CN108863864B - Florfenicol-citric acid eutectic crystal and preparation method thereof - Google Patents
Florfenicol-citric acid eutectic crystal and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a florfenicol-citric acid eutectic crystal and a preparation method thereof, wherein a saturated organic solution of florfenicol and citric acid at a temperature of 25-45 ℃ is prepared under the stirring action, then florfenicol and citric acid solid are added into the saturated solution, the mass ratio of the newly added florfenicol to citric acid is 1: 1-3: 1, suspension is stirred for 5-8 hours to ensure the formation of the eutectic crystal, the obtained suspension is separated and dried to obtain a florfenicol-citric acid eutectic crystal product, the water solubility of the obtained florfenicol-citric acid eutectic crystal is compared with that of the florfenicol, and the molar fraction solubility of the florfenicol-citric acid eutectic crystal and the commercially available florfenicol in water is 17.1 × 10 at 25 ℃ respectively‑5And 5.13 × 10‑5The molar solubility of the florfenicol-citric acid co-crystal is 3.3 times that of florfenicol. The problem of low florfenicol water solubility in the prior art is solved.
Description
Technical Field
The invention belongs to the technical field of drug crystallization, and particularly relates to a novel florfenicol drug cocrystal and a preparation method thereof.
Background
Active Pharmaceutical Ingredients (API) are self-assembled with suitable co-crystal formers (CCF) by hydrogen bonding, or by non-covalent bonds with saturation and directionality (e.g. van der waals forces of aromatic hydrocarbons or benzene rings, pi-pi conjugation and halogen bonding), forming a novel structure, i.e. a pharmaceutical co-crystal. Pharmaceutical co-crystals are crystals formed by the pharmaceutical active ingredient and the co-crystal former by virtue of intermolecular interaction forces. The co-crystals may have significant differences in properties of the pharmaceutically active ingredient, such as melting point, boiling point, solubility, dissolution rate, stability, and bioavailability, thereby affecting the therapeutic efficacy of the drug.
Pharmaceutical co-crystal research is also an important component of pharmaceutical crystal form research. The pharmaceutical co-crystal is therefore very attractive to the pharmaceutical industry in that it offers an opportunity to modify the physical or chemical properties of a pharmaceutical active ingredient (API) without the need to break and create covalent bonds. Pharmaceutical co-crystals are mostly formed on the basis of hydrogen bonds, and are generally formed by the linkage of a hydrogen bond acceptor and a hydrogen bond donor. The pharmaceutical co-crystal formed by the hydrogen bond does not need to form a new covalent bond and does not need to destroy the existing covalent bond; the method achieves the purpose of modifying the physicochemical property of the medicament while retaining the pharmacological property of the medicament, and provides a wider development space for the application of pharmaceutical co-crystals in the pharmaceutical industry. Under the condition of not changing the structure and pharmacological properties of the medicine, the formed new crystal can improve the solubility, dissolution rate, bioavailability and stability of the medicine, reduce hygroscopicity, improve mechanical properties and the like. Therefore, it is of great practical significance to obtain more novel, practical and inventive pharmaceutical co-crystals, especially some water-insoluble drugs.
Florfenicol (Florfenicol) has the chemical name [ [ R- - - (R1.T) ]]-2, 2-dichloro-N- { fluoromethyl) -2-hydroxy-2- [4- (methylsulfonyl) phenyl]Ethyl } acetamide. The molecular formula is: c12H14Cl2FNO4S, molecular weight: 358.2, CAS number: 73231-34-2, and is white or off-white crystalline powder in appearance. The structural formula is as follows:
florfenicol is a broad-spectrum antibiotic drug which can effectively treat various livestock diseases. 1990, it was approved to market in japan to cope with the problem of bacterial diseases in aquaculture; in 1996, florfenicol was approved for marketing in the united states and was specifically designed to meet the antibiotic needs of animals; in 1999, florfenicol was approved in China for use in the fields of aquaculture, veterinary medicine, livestock infection, and the like. Furthermore, florfenicol is also approved for marketing in time in most countries around the world, even for use as a feed additive to increase feed conversion ratio and promote animal growth.
Although the in vitro pharmacological effects of florfenicol are satisfactory, solubility is low due to the mole fraction in water (5.13 × 10)-5At 25 ℃ C.), makes it difficult to directly apply to the antibacterial treatment of organisms due to insufficient metabolism and absorption. If absorption is promoted by increasing the dose, the risk of adverse reactions increases, and particularly in the case of antibacterial drugs, the development of drug-resistant bacteria is also likely to occur. In most cases, the effective absorption and metabolism of a drug after entering an organism depends mainly on the water solubility and permeability of the drug. The water solubility of the drug is increased, so that the drug has good effects in the aspects of slow release, delay of peak reaching time, reduction of drug peak concentration and the like. Poor water solubility also limits the diversification of pharmaceutical formulations and their success on the market. 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 obvious method for improving the solubility and less toxicity, but generally needs higher inclusion temperatureThe mixture can play a role only 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.
Disclosure of Invention
The invention aims to provide a florfenicol-citric acid eutectic crystal and a preparation method thereof, and solves the problem of low florfenicol water solubility in the prior art.
The preparation method of the florfenicol-citric acid eutectic crystal comprises the following steps:
preparing an organic solution with saturated florfenicol and citric acid at the temperature under the stirring action at 25-45 ℃, wherein the concentration of the organic solution is 5.5mg/m L-263 mg/m L and 7.5mg/m L-304 mg/m L respectively, then adding florfenicol and citric acid solid into the saturated solution, wherein the mass ratio (molar ratio) of the newly added florfenicol and citric acid is 1: 1-3: 1, meanwhile, in order to prevent uneven stirring, the adding amount of the florfenicol is not more than 60mg/m L of solvent, stirring the suspension for 5-8 hours to ensure the formation of eutectic, separating and drying the obtained suspension to obtain the florfenicol-citric acid eutectic product.
The organic solvent is selected from one or more mixed solvents of ethanol, acetonitrile or isopropanol; the mother liquor obtained after the suspension is separated can be recycled.
In the method, the preferable temperature is 35-45 ℃.
In the method, 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-citric acid eutectic crystal prepared by the method has a powder X-ray diffraction pattern with characteristic peaks at diffraction angles 2 theta of 10.0 +/-0.2, 13.0 +/-0.2, 13.6 +/-0.2, 14.0 +/-0.2, 15.0 +/-0.2, 16.9 +/-0.2, 17.7 +/-0.2, 18.0 +/-0.2, 18.2 +/-0.2, 18.6 +/-0.2, 19.6 +/-0.2, 20.4 +/-0.2, 20.8 +/-0.2, 23.9 +/-0.2, 24.7 +/-0.2, 25.1 +/-0.2, 25.9 +/-0.2, 26.7 +/-0.2, 27.7 +/-0.2, 29.6 +/-0.2 degrees, as shown in figure 1, the X-ray diffraction patterns of florfenicol and citric acid, and has characteristic peaks at diffraction angles of 10.0 +/-2, 17 +/-2, 17.9 +/-0.2, 17 +/-2, 17.8 +/-0.2, 17.2, 17 +/-2, 17.9 +/-0.2, 17.2 and 17 +/-2.2, 14.2.
The TGA and DSC of the florfenicol-citric acid eutectic crystal prepared by the method are melted at the temperature of 132 +/-2 ℃ and have no weight loss, as shown in figure 2, and the florfenicol-citric acid eutectic crystal starts to decompose at the temperature of 210 +/-2 ℃, as shown in figure 3.
The florfenicol-citric acid eutectic crystal prepared by the method has water solubility which is compared with that of florfenicol, and the molar fraction solubility of the florfenicol-citric acid eutectic crystal and the commercially available florfenicol in water is 17.1 × 10 respectively at 25 DEG C-5And 5.13 × 10-5The molar solubility of the florfenicol-citric acid co-crystal was 3.3 times greater than that of florfenicol, as shown in figure 4.
The florfenicol-citric acid eutectic crystal prepared by the method has the dissolution performance compared with that of florfenicol, the highest dissolution concentration point of the florfenicol-citric acid eutectic crystal in 1L water is 5.39mg/m L (calculated by the florfenicol) at 37 ℃, the corresponding dissolution time is 15min, and the dissolution rate obtained by calculation is 359 mu g m L-1·min-1The highest dissolution concentration of florfenicol in 1L water is 1.94mg/m L, the corresponding dissolution time is 400min, and the dissolution rate obtained by calculation is 4.85 mug m L-1·min-1. It can be seen that the florfenicol-citric acid co-crystal dissolves 74.0 times faster than florfenicol, as shown in figure 5. After the florfenicol-citric acid eutectic is dissolved in water for 15min, the florfenicol-citric acid eutectic is gradually destroyed due to the breakage of hydrogen bonds in the water, so that the florfenicol and the citric acid exist in a monomer form, while the monomer florfenicol is low in solubility in the water and gradually separated out, and the concentration in the water is reduced after 15min, so that the florfenicol-citric acid eutectic is obtainedThe highest point corresponding to 15min is selected as the dissolution concentration in water.
The florfenicol-citric acid eutectic crystal prepared by the method is flaky, and is shown in figure 6. The morphology of the commercially available florfenicol is plate-like, as shown in fig. 7.
Drawings
FIG. 1: florfenicol, citric acid, X-ray powder diffraction patterns of the florfenicol-citric acid eutectic product of the application;
FIG. 2: the application discloses a DSC (differential scanning calorimetry) map of a florfenicol-citric acid eutectic product;
FIG. 3: the TGA spectrum of the florfenicol-citric acid eutectic product is disclosed.
FIG. 4: the florfenicol-citric acid eutectic crystal is compared with the water-solubility map of a commercial florfenicol product.
FIG. 5: the florfenicol-citric acid eutectic crystal and a florfenicol product sold in the market dissolve performance map in water.
FIG. 6: florfenicol-citric acid eutectic microscopic picture of the application.
FIG. 7: microscope pictures of commercially available florfenicol product.
Detailed Description
The invention is illustrated by, but not limited to, the following examples:
example 1:
adding 0.22g of florfenicol and 0.30g of citric acid into 40m L isopropanol solvent under the stirring action at 25 ℃ to prepare a solution with saturated florfenicol and citric acid, then adding 0.2g of florfenicol and 0.11g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 1:1 to form a suspension, stirring the suspension for 5 hours, separating and drying the obtained suspension, wherein the drying temperature is 20 ℃, the vacuum degree is 0.1Mpa, and the drying time is 1 hour, thus obtaining the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 10.1, 13.0, 13.7, 14.1, 15.0, 16.9, 17.7, 18.0, 18.2, 18.6, 19.8, 20.6, 20.9, 23.9, 24.9, 25.3, 26.0, 26.8, 27.8 and 29.7 degrees; its TGA and DSC analysis showed no weight loss upon melting at 132 ℃ and onset of decomposition at 211 ℃.
The molar fraction solubility of the florfenicol-citric acid eutectic in water at 25 ℃ is 17.1 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.37mg/m L (calculated by florfenicol), the corresponding dissolution time is 16min, and the dissolution rate obtained by calculation is 336 mu g.m L-1·min-1。
Example 2:
adding 15.77g of florfenicol and 15.17g of citric acid into 60m of L acetonitrile solvent at 45 ℃ under the stirring action to prepare a solution with saturated florfenicol and citric acid, then adding 0.8g of florfenicol and 0.21g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 2:1 to form a suspension, stirring the suspension for 6 hours, separating and drying the obtained suspension, wherein the drying temperature is 40 ℃, the vacuum degree is 0.05Mpa, and the drying time is 8 hours, thus obtaining the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 10.0, 13.1, 13.6, 14.0, 15.1, 16.9, 17.8, 18.0, 18.4, 18.7, 19.7, 20.4, 20.8, 23.9, 24.8, 25.1, 26.0, 26.8, 27.8 and 29.6 degrees; its TGA and DSC analysis showed no weight loss upon melting at 133 ℃ and the onset of decomposition at 208 ℃.
The molar fraction solubility of the florfenicol-citric acid eutectic in water at 25 ℃ is 17.2 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.38mg/m L (calculated by florfenicol), the corresponding dissolution time is 15min, and the dissolution rate obtained by calculation is 359 mu g m L-1·min-1。
Example 3:
adding 13.12g of florfenicol and 15.19g of citric acid into 50m L ethanol solvent under the stirring action at 45 ℃ to prepare a solution with saturated florfenicol and citric acid, then adding 3g of florfenicol and 0.54g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 3:1 to form a suspension, stirring the suspension for 8 hours, separating and drying the obtained suspension, wherein the drying temperature is 60 ℃, the vacuum degree is 0.01MPa, and the drying time is 10 hours to obtain the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 10.0, 13.0, 13.5, 14.0, 15.0, 16.8, 17.6, 18.0, 18.2, 18.6, 19.5, 20.3, 20.6, 23.7, 24.6, 24.9, 25.9, 26.7, 27.6 and 29.5 degrees; its TGA and DSC analysis showed no weight loss upon melting at 132 ℃ and onset of decomposition at 211 ℃.
The molar fraction solubility of the florfenicol-citric acid eutectic in water at 25 ℃ is 17.0 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.40mg/m L (calculated by florfenicol), the corresponding dissolution time is 16min, and the dissolution rate obtained by calculation is 338 mu g.m L-1·min-1。
Example 4:
adding 0.62g of florfenicol and 4.54g of citric acid into 60m L ethanol solvent under the stirring action at the temperature of 35 ℃ to prepare a solution with saturated florfenicol and citric acid, then adding 0.8g of florfenicol and 0.43g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 1:1 to form a suspension, stirring the suspension for 7 hours, separating and drying the obtained suspension, wherein the drying temperature is 50 ℃, the vacuum degree is 0.05Mpa, and the drying time is 5 hours to obtain the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 9.9, 13.0, 13.6, 14.1, 15.1, 16.8, 17.7, 18.0, 18.2, 18.6, 19.5, 20.5, 20.9, 23.9, 24.7, 25.0, 25.9, 26.7, 27.7 and 29.7 degrees; its TGA and DSC analysis showed no weight loss upon melting at 133 ℃ and onset of decomposition at 212 ℃.
The molar fraction solubility of the florfenicol-citric acid eutectic in water at 25 ℃ is 17.3 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.41mg/m L (calculated by florfenicol), the corresponding dissolution time is 16min, and the dissolution rate obtained by calculation is 338 mu g.m L-1·min-1。
Example 5:
taking acetonitrile and isopropanol, respectively taking 40m L, adding 11.21g of florfenicol and 17g of citric acid into the acetonitrile and the isopropanol under the stirring action to prepare a solution with saturated florfenicol and citric acid, then adding 2g of florfenicol and 0.54g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 2:1 to form a suspension, stirring the suspension for 8 hours, separating and drying the obtained suspension, wherein the drying temperature is 60 ℃, the vacuum degree is 0.1Mpa, and the drying time is 10 hours to obtain the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 9.9, 13.1, 13.6, 14.1, 15.0, 16.9, 17.6, 18.1, 18.3, 18.6, 19.7, 20.4, 20.8, 23.8, 24.6, 25.1, 25.9, 26.8, 27.8 and 29.6 degrees; its TGA and DSC analysis showed no weight loss upon melting at 132 ℃ and onset of decomposition at 210 ℃.
The molar fraction solubility of the florfenicol-citric acid eutectic in water at 25 ℃ is 17.2 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.40mg/m L (calculated by florfenicol), the corresponding dissolution time is 15min, and the dissolution rate obtained by calculation is 360 mu g.m L-1·min-1。
Example 6:
taking ethanol and isopropanol, respectively taking 50m L, adding 14 g of florfenicol and 23.79g of citric acid under the stirring action at 45 ℃ to prepare a solution with saturated florfenicol and citric acid, then adding 2.5g of florfenicol and 0.45g of citric acid into the saturated solution according to the mass ratio (molar ratio) of 3:1 to form a suspension, stirring the suspension for 8 hours, separating and drying the obtained suspension, wherein the drying temperature is 50 ℃, the vacuum degree is 0.03Mpa, and the drying time is 10 hours to obtain the florfenicol-citric acid eutectic product.
The powder X-ray diffraction pattern of the product has characteristic peaks at diffraction angles 2 theta of 10.0, 12.9, 13.6, 13.9, 15.0, 16.9, 17.7, 18.1, 18.3, 18.6, 19.7, 20.3, 20.8, 23.9, 24.8, 25.2, 25.9, 26.8, 27.8 and 29.7 degrees; its TGA and DSC analysis showed no weight loss upon melting at 132 ℃ and onset of decomposition at 209 ℃.
Florfenicol-citric acid at 25 DEG CThe mole fraction solubility of the co-crystal in water was 17.1 × 10-5The highest dissolution concentration of the florfenicol-citric acid eutectic in 1L water at 37 ℃ is 5.39mg/m L (calculated by florfenicol), the corresponding dissolution time is 16min, and the dissolution rate obtained by calculation is 337 mu g.m L-1·min-1。
The florfenicol-citric acid eutectic preparation method disclosed and provided by the invention can be used for appropriately changing raw materials, process parameters and other link experiments 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 (7)
1. A florfenicol-citric acid eutectic crystal which is characterized in that a powder X-ray diffraction pattern has characteristic peaks at diffraction angles 2 theta of 10.0 +/-0.2, 13.0 +/-0.2, 13.6 +/-0.2, 14.0 +/-0.2, 15.0 +/-0.2, 16.9 +/-0.2, 17.7 +/-0.2, 18.0 +/-0.2, 18.2 +/-0.2, 18.6 +/-0.2, 19.6 +/-0.2, 20.4 +/-0.2, 20.8 +/-0.2, 23.9 +/-0.2, 24.7 +/-0.2, 25.1 +/-0.2, 25.9 +/-0.2, 26.7 +/-0.2, 27.7 +/-0.2 and 29.6 +/-0.2 degrees; melting at 132 + -2 deg.C, and decomposing at 210 + -2 deg.C without weight loss;
the preparation method of the florfenicol-citric acid eutectic comprises the following steps: preparing a saturated organic solution of florfenicol and citric acid at the temperature of 25-45 ℃ under the stirring action; then, adding florfenicol and citric acid solid into the saturated solution, wherein the mass ratio of the newly added florfenicol to citric acid is 1: 1-3: 1; and stirring the suspension for 5-8 h to ensure formation of a eutectic, and separating and drying the obtained suspension to obtain the florfenicol-citric acid eutectic product.
2. The preparation method of the florfenicol-citric acid eutectic crystal as claimed in claim 1, which is characterized in that under the stirring action at the temperature of 25-45 ℃, a saturated organic solution of florfenicol and citric acid is prepared at the temperature; then, adding florfenicol and citric acid solid into the saturated solution, wherein the mass ratio of the newly added florfenicol to citric acid is 1: 1-3: 1; and stirring the suspension for 5-8 h to ensure formation of a eutectic, and separating and drying the obtained suspension to obtain the florfenicol-citric acid eutectic product.
3. The process according to claim 2, wherein the florfenicol and citric acid saturated organic solutions are prepared at concentrations of 5.5mg/m L-263 mg/m L and 7.5mg/m L-304 mg/m L, respectively.
4. The process according to claim 2, wherein the amount of florfenicol added is not more than 60mg/m L solvent.
5. The method according to claim 2, wherein the organic solvent of the saturated organic solution is one or more selected from ethanol, acetonitrile and isopropanol.
6. The method according to claim 2, wherein the temperature is 35 to 45 ℃.
7. The method according to claim 2, 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1829503A (en) * | 2003-07-31 | 2006-09-06 | 科鲁纳制药公司 | Veterinary aqueous injectable suspensions containing florfenicol |
| CN103980166A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | New florfenicol crystal form and preparation method thereof |
| CN105503802A (en) * | 2016-01-15 | 2016-04-20 | 中山大学 | Preparation method of dapagliflozin-citric acid eutectic |
| CN106866638A (en) * | 2017-03-23 | 2017-06-20 | 中山大学 | A kind of avanaphil citric acid eutectic and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829503A (en) * | 2003-07-31 | 2006-09-06 | 科鲁纳制药公司 | Veterinary aqueous injectable suspensions containing florfenicol |
| CN103980166A (en) * | 2014-04-17 | 2014-08-13 | 天津大学 | New florfenicol crystal form and preparation method thereof |
| CN105503802A (en) * | 2016-01-15 | 2016-04-20 | 中山大学 | Preparation method of dapagliflozin-citric acid eutectic |
| CN106866638A (en) * | 2017-03-23 | 2017-06-20 | 中山大学 | A kind of avanaphil citric acid eutectic and preparation method thereof |
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