WO2011071314A2 - Processes for preparing crystalline forms a and b of ilaprazole and process for converting the crystalline forms - Google Patents

Processes for preparing crystalline forms a and b of ilaprazole and process for converting the crystalline forms Download PDF

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WO2011071314A2
WO2011071314A2 PCT/KR2010/008767 KR2010008767W WO2011071314A2 WO 2011071314 A2 WO2011071314 A2 WO 2011071314A2 KR 2010008767 W KR2010008767 W KR 2010008767W WO 2011071314 A2 WO2011071314 A2 WO 2011071314A2
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ilaprazole
acid
crystalline form
reaction solvent
preparing
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PCT/KR2010/008767
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English (en)
French (fr)
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WO2011071314A3 (en
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Dong Yeon Kim
Jae Soo Shin
Jun Yeoun Lee
Kwi Hyung Cho
Sung Tae Park
Jung Woo Kim
Sang Don Nam
Hee Yun Kim
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Il-Yang Pharm. Co., Ltd.
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Priority to BR112012012212A priority Critical patent/BR112012012212A2/pt
Priority to IN3176DEN2012 priority patent/IN2012DN03176A/en
Priority to UAA201207006A priority patent/UA102787C2/ru
Priority to EA201200716A priority patent/EA019058B1/ru
Publication of WO2011071314A2 publication Critical patent/WO2011071314A2/en
Publication of WO2011071314A3 publication Critical patent/WO2011071314A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to novel processes for preparing crystalline forms A and B of ilaprazole and the conversion of these crystalline forms.
  • Gastric and duodenal ulcers are a gastrointestinal disease caused by various factors such as mental stress, dietary habits, intake of irritable food, and the like.
  • the direct cause of peptic ulcers is damage to the gastric membrane due to excessive secretion of gastric acid.
  • therapeutic agents which have been commonly used for treatment of the peptic ulcers include, for example, antacids for neutralizing gastric acid, anti-pepsin agents, agents for protecting the gastric mucous membrane, anti-cholinergic agents for inhibiting gastric secretion, para-sympatholytic agents, H 2 -receptor antagonists, and the like.
  • H 2 -receptor antagonists as agents for treating gastric and duodenal ulcers has increased.
  • PPI formulations such as omeprazole have demonstrated excellent anticancer effects compared to existing H 2 receptor antagonists, including cimetidine, famotidine and ranitidine, and thus various PPI formulations have been developed and widely used.
  • the present inventors conducted studies for a long timeto develop a novel PPI compound and, as a result, invented ilaprazole, a compound having reduced side effects and high therapeutic effects compared to existing PPI compounds.
  • the invented ilaprazole was patented in many countries, including Korea (Korean Patent Application No. 10-1994-3833).
  • the following reaction scheme 1 shows a general process for preparing ilaprazole.
  • the physical or chemical properties of a drug can vary depending on the crystalline form of the drug, and such physical and chemical properties can greatly influence a suitable dosage form of the drug, the optimization of a process for preparing the drug, and the in vivo absorption of the drug.
  • the discovery of the most appropriate crystalline form of a drug in a procedure for developing the drug enables the development time and cost to be reduced.
  • International Patent Publication No. WO 2008/083333 discloses polymorphic forms of racemic ilaprazole and processes for preparing the same. According to the disclosure of WO 2008/083333, the crystalline form A of racemic ilaprazole is the most thermodynamically stable of these crystalline forms.
  • the crystalline form A is not easily dissolved in organic solvents containing water, but it is the most bio-available form, and thus is the most appropriate dosage form.
  • the crystalline form B of racemic ilaprazole can crystallize in pure form from aprotic solvents such as acetone/TEA, and thus has an advantage in that it can be purified during the preparation process.
  • the XRPD diffraction patterns of the crystalline forms A and B of racemic ilaprazole disclosed in International Patent Publication No. WO 2008/083333 are shown in Tables 1 and 2 below.
  • the DSC onset temperature of the crystalline form A of ilaprazole is 167 °C (max 170 °C)
  • the DSC onset temperature of the crystalline form of ilaprazole is 159 °C (max 163 °C).
  • the following reaction schemes 2 and 3 show processes for preparing crystalline forms A and B of ilaprazole, disclosed in International Patent Publication No. 2008/083333.
  • the process for preparing the crystalline form A of ilaprazole according to reaction scheme 2 above has the following shortcomings: 1) large amounts of various solvents are used in crystallization; 2) the preparation process is complex, because a concentration process should be carried out several times; 3) it is difficult to obtain the pharmaceutically required purity; and 4) a complex crystallization process is used, thus making it difficult to obtain the pure crystalline form A of ilaprazole.
  • the yield of the crystalline form A can be reduced when a process for increasing the purity is carried out, and also in that, because the amount of solvent used is large, the preparation process is not economical and can adversely affect the health of workers.
  • the process for preparing the crystalline form B of ilaprazole according to reaction scheme 3 above has the following shortcomings: 1) because the preparation process is a process of treating the already prepared crystalline form A, a process of preparing the crystalline form B is required; 2) the preparation process is time-consuming, because the crystallization process for obtaining the crystalline form B is continuously carried out for 11 days; and 3) the preparation process is not economical, because the use of an additional solvent is required in order to further treat the already prepared crystalline form A and because the additional process for treating the crystalline form A is carried out to reduce the yield of the crystalline form B. In addition, the preparation process is not suitable for mass production, and thus in some cases, the uniform crystalline form B is not obtained and the partially crystalline or non-uniform crystalline form B is obtained.
  • the present invention has been made in order to more efficiently solve the above-described problems occurringin the prior art.
  • the present invention adopts an industrially simple process compared to existing processes, enables a large amount of the pure crystalline form A of ilaprazole to be reproducibly obtained, is suitable for mass production, and allows the uniform crystalline form B of ilaprazole to be reproducibly obtained.
  • the present invention provides processes for preparing crystalline forms A and B of ilaprazole of the following formula 1 and a process for converting the crystalline forms, which enable the compounds to be obtained with high purity at low production cost in a shortened reaction time and show a reduced number of reaction processes and a high yield:
  • the present invention provides processes for preparing crystalline forms A and B of ilaprazole of the following formula 1 and a process for converting the crystalline forms:
  • the process for preparing crystalline A of ilaprazole according to the present invention includes the steps of: 1) preparing an inorganic salt of ilaprazole or a hydrate thereof from ilaprazole in the presence of an inorganic base and a reaction solvent; and 2) neutralizing the produced inorganic salt of ilaprazole or the hydrate thereof with an acid in a reaction solvent to prepare the crystalline form A of ilaprazole.
  • the process for preparing the crystalline form A of ilaprazole A according to the present invention may additionally include, after step 1), a step of adding a heterogeneous inorganic salt to prepare a heterogeneous inorganic salt of ilaprazole or a hydrate thereof.
  • the inorganic base or inorganic salt that is used in the step of preparing the inorganic salt or inorganic salt hydrate of ilaprazole may include lithium, titanium, barium, zinc, sodium, potassium, calcium, magnesium and/or strontium.
  • it may include zinc, sodium, potassium, calcium, magnesium and/or strontium. More preferably, it may include sodium, potassium, calcium, magnesium and/or strontium.
  • reaction solvent that is used in the step of preparing the inorganic salt or inorganic salt hydrate of ilaprazole may be a lower (C 1 ⁇ C 6 ) alkanol and/or a polar solvent.
  • the reaction solvent that is used in step 1 may be at least one selected from the group consisting of methanol, ethanol, propanol, xylene, toluene, tetrahydrofuran, 1,2-dichloroethane, acetone, ether, dichloromethane, acetonitrile, dimethylsulfoxide, dimethylformamide, and mixtures thereof.
  • it may be at least one selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, acetone, and mixtures thereof. More preferably, it may be methanol, ethanol and/or propanol.
  • step 1) of preparing the inorganic salt or inorganic salt hydrate of ilaprazole may be performed by stirring the mixture at a temperature of 0 to 150 °C preferably 0 to 80 °C and more preferably room temperature to 50 °C but the stirring temperature is not specifically limited. Also, the stirring may preferablybe carried out, but the stirring time is not specifically limited.
  • the acid that is used in step 2) of preparing the crystalline form A of ilaprazole by neutralization with the acid may be at least one selected from the group consisting of chloroacetic acid, benzoic acid, butyric acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, hydroxybenzenesulfonic acid and tartaric acid.
  • it may be at least one selected from the group consisting of chloroacetic acid, benzoic acid, butyric acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, perchloric acid, formic acid and acetic acid. More preferably, it may be benzoic acid, formic acid and/or acetic acid.
  • the reaction solvent that is used in step 2) of preparing the crystalline form A of ilaprazole may be a lower (C 1 ⁇ C 6 ) alkanol and/or a polar solvent.
  • the reaction solvent that is used in step 2) may be at least one selected from the group consisting of methanol, ethanol, propanol, xylene, toluene, tetrahydrofuran, 1,2-dichloromethane, acetone, ether, dichloromethane, acetonitrile, dimethylsulfoxide, dimethylformamide, and mixtures thereof.
  • it may be at least one selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, acetone, and mixtures thereof. More preferably, it may be methanol, ethanol and/or propanol.
  • step 2) of preparing the crystalline form A of ilaprazole may be performed by stirringthe mixture at a temperature of 0 to 150 °C, preferably 0 to 80 °C, and more preferably room temperature to 50 °C, but the stirring temperature is not specifically limited. Also, the stirring may preferably be carried out for 1-6 hours, but the stirring time is not specifically limited.
  • the process for preparing the crystalline form B of ilaprazole according to the present invention may include a step of preparing the crystalline form B of ilaprazole from ilaprazole in a reaction solvent.
  • the reaction solvent that is used in the step of preparing the crystalline form B of ilaprazole may be a lower (C 1 ⁇ C 6 ) alkanol and/or a polar solvent.
  • the reaction solvent that is used in this step may be at least one selected from the group consisting of tetrahydrofuran, 1,2-dichloroethane, methanol, ethanol, propanol, acetone, dichloromethane, diethylether, ethylacetate, and mixtures thereof. More preferably, it may be at least one selected from the group consisting of methanol, ethanol, acetone, dichloromethane, diethylether, ethylacetate, and mixtures thereof.
  • a stabilizing agent may be added to the reaction solvent.
  • a stabilizing agent that may be used in this step is not specifically limited, but it may be at least one selected from the group consistingof, for example, triethylamine, diethylamine, ethylenediamine, trimethylamine, diisopropylethylamine and pyridine.
  • the step of preparing the crystalline form B of ilaprazole may be performed by stirring the mixture at a temperature of 30 to 150 °C, preferably 0 to 150 °C, more preferably 0 to 80 °C, and even more preferably room temperature to 50 °C,but the stirring temperature is not specifically limited. Also, the stirring may preferably be carried out for 1-6 hours, but the stirring time is notspecifically limited.
  • the starting material ilaprazole may be non-crystallized ilaprazole such as crude ilaprazole.
  • the process for converting crystalline forms of ilaprazole according to the present invention may include a step of converting the crystalline form A into crystalline form B of ilaprazole or converting the crystalline form B into crystalline form A of ilaprazole.
  • a solvent that may be used when preparing the crystalline form B from ilaprazole may be used.
  • an inorganic salt, a reaction solvent and/or an acid which may be used when preparing the crystalline form A from ilaprazole, may be used.
  • FIG. 1 is the XRPD diffraction pattern of the crystalline form A of ilaprazole according to the present invention
  • FIG. 2 is the DSC thermogram of the crystalline form A of ilaprazole according to the present invention
  • FIG. 3 is the IR spectrum of the crystalline form A of ilaprazole according to the present invention.
  • FIG. 4 is the 1 H-NMR spectrum of the crystalline form A of ilaprazole according to the present invention.
  • FIG. 5 is the XRPD diffraction pattern of the crystalline form B of ilaprazole according to the present invention.
  • FIG. 6 is the DSC thermogram of the crystalline form B of ilaprazole according to the present invention.
  • FIG. 7 is the IR spectrum of the crystalline form B of ilaprazole according to the present invention.
  • FIG. 8 is the 1 H-NMR spectrum of the crystalline form B of ilaprazole according to the present invention.
  • Ilaprazole sodium salt (12.87 mole, 5.0 kg) was added to 100 L of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acid. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 20 L of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °Cfor 12 hours, thereby obtaining 4.06 kg (86% yield) of the pure title compound as white crystalline powder.
  • the results of analysis of the obtained powder are as follows.
  • Ilaprazole sodium salt (25.7 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of benzoic acid. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °Cfor 12 hours, thereby obtaining 7.7 g (82% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole sodium salt (25.7 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of formic acid. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °Cfor 12 hours, thereby obtaining 8.1 g (86% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole potassium salt (24.7 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acid. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °C for 12 hours, thereby obtaining 7.4 g (82% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole calcium salt trihydrate (12.1 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acid. Then, the mixture was stirred at room temperature for 2 hours.Then, the produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °C for 12 hours, thereby obtaining 7.5 g (84% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole potassium salt (24.7 mmole, 10.0 g) was dissolved in 20 ml of water, and magnesium chloride (49.4 mmole, 4.7 g)was added thereto. Then, the mixture was stirred at room temperature for 4 hours. The produced solid was filtered, washed with 25 ml of methanol, and then dried at 40 °C for 12 hours, thereby obtaining 8.7 g (89% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole potassium salt (24.7 mmole, 10.0 g) was dissolved in 20 ml of water, and magnesium chloride (49.4 mmole, 4.7 g)was added thereto. Then, the mixture was stirred at room temperature for 4 hours. The produced solid was filtered, added to 75 ml of water and stirred at room temperature for 6 hours. The resulting solid was filtered, washed with 25 ml of methanol, and then dried at 40 °C for 12 hours, thereby obtaining 7.5 g (75% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole sodium salt (25.7 mmole, 10.0 g) was dissolved in 130 ml of water, and a solution of magnesium chloride (12.9 mmole, 1.2 g)in 48 ml of water was added thereto. Then, the mixture was stirred at room temperature for 1 hour. The produced solid was filtered, washed with 30 ml of water, and then dried at 40 °Cfor 12 hours, thereby obtaining 9.8 g (92% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole magnesium salt tetrahydrate (12.1 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acd. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °C for 12 hours, thereby obtaining 7.4 g (83% yield) of the pure title compound as white crystalline powder.
  • Strontium chloride (hexahydrate) (30.9 mmole, 8.2 g) was dissolved in 120 mlof methanol, and a solution of ilaprazole sodium salt (51.5 mmole, 20.0 g) in 120 ml of water was added thereto. Then, the produced solid was filtered, washed with 120 ml of a mixed solvent of water and methanol, and then dried at 40 °C for 12hours, thereby obtaining 17.2 g (78% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole strontium salt dehydrate (11.7 mmole, 10.0 g) was added to 200 ml of ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acid. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 40 ml of a 50% (v/v) ethanol aqueous solution, and then dried at 40 °Cfor 12 hours, thereby obtaining 7.0 g (82% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole (16.38 mole, 6.0 kg) was dissolved in 30 L of a mixed solvent of methanol and dichloromethane and added slowly to 150 L of diethylether. Then, the mixture was stirred at room temperature for 45 minutes. The producedsolid was filtered, washed with 3 L of diethylether, and then dried at 30 °C for 12 hours, thereby obtaining 5.1 kg (85% yield) of the pure title compound as white crystalline powder.
  • the results of analysis of the obtained powder are as follows.
  • Ilaprazole (54.6 mmole, 20.0 g) was dissolved in 260 ml of dichloromethane, and the solutionwas concentrated under reduced pressure to a volume of 80 ml.
  • the concentrated ethyl acetate solution was added slowly to 266 ml of ethyl acetate, and then stirred at a temperature between -10 °C and -15 °C for about 3-4 hours.
  • the produced solid was filtered, washed with 100 ml of diethylether, and then dried at 30 °C for 12 hours, thereby obtaining 17.8 g (89% yield) of the pure title compound as white crystalline powder.
  • Ilaprazol (27.3 mmole, 10.0 g) was dissolved in 130 ml of a mixed solvent of dichloromethane and triethylamine (1%, v/v), and 150 ml of acetone was added thereto. Then, the solution was concentrated under reduced pressure to a volume of 130 ml.130 ml of diethylether was added slowly to the concentrated solution, and the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 100 ml of diethylether, and then dried at 30 °C for 12 hours, thereby obtaining 8.1 g (81% yield) of the pure title compound as white crystalline powder.
  • Ilaprazole (27.3 mmole, 10.0 g) was dissolved in 130 ml of a mixed solvent of dichloromethane and triethylamine (1%, v/v), and 130 ml of diethylether was slowly added thereto. Then, the mixture was stirred at room temperature for 2 hours. The produced solid was filtered, washed with 100 ml of diethylether, and then dried at 30 °C for 12 hours, thereby obtaining 7.6 g (76%yield) of the pure title compound as white crystalline powder.
  • Example 23 Conversion of crystalline form B of ilaprazole into crystalline form A of illaprazole
  • ilaprazole sodium salt (49.2 mmole, 19.1 g) was added to 380 mlof ethanol and neutralized by slow addition of a 10% (w/w) ethanol solution of acetic acid.
  • Example 24 Conversion of crystalline form A of ilaprazole into crystalline form B of ilaprazole
  • the crystalline form A of ilaprazole (54.6 mmole, 20.0 g) was dissolved in 100 ml of a mixed solvent of methanol and dichloromethane and added slowly to 500 ml of diethylether. Then, the mixture was stirred at room temperature for 45 minutes. The produced solid was filtered, washed with 200 ml of diethylether, and then dried at 30 °C for 12 hours, thereby obtaining 16.6 g (83% yield) of the pure title compound as white crystalline powder.
  • 0.5% ammonia water/ethanol (1.0 kg) was placed in the flask, and dichloromethane (2.4 kg) was added thereto. Then, the solution was concentrated under reduced pressure at a temperature of 20 to 25 °C to a volume of about 1.0 L. 0.5% ammonia water/ethanol (1.2 kg) was placed in the flask, and the solution was concentrated again under reduced pressure at a temperature of 20 to 25 °C to a volume of about 1.2 L. 0.5% ammonia water/ethanol (0.2 kg) was added to the concentrated solution, and the solution was cooled to about 5 °C and then stirred for 45 minutes.
  • the resulting slurry was filtered and washed with 0.5% ammonia water/ethanol (0.2 kg), ethanol (0.2 kg) and MTBE (2 x 0.2 kg).
  • the filtered solid was dried for 2 hours and vacuum-dried at a temperature of 92 °C or below for 92 hours, thereby obtaining 0.338 kg (85% yield) of the crystalline form A of ilaprazole.
  • the crystalline form A of ilaprazole was added to 10 ml of acetone/triethylamine and sonicated at room temperature for about 5 minutes to make a saturated solution of ilaprazole.
  • the slurry was filtered through a nylon filter into a glass vial.
  • the filtered slurry was allowed to stand in a refrigerator for 11 days and then filtered, thereby obtaining a white crystalline form B of ilaprazole.
PCT/KR2010/008767 2009-12-08 2010-12-08 Processes for preparing crystalline forms a and b of ilaprazole and process for converting the crystalline forms WO2011071314A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BR112012012212A BR112012012212A2 (pt) 2009-12-08 2010-12-08 processos de preparo de formas cristalinas a e b de ilaprazol e processo para conversão das formas cristalinas
IN3176DEN2012 IN2012DN03176A (ru) 2009-12-08 2010-12-08
UAA201207006A UA102787C2 (ru) 2009-12-08 2010-12-08 Способ приготовления кристаллических форм а и в илапразола и способ преобразования кристаллических форм
EA201200716A EA019058B1 (ru) 2009-12-08 2010-12-08 Способ получения кристаллических форм а и в илапразола и способ превращения указанных кристаллических форм

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KR1020090121209A KR101144600B1 (ko) 2009-12-08 2009-12-08 일라프라졸의 결정형 ａ, ｂ의 제조방법 및 이들 결정형의 변환방법
KR10-2009-0121209 2009-12-08

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WO2013114232A1 (en) 2012-02-02 2013-08-08 Lupin Limited Process for preparation of crystalline form l of ilaprazole
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KR20220065235A (ko) 2020-11-13 2022-05-20 주식회사 파마코스텍 일라프라졸 혼형 결정의 신규한 제조방법
KR102250509B1 (ko) * 2020-12-09 2021-05-11 유니셀랩 주식회사 새로운 일라프라졸/자일리톨 공결정
KR20210019469A (ko) 2021-02-02 2021-02-22 주식회사 파마코스텍 일라프라졸 나트륨 결정형 및 신규한 제조방법

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CN103204843B (zh) * 2012-01-13 2014-12-31 丽珠医药集团股份有限公司 结晶型艾普拉唑钠乙醇化物及其制备方法
CN103204842B (zh) * 2012-01-13 2014-10-15 丽珠医药集团股份有限公司 结晶型艾普拉唑钠水合物及其制备方法
CN103204842A (zh) * 2012-01-13 2013-07-17 丽珠医药集团股份有限公司 结晶型艾普拉唑钠水合物及其制备方法
CN103204843A (zh) * 2012-01-13 2013-07-17 丽珠医药集团股份有限公司 结晶型艾普拉唑钠乙醇化物及其制备方法
WO2013114232A1 (en) 2012-02-02 2013-08-08 Lupin Limited Process for preparation of crystalline form l of ilaprazole
CN102746275B (zh) * 2012-06-21 2014-07-16 丽珠医药集团股份有限公司 结晶型艾普拉唑钠及其制备方法
CN102746276A (zh) * 2012-06-21 2012-10-24 丽珠医药集团股份有限公司 一种艾普拉唑钠晶型及其制备方法
CN102746277A (zh) * 2012-06-21 2012-10-24 丽珠医药集团股份有限公司 一种结晶形式的艾普拉唑钠及其制备方法
CN102746275A (zh) * 2012-06-21 2012-10-24 丽珠医药集团股份有限公司 结晶型艾普拉唑钠及其制备方法
CN105461692A (zh) * 2014-09-04 2016-04-06 江苏奥赛康药业股份有限公司 艾普拉唑钠化合物及其药物组合物
CN113045544A (zh) * 2014-09-04 2021-06-29 江苏奥赛康药业有限公司 艾普拉唑钠化合物及其药物组合物
CN107857756A (zh) * 2017-11-06 2018-03-30 丽珠医药集团股份有限公司 一种艾普拉唑镁晶型及其制备方法
CN115403560A (zh) * 2017-11-06 2022-11-29 丽珠医药集团股份有限公司 一种艾普拉唑镁晶型及其制备方法
CN111187255A (zh) * 2020-01-13 2020-05-22 丽珠医药集团股份有限公司 右旋艾普拉唑钾盐的制备方法和右旋艾普拉唑的制备方法
CN111187255B (zh) * 2020-01-13 2021-07-20 丽珠医药集团股份有限公司 右旋艾普拉唑钾盐的制备方法和右旋艾普拉唑的制备方法

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IN2012DN03176A (ru) 2015-09-25
KR101144600B1 (ko) 2012-05-16
EA201200716A1 (ru) 2012-10-30
KR20110064545A (ko) 2011-06-15
UA102787C2 (ru) 2013-08-12

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