CN105399693A - Fluconazole monohydrate crystal form and preparation method thereof - Google Patents
Fluconazole monohydrate crystal form and preparation method thereof Download PDFInfo
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- CN105399693A CN105399693A CN201410487541.1A CN201410487541A CN105399693A CN 105399693 A CN105399693 A CN 105399693A CN 201410487541 A CN201410487541 A CN 201410487541A CN 105399693 A CN105399693 A CN 105399693A
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Abstract
The present invention relates to a fluconazole monohydrate crystal form and a preparation method thereof, and belongs to the technical field of medicine. According to the present invention, the crystal form of the fluconazole monohydrate is prepared, the chemical stability is good, the cell parameters are as the follows: a is 5.6253 (1) angstrom, b is 11.738 (2) angstrom, c is 12.299 (3) angstrom, alpha is 71.24 (3) DEG, beta is 79.84 (3)DEG, and gamma is 84.39 (3) DEG, the crystal belongs to a triclinic system, the space group is P-1, the X-ray powder diffraction determination results show that the crystal form has the characteristic peaks when the diffraction angle 2[theta] is 8.0 DEG, 9.2 DEG, 12.7 DEG, 15.4 DEG, 16.0 DEG, 17.6 DEG, 18.8 DEG, 19.8 DEG, 21.2 DEG, 22.1 DEG, 23.2 DEG, 23.9 DEG, 25.5 DEG, 25.9 DEG, 26.6 DEG, 27.5 DEG, 28.4 DEG, 29.5 DEG, 30.3 DEG and 30.7 DEG, and the relative diffraction intensities are substantially and respectively the detail spectrum represented by the figure 2. According to the present invention, the fluconazole can be completely dissolved in the organic solvent or the organic solvent mixing solution, and then the organic solvent or mixing solution is evaporated to prepare the product; and the preparation method has advantages of simple and easy-performing process, low requirements on equipment, low raw material cost, high yield, less pollution, and the like.
Description
Invention field
The invention belongs to medical art.Be specifically related to fluconazole monohydrate crystal form and preparation method thereof.
Background technology
Fluconazole (fluconazole, Diflucan), CASNO.:86386-73-4, MerckIndex4158, chemical name: α-(2,4 difluorobenzene base)-α-(1H-1,2,4-triazole-1-methyl)-1H-1,2,4-triazole-1-methyl alcohol, English name: α-(2,4-difuorophenyl)-α-(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-l-ethanol.Outward appearance is white extremely band yellow-white crystalline powder, and slightly foreign odor, bitter, is soluble in acetic acid, methyl alcohol, ethanol, is comparatively soluble in Glacial acetic acid, be insoluble in water, almost insoluble in ether.Fusing point 138-140 DEG C.Molecular formula: C
13h
12f
2n
6o, molecular weight: 306.27, structural formula is as follows:
Fluconazole is as a kind of antifungal drug, and its mechanism of action is Antifungi cytolemma neccessary composition ergosterol synthetic enzyme, makes ergosterol biosynthesis block, destroys the integrity of fungal cell wall, thus affects growth, the breeding of fungi.This product has extremely strong anti-microbial effect to fungies such as Candida albicans, trichophyton mentagrophytes, the little leopard bacterium of dog, acrothesium floccosum, mouse coccidioides immitis, Histoplasma capsulatum, Cryptococcus neoformans, aspergillus fumigatuses.
Clinically be mainly used in the acute or recurrent vaginal candidiasis for the treatment of, white mouth (comprising the immune function depression person of Secondary cases malignant disease or AIDS), atrophic oral candidiasis, fungal meningitis or intracranial infection, the cryptococcal meningitis of the AIDS that occurs together, Coccidioidomycosis, shallow table dermatophytid infection, the mycotic peritonitis etc. relevant with Continual Ambulatory Peritoneal Dialysis.Amphotericin B can be replaced as the long-term treatment of the hidden feel of the ball dye of AIDS VICTIMS, and likely as the medicine of Pulmonary Fungal Infections.This medicine can external application, for oral administration, injection, apply very extensive.
Summary of the invention
The invention provides a kind of monohydrate of fluconazole, be insoluble in water, methyl alcohol, ethanol equal solvent, the chemical stability under its high temperature, illumination, high humidity comparatively fluconazole will be got well, and improves medication stability.
Technical scheme of the present invention is as follows:
Fluconazole monohydrate, is characterized in that containing 1 water molecules in 1 molecule fluconazole, shown in its structural formula (I):
Fluconazole monohydrate unit cell parameters provided by the present invention is as follows:
α=71.24 (3) °, β=79.84 (3) °, γ=84.39 (3) ° are triclinic(crystalline)system,
spacer.
Present invention also offers the preparation method of fluconazole monohydrate, be dissolved in by fluconazole solvable or easily in broad dose, or be dissolved in can with miscible solvable of water or easily in the broad dose of mixed solvent formed with water, left at room temperature, crystallize out.It is few that this preparation method has flow process, and technique is simple, low for equipment requirements.
Described solvable or easily broad dose comprise one or more the mixed solvent in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., ethyl acetate, ethyl formate, pyridine, acetone, butanone, methylene dichloride, chloroform, THF, toluene, chlorobenzene, ethylene glycol, ethylene glycol monomethyl ether.
After described fluconazole dissolves during left at room temperature, adopt solution-air diffusion process or liquid-liquid diffusion process also obtained above-mentioned crystal formation, employing can be miscible with water the mixed solvent of easily molten or soluble solvent and water fluconazole is dissolved after, left at room temperature, equally also obtains above-mentioned crystal formation.
Described fluconazole monohydrate is treated in preparation and is prevented the application in the medicine of fungus-caused disease.
The injection that described fluconazole monohydrate is made or slow releasing tablet.
The solubility experiment test of the present invention to fluconazole draws, fluconazole is organic neutral molecule, be soluble in general organic solvent, indissoluble or insoluble in water, tetracol phenixin, hexanaphthene, normal hexane, ether, sherwood oil equal solvent, easily molten or soluble solvent comprises methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., ethyl acetate, ethyl formate, pyridine, acetone, butanone, methylene dichloride, chloroform, THF, toluene, chlorobenzene, ethylene glycol, ethylene glycol monomethyl ether.Cinepazide is dissolved in easily in molten or soluble solvent or its mixed solvent, under left at room temperature, obtains single crystal samples.
PXRD (powderX-raydiffraction) and simulation PXRD (powderX-raydiffraction) figure is known by experiment, and it has identical diffraction peak, illustrates that gained laboratory sample is sterling.This crystal formation 2 θ is about 16.7,21.2,23.9,25.5, the characteristic peak relative intensity (I/I at 25.9,30.7 places
0) more than 50%.
In the present invention, the mensuration of 2 θ values uses CuK α light source, precision is ± 0.2 °, therefore, " about " in above-mentioned " X-ray powder diffraction pattern charateristic avsorption band reflection angle 2 θ is about " should be defined as 2 θ ± 0.2 °, represent 2 above-mentioned got θ values and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Shown by thermogravimetric-heating differential analysis experiment and ultimate analysis, this crystal formation is fluconazole monohydrate.And shown by thermogravimetric analysis collection of illustrative plates: before 120 DEG C, all lose crystal water, differential scanning calorimetric analysis (DTA) collection of illustrative plates of this crystal formation is at 103.6 DEG C, and there are three endotherm(ic)peaks at 138.8 DEG C, 319.1 DEG C places.
Measure with KBr compressing tablet the infrared absorption spectrum that obtains this crystal formation 3107,1620,1591,1421,1275,1248,1217,1209,1140,1111,1082,1020,966,916,852,833,766,681,654,617,571,530cm
-1there is absorption peak (see Fig. 4) at place
Accompanying drawing explanation
Fig. 1 is the molecular structure of fluconazole monohydrate of the present invention;
Fig. 2 is the comparison diagram that PXRD collection of illustrative plates simulated by the PXRD collection of illustrative plates of fluconazole monohydrate of the present invention and monocrystalline;
Fig. 3 is the TG-DTA graphic representation of fluconazole monohydrate of the present invention;
Fig. 4 is the infrared spectrogram of fluconazole monohydrate of the present invention.
Embodiment
Below in conjunction with accompanying drawing embodiment, the present invention is described in further detail.
Embodiment 1
1.1 fluconazole solvability tests
Common solvent is selected to comprise: water, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., ethyl acetate, ethyl formate, pyridine, acetone, butanone, methylene dichloride, chloroform, tetracol phenixin, THF, hexanaphthene, normal hexane, benzene,toluene,xylene, chlorobenzene, ethylene glycol, ether, ethylene glycol monomethyl ether, sherwood oil etc. 32 kinds.
Because fluconazole is organic neutral molecule, be soluble in general organic solvent.Solvability test result shows to dewater, tetracol phenixin, hexanaphthene, normal hexane, ether, sherwood oil are indissoluble or outside insoluble solvent, all the other belong to easily molten or soluble solvent.
The preparation of 1.2 fluconazole monohydrate crystal forms
Method 1: adopt single solvable or easily broad dose prepare monocrystalline
Specific experiment is operating as: at ambient temperature, takes the fluconazole sample of 0.306g (1mmol), add appropriate solvable or easily broad dose dissolved, constantly stir simultaneously, after 30min, this solution is filtered, ambient temperatare is put, and obtains single crystal samples after several days.
Wherein solvable or easily broad dose be methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., ethyl acetate, ethyl formate, pyridine, acetone, butanone, methylene dichloride, chloroform, THF, toluene, chlorobenzene, ethylene glycol, ethylene glycol monomethyl ether etc. 24 kinds.
Method II: adopt mixed solvent to cultivate monocrystalline
A, two kinds of solvable or easily mixing between broad dose
Specific experiment is operating as: at ambient temperature, takes the fluconazole sample of 0.306g (1mmol), two kinds solvable or easily broad dose mix according to a certain percentage and dissolved, constantly stir simultaneously, after 30min, this solution is filtered, ambient temperatare is put, and obtains single crystal samples after several days.
Wherein solvable or easily broad dose be methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., ethyl acetate, ethyl formate, pyridine, acetone, butanone, methylene dichloride, chloroform, THF, toluene, chlorobenzene, ethylene glycol, ethylene glycol monomethyl ether etc. 24 kinds.
Miscible solvable of b, energy and water or easily broad dose mix with between water
Specific experiment is operating as: at ambient temperature, takes the fluconazole sample of 0.306g (1mmol), and two kinds of solvents mix according to a certain percentage and dissolved, constantly stir simultaneously, after 30min, this solution is filtered, ambient temperatare is put, and obtains single crystal samples after several days.
Wherein use can be miscible with water solvent have methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., acetone, THF, ethylene glycol, ethylene glycol monomethyl ether etc. 16 kinds.
Method III: the method adopting " solution-air " to spread cultivates monocrystalline
Specific experiment is operating as: at ambient temperature, take the fluconazole sample of 0.306g (1mmol), add appropriate solvable or easily broad dose dissolved, constantly stir simultaneously, after 30min, filtered by this solution, filtrate is placed in encloses container and places, with ether as gas diffusant, after several days, obtain single crystal samples.
Wherein use solvable or easily broad dose have propyl carbinol, DMF, DMSO, ethylene glycol, ethylene glycol monomethyl ether etc. 5 kinds.
Method IV: the method adopting " liquid-liquid " to spread cultivates monocrystalline
Specific experiment is operating as: at ambient temperature, take the fluconazole sample of 0.306g (1mmol), add suitable solvable or easily broad dose dissolved, constantly stir simultaneously, after 30min, this solution is filtered, choose indissoluble or insoluble solvent as diffusant, on filtrate lay one deck diffusant or by filtrate lay on diffusant, ambient temperatare is put, and obtains single crystal samples after several days.
Wherein use solvable or easily broad dose be ethanol, propyl alcohol, Virahol, propyl carbinol, DMF, DMSO, toluene, Isosorbide-5-Nitrae-dioxane, acetonitrile, ethylene glycol, ethylene glycol monomethyl ether etc. 11 kinds; Indissoluble or insoluble solvent are 5 kinds, hexanaphthene, normal hexane, ether, sherwood oil, tetracol phenixin etc.
Embodiment 2: the collection of illustrative plates of fluconazole monohydrate crystal form characterizes
PXRD: the X-ray powder of fluconazole monohydrate crystal spreads out and Tu not adopt Cu target, Ni filter
the diffraction data of BrukerD8Focus Powder X-ray Diffractometer record sample at room temperature in the 2 θ angular ranges of 5-50 °, scanning speed is 8 °/min.
TG/DTA: adopt SeikoExtra6000TG/DTA6300 type Differential Thermal Analysis instrument, and with α-Al
2o
3for reference substance, live in the N of 200mL/min
2air-flow protection, temperature rise rate is the TG-DTA curve measuring powder under the condition of 10 DEG C/min.
Infrared: to adopt Japanese Shimadzu FTIR-8900 Fourier transform infrared spectrometer.KBr compressing tablet, record sample is at 4000-400cm
-1infrared spectra in wave-number range, resolving power is 4cm
-1.
Ultimate analysis: adopt Perkin-Elmer2400 type elemental analyser to carry out ultimate analysis test to title complex.
Single crystal diffractometer: application RigakuR-AxisRapid single crystal diffractometer, adopts graphite monochromatised
collect the diffraction data of crystal at 293k.
The sign of 2.1 fluconazole monohydrate crystal forms
2.1.1 the monocrystalline figure (see Fig. 1) of fluconazole monohydrate crystal form
2.1.2 the unit cell parameters of the monocrystalline of gained under fluconazole monohydrate multi-solvents
2.1.3 experiment X-powdery diffractometry (PXRD) figure (see Fig. 2) of fluconazole monohydrate crystal form
The powder that the single crystal samples of gained crystal formation is made is obtained PXRD figure by experiment X-powdery diffractometry (PXRD) figure.
Solvent: ethanol/water
Wherein characteristic peak statistics sees the following form:
| 2θ | 7.984 | 9.177 | 12.698 | 15.380 | 16.000 | 16.697 | 17.612 |
| I％ | 14.2 | 44.6 | 14.7 | 41.2 | 24.5 | 100 | 42.6 |
| 2θ | 18.845 | 19.830 | 21.153 | 22.127 | 23.201 | 23.918 | 25.529 |
| I％ | 14.0 | 36.5 | 55.4 | 20.3 | 45.3 | 66.2 | 75.2 |
| 2θ | 25.867 | 26.583 | 27.518 | 28.413 | 29.547 | 30.303 | 30.681 |
| I％ | 89.2 | 24.8 | 27.2 | 23.5 | 15.9 | 36.3 | 62.5 |
Simulation X-powdery diffractometry (PXRD) figure (see Fig. 2) of 2.14 fluconazole monohydrate crystal forms
Simulation X-powdery diffractometry (PXRD) figure is the PXRD figure simulating out by simulation software mercury by single crystal diffraction data.
2 θ of experiment PXRD and simulation PXRD diffraction peak compare and see the following form
| Experimental(2θ) | 7.98 | 9.18 | 12.70 | 15.38 | 16.00 | 16.70 | 17.61 |
| Simulated(2θ) | 7.96 | 9.18 | 12.68 | 15.40 | 16.00 | 16.66 | 17.58 |
| Experimental(2θ) | 18.85 | 19.83 | 21.15 | 22.13 | 23.20 | 23.92 | 25.53 |
| Simulated(2θ) | 18.82 | 19.78 | 21.12 | 22.16 | 23.18 | 23.94 | 25.50 |
| Experimental(2θ) | 25.87 | 26.58 | 27.52 | 28.41 | 29.55 | 30.30 | 30.68 |
| Simulated(2θ) | 25.86 | 26.56 | 27.48 | 28.40 | 29.54 | 30.30 | 30.66 |
Schemed from experiment PXRD and simulation PXRD: experiment PXRD and simulation PXRD diffraction peak are coincide very well, and this illustrates that gained laboratory sample is single-phase.
2.1.5 Fig. 3 is shown in the TG-DTA analysis (TG/DTA) of fluconazole monohydrate crystal form
Show from this thermogravimetric analysis collection of illustrative plates: before 120 DEG C, all lose crystal water.Differential scanning calorimetric analysis (DTA) collection of illustrative plates of this crystal formation is at 103.6 DEG C, and there are three endotherm(ic)peaks at 138.8 DEG C, 319.1 DEG C places.
2.1.6 the infrared analysis of fluconazole monohydrate crystal form is shown in Fig. 4
Show from this infrared analysis collection of illustrative plates: measure with KBr compressing tablet the infrared absorption spectrum that obtains this crystal about 3107,1620,1591,1421,1275,1248,1217,1209,1140,1111,1082,1020,966,916,852,833,766,681,654,617,571,530cm
-1there is absorption peak at place.
2.1.7 the ultimate analysis of fluconazole monohydrate crystal form
Solvent: ethanol/water
| N％ | C％ | H％ | |
| Theoretical | 25.92 | 48.15 | 4.35 |
| Experiment | 25.78 | 48.02 | 4.51 |
Ultimate analysis shows: this crystal formation is the hydrate containing a water, and this point is consistent with monocrystalline XRD and thermal gravimetric analysis results.
Claims (6)
1. fluconazole monohydrate, is characterized in that its structural formula is as shown in (I) containing 1 water molecules in 1 molecule fluconazole:
Its crystalline structure has following feature: the X-ray powder diffraction represented with 2 θ angles is 9.2 ± 0.2,15.4 ± 0.2,16.7 ± 0.2,17.6 ± 0.2,19.8 ± 0.2,21.2 ± 0.2,23.2 ± 0.2,23.9 ± 0.2,25.5 ± 0.2,25.9 ± 0.2,30.3 ± 0.2, there is characteristic peak at 30.7 ± 0.2 places.
2. the preparation method of fluconazole monohydrate according to claim 1, that be dissolved in by fluconazole can with miscible solvable of water or easily in the broad dose of mixed solvent formed with water, left at room temperature, crystallize out, one or more mixed solvent in described solvable and easy molten solvent selected from methanol, ethanol, propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, the trimethyl carbinol, DMF, DMSO, acetonitrile, Isosorbide-5-Nitrae-dioxane, Nitromethane 99Min., acetone, THF, ethylene glycol, ethylene glycol monomethyl ether.
3. preparation method according to claim 2, after described fluconazole dissolves during left at room temperature, adopts solution-air diffusion process or liquid-liquid diffusion process to obtain crystal.
4. fluconazole monohydrate crystal form according to claim 1, it is characterized in that differential scanning calorimetric analysis (DTA) collection of illustrative plates is at 103.6 DEG C, there are three endotherm(ic)peaks at 138.8 DEG C, 319.1 DEG C places.
5. the crystal formation of fluconazole monohydrate according to claim 1, it is characterized in that with KBr compressing tablet measure the infrared absorption spectrum that obtains 3107,1620,1591,1421,1275,1248,1217,1209,1140,1111,1082,1020,966,916,852,833,766,681,654,617,571,530cm
-1there is absorption peak at place.
6. described in claim 1, the preparation of fluconazole monohydrate is treated and prevents the application in the medicine of fungus-caused disease.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383859A (en) * | 2018-04-19 | 2018-08-10 | 西南大学 | Imidazo benzothiazole ether compound and its officinal salt preparation method and application |
-
2014
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| A. DUGARTE ET AL.: "X-ray powder diffraction data of the antifungal agents, clotrimazole and fluconazole monohydrate", 《POWDER DIFFRACTION》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383859A (en) * | 2018-04-19 | 2018-08-10 | 西南大学 | Imidazo benzothiazole ether compound and its officinal salt preparation method and application |
| CN108383859B (en) * | 2018-04-19 | 2020-06-26 | 西南大学 | Imidazobenzothiazole ether compound and preparation method and application of pharmaceutically acceptable salt thereof |
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Application publication date: 20160316 |