CN103980166B - A kind of novel crystal forms of florfenicol and preparation method thereof - Google Patents

Abstract

The invention provides a new crystal form of florfenicol, whose characteristics are described by X-ray powder diffraction pattern and differential scanning calorimetry data. At a temperature of 40-55°C, dissolve florfenicol with a purity greater than or equal to 92% in an organic solvent to form a solution with a concentration of 0.05-0.15g/mL. After stirring and dissolving, cool the solution at a cooling rate of 1-3°C/min to 25-30°C; then add the eluent dropwise to the obtained solid-liquid suspension; after adding the eluent, cool the solution to 5-10°C at a cooling rate of 0.2-1°C/min, and continue to stir for 0.5-2 hours ; Then the resulting solid-liquid suspension is separated and dried to obtain the Florfenicol crystalline product. The obtained product has high crystallinity, complete crystal form, a purity of more than 99%, a yield of more than 87%, and a solubility in water at 25° C. of about 7%, thereby improving its bioavailability.

Description

A new crystal form of Florfenicol and its preparation method

technical field

The invention belongs to the technical field of chemical engineering crystallization, and in particular relates to a new crystal form of Florfenicol and a preparation method thereof.

Background technique

Florfenicol (Florfenicol) is also known as chlorthiamphenicol, and its chemical name is [R--(R*,R*)]-2,2-dichloro-N-{1-(fluoromethyl)-2 -Hydroxy-2-[4-(methylsulfonyl)phenyl]ethyl}acetamide, molecular formula is C ₁₂ H ₁₄ Cl ₂ FNO ₄ S, molecular weight is 358.2, CAS number: 73231-34-2, its chemical The structural formula is shown below.

Florfenicol is an excellent broad-spectrum antibiotic of chloramphenicol, which can tightly combine with bacterial 70S ribosome and 50S subunit, reduce the activity of peptide acyltransferase, interfere with the synthesis of bacterial protein, and its antibacterial activity is stronger than chlorine thiamphenicol and thiamphenicol. Moreover, Florfenicol overcomes the problems of chloramphenicol’s easy drug resistance and aplastic anemia, and has the characteristics of broad-spectrum antibacterial, good oral absorption, wide distribution in the body, safety and high efficiency.

Florfenicol is a product developed by Schering-Plough-America in the 1970s. It was approved for marketing in my country in 1999. At present, Florfenicol has been gradually popularized and applied. At present, thiamphenicol is mainly used to prepare florfenicol, but because the preparation method of florfenicol has low yield and high requirements for production equipment, the price of the drug cannot be reduced at present. Patent CN101265220 provides the preparation method of florfenicol: L-threo-[p-(thysulfonyl)phenyl]serine ethyl ester is refluxed with hydrochloric acid and water for 4 hours, then extracted and concentrated with dichloromethane, and Cooling crystallization was carried out in petroleum ether, and the yield was 66%. The method has harsh operating conditions, high equipment requirements, and low product yield. In the patent US5382673A, the reaction mixture is distilled and filtered, and then eluted and crystallized in a mixed solvent of organic solvent and water to obtain Florfenicol with a yield of 82% and a purity of 98.4%. The florfenicol product obtained by this method has complicated process and low yield, and the problem of its crystal form has not been characterized and explained. The Florfenicol product obtained by the applicant in repeated experiments according to this method has an X-ray powder diffraction pattern as shown in Figure 1.

Compared with similar antibiotics, although florfenicol has excellent performance, its solubility in water is too poor, which affects its bioavailability. Patent CN101279941A improves water solubility by making florfenicol into sodium salt of florfenicol succinate, which is convenient for animals to absorb. However, the preparation conditions of this process are harsh, and the product quality stability is poor. During the use process after the preparation is made, the active ingredients degrade rapidly, which greatly affects its use effect.

Therefore, it is necessary to develop a new crystal form of florfenicol and a preparation method thereof to improve indicators such as its yield, product stability and solubility, and then improve its bioavailability.

Contents of the invention

In order to overcome the shortcomings of low yield and low water solubility of the existing florfenicol crystallization, the invention provides a new crystal form of florfenicol and a preparation method thereof, which improves the crystallinity of florfenicol products , yield and water solubility.

The new crystal form of Florfenicol provided by the present invention has an X-ray powder diffraction spectrum at diffraction angles 2θ=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± There are characteristic peaks at 0.1, 20.8±0.1, 23.6±0.1, 24.1±0.1, 24.6±0.1, 27.4±0.1, 31.8±0.1 and 41.6±0.1 degrees, as shown in Figure 2.

The new crystal form of Florfenicol according to the present invention is measured by differential scanning calorimeter DSC, and has a melting endothermic peak at 155±1°C, as shown in Figure 3. Test conditions: temperature range 25-200°C, heating rate 5°C/min, protective nitrogen 80mL/min.

The new crystal form of Florfenicol according to the present invention has a Raman spectrum at 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 ^-1 have characteristic peaks, as shown in Figure 4.

The preparation method of Florfenicol new crystal form crystal of the present invention is as follows:

At a temperature of 40-55°C, dissolve florfenicol with a purity greater than or equal to 92% in an organic solvent to form a solution with a concentration of 0.05-0.15g/mL. After stirring and dissolving, cool the solution at a cooling rate of 1-3°C/min to 25-30°C; then add a dissolving agent dropwise to the obtained solid-liquid suspension, the amount of dissolving agent is 1-3 times the volume of the organic solvent; after adding the dissolving agent, the cooling rate is 0.2-1°C/min Cool the solution to 5-10°C and continue to stir for 0.5-2 hours; then separate and dry the obtained solid-liquid suspension to obtain the florfenicol crystalline product.

The organic solvent is selected from methanol, acetonitrile, acetone or tetrahydrofuran.

The solvent is selected from water or n-hexane. The dropping time of eluting agent is 2～5h.

The drying conditions are that the temperature is 50-80° C., the vacuum degree is 0.08-0.1 MPa, and the drying time is 4-12 hours.

The advantage of the preparation method of the new crystal form of Florfenicol provided by the present invention is that the operating conditions are simple and easy to control, and the product magma is easy to filter, wash and dry. The X-ray powder diffraction spectrum shown in accompanying drawing 2 and accompanying drawing 5 crystal The results of microscopic photos show that the product has high crystallinity and complete crystal form, and the single-pass molar yield of the crystallization process is more than 87%, and the purity of the product by liquid chromatography analysis is more than 99%. By measuring the solubility of the new crystalline form of Florfenicol, it is found that the crystalline form prepared according to the literature method US5382673A has a solubility in water of 1.0508 mg/g water at 25° C. The solubility at ℃ was 1.1316mg/g, and the solubility increased by 7.69%, which improved its bioavailability.

Description of drawings

Figure 1: X-ray powder diffraction pattern of Florfenicol crystals prepared according to the literature method;

Figure 2: X-ray powder diffraction pattern of the new crystal form of Florfenicol;

Figure 3: DSC spectrum of the new crystal form of Florfenicol;

Figure 4: Raman spectrum of the new crystal form of Florfenicol;

Fig. 5 Microscopic photograph of the new crystal form of Florfenicol (40 times magnification).

detailed description

Example 1

Add 15g of florfenicol solid with a purity of 92% into 100mL of methanol, heat it up to 45°C with stirring to dissolve it completely, then cool the solution to 25°C at a cooling rate of 2°C/min, and transfer to solid-liquid Add 100mL of water dropwise to the suspension for 2 hours. After adding the dissolution agent, cool the solution to 10°C at a cooling rate of 0.2°C/min, and continue stirring for 0.5h; The obtained filter cake was dried under 0.08MPa, and the molar yield of the final product was 87.1%, and the purity was 99.2%.

The PXRD pattern of the product has characteristic peaks at diffraction angles 2θ=4.04, 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 degrees; DSC has a melting endotherm at 155.4°C Peak; Raman spectrum has characteristic peaks at 1688, 1599, 1202, 1142, 1102, 970, 919, 899, 850, 814, 771, 694, 676, 631 and 310cm ^-1 . The solubility of the new florfenicol crystal form product of the present invention is 1.1327mg/g at 25°C in aqueous solution, which is 7.79% higher than that of the crystal form prepared according to the literature method US5382673A, and its bioavailability is improved.

Example 2

Add 5 g of florfenicol solid with a purity of 93% into 100 mL of acetone, heat up to 55 °C under stirring to dissolve completely, then cool the solution to 30 °C at a cooling rate of 3 °C/min, and transfer to solid-liquid Add 200mL of water dropwise to the suspension for 4 hours. After adding the dissolution agent, cool the solution to 5°C at a cooling rate of 0.5°C/min, and continue stirring for 1.5h; The obtained filter cake was dried under 0.09MPa, and the molar yield of the final product was 89.3%, and the purity was 99.3%.

The PXRD pattern of the product has characteristic peaks at diffraction angles 2θ=4.03, 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 degrees; DSC has a melting endotherm at 155.1°C Peak; Raman spectrum has characteristic peaks at 1688, 1599, 1203, 1142, 1101, 970, 920, 900, 850, 814, 771, 694, 676, 632 and 311cm ^-1 . The solubility of the new florfenicol crystal form product of the present invention is 1.1293mg/g in aqueous solution at 25°C, which is 7.47% higher than that of the crystal form prepared according to the literature method US5382673A, and its bioavailability is improved.

Example 3

Add 8 g of florfenicol solid with a purity of 94% into 100 mL of acetonitrile, heat it up to 40 °C under stirring, and dissolve it completely, then cool the solution to 27 °C at a cooling rate of 1.5 °C/min. Add 300mL of water dropwise to the suspension for 5 hours. After adding the dissolution agent, cool the solution to 8°C at a cooling rate of 1°C/min and continue stirring for 0.5h; The obtained filter cake was dried under 0.09MPa, and the molar yield of the final product was 93.0%, and the purity was 99.5%.

The PXRD pattern of the product has characteristic peaks at diffraction angles 2θ=4.04, 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 degrees; DSC has a melting endotherm at 154.9°C Peak; Raman spectrum has characteristic peaks at 1689, 1600, 1202, 1143, 1102, 971, 920, 900, 850, 814, 772, 694, 676, 632 and 309cm ^-1 . The solubility of the new florfenicol crystal form product of the present invention is 1.1309mg/g in aqueous solution at 25°C, which is 7.62% higher than that of the crystal form prepared according to the literature method US5382673A, and its bioavailability is improved.

Example 4

Add 10 g of florfenicol solid with a purity of 95% into 100 mL of tetrahydrofuran, heat it up to 55 °C under stirring to dissolve it completely, then cool the solution to 26 °C at a cooling rate of 1 °C/min, and transfer to solid-liquid Add 300mL of n-hexane dropwise to the suspension for 4 hours. After adding the dissolving agent, cool the solution to 6°C at a cooling rate of 0.3°C/min, and continue stirring for 1h; The obtained filter cake was dried under 0.1MPa, and the molar yield of the final product was 91.2%, and the purity was 99.3%.

The PXRD pattern of the product has characteristic peaks at diffraction angles 2θ=4.03, 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 degrees; DSC has a melting endotherm at 154.7°C Peak; Raman spectrum has characteristic peaks at 1687, 1599, 1201, 1142, 1102, 970, 918, 899, 850, 814, 771, 694, 675, 631 and 310cm ^-1 . The solubility of the new florfenicol crystal form product of the present invention is 1.1327mg/g at 25°C in aqueous solution, which is 7.79% higher than that of the crystal form prepared according to the literature method US5382673A, and its bioavailability is improved.

Example 5

Add 6g of florfenicol solid with a purity of 93.5% into 100mL of acetone, heat up to 50°C under stirring to dissolve completely, then cool the solution to 28°C at a cooling rate of 2°C/min, and transfer to solid-liquid Add 200mL of n-hexane dropwise to the suspension for 2 hours. After adding the dissolving agent, cool the solution to 5°C at a cooling rate of 0.8°C/min, and continue to stir for 2h; The obtained filter cake was dried under 0.09MPa, and the molar yield of the final product was 90.2%, and the purity was 99.5%.

The PXRD pattern of the product has characteristic peaks at diffraction angles 2θ=4.04, 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 degrees; DSC has a melting endotherm at 155.3°C Peak; Raman spectrum has characteristic peaks at 1688, 1599, 1201, 1143, 1102, 970, 918, 899, 850, 814, 771, 694, 675, 631 and 310cm ^-1 . The solubility of the new florfenicol crystal form product of the present invention is 1.1316mg/g at 25°C in aqueous solution, which is 7.69% higher than that of the crystal form prepared according to the literature method US5382673A, and its bioavailability is improved.

The florfenicol crystal form disclosed and proposed by the present invention and its preparation method can be realized by those skilled in the art by referring to the contents of this article and appropriately changing raw materials, process parameters and other links. The methods and products of the present invention have been described through preferred implementation examples, and those skilled in the art can obviously make changes or appropriate changes and combinations to the methods and products described herein without departing from the content, spirit and scope of the present invention to realize The technology of the present invention. In particular, it should be pointed out that all similar substitutions and modifications will be obvious to those skilled in the art, and they are all considered to be included in the spirit, scope and content of the present invention.

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。