as a binder was dissolved in 165 g of purified water to prepare a binder solution. Binder was slowly added to the mixture prepared in the High Speed Mixer (SM-5C, SEJONG) and granulated for 3 minutes under the conditions of Agitator 100 rpm and Chopper 2000 rpm. The granules were then put in a tray dryer and dried at 60 ° C. for 4 hours.
  • S-5C High Speed Mixer
  • the loss on drying after the granulation drying process was determined to be 1.8%.
  • the particle size of the fimasartan potassium salt monohydrate prepared according to Example 1 was measured using a HELOS System (Sympatec), R5 lens. Measurement of particle size distribution was performed using RODOS / M Dry Powder Dispersion System and Sympatec HELOS System.
  • D10 * means the particle size is distributed within the 10% range.
  • D50 ** means the particle size is distributed within the 50% range.
  • D90 *** means the particle size is distributed within the 90% range.
  • fimasartan potassium salt monohydrate exhibits a relatively homogeneous particle size, and the particle size also has a size of several micrometers which can be obtained by milling.
  • the novel fimasartan potassium salt monohydrate of the present invention is excellent in stability against moisture and temperature and can maintain a stable state without changing moisture content for a long time, and the crystal grain size is easy to prepare and excellent in homogeneity. Therefore, the novel fimasartan potassium salt monohydrate of the present invention can be maintained in a constant state without a change in moisture content during the formulation process, so that it is easy to formulate and can be effectively used for mass production.

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PCT/KR2013/009097 2012-10-12 2013-10-11 피마살탄 포타슘염의 일수화물 결정, 그 제조방법, 및 그를 포함하는 약제학적 조성물 WO2014058268A1 (ko)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IN3975DEN2015 IN2015DN03975A (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2012-10-12 2013-10-11
EP13845572.0A EP2927226A4 (en) 2012-10-12 2013-10-11 MONOHYDRATE CRYSTAL FROM FIMASARTANKALIUM SALT, PROCESS FOR THE PREPARATION THEREOF AND PHARMACOLOGICAL COMPOSITION THEREWITH
BR112015008170A BR112015008170A2 (pt) 2012-10-12 2013-10-11 cristal mono-hidratado de sal de potássio fimasartana, método para a preparação do mesmo e composição farmacológica compreendendo o mesmo
CN201380063465.5A CN104854099B (zh) 2012-10-12 2013-10-11 非马沙坦钾盐的一水合物晶体、其制备方法及包含其的药物组合物
RU2015117524A RU2613555C2 (ru) 2012-10-12 2013-10-11 Моногидратный кристалл калиевой соли фимасартана, способ его получения и содержащая его фармакологическая композиция
AU2013330603A AU2013330603B2 (en) 2012-10-12 2013-10-11 Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same
CA2887056A CA2887056C (en) 2012-10-12 2013-10-11 Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same
MX2015004573A MX353635B (es) 2012-10-12 2013-10-11 Cristal monohidratado de sal de potasio con fimasartan, método para preparar el mismo, y composición farmacéuticas que comprende el mismo.
PH12015500794A PH12015500794A1 (en) 2012-10-12 2015-04-10 Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same
SA515360275A SA515360275B1 (ar) 2012-10-12 2015-04-12 بلورة مونوهيدرات لملح بوتاسيوم لفيماسارتان، طريقة لتحضيره، وتركيبة دوائية تشتمل عليه

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CN106176641A (zh) * 2015-02-05 2016-12-07 保宁制药株式会社 片剂及其制备方法

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KR102247408B1 (ko) 2017-09-18 2021-05-03 보령제약 주식회사 피마살탄 프로드러그
KR102402501B1 (ko) * 2018-04-24 2022-05-26 (주)국전약품 피마살탄 트로메타민염 및 이를 포함하는 약제학적 조성물
KR102221856B1 (ko) 2020-10-12 2021-03-02 유니셀랩 주식회사 신규한 피마살탄 결정형의 다형체
KR20230062916A (ko) 2021-11-01 2023-05-09 그린케미칼 주식회사 피마살탄 무수물 a형 결정다형 및 그 제조방법
KR20230062917A (ko) 2021-11-01 2023-05-09 그린케미칼 주식회사 피마살탄 일수화물 b형 결정다형 및 그 제조방법
KR20240146734A (ko) 2023-03-30 2024-10-08 (주) 에프엔지리서치 피마살탄의 신규 염 및 이의 제조방법

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Free format text: APRESENTE A TRADUCAO SIMPLES DA FOLHA DE ROSTO DA CERTIDAO DE DEPOSITO DA PRIORIDADE KR 10-2012-0113848; OU DECLARACAO DE QUE OS DADOS DO PEDIDO INTERNACIONAL ESTAO FIELMENTE CONTIDOS NA PRIORIDADE REIVINDICADA, CONTENDO TODOS OS DADOS IDENTIFICADORES DESTA (TITULARES, NUMERO DE REGISTRO, DATA E TITULO), CONFORME O PARAGRAFO UNICO DO ART. 25 DA RESOLUCAO 77/2013. CABESALIENTAR QUE NAO FOI POSSIVEL IDENTIFICAR OS TITULARES DO PEDIDO PRIORITARIO NOS DOCUMENTOS JUNTADOS AO PROCESSO, TAMPOUCO NOS APRESENTADOS NA OMPI, POIS SE ENCONTRAM EM COREANO.