CN109053506B - Method for preparing florfenicol nano crystal - Google Patents
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- CN109053506B CN109053506B CN201810931971.6A CN201810931971A CN109053506B CN 109053506 B CN109053506 B CN 109053506B CN 201810931971 A CN201810931971 A CN 201810931971A CN 109053506 B CN109053506 B CN 109053506B
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Abstract
The invention relates to a method for preparing florfenicol nanocrystals, which comprises the steps of preparing a saturated solution of florfenicol under the stirring action at 40-60 ℃; adding methyl cellulose with the mass fraction of 0.5-2% of florfenicol, and keeping the temperature for 0.5-2h to completely dissolve the methyl cellulose solid; and then cooling to 10-20 ℃ at a cooling rate of 0.1-1 ℃/min, growing crystals at a constant temperature for 0.5-2h, and then separating and drying the obtained suspension to obtain the florfenicol nanocrystal. The prepared florfenicol nanocrystal is a nanorod crystal with the diameter of 100-900 nm under SEM observation. The dispersant methylcellulose adopted by the invention has good biodegradability, biocompatibility and bioabsorbability, does not leave any environmental protection problem after degradation, and is nontoxic, non-allergenic and non-irritant. The cost of the required raw materials and solvents is low, and the preparation process is simple and quick.
Description
Technical Field
The invention belongs to the technical field of chemical engineering industrial crystallization, and particularly relates to a method for preparing florfenicol nanocrystals.
Background
Florfenicol (Florfenicol) has the chemical name [ R- (R1.T)]-2, 2-dichloro-N- [1- (fluoromethyl) ether2-hydroxy-2- [4- (methylsulfonyl) phenyl]Ethyl radical]An acetamide. The molecular formula is: c12H14Cl2FNO4S, molecular weight: 358.21, CAS number: 73231-34-2, and is white or off-white crystalline powder in appearance. The structural formula is as follows:
florfenicol is a novel broad-spectrum antibiotic special for animals and is used for bacterial diseases of gram-positive bacteria, gram-negative bacteria and thiamphenicol resistant fishes, cattle, pigs and birds. The preparation has the characteristics of wide antibacterial spectrum, good absorption, wide distribution in vivo, no residue or low residual quantity in vivo, and particularly no potential effect of causing aplastic anemia.
Although florfenicol has a satisfactory in vitro pharmacological effect, its metabolic and absorption are insufficient for direct use in biological antibacterial therapy due to its low molar fraction solubility in water (1.09mg/mL, 25 ℃). Therefore, how to improve the water solubility becomes a problem to be solved in industrial production and practical application of florfenicol. Conventional florfenicol solubilization methods include: auxiliary agent micro-emulsification method, cyclodextrin inclusion method, solid dispersion method, prodrug design method, etc. However, these methods have certain limitations: the auxiliary agent micro-emulsification method has simple operation and lower cost, but potential biological toxicity can exist because of adding a larger amount of auxiliary agent; the cyclodextrin inclusion method has the advantages that the method for improving the solubility is obvious and has low toxicity, but generally needs high inclusion temperature and can play a role by being matched with other auxiliary agents; the solid dispersion method is one of the methods which are used for improving the water solubility of the medicine at the earliest time, but the effect on the florfenicol is not obvious; the prodrug design method can greatly improve the solubility of florfenicol, and simultaneously, a plurality of well-designed prodrugs can be effectively converted into components with pharmacological activity in vivo, and the disadvantages are that the commercialization of the prodrugs is limited due to the problems of high production cost, complex approval and the like. It is therefore desirable to develop new methods for increasing the aqueous solubility of florfenicol.
The drug micro-nano technology is a technology for reducing the particle size of a drug to a micron or even nano level while keeping the physicochemical property of the drug stable. Compared with the traditional method, the micro-nano technology is developed for less than 30 years, but has shown good development prospect in the aspects of improving the water solubility and bioavailability of the medicine and the like.
The nano medicament exists in various different forms, such as a suspension agent, a nano emulsion, a nano carrier medicament, a nano particle, a liposome and the like, and mainly depends on a preparation method of the nano medicament, and different methods have different effects on the aspects of improving the water solubility and the pharmacological property of the medicament, controlling the release process in vivo and the like. The traditional methods for preparing florfenicol nanocrystals include wrapping methods, emulsion diffusion evaporation methods, thermal homogenization, ultrasonic techniques, and the like. However, these methods have certain limitations: the coating method utilizes polymers such as polylactic acid and the like and common coating materials such as esters and the like to prepare the nano medicament, and the added coating materials are too much, so that the florfenicol product is impure and the yield is low; the method of emulsification, diffusion and evaporation develops the polylactide-glycolide nano particles loaded with florfenicol, but the preparation needs higher temperature, the operation is complex, and the industrialization is difficult to realize; thermal homogenization and ultrasonic wave techniques yielded a suspension of florfenicol-loaded solid lipid nanoparticles (florfenicol-SLN) with an average diameter of 253 ± 3nm, but the energy required was large and the cost was high. It is therefore desirable to develop new methods for increasing the aqueous solubility of florfenicol.
Disclosure of Invention
The invention aims to provide a method for preparing florfenicol nanocrystals, which solves the problem of low florfenicol water solubility in the prior art.
The technical scheme of the invention is as follows:
a method for preparing florfenicol nanocrystals comprises the steps of preparing a saturated solution of florfenicol under the stirring action at 40-60 ℃; adding methyl cellulose with the mass fraction of 0.5-2% of florfenicol, and keeping the temperature for 0.5-2h to completely dissolve the methyl cellulose solid; and then cooling to 10-20 ℃ at a cooling rate of 0.1-1 ℃/min, growing crystals at a constant temperature for 0.5-2h, and then separating and drying the obtained suspension to obtain the florfenicol nanocrystal.
The solvent of the saturated solution is one or a mixture of methanol, ethanol, water, isopropanol and acetone.
The mass content of the methyl cellulose is 1-2%.
The drying temperature is 20-60 ℃, the vacuum degree is 0.01-0.1 Mpa, and the drying time is 1-10 h.
The florfenicol nanocrystal prepared by the method is a nanorod crystal with the diameter of 100-900 nm under SEM observation. As shown in fig. 1. The florfenicol sold in the market is a flaky crystal, and the length and the width of the crystal are 40-120 mu m, as shown in a figure 2.
The florfenicol nanocrystal product obtained by the method has water solubility which is compared with that of florfenicol, and the molar fraction solubilities of the nanocrystal and a commercially available florfenicol product in water are respectively 8.99 multiplied by 10 at 25 DEG C-5And 5.13X 10-5The nanocrystals were 1.75 times larger than the commercially available florfenicol, as shown in figure 3.
The florfenicol nanocrystal prepared by the method has the dissolution performance compared with that of florfenicol, the highest dissolution concentration point of the florfenicol nanocrystal in 1L of water at 37 ℃ is 2.80mg/mL (calculated by the florfenicol), the corresponding dissolution time is 200min, and the dissolution rate obtained by calculation is 14.0 mu g/mL-1·min-1(ii) a The maximum dissolution concentration of florfenicol in 1L of water is 1.94mg/mL, the corresponding dissolution time is 400min, and the dissolution rate calculated by the calculation is 4.85 mug/mL-1·min-1. It can be seen that the florfenicol-citric acid co-crystal dissolves 2.9 times faster than florfenicol, as shown in figure 4.
The dispersant methylcellulose adopted by the invention has good biodegradability, biocompatibility and bioabsorbability, does not leave any environmental protection problem after degradation, and is nontoxic, non-allergenic and non-irritant. The cost of the required raw materials and solvents is low, and the preparation process is simple and quick.
Drawings
FIG. 1: SEM pictures of florfenicol nanocrystals;
FIG. 2 is a microscopic image of a commercially available florfenicol product;
FIG. 3: the florfenicol nanocrystals of the present application have a water-soluble contrast profile with commercially available florfenicol products;
FIG. 4: the florfenicol nanocrystal and a florfenicol product sold in the market have a water dissolution performance comparison map.
Detailed Description
The invention is illustrated by, but not limited to, the following examples:
example 1:
20mL of methanol and 2.992g of florfenicol are added into a 50mL crystallizer to prepare a saturated methanol solution of the florfenicol at the temperature of 40 ℃, 0.0150g of methyl cellulose with the mass fraction of 0.5 percent of the florfenicol is added, the temperature is kept for 0.5h to ensure that the methyl cellulose solid is completely dissolved, then the temperature is reduced to 10 ℃ at the cooling rate of 0.1 ℃/min, and the crystal is grown at the constant temperature for 0.5 h. And separating and drying the obtained suspension at the drying temperature of 20 ℃, the vacuum degree of 0.1Mpa and the drying time of 1h to obtain the florfenicol nanocrystal.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 200-900 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 9 x 10-5(ii) a The highest dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.81mg/mL (calculated by florfenicol), the corresponding dissolution time is 201min, and the dissolution rate obtained by calculation is 13.98 mu g/mL-1·min-1。
Example 2:
adding 50mL of ethanol and 13.12g of florfenicol into a 100mL crystallizer to prepare a saturated ethanol solution of the florfenicol at 45 ℃, adding 0.1312g of methylcellulose with the mass fraction of 1% of the florfenicol, keeping the temperature for 1h to ensure that the methylcellulose solid is completely dissolved, then cooling to 10 ℃ at the cooling rate of 0.3 ℃/min, and keeping the temperature for 1h to grow crystals. And separating and drying the obtained suspension, wherein the drying temperature is 30 ℃, the vacuum degree is 0.07Mpa, and the drying time is 3 hours, so that the florfenicol nanocrystal is obtained.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 100-900 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 8.99 x 10-5(ii) a The maximum dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.82mg/mL (calculated by florfenicol), the corresponding dissolution time is 202min, and the dissolution rate obtained by calculation is 13.96 mu g/mL-1·min-1。
Example 3:
adding 80mL of water and 0.3025g of florfenicol into a 150mL crystallizer to prepare a saturated aqueous solution of florfenicol at 50 ℃, adding 0.005g of methyl cellulose with the mass fraction of 1.5% of the florfenicol, keeping the temperature for 1.5h to ensure that the methyl cellulose solid is completely dissolved, then cooling to 15 ℃ at the cooling rate of 0.5 ℃/min, and keeping the temperature for crystal growth for 1.5 h. And separating and drying the obtained suspension at the drying temperature of 40 ℃, the vacuum degree of 0.05Mpa and the drying time of 5 hours to obtain the florfenicol nanocrystal.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 200-700 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 8.98 x 10-5(ii) a The maximum dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.81mg/mL (calculated by florfenicol), the corresponding dissolution time is 198min, and the dissolution rate obtained by calculation is 14.19 mu g/mL-1·min-1。
Example 4:
100mL of acetone and 42.07g of florfenicol are added into a 200mL crystallizer to prepare a saturated acetone solution of the florfenicol at 55 ℃, 0.8414g of methyl cellulose with the mass fraction of 2% of the florfenicol is added, the temperature is kept for 2h to ensure that the methyl cellulose solid is completely dissolved, then the temperature is reduced to 15 ℃ at the cooling rate of 0.7 ℃/min, and the crystal is grown for 2h at the constant temperature. And separating and drying the obtained suspension at the drying temperature of 60 ℃, the vacuum degree of 0.03Mpa and the drying time of 8 hours to obtain the florfenicol nanocrystal.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 100-700 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 8.99 x 10-5(ii) a The maximum dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.79mg/mL (calculated by florfenicol), the corresponding dissolution time is 201min, and the dissolution rate obtained by calculation is 13.88 mu g/mL-1·min-1。
Example 5:
adding 70mL of acetone and 70mL of water mixed solvent and 20.60g of florfenicol into a 250mL crystallizer to prepare saturated acetone and aqueous solution of the florfenicol at the temperature of 40 ℃, adding 0.103g of methyl cellulose with the mass fraction of 0.5% of the florfenicol, keeping the temperature for 1h to ensure that the methyl cellulose solid is completely dissolved, then cooling to 10 ℃ at the cooling rate of 0.9 ℃/min, and keeping the temperature for 1.5h to grow crystals. And separating and drying the obtained suspension at the drying temperature of 60 ℃, the vacuum degree of 0.01Mpa and the drying time of 10h to obtain the florfenicol nanocrystal.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 200-900 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 9 x 10-5(ii) a The highest point of the dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.8mg/mL (calculated by florfenicol), the corresponding dissolution time is 198min, and the dissolution rate obtained by calculation is 14.14 mu g/mL-1·min-1。
Example 6:
adding 80mL of methanol-80 mL of water mixed solvent and 14.7g of florfenicol into a 300mL crystallizer to prepare saturated methanol and aqueous solution of the florfenicol at 45 ℃, adding 0.294g of methylcellulose with the mass fraction of 2% of the florfenicol, keeping the temperature for 2h to completely dissolve the methylcellulose solids, then cooling to 10 ℃ at the cooling rate of 1 ℃/min, and keeping the temperature for 1h to grow crystals. And separating and drying the obtained suspension at the drying temperature of 60 ℃, the vacuum degree of 0.01Mpa and the drying time of 9 hours to obtain the florfenicol nanocrystal.
The florfenicol nanocrystal product obtained is in a rod-like structure when observed under SEM, and the diameter of the nanocrystal is 100-900 nm.
The molar fraction solubility of the florfenicol nanocrystals in water at 25 ℃ is 8.98 x 10-5(ii) a The highest dissolution concentration of the florfenicol nanocrystals in 1L of water at 37 ℃ is 2.82mg/mL (calculated by florfenicol), the corresponding dissolution time is 198min, and the dissolution rate obtained by calculation is 14.24 mu g/mL-1·min-1。
The invention discloses and provides a method for preparing florfenicol nanocrystals, and a person skilled in the art can change the raw materials, process parameters and other link experiments properly by referring to the content in the text. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and products described herein may be made and equivalents employed to implement the techniques of the present invention without departing from the spirit and scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (3)
1. A method for preparing florfenicol nanocrystals is characterized in that a saturated solution of florfenicol is prepared under the stirring action at the temperature of 40-60 ℃; adding methyl cellulose with the mass fraction of 0.5-2% of florfenicol, and keeping the temperature for 0.5-2h to completely dissolve the methyl cellulose solid; then cooling to 10-20 ℃ at a cooling rate of 0.1-1 ℃/min, growing crystals at a constant temperature for 0.5-2h, and then separating and drying the obtained suspension to obtain the florfenicol nanocrystals; the solvent of the saturated solution is selected from one of methanol, ethanol, water and acetone.
2. The method according to claim 1, wherein the methylcellulose is contained in an amount of 1 to 2% by mass.
3. The method according to claim 1, wherein the drying temperature is 20 to 60 ℃, the vacuum degree is 0.01 to 0.1MPa, and the drying time is 1 to 10 hours.
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| CN103145594B (en) * | 2013-03-26 | 2014-12-17 | 四川农业大学 | Method for preparing florfenicol microcrystal |
| CN105477642B (en) * | 2015-12-15 | 2019-08-06 | 中牧南京动物药业有限公司 | A kind of florfenicol composition of high bioavilability and preparation method thereof |
| CN106390136A (en) * | 2016-08-31 | 2017-02-15 | 河北维尔利动物药业集团有限公司 | Water-soluble florfenicol clathrate with high bioavailability and preparation method of water-soluble florfenicol clathrate |
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