CN102532226A - Ribavirin crystal form and preparation method thereof - Google Patents
Ribavirin crystal form and preparation method thereof Download PDFInfo
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- CN102532226A CN102532226A CN2010105888707A CN201010588870A CN102532226A CN 102532226 A CN102532226 A CN 102532226A CN 2010105888707 A CN2010105888707 A CN 2010105888707A CN 201010588870 A CN201010588870 A CN 201010588870A CN 102532226 A CN102532226 A CN 102532226A
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Abstract
The invention discloses a ribavirin new crystal form and a preparation method thereof. The invention is characterized in that 2theta angle degrees of a powder diffraction spectrum of the crystal form are: 11.12+/-0.2 degrees, 13.86+/-0.2 degrees, 15.99+/-0.2 degrees, 16.43+/-0.2 degrees, 19.07+/-0.2 degrees, 21.49+/-0.2 degrees, 26.29+/-0.2 degrees, and 30.94+/-0.2 degrees. In addition, the invention also discloses a preparation method of the substance with multiple crystal forms. The ribavirin new crystal form preparation method of the invention is simple in process, high in yield, and is applicable to industrial production.
Description
Technical field
The present invention relates to a kind of ribavirin crystal formation and preparation method thereof.
Background technology
Ribavirin, Chinese are 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-methane amide (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), be a kind of broad-spectrum antiviral medicament, commodity are called virazole, and structural formula is following:
Formula (I)
The ribavirin mechanism of action mainly is through the inhibition to the inosine desaturase, and blocking-up inosine-phosphoric acid is to the effects such as conversion of xanthosine--phosphoric acid, and it is synthetic to suppress nucleic acid, stops virus replication.Being applicable to viral upper respiratory tract infection, like viral rhinitis, angor, pharyngo-conjunctival fever or pars oralis pharyngis virus infection, is widely used clinically extensive pedigree antibiotic.
The physical properties of compound specific crystal formation has different with any other crystal formation of this compound or armorphous physical properties; Such physical properties can obviously influence the chemistry and the pharmacy processing characteristics of this compound, and is particularly important when this compound carries out scale operation.The difference of each crystal formation on physical properties like this compound; Particularly mobile three little (dosage is little, volume is little, packing little), five convenience (conveniently produce, use, carry, store, transport) that are related to pharmaceutical prepn; And the improvement of flowing property can solve high viscosity, water absorbability, content unhomogeneity in the preparation process, problems such as storage unstable.The different crystal forms of compound also has different thermodynamic stabilities, and in general, comparatively stable crystal formation is to be more suitable for carrying out scale operation.
J.T.Witkowski et al., J.Med.Chem.15,1150 (1972), the compound method that discloses this compound in 1972.1976, Prusiner.P, people such as M.Sundaralingam are at Acta Crystallographica; Section B:Structural Crystallography and Crystal Chemistry (1976); B32 (2), the last ribavirin that provides of 419-26. exists two kinds of different crystal form Vs 1 and V2 (being referred to as R-I type and R-II type such as JP2008222630A afterwards in the industry); Two kinds are rhombic system, and the monocrystalline data are following:
Japanese Patent JP2008222630A has reported the preparation method of these two kinds of crystal formations; The method that wherein prepares the R-II type is: with the mixed solvent dissolving ribavirin of a variety of organic solvents such as the mixed solvent of Virahol, acetonitrile, acetone, THF etc. and water or two kinds of organic solvents and water; Gradually the cold analysis crystalline substance obtains the crystallization of R-II type, and the highest yield can reach 93%.The method for preparing the R-I type is: ribavirin is dissolved in the mixed solvent of first alcohol and water, gradually the cold analysis crystalline substance obtains the crystallization of R-I type, and yield has only 77%.
The monocrystalline data of having only R-I type, R-II type of present bibliographical information; Do not see powder diffraction data; The contriver has prepared this two kinds of crystal formations according to Japanese Patent JP2008222630A reported method; And carried out X-ray diffraction mensuration respectively, 2 θ angle numbers of the R-I type that obtains, R-II type x-ray diffractogram of powder spectrum are respectively:
The R-I type:
13.16±0.2°，15.45±0.2°，16.56±0.2°20.10±0.2°，23.40±0.2°，23.66±0.2°，26.39±0.2°，27.01±0.2°28.56±0.2°，29.56±0.2°，31.44±0.2°，33.52±0.2°。
The R-II type:
11.99±0.2°，13.47±0.2°，15.63±0.2°18.23±0.2°，20.64±0.2°，23.05±0.2°，23.33±0.2°，24.14±0.2°25.43±0.2°，27.14±0.2°，29.22±0.2°。
Used x-ray diffractogram of powder spectrum determining instrument model is: the D8-advance-SSS of Bruker company.
Condition determination is: initial: 2.000 °, finish: 50.000 °, and step-length: 0.020 °, the step-length time: 0.1 second, temperature: 25 ℃.
In the experiment contriver find the crystallization of R-I type not only its flowability obviously be better than the crystallization of R-II type, and than R-II type crystallization-stable.So need find the preparation R-I type crystalline method that a kind of yield is high, be easy to suitability for industrialized production.
Summary of the invention
For addressing the above problem, the present invention's purpose at first provides a kind of preparation ribavirin R-I type crystalline novel method.In experimentation, the contriver finds through obtaining the crystallization of R-I type easily after a kind of ribavirin new crystal oven dry that will obtain in will testing.This new crystal is a kind of DMSO solvate of ribavirin, the good flowing properties of this solvated compounds, stability height, and key is can be converted into easily can be the R-I type crystallization of clinical acceptance.
One side of the present invention provides a kind of new crystal of ribavirin DMSO solvate.
This new crystal at 2 θ angle numbers of x-ray diffractogram of powder spectrum is: 15.99 ± 0.2 °, and 19.07 ± 0.2 °, 21.49 ± 0.2 °.
This new crystal further is expressed as at 2 θ angle numbers of x-ray diffractogram of powder spectrum: 11.12 ± 0.2 °, and 13.86 ± 0.2 °, 15.99 ± 0.2 °, 16.43 ± 0.2 °, 19.07 ± 0.2 °, 21.49 ± 0.2 °, 26.29 ± 0.2 °, 30.94 ± 0.2 °.
This new crystal further is expressed as at 2 θ angle numbers of x-ray diffractogram of powder spectrum: 11.12 ± 0.2 °, and 13.86 ± 0.2 °, 15.59 ± 0.2 ° 15.99 ± 0.2 °; 16.43 ± 0.2 °, 19.07 ± 0.2 °, 21.49 ± 0.2 °; 25.93 ± 0.2 °; 26.29 ± 0.2 °, 28.66 ± 0.2 °, 30.94 ± 0.2 °.
This new crystal is as shown in Figure 2 basically in the x-ray diffractogram of powder spectrum.
Through microscopic examination, this ribavirin DMSO solvate new crystal is a hexa-prism, has good flowability, and recording the slope of repose is 20.1 °.
The inventor has also obtained the monocrystalline of this new crystal; Its unit cell parameters is following: a=8.2511 (3)
b=7.7199 (2)
; C=11.7814 (4)
; α=γ=90 °, β=105.455 (1) °.
More specifically; The monocrystalline of this new crystal is an oblique system; Spacer: P2 (1); Unit cell parameters: a=8.2511 (3)
b=7.7199 (2)
; C=11.7814 (4)
; α=γ=90 °, β=105.455 (1) °.
More specifically, the monocrystalline of this new crystal is an oblique system, spacer: P2 (1), unit cell parameters: a=8.2511 (3)
, b=7.7199 (2)
, c=11.7814 (4)
, α=γ=90 °, β=105.455 (1) °, V=723.31 (4)
, Z=2, D=1.480g/cm
3, modifying factor: R1=0.0215, wR2=0.0597.
Second aspect present invention provides a kind of method for preparing the ribavirin new crystal, comprises the steps: ribavirin is dissolved in the methyl-sulphoxide, in the solution that obtains, adds acetone, obtains the ribavirin new crystal behind the crystallization.
One preferred embodiment in, 1 weight part ribavirin is dissolved in the 1-50 weight part methyl-sulphoxide, add the acetone that the 1-50 of methyl-sulphoxide weight doubly measures, slowly cooling behind the crystallization is filtered and is obtained the ribavirin new crystal.More preferably 1 weight part ribavirin is dissolved in 2-10 weight part methyl-sulphoxide, the acetone that the 3-20 of adding methyl-sulphoxide weight doubly measures, slowly cooling behind the crystallization is filtered and is obtained the ribavirin new crystal.
One preferred embodiment in, 1 weight part ribavirin is dissolved in the 1-50 weight part methyl-sulphoxide, gained solution is remained on 30-60 ℃; The acetone that the 1-50 of adding methyl-sulphoxide weight doubly measures, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min; Be incubated 1 hour, filter, obtain the Ba Weilin new crystal at 40-50 ℃ of drying under reduced pressure.
One preferred embodiment in, gained solution is remained on 40-50 ℃.
Aforesaid method order of addition(of ingredients) is changed, be about to ribavirin and be dissolved in the methyl-sulphoxide, the solution that obtains is added in the acetone, also can obtain the ribavirin new crystal behind the crystallization, but operate waywardly, yield is unstable.
The third aspect of the invention provides a kind of ribavirin crystal formation R-I crystalline method, comprises the steps: that with ribavirin new crystal of the present invention be raw material, can obtain ribavirin crystal formation R-I crystallization after the 60-80 ℃ of decompression oven dry.
According to the R-I crystallization that the inventive method obtains, yield can reach more than 95%, and is simple to operate, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is the monocrystalline space structure synoptic diagram of ribavirin DMSO solvate of the present invention;
Fig. 2 is the X ray diffracting spectrum of ribavirin DMSO solvate of the present invention;
Fig. 3 is the X ray diffracting spectrum of the ribavirin R-I crystal formation that makes according to the JP2008222630A reported method;
Fig. 4 is the X ray diffracting spectrum of the ribavirin R-II crystal formation that makes according to the JP2008222630A reported method.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is done further detailed explanation:
X-ray powder diffraction instrument of the present invention: the D8-advance-SSS of Bruker company.
Condition determination is: initial: 2.000 °, finish: 50.000 °, and step-length: 0.020 °, the step-length time: 0.1 second, temperature: 25 ℃.
Embodiment 1:
The 0.5g ribavirin is dissolved in the 5.0g methyl-sulphoxide, behind the formation settled solution, 5.0g acetone is slowly dripped in above-mentioned solution, drip half a hour, placed 15 days, filter, obtain the DMSO solvate monocrystalline of ribavirin.Through the X ray single crystal diffraction, get the monocrystalline data: molecular formula: C
10H
18N
4O
6S, molecular weight: 322.34, crystallographic system: oblique system, spacer: P2 (1), unit cell parameters: a=8.2511 (3)
, b=7.7199 (2)
, c=11.7814 (4)
, α=γ=90 °, β=105.455 (1) °, V=723.31 (4)
, Z=2, D=1.480g/cm
3, modifying factor: R1=0.0215, wR2=0.0597.Monocrystalline space structure synoptic diagram is as shown in Figure 1, and its x-ray diffractogram of powder spectrum is as shown in Figure 2.
Embodiment 2:
The 10g ribavirin is dissolved in the 27.5g methyl-sulphoxide, is heated to about 50 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 55g acetone is being dripped in above-mentioned solution, the about 4-5g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 50 ℃ of drying under reduced pressure obtain the DMSO solvate of ribavirin, weight yield 125.6%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 2.
Embodiment 3:
70 ℃ of drying under reduced pressure of ribavirin DMSO solvate with embodiment 2 obtains obtain the R-I crystallization of ribavirin, quantitative yield.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 4:
The 10g ribavirin is dissolved in the 20g methyl-sulphoxide, is heated to about 60 ℃, behind the formation settled solution, solution is incubated to 50 ℃; Under 50 ℃ 60g acetone is being dripped in above-mentioned solution, the about 4-5g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 70 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 95.6%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 5:
The 10g ribavirin is dissolved in the 20g methyl-sulphoxide, is heated to about 60 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 200g acetone is being dripped in above-mentioned solution, the about 5-6g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 60 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 96.5%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 6:
The 10g ribavirin is dissolved in the 100g methyl-sulphoxide, is heated to about 50 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 100g acetone is being dripped in above-mentioned solution, the about 4-5g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 80 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 90.2%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 7:
The 10g ribavirin is dissolved in the 100g methyl-sulphoxide, is heated to about 50 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 300g acetone is being dripped in above-mentioned solution, the about 9-10g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 70 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 95.3%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 8:
The 10g ribavirin is dissolved in the 50g methyl-sulphoxide, is heated to about 50 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 250g acetone is being dripped in above-mentioned solution, the about 8-9g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 70 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 96.3%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 9:
The 10g ribavirin is dissolved in the 20g methyl-sulphoxide, is heated to about 60 ℃, behind the formation settled solution, solution is incubated to 40 ℃; Under 40 ℃ 1000g acetone is being dripped in above-mentioned solution, the about 9-10g/min of drop rate, insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃; Rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filters; 75 ℃ of vacuum-dryings obtain the R-I crystallization of ribavirin, weight yield 95.9%.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Claims (10)
1. a ribavirin DMSO solvate crystal formation is characterized in that, this crystal formation at 2 θ angle numbers of x-ray diffractogram of powder spectrum is: 15.99 ± 0.2 °, and 19.07 ± 0.2 °, 21.49 ± 0.2 °.
2. crystal formation as claimed in claim 1 is characterized in that, this crystal formation at 2 θ angle numbers of x-ray diffractogram of powder spectrum is: 11.12 ± 0.2 °; 13.86 ± 0.2 °, 15.99 ± 0.2 °, 16.43 ± 0.2 °; 19.07 ± 0.2 °; 21.49 ± 0.2 °, 26.29 ± 0.2 °, 30.94 ± 0.2 °.
3. crystal formation as claimed in claim 1 is characterized in that, this crystal formation at 2 θ angle numbers of x-ray diffractogram of powder spectrum is: 11.12 ± 0.2 °; 13.86 ± 0.2 °, 15.59 ± 0.2 ° 15.99 ± 0.2 °, 16.43 ± 0.2 °; 19.07 ± 0.2 °, 21.49 ± 0.2 °, 25.93 ± 0.2 °; 26.29 ± 0.2 °, 28.66 ± 0.2 °, 30.94 ± 0.2 °.
4. crystal formation as claimed in claim 1 is characterized in that, the x-ray diffractogram of powder spectrum of this crystal formation is as shown in Figure 2.
5. ribavirin DMSO solvate crystal formation; It is characterized in that; The monocrystalline unit cell parameters of this crystal formation is following: a=8.2511 (3)
; B=7.7199 (2)
; C=11.7814 (4)
; α=γ=90 °, β=105.455 (1) °.
6. crystal formation as claimed in claim 5; It is characterized in that; The monocrystalline of this crystal formation is an oblique system; Spacer: P2 (1); Unit cell parameters: a=8.2511 (3)
; B=7.7199 (2)
; C=11.7814 (4)
; α=γ=90 °, β=105.455 (1) °.
7. a method for preparing the ribavirin DMSO solvate crystal formation of claim 1 is characterized in that, ribavirin is dissolved in the methyl-sulphoxide, in the solution that obtains, adds acetone, obtains the ribavirin crystal formation behind the crystallization.
8. method as claimed in claim 7; It is characterized in that, 1 weight part ribavirin is dissolved in the 1-50 weight part methyl-sulphoxide, the acetone that the 1-50 of adding methyl-sulphoxide weight doubly measures; Slowly cooling behind the crystallization is filtered and is obtained ribavirin DMSO solvate crystal formation.
9. method as claimed in claim 7 is characterized in that, 1 weight part ribavirin is dissolved in the 1-50 weight part methyl-sulphoxide; Gained solution is kept 30-60 ℃, preferred 40-50 ℃, the acetone that the 1-50 of adding methyl-sulphoxide weight doubly measures; Insulation is 2 hours behind the crystallization, slowly is cooled to 0-5 ℃, and rate of temperature fall is 1 ℃/3min; Be incubated 1 hour, filter, obtain Ba Weilin DMSO solvate crystal formation at 40-50 ℃ of drying under reduced pressure.
10. method for preparing Ba Weilin crystal formation R-I; Comprise with the ribavirin DMSO solvate crystal formation described in the claim 1-4 or be raw material, can obtain ribavirin crystal formation R-I crystallization after the 60-80 ℃ of decompression oven dry with the ribavirin DMSO solvate crystal formation that each described method among the claim 7-9 makes.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786572A (en) * | 2011-05-17 | 2012-11-21 | 中国医学科学院药物研究所 | Ribavirin crystal C characterization and preparation methods, and applications of Ribavirin crystal C in medicines and healthcare products |
| CN109134565A (en) * | 2017-08-15 | 2019-01-04 | 李双喜 | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition |
| CN109134566A (en) * | 2017-08-18 | 2019-01-04 | 樊艳芳 | A kind of 1/20 water Ribavirin compound |
Citations (1)
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| CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
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2010
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
Non-Patent Citations (1)
| Title |
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| 张效林 等: "利巴韦林生产废液处理的工艺研究", 《河南化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786572A (en) * | 2011-05-17 | 2012-11-21 | 中国医学科学院药物研究所 | Ribavirin crystal C characterization and preparation methods, and applications of Ribavirin crystal C in medicines and healthcare products |
| CN109134565A (en) * | 2017-08-15 | 2019-01-04 | 李双喜 | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition |
| CN109134566A (en) * | 2017-08-18 | 2019-01-04 | 樊艳芳 | A kind of 1/20 water Ribavirin compound |
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Address after: 201203, Zhang Heng road 1479, Zhangjiang hi tech park, Shanghai, Pudong New Area Patentee after: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. Patentee after: SHANGHAI DESANO PHARMACEUTICALS INVESTMENT Co.,Ltd. Patentee after: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: 201203, Zhang Heng road 1479, Zhangjiang hi tech park, Shanghai, Pudong New Area Patentee before: Shanghai Desano Pharmaceutical Holding Co.,Ltd. Patentee before: SHANGHAI DESANO PHARMACEUTICALS INVESTMENT Co.,Ltd. Patentee before: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20201216 Address after: 331208 salt chemical industrial base of Zhangshu City, Yichun City, Jiangxi Province Patentee after: Jiangxi desino Pharmaceutical Co.,Ltd. Address before: 201203, Zhang Heng road 1479, Zhangjiang hi tech park, Shanghai, Pudong New Area Patentee before: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. Patentee before: SHANGHAI DESANO PHARMACEUTICALS INVESTMENT Co.,Ltd. Patentee before: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. |