CN106279367B - A kind of atosiban acetate crystal and preparation method thereof - Google Patents
A kind of atosiban acetate crystal and preparation method thereof Download PDFInfo
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- CN106279367B CN106279367B CN201610665665.3A CN201610665665A CN106279367B CN 106279367 B CN106279367 B CN 106279367B CN 201610665665 A CN201610665665 A CN 201610665665A CN 106279367 B CN106279367 B CN 106279367B
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- SVDWBHHCPXTODI-QIWYXCRTSA-N acetic acid (2S)-N-[(2S)-5-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxopentan-2-yl]-1-[(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-[(2S)-butan-2-yl]-16-[(4-ethoxyphenyl)methyl]-10-[(1R)-1-hydroxyethyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carboxamide Chemical compound CC(O)=O.C1=CC(OCC)=CC=C1C[C@@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)CSSCCC(=O)N1 SVDWBHHCPXTODI-QIWYXCRTSA-N 0.000 title claims abstract description 72
- 229950010486 atosiban acetate Drugs 0.000 title claims abstract description 72
- 239000013078 crystal Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 7
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 7
- 230000005260 alpha ray Effects 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- -1 dichloromethane Alkane Chemical class 0.000 claims description 2
- 238000005259 measurement Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 230000006866 deterioration Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229960002403 atosiban Drugs 0.000 description 5
- 108700007535 atosiban Proteins 0.000 description 5
- 239000013068 control sample Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 102400000050 Oxytocin Human genes 0.000 description 4
- 101800000989 Oxytocin Proteins 0.000 description 4
- VWXRQYYUEIYXCZ-OBIMUBPZSA-N atosiban Chemical compound C1=CC(OCC)=CC=C1C[C@@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)CSSCCC(=O)N1 VWXRQYYUEIYXCZ-OBIMUBPZSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 2
- 206010036600 Premature labour Diseases 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 208000026440 premature labor Diseases 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 208000035010 Term birth Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000002219 extraembryonic membrane Anatomy 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention provides a kind of atosiban acetate crystal, the atosiban acetate crystal is as shown in Figure 1 using the X-ray powder diffraction spectrogram that Cu-K alpha ray measurement obtains.The present invention is prepared for a kind of new atosiban acetate crystal, which has better dissolubility and stability, place undergo no deterioration for a long time；The present invention has selected specific preparation condition by the repeated multiple times experiment to preparation condition, produces unexpected technical effect, provides a kind of preparation method for preparing atosiban acetate, and the method is very suitable to large-scale production, high income.
Description
Technical field
The invention belongs to pharmaceutical technology fields, specifically, are related to a kind of atosiban acetate crystal and preparation method thereof.
Background technique
Atosiban acetate injection is a kind of new anti-premature labor medicine developed by Ferring GmbH, for European medical association
The fiest-tire medication of recommendation is a kind of Oxitocin analogues, is the competitive antagonism of ocytocin receptor on intrauterine and demoulding, fetal membrane
Agent, can agent directly compete ocytocin receptor with oxytocins, inhibit oxytocins and ocytocin receptor to combine, to directly inhibit to hasten parturition
Element acts on uterus, inhibits uterine contraction, can also with the hydrolysis of inhibition of phosphatidylinositol3, block the generation of second messenger with
And Ca2+Activity so that uterine contraction is inhibited to inhibit reaction of the uterus to oxytocins indirectly, postpone not term birth,
Achieve the purpose that prevent miscarriage, is used clinically for treatment premature labor.
Atosiban is the cyclic peptide polypeptide of a disulfide bond type being made of 9 amino acid, is 1,2,4 and 8 modification
Oxytocin molecule, the N-terminal of peptide are 3- mercaptopropionic acid (sulfydryl and [Cys]6Sulfydryl formed disulfide bond), C-terminal be amide form.
The second amino acid of N-terminal is the modification [D-Tyr (Et)] that ethylizes2.Atosiban exists in the form of acetate in drug, leads to
With entitled atosiban acetate, peptide sequence is as follows:
Mpa-D-Tyr(Et)-IIe-Thr-Asn-Cys-Pro-Orn-Gly-NH2XCH3COOH。
Atosiban acetate is that one of gynemetrics's drug breaks through product, and in the past few years, many clinical tests are
Its efficacy and saferry is assessed, atosiban acetate can rapidly inhibit uterine contraction, extend gestation, and to mother, fetus and baby
There is no adverse effect, therefore atosiban acetate clinically has good application prospect, Development volue with higher.
Currently, the dissolubility and stability of atosiban acetate in the market are poor, phase oxidative is used in the prior art,
Technique is simplified, but gained crude product purity is low, yield is not high, and application value is not high, and foreign countries are about Atosiban synthesis technology
Report, mostly use Boc synthesis in solid state route greatly, liquefied ammonia cuts peptide, then uses liquid phase oxidation, purify to obtain atosiban acetate,
It is complicated for operation, a large amount of three wastes are generated, industrial production is unfavorable for.
Publication number CN102127146A discloses a kind of method for preparing atosiban acetate, and linear Atosiban is dissolved in
In acetonitrile solution, pH is adjusted with ammonium hydroxide, H is added2O2Oxidation is filtered, and purifying turns salt, obtains atosiban acetate, although should
The atosiban acetate of method preparation improves dissolubility to a certain extent, but its stability is poor.
" formulation and technology of atosiban acetate injection is developed " [Yao Zhiyong, Li Xinyu, Zhi Qin, Contemporary Chinese medicine
[J], 2014,10 (21), 28] disclose a kind of atosiban acetate injection formula optimized production process, increase acetic acid Ah
The stability of Tosi class injection is separately added into different types of antioxidant wherein, obtains on the basis of commercially available formulation and technology
To atosiban acetate injection liquid samples, by measuring appearance luster, pH value, the indexs such as clarity of solution, related substance, content
It is investigated with Local security, preferably stability is more preferable compared with commercial product out, uses safe atosiban acetate injection.Although
The stability of atosiban acetate is improved, but its dissolubility and purity is not high.
Have no the report of atosiban acetate crystal in the prior art, however substance in crystallization due to by various factors shadow
It rings, intramolecular or molecular linkage mode is made to change, cause molecule or atom to arrange in lattice vacancy different, formed different
One of an important factor for crystal structure, polymorph in pharmaceuticals phenomenon is influence drug quality and clinical treatment, therefore in drug quality
In control, crystal form is one of those important quality control index.The different compound of crystal structure, the difference of molecules align order
It is different, it is respectively at different energy state, usual unformed drug has biggish position energy, and interparticle bond strength is more brilliant
Type is small, and total per surface free energy is larger, the easy aquation in surface between particle, to cause and the deliquescent difference of crystalline azithromycin
Different, molecule is different from arrangement in steric configuration, composition in the structure cell of different crystal forms, and there are significant differences for making it dissolve property, causes
Preparation has different dissolution rates in vivo, absorption, distribution, excretion and the metabolism of preparation in vivo is directly affected, finally because of it
Bioavilability is different and leads to the difference of clinical drug effect.
For these reasons, the present invention is specifically proposed.
Summary of the invention
For overcome the deficiencies in the prior art, the present inventor has been after having carried out a large amount of test, be made a kind of acetic acid Ah
Tosi class crystal finds crystal dissolubility with higher through dissolubility test, by stability test, it is found that the crystal has
There is preferable stability.
To achieve the purpose of the present invention, the invention adopts the following technical scheme:
A kind of atosiban acetate crystal, the X- that the atosiban acetate crystal is obtained using Cu-K alpha ray measurement
Ray powder diffractogram is as shown in Figure 1.
Due to same drug, different interior molecules arrangement architectures causes its lattice energy different, the size of lattice ability
Difference reflects lattice to the size of the binding force of molecule, therefore physical property when compound is in different crystal forms is also different,
Rate of dissolution, stability, solubility when being in different crystal forms such as compound also can be different, therefore different crystal forms can change
The chemical combination of stability difference, improves its stability and dissolubility.
The present invention provides a kind of new atosiban acetate crystalline compounds, which has completely new molecule
Arrangement architecture, lattice weakens the molecule binding force of atosiban acetate provided by the invention, thus atosiban acetate molecule
More easily shake off out in lattice enter solvent, solubility is bigger, rate of dissolution faster, atosiban acetate solution and solvent
In conjunction with good stability, it is not easy to generate impurity.
The X-ray powder diffraction of atosiban acetate 2 θ be 7.93 °, 9.69 °, 11.54 °, 12.46 °, 14.03 °,
Characteristic peak is shown at 17.38 °, 22.13 °, 25.08 °, 28.61 °, 32.09 °.
Second mesh of the invention provides a kind of preparation method of atosiban acetate crystal, and the method includes as follows
Step:
(1) at 40-45 DEG C of temperature, atosiban acetate is dissolved in the in the mixed solvent of organic solvent and water, is stirred molten
Solution；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 38-42 DEG C after control filtering；
(3) under ultrasonic field, esters dissolved agent is slowly dropped into the filtrate, is cooled down twice after dripping, stood,
Crystallization is precipitated；
(4) washed, it filters, vacuum drying obtains the atosiban acetate crystal.
As a kind of preferred embodiment of preparation method of the present invention, (1) atosiban acetate the step of preparation method of the present invention,
The mass volume ratio of organic solvent and water is 0.2-0.3g:8-10ml:100ml.
Further, organic solvent described in step (1) is molten for the mixing of n,N-Dimethylformamide and methylene chloride
Agent.
Further, n,N-Dimethylformamide, methylene chloride volume ratio are 2.5-3:1.
Further, esters described in step (3) are methyl acetate or ethyl acetate.
Further, the rate of addition of dissolved agent described in step (3) is 3-3.5%/min.
Further, the cooling twice in step (3) is to be cooled to 8- with rate of temperature fall for the first time for 3.5-4 DEG C/min
10 DEG C, second with 1.8-2.0 DEG C/min of rate of temperature fall.It is cooled to -8~-6 DEG C.
Further, quiescent time is 21-23 hours in step (3).
Further, the content for controlling moisture in step (4) after drying is 3%-4%.
Crystallization is a complicated process, each factor in crystallization process, the wherein selection and its dosage of solvent, growing the grain
Time, rate of temperature fall and cooling number all have an impact, and the present invention is using cooling down twice and crystallizing under conditions of ultrasound, strictly
The factors such as rate of temperature fall are controlled, above-mentioned preparation method is the present inventor's preparation method finally determining after many experiments.
Compared with prior art, beneficial effects of the present invention are as follows:
(1) present invention is prepared for a kind of new atosiban acetate crystal, which has better dissolubility
And stability, it places undergo no deterioration for a long time.
(2) present invention has selected specific preparation condition, has produced anticipation by the repeated multiple times experiment to preparation condition
Less than technical effect, provide a kind of preparation method for preparing atosiban acetate, and the method is very suitable to scale
Metaplasia produces, high income.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of crystal prepared by the embodiment of the present invention 1.
Specific embodiment
Embodiment in following embodiment can be further combined or replace, and embodiment is only to of the invention
Preferred embodiment is described, and it is not intended to limit the concept and scope of the present invention, is not departing from design philosophy of the present invention
Under the premise of, the various changes and modifications that professional and technical personnel in the art make technical solution of the present invention belong to this hair
Bright protection scope.
The preparation of 1 atosiban acetate crystal of embodiment
(1) at 43 DEG C of temperature, by 2.5g atosiban acetate be dissolved in n,N-Dimethylformamide, methylene chloride and
The in the mixed solvent of 1000ml water, wherein n,N-Dimethylformamide and methylene chloride volume are 9ml, and volume ratio 2.8:1 is stirred
Mix dissolution；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 40 DEG C after control filtering；
(3) under ultrasonic field, 20ml methyl acetate is slowly dropped in the filtrate with rate of addition 3.2%/min,
9 DEG C are cooled to for 3.8 DEG C/min with rate of temperature fall after dripping, second with 1.9 DEG C/min of rate of temperature fall.- 7 DEG C are cooled to,
22 hours are stood, crystallization is precipitated；
(4) washed, it filters, vacuum drying, the moisture after control is dry is 3%, obtains the atosiban acetate
Crystal.
X-ray powder diffraction spectrogram such as Fig. 1 that obtained atosiban acetate crystal is obtained using Cu-K alpha ray measurement
It is shown.
The preparation of 2 atosiban acetate crystal of embodiment
(1) at 40 DEG C of temperature, 2g atosiban acetate is dissolved in n,N-Dimethylformamide, methylene chloride and 1000ml
The in the mixed solvent of water, wherein n,N-Dimethylformamide and methylene chloride volume are 8ml, volume ratio 2.5:1, are stirred molten
Solution；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 38 DEG C after control filtering；
(3) under ultrasonic field, 20ml ethyl acetate is slowly dropped in the filtrate with rate of addition 3%/min, is dripped
8 DEG C are cooled to for 3.5 DEG C/min with rate of temperature fall after adding, second with 1.8 DEG C/min of rate of temperature fall.It is cooled to -8 DEG C, it is quiet
It sets 21 hours, crystallization is precipitated；
(4) washed, it filters, vacuum drying, the moisture after control is dry is 4%, obtains the atosiban acetate
Crystal.
The X-ray powder diffraction spectrogram and Fig. 1 that obtained atosiban acetate crystal is obtained using Cu-K alpha ray measurement
It is almost the same.
The preparation of 3 atosiban acetate crystal of embodiment
(1) under temperature 45 C, 3g atosiban acetate is dissolved in n,N-Dimethylformamide, methylene chloride and 1000ml
The in the mixed solvent of water, wherein n,N-Dimethylformamide and methylene chloride volume are 10ml, volume ratio 3:1, stirring and dissolving；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 42 DEG C after control filtering；
(3) under ultrasonic field, 20ml ethyl acetate is slowly dropped in the filtrate with rate of addition 3.5%/min,
10 DEG C are cooled to for 4 DEG C/min with rate of temperature fall after dripping, second with 2 DEG C/min of rate of temperature fall.It is cooled to -6 DEG C, it is quiet
It sets 23 hours, crystallization is precipitated；
(4) washed, it filters, vacuum drying, the moisture after control is dry is 4%, obtains the atosiban acetate
Crystal.
The X-ray powder diffraction spectrogram and Fig. 1 that obtained atosiban acetate crystal is obtained using Cu-K alpha ray measurement
It is almost the same.
The preparation of 4 atosiban acetate crystal of embodiment
(1) at 44 DEG C of temperature, by 2.8g atosiban acetate be dissolved in n,N-Dimethylformamide, methylene chloride and
The in the mixed solvent of 1000ml water, wherein n,N-Dimethylformamide and methylene chloride volume are 10ml, and volume ratio 3:1 is stirred
Mix dissolution；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 41 DEG C after control filtering；
(3) under ultrasonic field, 20ml methyl acetate is slowly dropped in the filtrate with rate of addition 3%/min, is dripped
10 DEG C are cooled to for 3.8 DEG C/min with rate of temperature fall after adding, second with 2 DEG C/min of rate of temperature fall.It is cooled to -7 DEG C, it is quiet
It sets 23 hours, crystallization is precipitated；
(4) washed, it filters, vacuum drying, the moisture after control is dry is 4%, obtains the atosiban acetate
Crystal.
The X-ray powder diffraction spectrogram and Fig. 1 that obtained atosiban acetate crystal is obtained using Cu-K alpha ray measurement
It is almost the same.
The test of 1 atosiban acetate crystal stability of test example
This test example is steady to the atosiban acetates of atosiban acetate crystalline compounds and the prior art of the invention
It is qualitative to be investigated, it is as follows that stability is measured according to two ministerial standard of Chinese Pharmacopoeia (version in 2005):
Test specimen 1: atosiban acetate crystalline compounds made from the embodiment of the present invention 1；
Test specimen 2: atosiban acetate crystalline compounds made from the embodiment of the present invention 2；
Control sample 1: the atosiban acetate prepared according to CN102127146A method；
Control sample 2: according to the formulation and technology of atosiban acetate injection " develop " [Yao Zhiyong, Li Xinyu, Zhi Qin,
Contemporary Chinese medicine [J], 2014,10 (21), 28] in method preparation atosiban acetate.
The stability of above-mentioned 4 samples is investigated according to following experimental factor:
1, hot test
Above-mentioned 4 samples are taken respectively, 10 days at a temperature of being placed in 60 DEG C, in the 5th day and the 10th day sampling and testing, are investigated related
Substance, content, pH value and clarity of solution, test result are as shown in table 1.
2, high humility is tested
Above-mentioned 4 samples are taken respectively, under the conditions of 25 DEG C, humidity 75% ± 5%, are placed 10 days, in the 5th day and the 19th day
Sampling and testing, investigates related substance, content, pH value and clarity of solution, and test result is as shown in table 1.
3, strong illumination is tested
Above-mentioned 4 samples are taken respectively, are respectively placed under conditions of illumination is 4500lx ± 500lx and are placed 10 days, with the 5th day
It was sampled with the 10th day, investigates related substance, content, pH value and clarity of solution, test result is as shown in table 1.
1 stability test result of table
As can be seen from the above table, the atosiban acetate of atosiban acetate crystal prepared by the present invention than in the prior art
Impurity content is few, and content increases, and shows that atosiban acetate stability prepared by the present invention increases, can increase the holding time.
Atosiban acetate crystal resulting for the other embodiment of the present invention has also carried out above-mentioned test, is tied
Fruit is close with the above results, since length is limited, no longer lists one by one.
2 dissolubility test of test example
Measurement dissolution rate: the acetic acid atropic in test specimen 1, test specimen 2, control sample 1 and control sample 2 is taken respectively
Western class, in 900ml pH1.0 medium, slurry processes, 60rpm, respectively at 10,15,30,45,60 minutes sample detection dissolution rates.It is molten
The results are shown in Table 2 for out-degree:
2 dissolution results of table
From the results shown in Table 2, the dissolution rate of atosiban acetate crystalline compounds of the invention is significantly faster than that
The dissolubility of control sample 1 and 2, surface atosiban acetate crystal of the invention is preferable.
Atosiban acetate crystal resulting for the other embodiment of the present invention has also carried out above-mentioned test, is tied
Fruit is close with the above results, since length is limited, no longer lists one by one.
Claims (6)
1. a kind of atosiban acetate crystal, which is characterized in that the atosiban acetate crystal is measured using Cu-K alpha ray
Obtained X-ray powder diffraction spectrogram as shown in Figure 1, its 2 θ be 7.93 °, 9.69 °, 11.54 °, 12.46 °, 14.03 °,
Characteristic peak is shown at 17.38 °, 22.13 °, 25.08 °, 28.61 °, 32.09 °.
2. a kind of preparation method of atosiban acetate crystal described in claim 1, which is characterized in that the method includes
Following steps:
(1) at 40-45 DEG C of temperature, atosiban acetate is dissolved in the in the mixed solvent of organic solvent and water, stirring and dissolving；
(2) active carbon is added in Xiang Shangshu solution, stirs, filtering, the temperature of filtrate is 38-42 DEG C after control filtering；
(3) under ultrasonic field, esters dissolved agent is slowly dropped into the filtrate, is cooled down twice after dripping, stood, crystallization
It is precipitated；
(4) washed, it filters, vacuum drying obtains the atosiban acetate crystal；
Wherein, the mass volume ratio of step (1) atosiban acetate, organic solvent and water is 0.2-0.3g:8-10ml:100ml,
The organic solvent is the mixed solvent of n,N-Dimethylformamide and methylene chloride, n,N-Dimethylformamide, dichloromethane
Alkane volume ratio is 2.5-3:1；
Esters described in step (3) are methyl acetate or ethyl acetate.
3. preparation method according to claim 2, which is characterized in that the rate of addition of dissolved agent described in step (3)
For 3-3.5%/min.
4. preparation method according to claim 2, which is characterized in that the cooling twice in step (3) is, for the first time with drop
Warm rate is 3.5-4 DEG C/min, is cooled to 8-10 DEG C, for the second time with 1.8-2.0 DEG C/min of rate of temperature fall, is cooled to -8~-6
℃。
5. preparation method according to claim 2, which is characterized in that time of repose is 21-23 hours in step (3).
6. preparation method according to claim 2, which is characterized in that the content of control moisture is after dry in step (4)
3%-4%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127146A (en) * | 2010-12-24 | 2011-07-20 | 深圳翰宇药业股份有限公司 | Method for preparing atosiban acetate |
| CN102584953A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
| CN103421092A (en) * | 2013-09-05 | 2013-12-04 | 杭州诺泰制药技术有限公司 | Atosiban purification method |
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2016
- 2016-08-15 CN CN201610665665.3A patent/CN106279367B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127146A (en) * | 2010-12-24 | 2011-07-20 | 深圳翰宇药业股份有限公司 | Method for preparing atosiban acetate |
| CN102584953A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
| CN103421092A (en) * | 2013-09-05 | 2013-12-04 | 杭州诺泰制药技术有限公司 | Atosiban purification method |
Non-Patent Citations (1)
| Title |
|---|
| 醋酸阿托西班制备工艺的研究;钟祥龙 等;《中国当代医药》;20140731;第21卷(第20期);17-21页 |
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