CN106866638A - A kind of avanaphil citric acid eutectic and preparation method thereof - Google Patents
A kind of avanaphil citric acid eutectic and preparation method thereof Download PDFInfo
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- CN106866638A CN106866638A CN201710178969.1A CN201710178969A CN106866638A CN 106866638 A CN106866638 A CN 106866638A CN 201710178969 A CN201710178969 A CN 201710178969A CN 106866638 A CN106866638 A CN 106866638A
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- avanaphil
- citric acid
- eutectic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of avanaphil citric acid eutectic and preparation method thereof.The mol ratio of avanaphil and citric acid is 1 in eutectic：1.A kind of preparation method of avanaphil citric acid eutectic is also disclosed that simultaneously, is comprised the following steps：1）It is in molar ratio with citric acid by avanaphil（0.9‑1.1）：（0.9‑1.1）Mixed；2）Solvent is added in mixture to avanaphil and citric acid, makes it be in suspension；3）Above-mentioned suspension is sufficiently stirred for, gained crystalline powder, drying to obtain avanaphil citric acid eutectic is collected.Avanaphil citric acid eutectic preparation method reaction condition disclosed in this invention is gentle, and simple to operate, impurity content is low, and favorable reproducibility, production cost is relatively low.Resulting avanaphil citric acid eutectic solubility effectively improves, and apparent solubility is 10.95 times of avanaphil.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to avanaphil-citric acid eutectic and preparation method thereof.
Background technology
Avanaphil (Avanafil) is a kind of 5 type phosphodiesterase (Phosphodiesterase Enzyme Type
5) inhibitor, by the exploitation of commission Vivus companies of the U.S. of Japanese Tanabe Mitsubishi Pharmaceutical Co for treating male erectile work(
The medicine of energy obstacle (Erectile Dysfunction), obtains FDA approvals in U.S.'s listing, business on April 27th, 2012
The name of an article isThe chemical Chinese of avanaphil is:(S) -4- (3- chloro-4-methoxy benzyls amino) -2- (2- hydroxyl first
Base -1- pyrrolidinyls)-N- (2- pyrimidines methyl) -5- pyrimidine carboxamides, chemical English name is:(S)-4-(3-chloro-4-
methoxybenzyl)amino-2-(2-hydroxymethyl-1-pyrrolidinyl)-N-(2-
Pyrimidinylmethyl) -5-pyrimidinecarboxamide, molecular formula:C23H26ClN7O3, molecular weight:483.95, change
Learn structural formula as follows：
Avanaphil compound structure is disclosed in patent US66656935.Its poor solubility in water, causes oral life
Thing availability is low, and only 38% -41%.Up to the present, the several patents about avanaphil crystal formation are had been disclosed for, specially
Sharp CN104628708 discloses avanaphil crystal formation I；Patent CN104628707A and patent WO2014174529A2 are disclosed respectively
Two kinds of avanaphil are unformed；Patent CN104151299A discloses avanaphil fumarate and avanaphil fumaric acid
Salt is crystallized.
The content of the invention
It is an object of the invention to provide the eutectic that a kind of avanaphil and citric acid are formed；
Preparation method another object of the present invention is to provide a kind of avanaphil-citric acid eutectic.
The eutectic that avanaphil is formed with citric acid, the wherein mol ratio of avanaphil and citric acid are 1：1.
The X-ray powder diffraction of avanaphil-citric acid eutectic is in the θ of angle of diffraction 2：6.3±0.2、7.2±0.2、
10.2±0.2、11.8±0.2、12.1±0.2、12.4±0.2、12.8±0.2、13.7±0.2、14.2±0.2、14.6±
0.2、15.4±0.2、15.8±0.2、16.9±0.2、17.7±0.2、18.2±0.2、18.4±0.2、18.7±0.2、
19.3±0.2、19.7±0.2、20.3±0.2、21.2±0.2、22.1±0.2、22.3±0.2、22.9±0.2、23.8±
0.2、24.3±0.2、24.7±0.2、25.2±0.2、25.4±0.2、26.7±0.2、27.2±0.2、29.0±0.2、
29.3±0.2、30.1±0.2、31.0±0.2、32.0±0.2、32.5±0.2、33.3±0.2、35.6±0.2、36.0±
0.2nd, 36.3 ± 0.2,38.5 ± 0.2,39.4 ± 0.2 when there is characteristic peak.
A kind of preparation method of avanaphil-citric acid eutectic, comprises the following steps：
1) it is in molar ratio (0.9-1.1) by avanaphil and citric acid：(0.9-1.1) is mixed；
2) to solvent is added in the mixture of avanaphil and citric acid, it is made to be in suspension；
3) above-mentioned suspension is sufficiently stirred for, collects gained crystalline powder, drying to obtain avanaphil-citric acid is common
It is brilliant.
Step 1) in avanaphil and citric acid be in molar ratio 1：1 is mixed.
Step 2) in the amount of solvent is added in mixture per 100mg avanaphils and citric acid is 0.1~10mL.
Step 2) in, described solvent is distilled water, ether, isopropyl ether, Ethyl formate, ethyl acetate, isopropyl acetate,
At least one in methyl alcohol, ethanol, isopropanol, acetonitrile, acetone.
Step 3) in stirring when temperature be 0~70 DEG C.
Step 3) in stirring time be not less than 2h.
The beneficial effects of the invention are as follows：
The present invention by avanaphil and citric acid in molar ratio (0.9-1.1)：(0.9-1.1) is mixed, and is preferably rubbed
You are than being 1：1, avanaphil-citric acid eutectic that yield is up to 90% can be prepared；Obtained avanaphil-citric acid eutectic
Preparation method reaction condition is gentle, and simple to operate, impurity content is low, and favorable reproducibility, production cost is relatively low.Present invention design is obtained
The solubility of avanaphil-citric acid eutectic effectively improve, apparent solubility is 10.95 times of avanaphil.
Brief description of the drawings
Fig. 1 is the actual measurement x-ray diffractogram of powder of avanaphil-citric acid eutectic；
Fig. 2 is the actual measurement x-ray diffractogram of powder of avanaphil；
Fig. 3 is the actual measurement x-ray diffractogram of powder of citric acid；
Fig. 4 is nuclear magnetic resonance (NMR) figure of avanaphil-citric acid eutectic；
Fig. 5 is thermogravimetric analysis (TG) figure of avanaphil-citric acid eutectic
Fig. 6 is differential scanning calorimeter (DSC) figure of avanaphil-citric acid eutectic；
Fig. 7 is differential scanning calorimeter (DSC) figure of avanaphil；
Fig. 8 is differential scanning calorimeter (DSC) figure of citric acid；
Fig. 9 is infrared spectrum (IR) figure of avanaphil-citric acid eutectic；
Figure 10 be avanaphil, avanaphil-citric acid eutectic at 37 DEG C, dissolution in the acetate buffers of pH 4.5 is bent
Line chart.
Specific embodiment
The eutectic that avanaphil is formed with citric acid, the wherein mol ratio of avanaphil and citric acid are 1：1.
The X-ray powder diffraction of avanaphil-citric acid eutectic is in the θ of angle of diffraction 2：6.3±0.2、7.2±0.2、
10.2±0.2、11.8±0.2、12.1±0.2、12.4±0.2、12.8±0.2、13.7±0.2、14.2±0.2、14.6±
0.2、15.4±0.2、15.8±0.2、16.9±0.2、17.7±0.2、18.2±0.2、18.4±0.2、18.7±0.2、
19.3±0.2、19.7±0.2、20.3±0.2、21.2±0.2、22.1±0.2、22.3±0.2、22.9±0.2、23.8±
0.2、24.3±0.2、24.7±0.2、25.2±0.2、25.4±0.2、26.7±0.2、27.2±0.2、29.0±0.2、
29.3±0.2、30.1±0.2、31.0±0.2、32.0±0.2、32.5±0.2、33.3±0.2、35.6±0.2、36.0±
0.2nd, 36.3 ± 0.2,38.5 ± 0.2,39.4 ± 0.2 when there is characteristic peak.
A kind of preparation method of avanaphil-citric acid eutectic, comprises the following steps：
1) it is in molar ratio (0.9-1.1) by avanaphil and citric acid：(0.9-1.1) is mixed；
2) to solvent is added in the mixture of avanaphil and citric acid, it is made to be in suspension；
3) above-mentioned suspension is sufficiently stirred for, collects gained crystalline powder, drying to obtain avanaphil-citric acid is common
It is brilliant.
Preferably, step 1) in avanaphil and citric acid be in molar ratio 1：1 is mixed.
Preferably, step 2) in add in mixture per 100mg avanaphils and citric acid the amount of solvent for 0.1~
10mL；It is further preferred that step 2) in the amount of solvent is added in mixture per 100mg avanaphils and citric acid is 0.2
~2.0mL.
Preferably, step 2) in, described solvent is distilled water, ether, isopropyl ether, Ethyl formate, ethyl acetate, acetic acid
At least one in isopropyl ester, methyl alcohol, ethanol, isopropanol, acetonitrile, acetone.
Preferably, step 3) in stirring when temperature be 0~70 DEG C；It is further preferred that step 3) in stirring when temperature
Spend is 25~50 DEG C.
Preferably, step 3) in stirring time be not less than 2h；It is further preferred that step 3) in stirring time be 2h
~2d.
With reference to specific embodiment, the present invention is further illustrated, but is not limited to this.
Embodiment 1：
49.2mg avanaphils are weighed with 19.2mg citric acids in test tube, addition 1mL ethanol is sealed, in 25 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 57.8mg, yield 85.5%.
Embodiment 2：
47.3mg avanaphils are weighed with 19.2mg citric acids in test tube, addition 1mL ether is sealed, in 25 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 53.1mg, yield 78.7%.
Embodiment 3：
49.0mg avanaphils are weighed with 20.1mg citric acids in test tube, addition 1mL isopropanols are sealed, in 25 DEG C of bars
32h is stirred under part to there is mass crystallization white solid to be formed, white crystals are collected by filtration, vacuum drying at room temperature obtains white
Pulverulent solids 55.4mg, yield 80.8%.
Embodiment 4：
48.5mg avanaphils are weighed with 20.4mg citric acids in test tube, addition 1mL acetone is sealed, in 25 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 56.6mg, yield 83.4%.
Embodiment 5：
48.6mg avanaphils are weighed with 19.5mg citric acids in test tube, addition 1mL isopropyl acetates are sealed, in 25
32h is stirred under the conditions of DEG C to there is mass crystallization white solid to be formed, white crystals are collected by filtration, vacuum drying at room temperature is obtained
White powdery solids 59.2mg, yield 87.0%.
Embodiment 6：
48.6mg avanaphils are weighed with 19.3mg citric acids in test tube, addition 1mL distilled water is sealed, in 25 DEG C of bars
32h is stirred under part to there is mass crystallization white solid to be formed, white crystals are collected by filtration, vacuum drying at room temperature obtains white
Pulverulent solids 49.0mg, yield 72.1%.
Embodiment 7：
96.6mg avanaphils are weighed with 39.0mg citric acids in test tube, addition 1mL ethanol is sealed, in 25 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 121.2mg, yield 89.6%.
Embodiment 8：
48.2mg avanaphils are weighed with 18.8mg citric acids in test tube, addition 1mL acetonitriles are sealed, in 50 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 61.6mg, yield 93.1%.
Embodiment 9：
48.2mg avanaphils are weighed with 20.8mg citric acids in test tube, addition 1mL isopropanols are sealed, in 25 DEG C of bars
32h is stirred under part to there is mass crystallization white solid to be formed, white crystals are collected by filtration, vacuum drying at room temperature obtains white
Pulverulent solids 65.0mg, yield 96.4%.
Embodiment 10：
48.7mg avanaphils are weighed with 18.9mg citric acids in test tube, addition 1mL methyl alcohol is sealed, in 25 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 47.7mg, yield 71.7%.
Embodiment 11：
144.6mg avanaphils are weighed with 57.6mg citric acids in test tube, addition 3mL ethanol is sealed, in 50 DEG C of conditions
Lower stirring 32h is collected by filtration white crystals to there is mass crystallization white solid to be formed, and vacuum drying at room temperature obtains white powder
Last shape solid 188.6mg, yield 93.2%.
Embodiment 12：
2.41g avanaphils are weighed with 0.97g citric acids in test tube, addition 50mL acetone is sealed, under the conditions of 25 DEG C
8h is to there is mass crystallization white solid to be formed for stirring, and white crystals are collected by filtration, and vacuum drying at room temperature obtains white powder
Shape solid 3.25g, yield 96.5%.
Comparative example 1：
48.7mg avanaphils are weighed with 29.2mg citric acids in test tube, addition 1mL isopropyl ethers are sealed, in 25 DEG C of bars
32h is stirred under part to there is mass crystallization white solid to be formed, products therefrom is collected.Detected through PXRD, DSC, still deposited in product
In more unreacted citric acid, the purity of product is have impact on, be unfavorable for raw material for further producing.
Comparative example 2：
48.4mg avanaphils are weighed with 20.8mg citric acids in test tube, addition 1mL dimethyl sulfoxide (DMSO)s are sealed, in 25
32d is stirred under the conditions of DEG C, nodeless mesh white powder is formed, that is, do not obtain forming avanaphil-citric acid eutectic powder.
Embodiment is not limited for the present invention preferably implementation method, but embodiments of the present invention by above-described embodiment
System, it is other it is any without departing from Spirit Essence of the invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Structural characterization：
The avanaphil prepared to embodiment 1-citric acid eutectic is determined and characterizes, specific as follows：
The X-ray powder diffraction figure of avanaphil-citric acid eutectic is determined using Bruker D2PHASER diffractometers, is surveyed
Fixed condition is as follows：Cu K α, 30kV, 10mV are light source, 0.12 ° of step-length, 10 °/min of sweep speed, 5.0~40 ° of sweep limits,
Carry out at room temperature.The gained X-ray powder diffraction figure of embodiment 1 is as shown in Figure 1.Accompanying drawing 2, accompanying drawing 3 represent respectively avanaphil,
The X-ray powder diffraction figure of citric acid.Comparison diagram 1, Fig. 2, Fig. 3, it is known that product obtained in embodiment 1 is a new crystallinity thing
Matter, i.e. avanaphil-citric acid eutectic.The characterize data of embodiment 1 see the table below：
The nuclear magnetic resonance figures of avanaphil-citric acid eutectic is determined using Bruker AvanceIII nuclear magnetic resonance spectrometers
Spectrum, magnetic field intensity：9.39T, resonant frequency：400MHz, uses solvent：Deuterated DMSO.The gained magnetic resonance detection figure of embodiment 1
Compose as shown in Figure 4, wherein, the peak of avanaphil is：δ 9.18 (d, 1H), 8.77 (d, 3H), 8.51 (d, 1H), 7.38 (t,
2H), 7.26 (d, 1H), 7.06 (d, 1H), 4.56 (d, 2H), 4.49 (d, 2H), 4.10 (s, 1H), 3.81 (s, 3H), 3.62 (d,
1H), 3.47-3.39 (m, 2H), 2.09-1.76 (m, 4H), the peak of citric acid is：δ 2.70 (dd, 4H).According to the product at each peak
The stoichiometric proportion for dividing result to understand avanaphil and citric acid in avanaphil-citric acid eutectic is 1：1.In addition, element point
Analysis result shows that C element content is 51.28% in avanaphil-citric acid eutectic, and H element content contains for 5.11%, O elements
Measure is 14.52%.According to C, tri- kinds of element ratios of H, O can avanaphil and lemon in secondary proof avanaphil-citric acid eutectic
The stoichiometric proportion of lemon acid is 1：1.The thermal multigraph (TG) of avanaphil-citric acid eutectic as shown in Figure 5, avanaphil-lemon
The differential scanning calorimeter figure (DSC) of lemon acid eutectic is as shown in Figure 6.As seen from the figure, avanaphil-citric acid eutectic is heated to
Start melting at 160.6 DEG C, continue to be heated to 175.8 DEG C and start to decompose.DSC results show the melting peak of only one of which eutectic,
There is no the melting peak of avanaphil or citric acid, illustrate that the purity of avanaphil-citric acid eutectic is higher.Accompanying drawing 7, Fig. 8 is distinguished
It is differential scanning calorimeter (DSC) figure of avanaphil and citric acid.As seen from the figure, the fusing point of avanaphil is 163.3 DEG C, lemon
The fusing point of lemon acid is 153.4 DEG C.As can be seen here, the fusing point of avanaphil-citric acid eutectic is different from avanaphil and citric acid,
Illustrate to form new crystal form.
The infrared spectrogram (IR) of avanaphil-citric acid eutectic as shown in Figure 9, its IR (KBr, cm-1) characteristic peak
Wave number is：3385,3301,3086,3059,2947,2929,2864,2600,1721,1688,1659,1638,1588,1488,
1330,1177,1062.
Stripping curve result (37 of avanaphil, avanaphil-the citric acid eutectic in the acetate buffers of pH 4.5
DEG C) as shown in Figure 10, as can be seen from the figure avanaphil and avanaphil-citric acid eutectic dissolve rapidly in 3min,
Reach maxima solubility.The solubility of avanaphil-citric acid eutectic effectively improves, and apparent solubility is avanaphil
10.95 times.
Claims (8)
1. the eutectic that avanaphil is formed with citric acid, the wherein mol ratio of avanaphil and citric acid are 1：1.
2. eutectic according to claim 1, it is characterised in that：The X-ray powder diffraction of avanaphil-citric acid eutectic exists
Angle of diffraction 2θFor：6.3±0.2、7.2±0.2、10.2±0.2、11.8±0.2、12.1±0.2、12.4±0.2、12.8±
0.2、13.7±0.2、14.2±0.2、14.6±0.2、15.4±0.2、15.8±0.2、16.9±0.2、17.7±0.2、
18.2±0.2、18.4±0.2、18.7±0.2、19.3±0.2、19.7±0.2、20.3±0.2、21.2±0.2、22.1±
0.2、22.3±0.2、22.9±0.2、23.8±0.2、24.3±0.2、24.7±0.2、25.2±0.2、25.4±0.2、
26.7±0.2、27.2±0.2、29.0±0.2、29.3±0.2、30.1±0.2、31.0±0.2、32.0±0.2、32.5±
0.2nd, 33.3 ± 0.2,35.6 ± 0.2,36.0 ± 0.2,36.3 ± 0.2,38.5 ± 0.2,39.4 ± 0.2 when there is characteristic peak.
3. a kind of preparation method of avanaphil-citric acid eutectic, comprises the following steps：
1）It is in molar ratio with citric acid by avanaphil（0.9-1.1）：（0.9-1.1）Mixed；
2）Solvent is added in mixture to avanaphil and citric acid, makes it be in suspension；
3）Above-mentioned suspension is sufficiently stirred for, gained crystalline powder, drying to obtain avanaphil-citric acid eutectic is collected.
4. preparation method according to claim 3, it is characterised in that：Step 1）Middle avanaphil is with citric acid in molar ratio
It is 1：1 is mixed.
5. preparation method according to claim 3, it is characterised in that：Step 2）In every 100 mg avanaphils and citric acid
Mixture in add solvent amount be 0.1~10 mL.
6. preparation method according to claim 5, it is characterised in that：Step 2）In, described solvent is distilled water, second
In ether, isopropyl ether, Ethyl formate, ethyl acetate, isopropyl acetate, methyl alcohol, ethanol, isopropanol, acetonitrile, acetone at least one
Kind.
7. preparation method according to claim 3, it is characterised in that：Step 3）Temperature during middle stirring is 0~70 DEG C.
8. preparation method according to claim 3, it is characterised in that：Step 3）The time of middle stirring is not less than 2 h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558861A (en) * | 2018-06-05 | 2018-09-21 | 上海工程技术大学 | Berberine hydrochloride eutectic, preparation method and application |
| CN108863864A (en) * | 2018-08-16 | 2018-11-23 | 天津大学 | A kind of Florfenicol-citric acid eutectic and preparation method thereof |
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| CN104151299A (en) * | 2014-08-22 | 2014-11-19 | 北京科莱博医药开发有限责任公司 | Compound, crystal form compound and preparation method thereof |
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2017
- 2017-03-23 CN CN201710178969.1A patent/CN106866638A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151299A (en) * | 2014-08-22 | 2014-11-19 | 北京科莱博医药开发有限责任公司 | Compound, crystal form compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 李全林: "《新医药开发与研究（下册）》", 31 December 2008 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558861A (en) * | 2018-06-05 | 2018-09-21 | 上海工程技术大学 | Berberine hydrochloride eutectic, preparation method and application |
| CN108558861B (en) * | 2018-06-05 | 2021-03-23 | 上海工程技术大学 | Berberine hydrochloride eutectic crystal, preparation method and application thereof |
| CN108863864A (en) * | 2018-08-16 | 2018-11-23 | 天津大学 | A kind of Florfenicol-citric acid eutectic and preparation method thereof |
| CN108863864B (en) * | 2018-08-16 | 2020-07-24 | 天津大学 | Florfenicol-citric acid eutectic crystal and preparation method thereof |
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Application publication date: 20170620 |