WO2012171377A1 - Formes cristallines d'un sel d'acide asiatique de trométamol et leurs procédés de préparation - Google Patents

Formes cristallines d'un sel d'acide asiatique de trométamol et leurs procédés de préparation Download PDF

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Publication number
WO2012171377A1
WO2012171377A1 PCT/CN2012/072701 CN2012072701W WO2012171377A1 WO 2012171377 A1 WO2012171377 A1 WO 2012171377A1 CN 2012072701 W CN2012072701 W CN 2012072701W WO 2012171377 A1 WO2012171377 A1 WO 2012171377A1
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WO
WIPO (PCT)
Prior art keywords
solvent
asiatic acid
acid tromethamine
acetonitrile
alcohol
Prior art date
Application number
PCT/CN2012/072701
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English (en)
Chinese (zh)
Inventor
任国宾
刘�英
陈金瑶
黄晓玲
齐明辉
刘珉宇
张瑱
肖璘
吴学军
邓轶方
陈仁海
汤生荣
刘全海
Original Assignee
上海医药工业研究院
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Application filed by 上海医药工业研究院 filed Critical 上海医药工业研究院
Publication of WO2012171377A1 publication Critical patent/WO2012171377A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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 crystals A and B of asiatic acid tromethamine salt and a process for the preparation thereof.
  • hydrophilic groups three alcoholic hydroxyl groups and one carboxyl group
  • it has poor wettability and is almost insoluble in water, and its physical and chemical properties require configuration suitable for local use.
  • Formulations, especially hydrophilic formulations require the use of unique methods and special excipients.
  • skin absorption is mainly carried out in an epidermal manner (intracellular and through cells) and is mainly controlled by the action of an effective component on the stratum corneum composed mainly of keratin and water. Therefore, in addition to the configuration problems, the problem of the appropriate bioavailability of asiatic acid at the epidermal level has still not been solved.
  • Snow oxalate is a protonated salt formed by the combination of asiatic acid and a medically acceptable base.
  • the water solubility of asiatic oxalate is greater than that of asiatic acid, which makes the development of asiatic acid oxalate very important.
  • snow oxalates that have been reported in the patents include the asiatic acid succinic acid and hemisuccinates disclosed in USP 3. 3,366,669, and the decylamino chain sterols and dimethylamino chain sterols of asiatic acid. salt.
  • a salt such as ethylenediamine, ethanolamine, diethanolamine, lysine, benzyltrimethylamine hydroxide or tetramethylammonium hydroxide of asiatic acid is disclosed in CN1238330C.
  • Ammonium, sodium, potassium, sodium carbonate, sodium phosphate, and triacetic acid amino salts of asiatic acid are disclosed in WO2009/089365 And tromethamine salt.
  • All of the above compounds can be used in the preparation of aqueous solutions for topical administration.
  • the solubility of asiatic acid tromethamine salt is better.
  • the asiatic acid tromethamine salt in the prior art is a semi-crystal
  • the technical problem to be solved by the present invention is to provide a new type of crystal form of asiatic acid tromethamine salt having excellent stability and a preparation method thereof in order to meet pharmaceutical needs.
  • the present invention also provides a method for preparing the crystal form of the asiatic acid tromethamine salt, which adopts any one of the following schemes:
  • the method comprises the steps of: suspending the raw material asiatic acid tromethamine in an organic solvent to form a paddle under stirring; separating the crystal form A of asiatic acid tromethamine salt, and drying;
  • the organic solvent is a single solvent or a mixed solvent of two or more solvents; when the organic solvent is a single solvent, the solvent is acetonitrile and/or butanone;
  • the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes one or more of methanol, ethanol, and isopropyl alcohol, and the non-alcohol solvent includes acetonitrile. And one or more of acetone and methyl ethyl ketone; and the volume ratio of the non-alcoholic solvent to the alcohol solvent is 4:1 or more.
  • the method comprises the steps of: dissolving the raw material asiatic acid tromethamine salt in an organic solvent; removing the organic solvent to obtain the crystal form A of asiatic acid tromethamine salt; wherein
  • the organic solvent is a single solvent or a mixed solvent of two or more solvents; when the organic solvent is a single solvent, the solvent is ethyl acetate and/or butyl acetate; when the organic solvent is a mixed solvent
  • the mixed solvent includes an alcohol solvent including methanol and/or ethanol, and the non-alcohol solvent includes acetonitrile, acetone, ethyl acetate, butyl acetate, and One or more of the butanone; the volume ratio of the alcohol solvent to the non-alcohol solvent is 1: 1 to 4: 1.
  • the method comprises the steps of: dissolving the raw material asiatic acid tromethamine salt in an alcohol solvent; adding an anti-solvent of asiatic acid tromethamine salt to obtain a suspension; filtering the obtained suspension, The filter cake is dried; wherein the alcohol solvent is methanol and/or ethanol; and the anti-solvent is one or more of ethyl acetate, butyl acetate, acetonitrile and methyl ethyl ketone.
  • the organic solvent is used in an amount such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 50 to 100 ml/g of asiatic acid tromethamine.
  • the organic solvent is a mixed solvent
  • the mixed solvent is preferably methanol and acetonitrile, methanol and methyl ethyl ketone, or isopropanol and acetonitrile.
  • the volume ratio of acetonitrile to methanol, the volume ratio of butanone to methanol, or the volume of acetonitrile and isopropyl alcohol is preferably 4:1 or more, more preferably 4:1.
  • the paddleting time is preferably 24 hours or longer, more preferably 24 to 72 hours.
  • the temperature at which the paddle is formed in the present invention may be a paddle temperature commonly used in the art, preferably 20 to 40 °C.
  • the separation can be carried out by a separation method conventional in the art, such as suction filtration.
  • the drying can be carried out by various conventional drying methods in the art, and is generally vacuum dried at room temperature.
  • the organic solvent is preferably used in an amount of 40 to 100 ml/g of asiatic acid tromethamine.
  • the mixed solvent is preferably methanol and ethyl acetate, methanol and acetonitrile, ethanol and methyl ethyl ketone, or ethanol and butyl acetate.
  • the volume ratio of methanol to ethyl acetate, the volume ratio of methanol to acetonitrile, the volume ratio of ethanol to methyl ethyl ketone, or the volume of ethanol and butyl acetate is preferably 1: 1 to 4: 1, more preferably 1: 1.
  • the dissolution can be carried out under agitation.
  • the temperature of the dissolution there is no particular requirement for the temperature of the dissolution, and it is preferably 20 to 40 ° C as long as the asiatic acid tromethamine salt can be dissolved.
  • the method for removing the organic solvent may be various conventional methods for removing the organic solvent in the art, preferably at a pressure of 0.05 to 0.1 MP.
  • the evaporation is carried out under force, and the evaporation temperature is preferably 20 to 50 °C.
  • the amount of the alcohol solvent is such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 10 to 20 ml/g of asiatic acid tromethamine.
  • the anti-solvent is preferably ethyl acetate or acetonitrile; and when the organic solvent is ethanol, the anti-solvent is preferably butyl acetate or methyl ethyl ketone.
  • the anti-solvent is used in an amount such that the crystal form A of the asiatic acid tromethamine salt can be analyzed, and the anti-solvent is used in an amount of from 1 to 4 times the volume of the alcohol solvent.
  • the temperature of the dissolution there is no particular requirement for the temperature of the dissolution, as long as the asiatic acid tromethamine salt can be dissolved, preferably 20 to 30 °C.
  • the drying can be carried out by various conventional drying methods in the art, generally at room temperature under vacuum drying.
  • There are main peaks at 14.29 and 15.18 degrees; at 2 ⁇ 9.28, 9.59, 12.43, 16.68, 17.03, 17.57, 18.16, 18.91, 19.24, 20.07, 20.68, 22.46, 24.84, 25.20, 26.86, 27.73, 28.30, 28.85, 30.43, 30.83
  • the invention also provides a preparation method of the crystal yttrium succinate salt crystal form bismuth, which comprises the following steps: suspending the raw material asiatic acid tromethamine in an organic solvent under stirring; Separating the crystal form of the asiatic acid tromethamine salt and drying it; wherein the organic solvent is a single solvent or a mixed solvent of two or more solvents, when the organic solvent is a single solvent, The solvent is acetone; when the organic solvent is a mixed solvent, the mixed solvent includes an alcohol solvent and a non-alcohol solvent, and the alcohol solvent includes n-butanol and/or n-propanol.
  • the non-alcoholic solvent includes one or more of acetonitrile, acetone and methyl ethyl ketone.
  • the organic solvent is used in an amount such that the asiatic acid tromethamine salt is sufficiently dissolved, preferably 40 to 60 ml/g of asiatic acid tromethamine.
  • the organic solvent is a mixed solvent
  • the volume of the non-alcoholic solvent and the alcohol solvent in the mixed solvent is preferably 4:1 or more.
  • the mixed solvent is preferably acetone and n-butanol, butanone and n-propanol, or acetonitrile and n-propanol, in which case acetone and n-butanol, butanone and n-propanol, or acetonitrile and n-propanol are compared in volume.
  • the good land is 4:1 or more.
  • the time for the paddle is preferably 24 hours or more, more preferably 24 to 72 hours; and the temperature of the paddle is preferably 20 to 40 °C.
  • the separation can be carried out by conventional separation methods in the art, such as suction filtration.
  • the drying can be carried out by various conventional drying methods in the art, generally at room temperature under vacuum drying.
  • the raw material asiatic acid tromethamine salt may be selected from a semi-crystal of amorphous stearoxylic acid tromethamine salt or asiatic acid tromethamine salt.
  • the amorphous asiatic acid tromethamine salt can be prepared according to the patent CN 201110069862.6, and is specifically prepared by the following method: (1) dissolving asiatic acid in an organic solvent under heating, heating temperature The reflux temperature of the organic solvent; (2) mixing with tromethamine at 50 to 100 ° C; (3) stirring and performing a salt formation reaction at 50 to 100 ° C for 0.5 to 9 hours, removing organic
  • the solvent may be: wherein the molar ratio of the asiatic acid to the tromethamine is 0.8:1 to 1:1.5; in the step (1), the organic solvent is an alcohol solvent, more preferably One or more of a saturated monohydric alcohol having 1 to 5 carbon atoms and an aromatic alcohol having 7 to 8 carbon atoms, more preferably methanol, absolute
  • the reagents and raw materials used are commercially available.
  • the present invention provides crystal forms of two new asiatic acid tromethamine salts which are more versatile than the amorphous asiatic acid tromethamine salt and the semi-crystalline asiatic acid tromethamine salt. Good stability, better able to meet the needs of pharmaceuticals.
  • the preparation method of the crystal form of asiatic acid tromethamine salt of the present invention is simple in operation and easy to realize industrial production.
  • Figure 1 is a PXRD pattern of crystal form A of asiatic acid tromethamine salt.
  • Figure 2 is a PXRD pattern of crystal form B of asiatic acid tromethamine salt.
  • Figure 3 is a PXRD pattern of semi-crystalline asiatic acid tromethamine salt.
  • Figure 4 is a PXRD pattern of amorphous stearic acid tromethamine salt
  • Figure 5 is a DSC spectrum of crystal form A of asiatic acid tromethamine salt.
  • Figure 6 is a DSC spectrum of crystal form B of asiatic acid tromethamine salt.
  • amorphous stearoxylic acid tromethamine salt is as follows: lg (2.046 mmol) of asiatic acid is mixed with 100 ml of absolute ethanol at room temperature, heated to 60 ° C until completely dissolved, and 0.31 g is added thereto. (2.559 mmol) tromethamine, after stirring at this temperature for 0.5 h, a clear solution was obtained, and the solvent was removed by evaporation at 60 ° C under normal pressure, and the product was dried in a vacuum oven at 50 ° C to obtain an amorphous type. Snow oxalate tromethamine salt.
  • the lg amorphous asiatic acid tromethamine salt was placed in a stirred vessel, 100 ml of acetonitrile was added thereto at 20 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered, and the filter cake was dried and tested.
  • the product is crystal form A of asiatic acid tromethamine salt.
  • the lg amorphous asiatic acid tromethamine salt was placed in a stirred vessel, 100 ml of methyl ethyl ketone was added thereto at 20 ° C, and the mixture was stirred for 72 hours, the suspension was suction filtered, and the filter cake was dried and tested.
  • This product is crystal form A of asiatic acid tromethamine salt.
  • the lg amorphous asiatic acid tromethamine salt was dissolved in 20 ml of methanol at room temperature, and 20 ml of ethyl acetate was added dropwise thereto under stirring to precipitate a solid, which was filtered, and the filter cake was dried and detected to be asiatic acid.
  • the lg amorphous stearoxylic acid tromethamine salt was placed in a stirred vessel, 100 ml of acetone was added thereto at 40 ° C, and the mixture was stirred for 72 hours, and then the suspension was suction filtered, and the filter cake was dried and tested.
  • the product is crystal form B of asiatic acid tromethamine salt.
  • the crystal form A of the asiatic acid tromethamine salt of Examples 1-15 the crystal form B of the asiatic acid tromethamine salt of Example 16-19, the semi-crystalline asiatic acid tromethamine salt and the absence Stigtamine
  • the butyl triolate was subjected to powder X-ray diffraction, and the radiation source was Cu- ⁇ .
  • the spectra are shown in Figure 1 - Figure 4, respectively.
  • the specific peaks of Form A and Form B are shown in Tables 1 and 2.
  • Example 6 The crystal form A of asiatic acid tromethamine in Example 6 was detected by differential scanning calorimetry (DSC), and the temperature was raised to 300 ° C at a rate of 10 ° C/min from 30 ° C. It has an endothermic peak at 162 ° C ⁇ 5 ° C, as shown in Figure 5.
  • the melting points of the other examples are the same as those of Example 6.
  • the crystal form B of the asiatic acid tromethamine salt of Example 16 was detected by differential scanning calorimetry (DSC), and the temperature was raised to 300 ° C at a rate of 10 ° C/min from 30 ° C. It has an endothermic peak at 153 ° C ⁇ 5 ° C, as shown in Figure 6.
  • the melting points of the other examples are the same as those of Example 16.
  • Crystallized Form A, B crystal form and amorphous stearoxylic acid tromethamine salt were placed in an environment of 80 ° C for one week. After detection, A and B crystal forms of triclosolic acid tromethamine were found. The salt did not change, and the amorphous asiatic acid tromethamine salt was partially decomposed.
  • the crystal forms of A and B were placed in a condition of 40 ° C and a relative humidity of 75% for one week. After the detection, the crystal form A was not changed, and the B crystal form was partially converted into the crystal form A. This proves that the B crystal form is not as stable as the crystal form A under this condition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une forme cristalline A d'un sel d'acide asiatique et de trométamol montrant des pics principaux à un angle de diffraction (2θ) de 5,98, 6,87, 9,12, 10,38, 12,00, 12,47, 12,93, 13,42, 14,72, 15,10, 17,01 et 18,14 degrés et des pics mineurs à un angle de diffraction (2θ) de 3,44, 13,87, 15,89, 19,04, 19,64, 20,17, 20,94, 21,75, 22,56, 23,33, 24,18, 26,38, 26,98 et 27,75 degrés. L'invention concerne également une forme cristalline B d'un sel d'acide asiatique et de trométamol montrant des pics principaux à un angle de diffraction (2θ) de 3,54, 7,05, 10,04, 11,88, 13,38, 14,29 et 15,18 degrés et des pics mineurs à un angle de diffraction (2θ) de 9,28, 9,59, 12,43, 16,68, 17,03, 17,57, 18,16, 18,91, 19,24, 20,07, 20,68, 22,46, 24,84, 25,20, 26,86, 27,73, 28,30, 28,85, 30,43, 30,83 et 33,93 degrés. L'invention concerne également des procédés de préparation desdites forme crstalline A et forme cristalline B. La forme cristalline A et la forme cristalline B du sel d'acide asiatique et de trométamol sont nouvelles et présentent une excellente stabilité. Les procédés de préparation sont facilement mis en œuvre et réalisés.
PCT/CN2012/072701 2011-06-17 2012-03-21 Formes cristallines d'un sel d'acide asiatique de trométamol et leurs procédés de préparation WO2012171377A1 (fr)

Applications Claiming Priority (2)

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CN201110164382.8A CN102827237B (zh) 2011-06-17 2011-06-17 一类积雪草酸氨丁三醇盐晶型及其制备方法
CN201110164382.8 2011-06-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104292210A (zh) * 2013-07-15 2015-01-21 天津药物研究院 含吡啶的一氧化氮供体类化合物、其制备方法及用途

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104829677B (zh) * 2014-02-10 2017-06-06 上海医药工业研究院 一种羟基积雪草酸盐及其制备方法和用途
CN104829678B (zh) * 2014-02-10 2017-01-11 上海医药工业研究院 积雪草酸盐及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3366669A (en) * 1963-08-28 1968-01-30 Ratsimamanga Albert Rakoto Hemisuccinates and salts of the hemisuccinates of asiatic acid
CN1347398A (zh) * 1999-04-21 2002-05-01 欧洲制药集团有限责任公司 适用于制备药物和化妆品组合物的亚细亚酸盐和羟基积雪草酸盐
CN101969942A (zh) * 2008-01-11 2011-02-09 上海医药工业研究院 基于积雪草酸及其特定盐的治疗剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3366669A (en) * 1963-08-28 1968-01-30 Ratsimamanga Albert Rakoto Hemisuccinates and salts of the hemisuccinates of asiatic acid
CN1347398A (zh) * 1999-04-21 2002-05-01 欧洲制药集团有限责任公司 适用于制备药物和化妆品组合物的亚细亚酸盐和羟基积雪草酸盐
CN101969942A (zh) * 2008-01-11 2011-02-09 上海医药工业研究院 基于积雪草酸及其特定盐的治疗剂

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104292210A (zh) * 2013-07-15 2015-01-21 天津药物研究院 含吡啶的一氧化氮供体类化合物、其制备方法及用途

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CN105237611B (zh) 2018-11-13
CN102827237B (zh) 2016-05-04
CN102827237A (zh) 2012-12-19
CN105237611A (zh) 2016-01-13

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