WO2012077138A1 - Methods of crystallizing (r) -1- (3 -hydroxypropyl) -5- [2- [2- [2- ( 2, 2, 2 - trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7 -carboxamide - Google Patents

Methods of crystallizing (r) -1- (3 -hydroxypropyl) -5- [2- [2- [2- ( 2, 2, 2 - trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7 -carboxamide Download PDF

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WO2012077138A1
WO2012077138A1 PCT/IN2011/000842 IN2011000842W WO2012077138A1 WO 2012077138 A1 WO2012077138 A1 WO 2012077138A1 IN 2011000842 W IN2011000842 W IN 2011000842W WO 2012077138 A1 WO2012077138 A1 WO 2012077138A1
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silodosin
solvent
dissolving crude
heating
ether
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PCT/IN2011/000842
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English (en)
French (fr)
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Rajesh Jain
Mahender Rao Siripragada
Jagadeeshwar R Rao
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Panacea Biotec Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • B01D9/0054—Use of anti-solvent

Definitions

  • the present invention relates to a process for crystallization of Silodosin ((R)-l-(3- hydroxypropyl)-5-[2-[2-[2-(2,2,2-trifluoroemoxy)phenoxy]ethylamino]propyl]indoline- 7-carboxamide) using novel crystallization techniques.
  • Silodosin is the adopted name of the drug compound chemically known as (R)-l-(3- hydroxypropyl)-5-[2-[2-[2-(2, 2,2-trifluoroethoxy) phenoxy]ethylamino]propyl]indoline-7-carboxamide and is represented by the below structural formula:
  • Silodosin is a selective alpha- 1 adrenergic receptor antagonist, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin developed by Kissei, is marketed as tablets for oral administration under the name Rapaflo.
  • Polymorphism refers to the occurrence of different crystalline forms of the same drug substance. It includes solvation products and amorphous forms. It is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Amorphous solids consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice. Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates. (Background Information for the October 2002 ACPS Meeting Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications).
  • polymorphic forms can be achieved by crystallizing the compound from different solvents under varying conditions. Polymorph formation is influenced by temperature of the solution, rate of stirring, rate of precipitation, mode of mixing and rate of addition of the mixing of solvents and time of stirring. Very often the different polymorphs can be isolated from the same solvent system by simply stirring the mixture for different period of times and one form can be converted into another. In view of the very tight limits of residual solvent specification norms as per ICH guidelines for the Active Pharmaceutical Ingredient (API), only a limited number of solvents, preferably C class solvents are being used for generating the new polymorphs. Thus choice is narrowed down to very few solvent systems.
  • API Active Pharmaceutical Ingredient
  • seeding plays an important role in crystallizing a specific form of a polymorph from same or different solvent systems in higher yields.
  • U.S. Patent no. 5,387,603 discloses Silodosin as therapeutic agents for the treatment of dysuria, urinary disturbance associated with benign prostatic hyperplasia. It also discloses processes for the preparation of Silodosin, wherein it was crystallized using solvents such as a mixture of trifluoroacetic acid and methylene chloride. Further, this patent discloses the physical properties of silodosin on data of IR (Infra Red Absorption Spectrum), specific rotation and NMR (Nuclear Magnetic Resonance Spectrum), but its appearance and crystalline polymorphs have not been reported.
  • IR Infra Red Absorption Spectrum
  • specific rotation and NMR Nuclear Magnetic Resonance Spectrum
  • JP 07,330,726 A discloses the crystallization of silodosin by dissolving crude silodosin crystals in heated ethyl acetate followed by drying it over anhydrous magnesium sulfate and allowing the solution to stand at room temperature.
  • the IR of the product obtained gave characteristic peaks at KBr: 3388, 3202, and 1637cm 1 .
  • European patent no. EP 1,541,554 Bl discloses three different crystal forms of silodosin viz., (1) a crystal characterized by main peaks of 5.5° ⁇ 0.2°, 6.1 ° ⁇ 0.2°, 9.8 ° ⁇ 0.2°, 11.1 ° ⁇ 0.2°, 12.2 ° ⁇ 0.2°, 16.4 ° ⁇ 0.2°, 19.7 ° ⁇ 0.2° and 20.0 ° ⁇ 0.2° as 2 ⁇ [hereinafter referred to as crystalline alpha (a) silodosin]; (2) a crystal characterized by main peaks of 7.0 ° ⁇ 0.2°, 12.5 ° ⁇ 0.2°, 18.5 ° ⁇ 0.2°, 19.5 ° ⁇ 0.2°, 20.7 ° ⁇ 0.2° and 21.1 ° ⁇ 0.2° as 2 ⁇ [hereinafter referred to as crystalline beta ( ⁇ ) silodosin]; and (3) a crystal characterized by main peaks of
  • EP '554 discloses that the crystalline alpha silodosin can be prepared by dissolving crude crystals thereof in appropriate amount of ethylacetate, ethyl formate, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran or a mixed solvent of acetone and acetonitrile (1 :1), ⁇ , preferably ethyl acetate is used under heating, further allowing to stand at room temperature, thereby enabling the gradual precipitation of crystals .
  • the crystalline beta silodosin can be prepared by dissolving crude crystals thereof in an appropriate amount of methanol under heating, adding petroleum ether as a poor solvent, stirring the mixture vigorously, such that the crystals ate forcibly and suddenly precipitated.
  • the crystalline beta silodosin can also be prepared by dissolving crude crystal thereof in ethanol or 1-propanol, and cooling quickly.
  • the crystalline gamma silodosin can be prepared by dissolving crude crystal thereof in an appropriate amount of toluene, a mixed solvent of acetonitrile and toluene (1:4) or a mixed solvent of ethyl acetate and toluene (1 :19), preferably toluene under heating, allowing to stand at room temperature thereby enabling the crystals to precipitate gradually.
  • the crystalline gamma silodosin can also be prepared by dissolving crude crystal thereof in 2-propanol and adding an appropriate amount of toluene thereto to precipitate a crystal.
  • EP '554 The inventors of EP '554 have reported that the crystalline alpha silodosin has improved stability and hygroscopicity, however the crystalline beta silodosin has a manufacturing issue during industrial preparation, since it is prepared by adding a poor solvent into warm solution to make crystal precipitates forcibly and suddenly. EP'554 further reports that since toluene or a mixed solvent comprising mainly of toluene is used for recrystallization crystalline gamma silodosin is, removal of the resuidual solvent becomes troublesome because of toluene's high boiling point.
  • the instant invention describes a method for crystallizing silodosin from a solvent and anti-solvent system and producing the pure crystalline product.
  • the desired final crystal form may be pure Form a and/or pure Form ⁇ . Summary:
  • the present invention relates to a process of preparation of various crystalline forms of silodosin using novel crystallization techniques.
  • the present invention relates to a process of preparation of various crystalline forms of silodosin from crude and pure silodosin using various crystallization techniques such as solvent evaporation, slow or sudden/rapid cooling, solvent/non-solvent diffusion, anti- solvent, pH shifting, vapor diffusion, sublimation and many variations on these processes.
  • the present invention provides a process for the crystallization of silodosin comprising the use of a solvent to effect the dissolution of silodosin followed by the addition of an anti-solvent to initiate the crystallization.
  • the present invention provides a process for the preparation of chemically pure silodosin comprising crystalising silodosin free base from a solvent selected from a group consisting of methyl isobutyl ketone (MIBK), dichloromethane (DCM), methyl t- butyl ether (MTBE), ethyl acetate (EtOAc), methanol (MeOH), ethanol, petroleum ether, hexane, heptane (HEP), cyclohexane, methyl ethyl ketone (MEK), methyl acetate, iso-butyl acetate, isopropyl acetate, toluene, 1-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-methyl-l-propanaol (iso amyl alcohol), tetrahydrofuran (THF), 2-methyl THF and isopropyl alcohol (IPA) and/or their
  • crystalline alpha silodosin is prepared by dissolving silodosin base in an alcohol and adding an anti-solvent which is an alkane solvent.
  • crystalline alpha silodosin is prepared by dissolving silodosin base in an alcohol like methanol, ethanol and the like and further adding an anti-solvent which is an alkane solvent selected from a group comprising of heptane, hexane, petroleum ether, cyclohexane and the like.
  • crystalline alpha silodosin is prepared by using halogenated solvents.
  • crystalline alpha silodosin is prepared by using halogenated solvents selected from a group comprising of MDC, chloroform and the like.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in ethyl acetate by heating followed by sudden cooling.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in ethyl acetate by heating and cooling to room temperature.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture of methanol and petroleum ether, heating and stirring for 12 h at room temperature.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture having methanol and ethyl acetate by heating and cooling to room temperature.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture having ethyl acetate and heptane by heating and adding heptane to the heated mixture.
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in DCM (dichloromethane) by heating and cooling to room temperature.
  • DCM diichloromethane
  • the present invention further relates to a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in MEK (methyl ethyl ketone) by heating followed by stirring at room temperature.
  • the present invention relates to a process of preparing crystalline beta silodosin. (Form ⁇ ).
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in an alcohol and adding an anti-solvent which is an alkane solvent.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in an alcohol like methanol, ethanol, isopropylalcohol and the like and further adding an anti-solvent which is an alkane solvent selected from a group comprising of heptane, hexane, cyclohexane, petroleum ether and the like.
  • crystalline beta silodosin is prepared by using ketone solvents.
  • crystalline beta silodosin is prepared by using ketone solvents like methyl isobutyl ketone, acetone and the like.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in a ketone solvent and adding an anti-solvent which is an alkane solvent.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in a ketone solvent selected from a group comprising of methyl isobutyl ketone, acetone, methyl ethyl ketone and the like and further adding an anti-solvent which is an alkane solvent selected from a group comprising of heptane, hexane, petroleum ether, cyclohexane and the like.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in a ketone solvent and adding an anti- solvent which is an ether solvent.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in a ketone solvent selected from a group comprising of methyl isobutyl ketone, acetone, methyl ethyl ketone and the like and further adding an anti-solvent which is an ether solvent selected from a group comprising of diethyl ether, isopropyl ether, methyl t-butyl ether and the like.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in an halogenated solvent and adding an anti-solvent which is an ether solvent.
  • crystalline beta silodosin is prepared by dissolving crude silodosin or silodosin base in an halogenated solvent like DCM and further adding an anti-solvent which is an ether solvent selected from a group comprising of diethyl ether, isopropyl ether, methyl t-butyl ether and the like.
  • crystalline silodosin can be prepared using a combination of solvents which may be DCM and MTBE, or DCM, MTBE and hexane.
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising: dissolving crude silodosin in methanol under heating at 50°C; adding petroleum ether as an antisolvent (methanol: petroleum ether ratio: 1 : 3-5); and evaporating the solvent mixture under reducing pressure.
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising dissolving crude silodosin in MIB (methyl isobutyl ketone) by heating followed by cooling to room temperature
  • MIB methyl isobutyl ketone
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising: (i) dissolving the crude silodosin in ethyl acetate; and
  • the present invention relates to a process of preparation of various crystalline forms of silodosin from crude and pure silodosin.
  • petroleum ether refers to the following distillation fractions of petroleum ether: 30 to 40 °C, 40 to 60 °C, 60 to 80 °C, 80 to 100 °C, 80 to 120 °C and sometimes 100 to 120 °C.
  • Crude is defined as less pure material (starting material) having purity of 98% and less.
  • room temperature refers to a temperature of about 20°C to about 40°C.
  • sudden cooling refers to a process of dissolving the crude material in an appropriate solvent followed by quickly cooling the solution to 0-5 °C in an ice bath.
  • the present invention relates to a process of preparing various crystalline forms of silodosin by various crystallization methods such as gradual or sudden cooling, anti- solvent technique, rapid evaporation and sudden crystallization.
  • the present invention relates to a process of preparing various forms of silodosin by anti-solvent technique.
  • the crude or pure compound used as starting material (herein after referred to as "starting material") for obtaining pure crystals using crystallization process of the present invention can be obtained from different sources.
  • the starting material is dissolved in a solvent or mixture of solvents by heating to obtain a heated solution and any or all of the following actions may be performed on the heated solution:
  • Common solvent (s) used for dissolving the starting material are selected from but are not limited to methyl isobutyl ketone (MIBK), dichloromethane (DCM), methyl t-butyl ether (MTBE), ethyl acetate (EtOAc), methanol (MeOH), ethanol, , methyl ethyl ketone (MEK), methyl acetate, iso-butyl acetate, isopropyl acetate, toluene, 1-propanol, 1- butanol, 2-butanol, 1-pentanol, 2-methyl-l-propanaol (iso amyl alcohol), tetrahydrofuran (THF), 2-methyl THF and isopropyl alcohol (IPA) and/or their mixtures.
  • MIBK methyl isobutyl ketone
  • DCM dichloromethane
  • MTBE methyl t-butyl ether
  • EtOAc eth
  • Heating temperature may vary from 30-100°C depending on the solubility of crude silodosin in the particular solvent. Preferably heating is done at a temperature range varying from 30-70°C.
  • the instant invention further describes a method for crystallizing silodosin by carrying out crystallization under specific cooling conditions and producing the pure crystalline product.
  • the desired final crystal form may be pure Form a and/or pure Form ⁇ .
  • the cooling condition may be slow or rapid cooling. Cooling may be carried out by dissolving the crude material in an appropriate solvent followed by quickly cooling the solution to 0-5°C in an ice bath. Alternatively cooling can also be gradual over a prior of time at a specific temperature (e.g 20-30°C) or at a gradient of temperature.
  • the second solvent /solvent mixture as used in the process is selected from but is not limited to petroleum ether, heptane, methyl t-butyl ether, cyclohexane, hexane, diethyl ether, toluene, xylene, isopropyl ether and mixtures thereof.
  • the present invention provides a process of preparing crystalline alpha silodosin (Form a).
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in ethyl acetate by heating followed by sudden cooling. In a preferred embodiment, the present invention provides a process of preparing crystalline alpha silodosin comprising
  • step (iii) concentrating the solution obtained in step (ii) to reduce the volume; and (iv) sudden cooling.
  • the concentration in step (iii) is done until the volume is reduced to one third.
  • the dissolution of crude silodosin in ethyl acetate is done by heating at 60°C for 5 hours followed by heating at 40°C for 18 hours and at room temperature for 2 days.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in ethyl acetate by heating and cooling to room temperature.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture of methanol and petroleum ether by heating and stirring overnight at room temperature.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture having methanol and ethyl acetate by heating and cooling to room temperature.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in a solvent mixture having ethyl acetate and heptane by heating and adding heptane to the heated mixture.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in DCM (dichloromethane) by heating and cooling to room temperature.
  • the present invention provides a process of preparing crystalline alpha silodosin comprising dissolving crude silodosin in MEK (methyl ethyl ketone) by heating followed by stirring at room temperature.
  • the present invention relates to a process of preparing crystalline beta silodosin.
  • Form ⁇ the present invention provides a process of preparing crystalline beta silodosin comprising dissolving crude silodosin in methanol under heating at 50°C; adding petroleum ether as an anti solvent (methanol : petroleum ether ratio: 1: 3- 5); and evaporating the solvent mixture under reducing pressure.
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising dissolving crude silodosin in MIBK (methyl isobutyl ketone) by heating followed by cooling to room temperature
  • MIBK methyl isobutyl ketone
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • the present invention further relates to process of preparing crystalline beta silodosin comprising:
  • the present invention provides a process of preparing crystalline beta silodosin comprising:
  • silodsin product was obtained as per following examples were identified by matching the IR values the alpha (a) and beta ( ⁇ ) forms of silodosin reported in EP 1,541,554 Bl and US5,387603.
  • the prominent peaks in alpha (a) form IR (KBr) is 3484, 3202, 1636 cm '1 and in beta ( ⁇ ) form is 3384, 3202, 1636 cm "1 .
  • Example- 1 Silodosin crude (0.5 g) was dissolved in 20 ml of ethyl acetate at 50°C and maintained for 30 min at 50°C. The solution was cooled to room temperature (20-30°C) and stirred for 1 hour. Solid obtained was filtered and dried to give 0.25 g of crystalline alpha silodosin (HPLC purity: 98.30 %).
  • Example-2 Silodosin crude (0.5 g) was dissolved in 20 ml of ethyl acetate at 50°C and the clear solution was dried by adding sodium sulphate. The solution was filtered and concentrated to half the volume and stirred for lh at room temperature (20-30°C). The solid obtained was filtered and dried to give 0.3 g of crystalline alpha silodosin (HPLC purity: 98.31%).
  • Example-3 Silodosin crude (0.5 g) was dissolved in 5 ml of DCM at 35°C and maintained for 30 min at same temperature. The solution was cooled to 0°C and stirred for 1 h. Solid obtained was filtered and dried to give 0.3 g of crystalline alpha silodosin (HPLC urity: 98.37%).
  • Example-4 Silodosin crude (0.5 g) was dissolved in 10 ml of Isopropyl alcohol at 65°C and maintained for 30 min at same temperature. The solution was cooled to 0°C and stirred for 1 h. The Solid obtained was filtered and dried to give 0.25 g of crystalline beta silodosin (HPLC purity 98.42%).
  • Example-5 Silodosin crude (2 g) was dissolved in 8 ml of Isopropyl alcohol at 65°C and the solution was allowed to cool to room temperature (20-30°C). To the mixture 8 ml of n-heptane was added and stirred for 30 min. The solid obtained was filtered and dried to give 1.35 g of crystalline beta silodosin (HPLC purity: 99.65%).
  • Example-6 Silodosin crude (0.5 g) was dissolved in 5 ml of MIBK at 65°C and maintained for 30 min at 65°C. The solution was allowed to cool to room temperature (20-30°C) and stirred for 2 h. Solid obtained was filtered and dried to give 0.18 g of crystalline beta silodosin (HPLC purity: 98.23%).
  • Example-7 Silodosin crude (0.5 g) was dissolved in 2 ml of MEK at 60°C and the solution was allowed to cool to room temperature (20-30°C). To the mixture 5 ml of MTBE was added and stirred for 30 min. The solid obtained was filtered and dried to give 0.26 g of crystalline beta silodosin (HPLC purity: 97.36%).
  • Example-8 Silodosin crude (0.5 g) was dissolved in 2 ml of MIBK at 60°C and the solution was allowed to cool to room temperature (20-30°C). To the mixture 5 ml of petroleum ether or n-Heptane was added and stirred for 10 min. The solid obtained was filtered and dried to give 0.23 g of crystalline beta silodosin (HPLC purity: 98.94%).
  • Example-9 Silodosin crude (0.5 g) was dissolved in 2 ml of MEK at 60°C and the solution was allowed to cool to room temperature (20-30°C). To the mixture 5 ml of Petroleum ether or n-Heptane was added and stirred for 10 min. The solid obtained was filtered and dried to give 0.25 g of crystalline beta silodosin (HPLC purity: 96.43%).
  • Example-10 Silodosin crude (0.5 g) was dissolved in 5 ml of MEK at 60°C and the solution was allowed to cool to room temperature (20-30°C). The mixture was stirred for 10 min. The solid obtained was filtered and dried to give 0.18 g of crystalline alpha silodosin (HPLC purity: 98.56%)
  • Example-11 Silodosin crude (0.5 g) was dissolved in 2 ml of acetone at 40°C and the solution was allowed to cool to room temperature (20-30°C). To the mixture 10 ml of MTBE was added and stirred for 30 min. The solid obtained was filtered and dried to give 0.4 gm of crystalline beta silodosin (HPLC purity 98.56%).

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PCT/IN2011/000842 2010-12-09 2011-12-08 Methods of crystallizing (r) -1- (3 -hydroxypropyl) -5- [2- [2- [2- ( 2, 2, 2 - trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7 -carboxamide WO2012077138A1 (en)

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CN103159664A (zh) * 2013-03-29 2013-06-19 深圳市海滨制药有限公司 一种赛洛多辛原料药及其制备方法、药物组合物
WO2015015512A3 (en) * 2013-07-29 2015-04-30 Ind-Swift Laboratories Limited Process for the preparation of silodosin and its gamma form
WO2015170827A1 (ko) * 2014-05-08 2015-11-12 한미정밀화학주식회사 실로도신 감마형 결정의 제조방법
KR20160048561A (ko) * 2014-10-24 2016-05-04 보령제약 주식회사 실로도신 γ 결정형의 제조방법
KR20160074769A (ko) * 2014-12-18 2016-06-29 (주)다산메디켐 실로도신의 결정형의 제조방법
KR101725061B1 (ko) * 2014-09-01 2017-04-27 (주)다산메디켐 실로도신의 제조방법
CN107903201A (zh) * 2017-12-27 2018-04-13 浙江天宇药业股份有限公司 一种β晶型西洛多辛的制备方法
CN109580790A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种液相色谱法分离测定西洛多辛及其光学异构体的方法
CN111410626A (zh) * 2019-01-04 2020-07-14 上海汇伦医药科技有限公司 赛洛多辛α-晶型的制备方法
WO2020237643A1 (zh) * 2019-05-31 2020-12-03 上海汇伦生命科技有限公司 赛洛多辛α-晶型的制备方法
RU2789325C2 (ru) * 2015-02-13 2023-02-01 Ховионе Сциентиа Лимитед Новые полиморфные формы миноциклинового основания и способы их получения

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WO2015170827A1 (ko) * 2014-05-08 2015-11-12 한미정밀화학주식회사 실로도신 감마형 결정의 제조방법
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CN107903201B (zh) * 2017-12-27 2020-09-25 浙江天宇药业股份有限公司 一种β晶型西洛多辛的制备方法
CN111410626A (zh) * 2019-01-04 2020-07-14 上海汇伦医药科技有限公司 赛洛多辛α-晶型的制备方法
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