CN103980166B - A kind of novel crystal forms of florfenicol and preparation method thereof - Google Patents
A kind of novel crystal forms of florfenicol and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of florfenicol novel crystal forms crystal, describe its feature with X-ray powder diffraction pattern and differential scanning amount dsc data。Temperature 40～55 DEG C, by the purity florfenicol be more than or equal to 92%, dissolves and forms solution in organic solvent, and concentration is 0.05～0.15g/mL, with 1～3 DEG C/min rate of temperature fall, solution is cooled to 25～30 DEG C after stirring and dissolving；Dissolved agent is dripped again in the solid-liquid suspension of gained；With 0.2～1 DEG C/min rate of temperature fall, solution is cooled to 5～10 DEG C after adding dissolved agent, continues stirring 0.5～2h；Then the solid-liquid suspension of gained separated, dry, obtain florfenicol crystalline product。Products obtained therefrom degree of crystallinity is high, and crystal formation is complete, and purity more than 99%, yield more than 87%, in 25 DEG C of water, dissolubility improves about 7%, improves its bioavailability。
Description
Technical field
The invention belongs to Chemical Engineering crystallization technique field, particularly to the novel crystal forms and preparation method thereof of a kind of florfenicol。
Background technology
Florfenicol (Florfenicol) has another name called chloromethyl sulfone mycin, chemistry [R--(R* by name, R*)]-2,2-bis-chloro-N-{1-(methyl fluoride)-2-hydroxyl-2-[4-(sulfonyloxy methyl) phenyl] ethyl } acetamide, molecular formula is C12H14Cl2FNO4S, molecular weight is 358.2, No. CAS: 73231-34-2, its chemical structural formula is as follows。
Florfenicol is a kind of excellent chloromycetin broad ectrum antibiotic, can combine closely with antibacterial 70S ribosome and 50S subunit, reduces the activity of peptidyl transferase, and the synthesis of interference bacterioprotein, its antibacterial activity is better than chloromycetin and thiamphenicol。And the features such as florfenicol overcomes chloromycetin and is easily generated drug resistance and causes the problem of aplastic anemia, has antibacterial wide spectrum, oral absorption is good, distribution in vivo is extensive, safe and efficient。
Florfenicol is the product developed in 20 century 70s by Ling-Bao Ya company of elder generation of the U.S., and China was in approval listing in 1999, and current florfenicol is popularization and application gradually。Currently mainly adopt thiamphenicol to prepare florfenicol, but to there is yield low due to the preparation method of florfenicol, to producing the high deficiency of equipment requirements, causes that the price of this medicine at present cannot reduce。The preparation method that patent CN101265220 gives florfenicol: L-Su Shi-[p-(methylsulfonyl) phenyl] serine ethyl ester adopts hydrochloric acid and water back flow reaction concentrate with dichloromethane extraction after 4 hours, and in petroleum ether, carry out crystallisation by cooling, yield 66%。The method operating condition is harsh, and equipment requirements is high, and the yield of product is not high。Patent US5382673A is by after reactant mixture distillating filtering, and the mixed solvent at organic solvent and water carries out dilution crystallization and obtains florfenicol, yield 82%, purity 98.4%。The florfenicol Product Process that the method obtains processes complexity, and productivity is low, does not carry out its crystal formation problem characterizing explanation。Applicant repeats to test the florfenicol product obtained in this way, and its X-ray powder diffraction figure is as shown in Figure 1。
Compared with similar antibiotic, though florfenicol function admirable, its dissolubility in water is too poor, thus affecting its bioavailability。Patent CN101279941A improves water solublity by florfenicol is made florfenicol sodium succinate salt, it is simple to animal absorbs。But this technique preparation condition is harsh, and constant product quality is poor, in the use procedure after making preparation, effective ingredient is degraded quickly, leverages its result of use。
Therefore, it is necessary to research and develop the novel crystal forms of a kind of florfenicol and preparation method thereof, improve the index such as stability and dissolubility of its yield, product, and then improve its bioavailability。
Summary of the invention
In order to overcome the deficiency that yield is low, water solublity is relatively low of existing florfenicol crystallization, the invention provides novel crystal forms of a kind of florfenicol and preparation method thereof, improve the degree of crystallinity of florfenicol product, yield and water solublity。
Florfenicol novel crystal forms crystal provided by the invention, its X-ray powder diffraction pattern in the angle of diffraction 2 θ=4.0 ± 0.1,8.1 ± 0.1,12.2 ± 0.1,16.3 ± 0.1,19.9 ± 0.1,20.1 ± 0.1,20.5 ± 0.1,20.8 ± 0.1,23.6 ± 0.1,24.1 ± 0.1,24.6 ± 0.1,27.4 ± 0.1,31.8 there is characteristic peak at ± 0.1 and 41.6 ± 0.1 degree of place, as shown in Figure 2。
Florfenicol novel crystal forms crystal of the present invention, measures with differential scanning calorimeter DSC, melts endothermic peak at 155 ± 1 DEG C one, as shown in Figure 3。Test condition: temperature range 25～200 DEG C, heating rate is 5 DEG C/min, protects nitrogen 80mL/min。
Florfenicol novel crystal forms crystal of the present invention, its Raman spectrum 1688 ± 2,1599 ± 2,1202 ± 2,1142 ± 2,1102 ± 2,970 ± 2,919 ± 2,899 ± 2,850 ± 2,814 ± 2,771 ± 2,694 ± 2,676 ± 2,631 ± 2 and 310 ± 2cm-1There is characteristic peak, as shown in Figure 4。
The preparation method of florfenicol novel crystal forms crystal of the present invention is as follows:
Temperature 40～55 DEG C, by the purity florfenicol be more than or equal to 92%, dissolves and forms solution in organic solvent, and concentration is 0.05～0.15g/mL, with 1～3 DEG C/min rate of temperature fall, solution is cooled to 25～30 DEG C after stirring and dissolving；Dripping dissolved agent again in the solid-liquid suspension of gained, dissolved agent consumption is 1～3 times of organic solvent volume；With 0.2～1 DEG C/min rate of temperature fall, solution is cooled to 5～10 DEG C after adding dissolved agent, continues stirring 0.5～2h；Then the solid-liquid suspension of gained separated, dry, obtain florfenicol crystalline product。
Described organic solvent one in methanol, acetonitrile, acetone or oxolane。
Described dissolved agent one in water or normal hexane。The time for adding of dissolved agent is 2～5h。
Described drying condition is temperature is 50～80 DEG C, and vacuum is 0.08～0.1MPa, and drying time is 4～12 hours。
The advantage of the preparation method of florfenicol novel crystal forms crystal provided by the invention is that operating condition is simple and easy to control, product magma easily filters, washs and dries, the result of the X-ray powder diffraction pattern shown in accompanying drawing 2 and accompanying drawing 5 crystallographic microscope photo shows that product degree of crystallinity is high, crystal formation is complete, the one way molar yield of crystallization process more than 87%, liquid-phase chromatographic analysis product purity more than 99%。Find by measuring the dissolubility of florfenicol novel crystal forms, it is 1.0508mg/g water by the dissolubility in water at the literature method US5382673A crystal formation 25 DEG C prepared, the florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1316mg/g, dissolubility improves 7.69%, improves its bioavailability。
Accompanying drawing explanation
Fig. 1: according to the X-ray powder diffraction pattern of the florfenicol crystal that literature method prepares；
Fig. 2: the X-ray powder diffraction pattern of florfenicol novel crystal forms；
Fig. 3: the DSC collection of illustrative plates of florfenicol novel crystal forms；
Fig. 4: the Raman spectrum of florfenicol novel crystal forms；
Fig. 5 florfenicol novel crystal forms microphotograph (amplifies 40 times)。
Detailed description of the invention
Embodiment 1
The florfenicol solid that 15g purity is 92% is added in 100mL methanol, under agitation it is heated to 45 DEG C, it is made to dissolve completely, then with the rate of temperature fall of 2 DEG C/min, solution is cooled to 25 DEG C, 100mL water is dripped in solid-liquid suspension, dropping 2h, is cooled to 10 DEG C with 0.2 DEG C/min rate of temperature fall by solution after adding dissolved agent, continues stirring 0.5h；The suspension of sucking filtration gained, 50 DEG C, vacuum be dry gained filter cake under 0.08MPa, the molar yield of final products is 87.1%, and purity is 99.2%。
The PXRD collection of illustrative plates of product is in the angle of diffraction 2 θ=4.04, and there is characteristic peak at 8.10,12.22,16.32,19.92,20.06,20.46,20.80,23.64,24.14,24.60,27.36,31.8 and 41.62 degree of places；DSC has fusing endothermic peak at 155.4 DEG C；Raman collection of illustrative plates is 1688,1599,1202,1142,1102,970,919,899,850,814,771,694,676,631 and 310cm-1There is characteristic peak。The florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1327mg/g, improve 7.79% than by the dissolubility of the literature method US5382673A crystal formation prepared, improve its bioavailability。
Embodiment 2
The florfenicol solid that 5g purity is 93% is added in 100mL acetone, under agitation it is heated to 55 DEG C, it is made to dissolve completely, then with the rate of temperature fall of 3 DEG C/min, solution is cooled to 30 DEG C, 200mL water is dripped in solid-liquid suspension, dropping 4h, is cooled to 5 DEG C with 0.5 DEG C/min rate of temperature fall by solution after adding dissolved agent, continues stirring 1.5h；The suspension of sucking filtration gained, 55 DEG C, vacuum be dry gained filter cake under 0.09MPa, the molar yield of final products is 89.3%, and purity is 99.3%。
The PXRD collection of illustrative plates of product is in the angle of diffraction 2 θ=4.03, and there is characteristic peak at 8.09,12.21,16.31,19.91,20.05,20.56,20.79,23.63,24.13,24.59,27.35,31.79 and 41.61 degree of places；DSC has fusing endothermic peak at 155.1 DEG C；Raman collection of illustrative plates is 1688,1599,1203,1142,1101,970,920,900,850,814,771,694,676,632 and 311cm-1There is characteristic peak。The florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1293mg/g, improve 7.47% than by the dissolubility of the literature method US5382673A crystal formation prepared, improve its bioavailability。
Embodiment 3
The florfenicol solid that 8g purity is 94% is added in 100mL acetonitrile, under agitation it is heated to 40 DEG C, it is made to dissolve completely, then with the rate of temperature fall of 1.5 DEG C/min, solution is cooled to 27 DEG C, 300mL water is dripped in solid-liquid suspension, dropping 5h, is cooled to 8 DEG C with 1 DEG C/min rate of temperature fall by solution after adding dissolved agent, continues stirring 0.5h；The suspension of sucking filtration gained, 60 DEG C, vacuum be dry gained filter cake under 0.09MPa, the molar yield of final products is 93.0%, and purity is 99.5%。
The PXRD collection of illustrative plates of product is in the angle of diffraction 2 θ=4.04, and there is characteristic peak at 8.09,12.21,16.31,19.92,20.06,20.48,20.79,23.64,24.13,24.60,27.35,31.79 and 41.62 degree of places；DSC has fusing endothermic peak at 154.9 DEG C；Raman collection of illustrative plates is 1689,1600,1202,1143,1102,971,920,900,850,814,772,694,676,632 and 309cm-1There is characteristic peak。The florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1309mg/g, improve 7.62% than by the dissolubility of the literature method US5382673A crystal formation prepared, improve its bioavailability。
Embodiment 4
The florfenicol solid that 10g purity is 95% is added in 100mL oxolane, under agitation it is heated to 55 DEG C, it is made to dissolve completely, then with the rate of temperature fall of 1 DEG C/min, solution is cooled to 26 DEG C, 300mL normal hexane is dripped in solid-liquid suspension, dropping 4h, is cooled to 6 DEG C with 0.3 DEG C/min rate of temperature fall by solution after adding dissolved agent, continues stirring 1h；The suspension of sucking filtration gained, 80 DEG C, vacuum be dry gained filter cake under 0.1MPa, the molar yield of final products is 91.2%, and purity is 99.3%。
The PXRD collection of illustrative plates of product is in the angle of diffraction 2 θ=4.03, and there is characteristic peak at 8.10,12.22,16.31,19.92,20.06,20.46,20.80,23.64,24.13,24.60,27.36,31.8 and 41.61 degree of places；DSC has fusing endothermic peak at 154.7 DEG C；Raman collection of illustrative plates is 1687,1599,1201,1142,1102,970,918,899,850,814,771,694,675,631 and 310cm-1There is characteristic peak。The florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1327mg/g, improve 7.79% than by the dissolubility of the literature method US5382673A crystal formation prepared, improve its bioavailability。
Embodiment 5
The florfenicol solid that 6g purity is 93.5% is added in 100mL acetone, under agitation it is heated to 50 DEG C, it is made to dissolve completely, then with the rate of temperature fall of 2 DEG C/min, solution is cooled to 28 DEG C, 200mL normal hexane is dripped in solid-liquid suspension, dropping 2h, is cooled to 5 DEG C with 0.8 DEG C/min rate of temperature fall by solution after adding dissolved agent, continues stirring 2h；The suspension of sucking filtration gained, 70 DEG C, vacuum be dry gained filter cake under 0.09MPa, the molar yield of final products is 90.2%, and purity is 99.5%。
The PXRD collection of illustrative plates of product is in the angle of diffraction 2 θ=4.04, and there is characteristic peak at 8.11,12.22,16.33,19.92,20.07,20.44,20.80,23.64,24.15,24.60,27.36,31.81 and 41.63 degree of places；DSC has fusing endothermic peak at 155.3 DEG C；Raman collection of illustrative plates is 1688,1599,1201,1143,1102,970,918,899,850,814,771,694,675,631 and 310cm-1There is characteristic peak。The florfenicol novel crystal forms product of the present invention in aqueous at 25 DEG C dissolubility be 1.1316mg/g, improve 7.69% than by the dissolubility of the literature method US5382673A crystal formation prepared, improve its bioavailability。
Florfenicol crystal formation of disclosure and proposition and preparation method thereof, those skilled in the art can by link realizations such as reference present disclosure, suitable feed change, technological parameters。The method of the present invention and product have passed through preferred embodiment and are described, method described herein and product substantially can be modified or suitably change and combination by person skilled in without departing from present invention, spirit and scope, realize the technology of the present invention。Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are considered as including in present invention spirit, scope and content。
Claims (5)
1. a crystal for florfenicol, is characterized in that, its X-ray powder diffraction pattern is in the angle of diffraction 2 θ=4.0 ± 0.1,8.1 ± 0.1,12.2 ± 0.1,16.3 ± 0.1,19.9 ± 0.1,20.1 ± 0.1,20.5 ± 0.1,20.8 ± 0.1,23.6 ± 0.1,24.1 ± 0.1,24.6 ± 0.1,27.4 there is characteristic peak at ± 0.1,31.8 ± 0.1 and 41.6 ± 0.1 degree of places。
2. florfenicol crystal as claimed in claim 1, is characterized in that, measures with differential scanning calorimeter DSC, melts endothermic peak at 155 ± 1 DEG C one。
3. the preparation method of florfenicol crystal as claimed in claim 1, it is characterized in that, temperature 40～55 DEG C, by the purity florfenicol be more than or equal to 92%, dissolve and form solution in organic solvent, concentration is 0.05～0.15g/mL, with 1～3 DEG C/min rate of temperature fall, solution is cooled to 25～30 DEG C after stirring and dissolving；Dripping dissolved agent again in the solid-liquid suspension of gained, dissolved agent consumption is 1～3 times of organic solvent volume；With 0.2～1 DEG C/min rate of temperature fall, solution is cooled to 5～10 DEG C after adding dissolved agent, continues stirring 0.5～2h；Then the solid-liquid suspension of gained separated, dry, obtain florfenicol crystalline product；Described organic solvent one in methanol, acetonitrile, acetone or oxolane, dissolved agent one in water or normal hexane。
4. method as claimed in claim 3, is characterized in that, the time for adding of dissolved agent is 2～5h。
5. method as claimed in claim 3, is characterized in that, described drying condition is temperature is 50～80 DEG C, and vacuum is 0.08～0.1MPa, and drying time is 4～12 hours。
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| CN108863864B (en) * | 2018-08-16 | 2020-07-24 | 天津大学 | Florfenicol-citric acid eutectic crystal and preparation method thereof |
| CN108721211B (en) * | 2018-08-24 | 2021-01-01 | 四川省欧邦动物药业有限公司 | Preparation method of florfenicol injection |
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| US20050075506A1 (en) * | 2003-10-06 | 2005-04-07 | Handa Vijay Kumar | Process for preparing florfenicol |
| CN101265220A (en) * | 2008-04-30 | 2008-09-17 | 上海立科药物化学有限公司 | Method for synthesizing florfenicol |
| CN102827042A (en) * | 2012-09-17 | 2012-12-19 | 湖北美天生物科技有限公司 | Chiral synthesis method of florfenicol |
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| US7601869B2 (en) * | 2005-06-20 | 2009-10-13 | Aurobindo Pharma Ltd. | Process for the preparation of Florfenicol |
| CN1331849C (en) * | 2005-08-12 | 2007-08-15 | 中国科学院上海有机化学研究所 | Novel method for synthesizing thiamphenicol and florfenicol and its key intermediate product |
| CN101784534A (en) * | 2007-05-30 | 2010-07-21 | 先灵-普劳有限公司 | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
| CN102417472B (en) * | 2011-12-12 | 2013-11-13 | 齐鲁动物保健品有限公司 | Preparation method of florfenicol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050075506A1 (en) * | 2003-10-06 | 2005-04-07 | Handa Vijay Kumar | Process for preparing florfenicol |
| CN101265220A (en) * | 2008-04-30 | 2008-09-17 | 上海立科药物化学有限公司 | Method for synthesizing florfenicol |
| CN102827042A (en) * | 2012-09-17 | 2012-12-19 | 湖北美天生物科技有限公司 | Chiral synthesis method of florfenicol |
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