CN102659644B - Crystal forms of 2-aminoethyl sulfonic acid and preparation processes for crystal forms - Google Patents

Crystal forms of 2-aminoethyl sulfonic acid and preparation processes for crystal forms Download PDF

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CN102659644B
CN102659644B CN201210143256.9A CN201210143256A CN102659644B CN 102659644 B CN102659644 B CN 102659644B CN 201210143256 A CN201210143256 A CN 201210143256A CN 102659644 B CN102659644 B CN 102659644B
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sulfonic acid
aminoethyl sulfonic
crystal form
aminoethyl
crystal forms
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CN102659644A (en
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车晓明
史为龙
张峰
闵涛
晁阳
叶海
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Nanjing Uniclever Biological Pharmaceutical Ltd By Share Ltd
Nanjing Yoko Biological Pharmaceutical Group Co ltd
Nanjing Yoko Biomedical R & D Ltd
NANJING YOKO PHARMACEUTICAL CO Ltd
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NANJING YOKO BIO-MEDICAL RESEARCH Co Ltd
NANJING YOKO PHARMACEUTICAL CO Ltd
NANJING YOKO BIOLOGICAL PHARMACEUTICAL CO Ltd
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Abstract

The invention mainly relates to crystal forms of 2-aminoethyl sulfonic acid and preparation processes for the crystal forms. 2-aminoethyl sulfonic acid is crystallized by water to form a crystal form I of the 2-aminoethyl sulfonic acid, and the crystal form I has characteristic diffraction peaks when 2 theta is about 12.23 degrees, 13.57 degrees, 22.48 degrees and 23.77 degrees on an X-ray powder diffraction pattern through Cu-K alpha ray detection; and the 2-aminoethyl sulfonic acid is crystallized by a mixed solvent to form a crystal form II of the 2-aminoethyl sulfonic acid, and the crystal form II has characteristic diffraction peaks when 2 theta is about 13.62 degrees and 16.90 degrees on the X-ray powder diffraction pattern through Cu-K alpha ray detection. The crystal form I and the crystal form II have advantages of high stability and high druggability, and are suitable to be prepared into medicinal formulations.

Description

The crystal formation of 2-aminoethyl sulfonic acid and preparation technology
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to crystal formation and the preparation technology of 2-aminoethyl sulfonic acid.
Background technology
2-aminoethyl sulfonic acid (2-Aminoethyl sulfonic acid, Cas №: be 107-35-7) to be separated from oxgall by Tidman and Gmelin for 1827, therefore have another name called taurine, taurocholic acid or Taurine, chemical structure is as follows.
Figure BDA00001623158400011
2-aminoethyl sulfonic acid is extensively present in animal tissues, do not participate in synthetic protein, but be a kind ofly free on extracellular special acid, can participate in maintaining organismic internal environment stable state, at maincenter, digestion, reproduction, the normal performance of the system physiological functions such as immunity and internal secretion plays important regulating effect, particularly, 2-aminoethyl sulfonic acid has cholagogic, protect the liver, removing toxic substances, anti-inflammatory, antipyretic, calm, anticonvulsion, anti-arrhythmia, treatment myocardial function is incomplete, regulate osmotic pressure, reduce blood pressure, treatment arteriosclerosis, suppress nervus centralis, vision protection, promote the effects such as childhood development.
The document such as CN101811995A, CN101838226A has disclosed the method for extracting natural 2-aminoethyl sulfonic acid from fish and shellfish (as squid, flower clam etc.), these methods often need through raw material pulverizing, removal of impurities, ion-exchange, the step such as concentrated, and process is complicated, cost is higher, productive rate is low.
The mass-producing of chemical synthesis energy provides high-quality 2-aminoethyl sulfonic acid, and current existing chemical synthesis process has:
(1) girbotol process, reaction process is roughly as follows:
Figure BDA00001623158400012
HOCH 2CH 2NH 3HSO 4→H 2NCH 2CH 2OSO 3H+H 2O
H 2NCH 2CH 2OSO 3H+Na 2SO 3→H 2NCH 2CH 2SO 3H+Na 2SO 4
(2) with dichloroethane law, reaction process is roughly as follows:
ClCH 2CH 2Cl+Na 2SO 4→ClCH 2CH 2SO 3Na+NaCl
ClCH 2CH 2SO 3Na1 2NH 3→NH 2CH 2CH 2SO 3Na+NH 4Cl
NH 2CH 2CH 2SO 3Na+HCl→H 2NCH 2CH 2SO 3H
(3) adopt epoxyethane method (US193207A, US1999614A), reaction process is roughly as follows:
HOCH 2CH 2SO 3Na+NH 3→NH 2CH 2CH 2SO 3Na+H 2O
NH 2CH 2CH 2SO 3Na+HCl→H 2NCH 2CH 2SO 3H+NaCl
(4) adopt vinyl alkylamide method (the clear 61-282354 of TOHKEMY), reaction process is roughly as follows:
RCONCHCH 2+NaHSO 4→RCONCH 2CH 2SO 3H→H 2NCH 2CH 2SO 3H
(5) adopt dialkyl group thiazole method, reaction process is roughly as follows:
Figure BDA00001623158400022
The patent documentations such as CN1403443A, CN101100449A, CN101508658A, CN102285905A have disclosed the method for similarly synthetic 2-aminoethyl sulfonic acid.
But above document has only been set forth 2-aminoethyl sulfonic acid and has been synthesized and/or process for purification, its crystal formation is furtherd investigate, without the report of crystal formation data.
Summary of the invention
Researchist, in to 2-aminoethyl sulfonic acid research process, has found two kinds of crystal formations stable, that become the 2-aminoethyl sulfonic acid that the property of medicine is good.
First the present invention provides 2-aminoethyl sulfonic acid crystal formation I, and the X-ray powder diffraction that this crystal formation is used Cu-K alpha-ray to record is about 12.23 ° at 2 θ, 13.57 °, has located characteristic diffraction peak for 22.48 ° and 23.77 °.It should be noted that it is D8 Advance X-ray Diffractometer that 2 θ in the present invention are worth measuring what use, Cu-K α light source, precision is ± 0.2 °.In addition, in presents, during reflection angle 2 θ of X-ray powder diffraction are about, " approximately " is defined as 2 θ ± 0.2 °, and 2 θ values have allowed certain error, and limit of error is ± 0.2 °.
Further, above-mentioned 2-aminoethyl sulfonic acid crystal formation I, the X-ray powder diffraction that this crystal formation is used Cu-K alpha-ray to record is about 12.23 ° at 2 θ, 13.57 °, 18.49 °, 18.92 °, 21.03 °, 22.48 °, 23.77 °, 24.89 °, 25.57 °, 27.27 °, 31.26 °, 33.08 °, 35.85 °, located characteristic diffraction peak for 37.28 ° and 37.54 °.
The present invention also provides the preparation method of 2-aminoethyl sulfonic acid crystal formation I, and the method comprises: get 2-aminoethyl sulfonic acid water dissolution, and suction filtration after activated carbon decolorizing, filtrate cooling crystallization, vacuum-drying, obtains 2-aminoethyl sulfonic acid crystal formation I.
Preferably, described prepares in 2-aminoethyl sulfonic acid crystal formation I method, and the temperature of cooling crystallization is at 5～20 ℃.
The present invention also provides 2-aminoethyl sulfonic acid crystal form II, and the X-ray powder diffraction that this crystal formation is used Cu-K alpha-ray to record is about 13.62 ° and 16.90 ° at 2 θ and has located characteristic diffraction peak.
Further, above-mentioned 2-aminoethyl sulfonic acid crystal form II, the X-ray powder diffraction that this crystal formation is used Cu-K alpha-ray to record is about 12.28 ° at 2 θ, 13.62 °, 16.90 °, 18.97 °, 21.07 °, 22.34 °, 23.80 °, located characteristic diffraction peak for 27.29 ° and 34.04 °.
Further, above-mentioned 2-aminoethyl sulfonic acid crystal form II, the X-ray powder diffraction that this crystal formation is used Cu-K alpha-ray to record is about 12.28 ° at 2 θ, 13.62 °, 16.90 °, 18.51 °, 18.97 °, 21.07 °, 22.34 °, 23.80 °, 24.91 °, 25.58 °, 27.29 °, 30.70 °, 31.27 °, 33.11 °, 34.04 °, located characteristic diffraction peak for 35.85 ° and 38.55 °.
The present invention also provides the method for preparing 2-aminoethyl sulfonic acid crystal form II, and the method comprises: with the mixed solvent of organic solvent and water, dissolve 2-aminoethyl sulfonic acid, and suction filtration after activated carbon decolorizing, filtrate cooling crystallization, vacuum-drying, obtains 2-aminoethyl sulfonic acid crystal form II.
Preferably, above-mentioned prepares in 2-aminoethyl sulfonic acid crystal form II method, and described organic solvent is one or more in methyl alcohol, ethanol, Virahol, DMF, DMSO.
Preferably, above-mentioned prepares in 2-aminoethyl sulfonic acid crystal form II method, and in described mixed solvent, the volume ratio of water and organic solvent is 1～10:1.
The crystal formation of two kinds of 2-aminoethyl sulfonic acid provided by the invention, compares with the 2-aminoethyl sulfonic acid of amorphous, have advantages of stable, become the property of medicine good, be applicable to very much making pharmaceutical dosage form.
Accompanying drawing explanation
The X-ray powder diffraction figure of Figure 12-taurine crystal formation I
The DSC figure of Figure 22-taurine crystal formation I
The TG figure of Figure 32-taurine crystal formation I
The X-ray powder diffraction figure of Figure 42-taurine crystal form II
The DSC figure of Figure 52-taurine crystal form II
The TG figure of Figure 62-taurine crystal form II
Embodiment
Below in conjunction with specific embodiment, further set forth technical scheme of the present invention.
the preparation of embodiment 1 2-aminoethyl sulfonic acid
The method disclosing according to JP61282354A is prepared 2-aminoethyl sulfonic acid acid 847.3g, standby.
the preparation of embodiment 22-taurine crystal formation I
Get embodiment 1the 2-aminoethyl sulfonic acid acid 50g making, water 150ml, reflux is dissolved, activated carbon decolorizing 30min, suction filtration while hot, filtrate is cooled to 5 ℃ of crystallizatioies, suction filtration, water washing, 60～80 ℃ of vacuum-dryings, obtains 31.4g 2-aminoethyl sulfonic acid crystal formation I.
the preparation of embodiment 3 2-aminoethyl sulfonic acid crystal formation I
Get embodiment 1the 2-aminoethyl sulfonic acid 50g making, water 100ml, reflux is dissolved, activated carbon decolorizing 30min, suction filtration while hot, filtrate is cooled to 10 ℃ of crystallizatioies, suction filtration, water washing, vacuum-drying at 60～80 ℃, obtains 32.1g 2-aminoethyl sulfonic acid crystal formation I.
the preparation of embodiment 4 2-aminoethyl sulfonic acid crystal formation I
Get embodiment 1the 2-aminoethyl sulfonic acid 50g making, water 200ml, reflux is dissolved, activated carbon decolorizing 30min, suction filtration while hot, filtrate is cooled to 20 ℃ of crystallizatioies, suction filtration, water washing, vacuum-drying at 60～80 ℃, obtains 29.7g2-taurine crystal formation I.
the preparation of embodiment 5 2-aminoethyl sulfonic acid crystal form IIs
Get embodiment 1the 2-aminoethyl sulfonic acid 100g making, water 1000ml and ethanol 1000ml make mixed solvent, reflux to dissolve, activated carbon decolorizing 40 minutes, suction filtration while hot, filtrate is cooled to 20 ℃ of crystallizatioies, suction filtration, vacuum-drying, obtains 72.6g2-taurine crystal form II.
the preparation of embodiment 6 2-aminoethyl sulfonic acid crystal form IIs
Get embodiment 1the 2-aminoethyl sulfonic acid 100g making, water 600ml and ethanol 100ml make mixed solvent, reflux to dissolve, activated carbon decolorizing 40 minutes, suction filtration while hot, filtrate is cooled to 10 ℃ of crystallizatioies, suction filtration, vacuum-drying, obtains 73.3g 2-aminoethyl sulfonic acid crystal form II.
the preparation of embodiment 7 2-aminoethyl sulfonic acid crystal form IIs
Get 2-aminoethyl sulfonic acid 100g, water 500ml and methyl alcohol 50ml make mixed solvent, reflux to dissolve, and activated carbon decolorizing 40 minutes, suction filtration while hot, 5 ℃ of crystallizatioies of filtrate, suction filtration, vacuum-drying, obtains 70.2g 2-aminoethyl sulfonic acid crystal form II.
the preparation of embodiment 8 2-aminoethyl sulfonic acid crystal form IIs
Get embodiment 1the 2-aminoethyl sulfonic acid 100g making, water 400ml and Virahol 50ml make mixed solvent, reflux to dissolve, activated carbon decolorizing 40 minutes, suction filtration while hot, filtrate is cooled to 15 ℃ of crystallizatioies, suction filtration, vacuum-drying, obtains 70.7g 2-aminoethyl sulfonic acid crystal form II.
the preparation of embodiment 9 2-aminoethyl sulfonic acid crystal form IIs
Get embodiment 1the 2-aminoethyl sulfonic acid 100g making, water 400ml and DMF100ml make mixed solvent, reflux to dissolve, activated carbon decolorizing 40 minutes, suction filtration while hot, filtrate is cooled to 15 ℃ of crystallizatioies, suction filtration, vacuum-drying, obtains 69.9g 2-aminoethyl sulfonic acid crystal form II.
the sign of embodiment 10 2-aminoethyl sulfonic acid crystal formation I and 2-aminoethyl sulfonic acid crystal form II
By X-ray method by 2-aminoethyl sulfonic acid crystal formation I (for example embodiment 3make) and crystal form II is (for example embodiment 6make) to be placed in respectively powder diffractometer (Bruker D8 Advance X-ray Diffractometer) upper, with Cu-K α 40kV～40mAX-x radiation x, with 8 degree/minute sweep velocity at 3～40 degree 2 θ, scan.
By differential thermal analysis (DSC) and thermogravimetric analysis (TG) method, on NETZSCH DSC 204 type differential thermal analyzers and NETZSCH TG209 type thermogravimetric analyzer, with 10 ℃/min temperature rise rate, 30-300 ℃ of temperature range interscan.
embodiment 11 2-aminoethyl sulfonic acid and 2-aminoethyl sulfonic acid crystal formation I, the comparison of crystal form II stability
The 2-aminoethyl sulfonic acid making, 2-aminoethyl sulfonic acid crystal formation I, crystal form II are carried out to influence factor test, accelerated stability test, and test method is referring to second appendix XIXC < < bulk drug of < < Chinese Pharmacopoeia (2010) > > and pharmaceutical preparation stability test governing principle > >.
(1), influence factor test:
1. high temperature test: get the above-mentioned 2-aminoethyl sulfonic acid making, 2-aminoethyl sulfonic acid crystal formation I, crystal form II, at 60 ℃ of temperature, place 10 days, in the 5th day and the 10th day sampling, measure indices and 0 o'clock sample and compare, test-results in Table.
2. high wet test: get the 2-aminoethyl sulfonic acid, 2-aminoethyl sulfonic acid crystal formation I, the crystal form II that make, under RH75%, place 10 days, in the 5th day and sampling in the 10th day, measure indices and 0 o'clock sample and compare, test-results in Table.
3. strong illumination test: get the above-mentioned 2-aminoethyl sulfonic acid making, 2-aminoethyl sulfonic acid crystal formation I, crystal form II, under the condition that is (4500 ± 500) lx in illumination, place 10 days, in the 5th day and the 10th day sampling, measure indices and 0 o'clock sample and compare, test-results in Table.
Figure BDA00001623158400061
(2) accelerated stability test:
2-aminoethyl sulfonic acid, 2-aminoethyl sulfonic acid crystal formation I, crystal form II are carried out in climatic chamber (MMM Medcenter Climacell) to the stability test of 6 months.Test conditions is respectively: 40 ℃/75% relative humidity (RH), and respectively at sampling in 1,2,3,6 month, carry out purity and foreign impurity matters test (high performance liquid chromatography) and XRPD and characterize, the results are shown in following table:
Figure BDA00001623158400062
Figure BDA00001623158400071
From upper table result, can find out, the stability of 2-aminoethyl sulfonic acid crystal formation I and 2-aminoethyl sulfonic acid crystal form II is all better than 2-aminoethyl sulfonic acid, and the stability of crystal form II is slightly better than crystal formation I.
It should be noted that and the foregoing is only preferred embodiment of the present invention, be not limited to scope of the present invention.

Claims (1)

1. the preparation method of a 2-aminoethyl sulfonic acid crystal form II, wherein said " 2-aminoethyl sulfonic acid crystal form II " refers to that the X-ray powder diffraction of using Cu-K alpha-ray to record is 12.28 ° at 2 θ, 13.62 °, 16.90 °, 18.51 °, 18.97 °, 21.07 °, 22.34 °, 23.80 °, 24.91 °, 25.58 °, 27.29 °, 30.70 °, 31.27 °, 33.11 °, 34.04 °, 35.85 ° and the 38.55 ° 2-aminoethyl sulfonic acid compounds of locating characteristic diffraction peak, it is characterized in that, the method comprises the steps:
(1) with the mixed solvent of DMF and water, dissolve 2-aminoethyl sulfonic acid;
(2) suction filtration after activated carbon decolorizing;
(3) filtrate cooling crystallization, vacuum-drying, obtains 2-aminoethyl sulfonic acid crystal form II,
Wherein, the volume ratio of water and DMF is 1～10:1.
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CN103848763B (en) * 2014-03-20 2015-08-12 天津大学 Organic carboxyl acid or organic carboxyl acid salt additives is adopted to change the method for taurine crystal habit
CN112457225B (en) * 2020-11-17 2022-04-19 江苏远洋药业股份有限公司 Taurine coarse crystal optimization method

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EP2239251A1 (en) * 2009-04-08 2010-10-13 Rheln Pharma Consult GmbH Process for refining 2-aminoethanesulfonic acid from crude 2-aminoethane-sulfonic acid, 2-aminoethanesulfonic acid obtained there from and use thereof
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