CN102532226B - Ribavirin crystal form and preparation method thereof - Google Patents
Ribavirin crystal form and preparation method thereof Download PDFInfo
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- CN102532226B CN102532226B CN201010588870.7A CN201010588870A CN102532226B CN 102532226 B CN102532226 B CN 102532226B CN 201010588870 A CN201010588870 A CN 201010588870A CN 102532226 B CN102532226 B CN 102532226B
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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 form and preparation method thereof.
Background technology
Ribavirin, Chinese is 1-β-D-RIBOSE base-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 as follows:
Formula (I)
Ribavirin mechanism of action is mainly by the inhibition to inosine desaturase, and blocking-up inosine-phosphoric acid, to effects such as the conversions of xanthosine-phosphoric acid, suppresses nucleic acid synthetic, stops virus replication.Being applicable to viral upper respiratory tract infection, as viral rhinitis, angor, pharyngo-conjunctival fever or pars oralis pharyngis virus infection, is widely used extensive pedigree antibiotic clinically.
The physical properties of compound specific crystal formation and any other crystal formation of this compound or armorphous physical properties have different, such physical properties can obviously affect chemistry and the pharmacy processing characteristics of this compound, particularly important when this compound carries out scale operation.As the difference of each crystal formation of this compound in physical properties, particularly mobility is related to three little (dosage is little, volume is little, pack little), five convenience (conveniently produce, apply, carry, store, transport) of pharmaceutical preparation, and the improvement of flowing property can solve high viscosity, water absorbability, content unhomogeneity in preparation process, the 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 synthetic method that discloses this compound in 1972.1976, Prusiner.P, the people such as M.Sundaralingam are at Acta Crystallographica, Section B:Structural Crystallography and Crystal Chemistry (1976), B32 (2), provides ribavirin and has two kinds of different crystal form Vs 1 and V2 (afterwards in the industry, such as JP2008222630A is referred to as R-I type and R-II type) on 419-26., two kinds are rhombic system, and monocrystalline data are as follows:
Japanese Patent JP2008222630A has reported the preparation method of these two kinds of crystal formations, the method of wherein preparing R-II type is: with a variety of organic solvents such as the mixed solvent of the mixed solvent of Virahol, acetonitrile, acetone, tetrahydrofuran (THF) etc. and water or two kinds of organic solvents and water dissolves ribavirin, gradually cold analysis crystalline substance obtains the crystallization of R-II type, and the highest yield can reach 93%.The method of preparing R-I type is: ribavirin is dissolved in the mixed solvent of first alcohol and water, gradually cold analysis crystalline substance obtains the crystallization of R-I type, and yield only has 77%.
The monocrystalline data of only having R-I type, R-II type of bibliographical information at present, have no powder diffraction data, contriver has prepared this two kinds of crystal formations according to the method for Japanese Patent JP2008222630A report, and carried out respectively X-ray diffraction mensuration, 2 θ angle numbers of the R-I type obtaining, R-II type x-ray diffractogram of powder spectrum are respectively:
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°。
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°。
X-ray diffractogram of powder spectrum determining instrument model used 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 experiment contriver find the crystallization of R-I type not only its mobility significantly better than the crystallization of R-II type, and compared with R-II type crystallization-stable.So need to find a kind of method of preparing the crystallization of R-I type that yield is high, be easy to suitability for industrialized production.
Summary of the invention
For addressing the above problem, the present invention's object is first to provide a kind of novel method of preparing the crystallization of ribavirin R-I type.In experimentation, contriver finds can obtain easily the crystallization of R-I type after a kind of ribavirin new crystal obtaining in experiment is dried.This new crystal is a kind of DMSO solvate of ribavirin, and good flowing properties, the stability of this solvated compounds are high, and key is that can be converted into easily can be the R-I type crystallization of clinical acceptance.
An aspect of of the present present invention is to provide 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 is further 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 is further expressed as at 2 θ angle numbers of x-ray diffractogram of powder spectrum: 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 °.
This new crystal is composed substantially as shown in Figure 2 at x-ray diffractogram of powder.
Through microscopic examination, this ribavirin DMSO solvate new crystal is hexa-prism, has good mobility, and recording slope of repose is 20.1 °.
The inventor has also obtained the monocrystalline of this new crystal, and its unit cell parameters is as follows: 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 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 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 of preparing ribavirin new crystal, comprises the steps: ribavirin to be dissolved in methyl-sulphoxide, in the solution obtaining, adds acetone, obtains ribavirin new crystal after crystallization.
One preferred embodiment in, 1 weight part ribavirin is dissolved in 1-50 weight part methyl-sulphoxide, the acetone that adds the 1-50 of methyl-sulphoxide weight doubly to measure, slow cooling after crystallization, filters and obtains ribavirin new crystal.More preferably 1 weight part ribavirin is dissolved in to 2-10 weight part methyl-sulphoxide, the acetone that adds the 3-20 of methyl-sulphoxide weight doubly to measure, slow cooling after crystallization, filters and obtains ribavirin new crystal.
One preferred embodiment in, 1 weight part ribavirin is dissolved in 1-50 weight part methyl-sulphoxide, gained solution is remained on to 30-60 ℃, the acetone that adds the 1-50 of methyl-sulphoxide weight doubly to measure, is incubated 2 hours after crystallization, slow cooling is to 0-5 ℃, rate of temperature fall is 1 ℃/3min, be incubated 1 hour, filter, at 40-50 ℃ of drying under reduced pressure, obtain Ba Weilin new crystal.
One preferred embodiment in, gained solution is remained on to 40-50 ℃.
Aforesaid method order of addition(of ingredients) is changed, be about to ribavirin and be dissolved in methyl-sulphoxide, the solution obtaining is added in acetone, also can obtain ribavirin new crystal, but operate waywardly after crystallization, yield is unstable.
A third aspect of the present invention is to provide the method for a kind of Ribavirin crystal form R-I crystallization, comprises the steps:, take ribavirin new crystal of the present invention as raw material, after 60-80 ℃ of decompression drying, can obtain Ribavirin crystal form R-I crystallization.
The R-I crystallization obtaining according to the inventive method, yield can reach more than 95%, simple to operate, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the monocrystalline space structure schematic 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 method for JP2008222630A report;
Fig. 4 is the X ray diffracting spectrum of the ribavirin R-II crystal formation that makes according to the method for JP2008222630A report.
Embodiment
Below in conjunction with drawings and Examples, the present invention is 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:
0.5g ribavirin is dissolved in 5.0g methyl-sulphoxide, forms after settled solution, 5.0g acetone is slowly dripped in above-mentioned solution, drip half an hour, place 15 days, filter, obtain the DMSO solvate monocrystalline of ribavirin.Through X ray single crystal diffraction, obtain 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 schematic diagram as shown in Figure 1, compose as shown in Figure 2 by its x-ray diffractogram of powder.
Embodiment 2:
10g ribavirin is dissolved in 27.5g methyl-sulphoxide, is heated to approximately 50 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 55g acetone is dripped in above-mentioned solution, the about 4-5g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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 that embodiment 2 is obtained, obtain the R-I crystallization of ribavirin, quantitative yield.Its x-ray diffractogram of powder spectrum is consistent with Fig. 3.
Embodiment 4:
10g ribavirin is dissolved in 20g methyl-sulphoxide, is heated to approximately 60 ℃, form after settled solution, solution is incubated to 50 ℃, at 50 ℃, 60g acetone is dripped in above-mentioned solution, the about 4-5g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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:
10g ribavirin is dissolved in 20g methyl-sulphoxide, is heated to approximately 60 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 200g acetone is dripped in above-mentioned solution, the about 5-6g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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:
10g ribavirin is dissolved in 100g methyl-sulphoxide, is heated to approximately 50 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 100g acetone is dripped in above-mentioned solution, the about 4-5g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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:
10g ribavirin is dissolved in 100g methyl-sulphoxide, is heated to approximately 50 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 300g acetone is dripped in above-mentioned solution, the about 9-10g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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:
10g ribavirin is dissolved in 50g methyl-sulphoxide, is heated to approximately 50 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 250g acetone is dripped in above-mentioned solution, the about 8-9g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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:
10g ribavirin is dissolved in 20g methyl-sulphoxide, is heated to approximately 60 ℃, form after settled solution, solution is incubated to 40 ℃, at 40 ℃, 1000g acetone is dripped in above-mentioned solution, the about 9-10g/min of drop rate, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, 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 (6)
1. a ribavirin DMSO solvate crystal formation, it is characterized in that, this crystal formation at 2 θ angle numbers of x-ray diffractogram of powder spectrum is: 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 °.
2. crystal formation as claimed in claim 1, is characterized in that, the x-ray diffractogram of powder of this crystal formation is composed as shown in Figure 2.
3. ribavirin DMSO solvate crystal formation as claimed in claim 1, is characterized in that, the monocrystalline of this crystal formation is oblique system, spacer: P2 (1), and unit cell parameters:
α=γ=90 °, β=105.455(1) °.
4. prepare the method for the ribavirin DMSO solvate crystal formation of claim 1 for one kind, it is characterized in that, 1 weight part ribavirin is dissolved in 1-50 weight part methyl-sulphoxide, gained solution is kept to 30-60 ℃, the acetone that adds the 1-50 of methyl-sulphoxide weight doubly to measure, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, at 40-50 ℃ of drying under reduced pressure, obtain Ba Weilin DMSO solvate crystal formation.
5. method as claimed in claim 4, it is characterized in that, 1 weight part ribavirin is dissolved in 1-50 weight part methyl-sulphoxide, gained solution is kept to 40-50 ℃, the acetone that adds the 1-50 of methyl-sulphoxide weight doubly to measure, after crystallization, be incubated 2 hours, slow cooling is to 0-5 ℃, and rate of temperature fall is 1 ℃/3min, is incubated 1 hour, filter, at 40-50 ℃ of drying under reduced pressure, obtain Ba Weilin DMSO solvate crystal formation.
6. prepare the method for Ba Weilin crystal formation R-I for one kind, comprise with the ribavirin DMSO solvate crystal formation described in any one in claim 1-3 or the ribavirin DMSO solvate crystal formation that makes take the method described in any one in claim 4-5 as raw material, after 60-80 ℃ of decompression drying, can obtain Ribavirin crystal form R-I crystallization.
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| 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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| CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
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| 利巴韦林生产废液处理的工艺研究;张效林 等;《河南化工》;20041231(第10期);第9-11页 * |
| 张效林 等.利巴韦林生产废液处理的工艺研究.《河南化工》.2004,(第10期),第9-11页. |
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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. |
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