A trihydrate crystal of tilmicosin phosphate and a method for preparing the same

Abstract

This invention relates to a tilmicosin phosphate trihydrate crystal. The X-ray powder diffraction pattern of the crystal shows characteristic peaks at 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. The crystal is in powder form. The preparation method involves dissolving a certain amount of tilmicosin phosphate solid in water at room temperature and stirring magnetically until the solution becomes clear. The aqueous solution is then heated to 25°C and maintained at this temperature. Acetone is added, and the mixture is kept at this temperature for 3-4 hours. The product is then filtered and dried in a 50°C drying oven. After drying, the final tilmicosin phosphate trihydrate product is obtained. The process of this invention is stable, simple to operate, consumes little energy, and achieves a crystal product yield of over 75% and a product purity of over 99%. The crystal product has a large particle size and good thermodynamic stability, making it suitable for the manufacture and long-term storage of pharmaceutical preparations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical separation technology, and specifically relates to a tilmicosin phosphate trihydrate and its crystallization preparation method. Background Technology

[0002] Tilmicosin phosphate, chemical formula C 46 H 80 N2O 13 2H3PO4, with a relative molecular mass of 967.14, is chemically named 4A-O-de(2,6-dideoxy-3-C-methyl-aL-ribopyranohexyl)-20-deoxy-20-(cis-3,5-dimethylpiperidinyl)tylosin phosphate, and its structure is shown in the figure below. The commercially available product is a pale yellow powder, readily soluble in water and alcohol, but with low solubility in ester solvents. This drug is not yet widely available in China and is still in the new drug development stage.

[0003]

[0004] Tilmicosin phosphate is a novel veterinary drug developed by Eli Lilly and Company in the early 21st century. It belongs to the macrolide class of broad-spectrum antibiotics specifically for animals and exhibits strong antibacterial activity against Gram-positive bacteria, some Gram-negative bacteria, mycoplasma, and spirochetes. It demonstrates a stronger antibacterial effect than tylosin against mycoplasma, Pasteurella, and Actinobacillus pleuropneumoniae in livestock and poultry. There is no cross-resistance between tilmicosin and other commonly used antibiotics in clinical practice.

[0005] Currently, no crystalline form of tilmicosin phosphate has been reported. Commercially available tilmicosin phosphate is usually in an amorphous form, prepared as tilmicosin phosphate injection or tilmicosin phosphate premix. Compared to tilmicosin phosphate injection and premix, which require porous materials for adsorption, the crystalline form of tilmicosin phosphate is more convenient, cost-effective, and simplifies the process. Polymorphism is a common phenomenon in drug molecules; different crystal forms exhibit different physicochemical properties, thus affecting the drug's efficacy. Currently, commercially available solid tilmicosin phosphate, being an amorphous product, suffers from poor product stability, inconsistent quality within batches, poor flowability, and small particle size. Therefore, it is necessary to conduct polymorphism research on tilmicosin phosphate and screen for the superior crystalline form. Summary of the Invention

[0006] This invention provides a trihydrate crystal of tilmicosin phosphate, wherein the X-ray powder diffraction pattern of the crystal has characteristic peaks at diffraction angles 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°.

[0007] Preferably, the crystal has the molecular formula C. 46 H 80 N2O 13 ·H3PO4·3H2O.

[0008] Preferably, the TGA analysis chart of the crystal shows dehydration at 60°C.

[0009] The present invention also provides a method for preparing tilmicosin phosphate trihydrate crystals as described in any one of the above claims, comprising the following steps:

[0010] Step 1: Dissolve tilmicosin phosphate solid in solvent I and stir until clear;

[0011] Step 2: Heat the solution obtained in Step 1 to 25°C and maintain this temperature, then add solvent II to it;

[0012] Step 3: Constant temperature crystal growth;

[0013] Step 4: Filter the product and dry it to obtain tilmicosin phosphate trihydrate crystals.

[0014] Preferably, in step 1, the initial temperature is room temperature, more preferably 25°C; solvent I is water and / or methanol.

[0015] Preferably, the mass-to-volume ratio of tilmicosin phosphate solid to solvent I is 0.6 g / ml to 1 g / ml.

[0016] In any of the above-mentioned preferred embodiments, in step 2, solvent II is one of acetone, butyl acetate, and isobutyl acetate;

[0017] In any of the above-mentioned preferred embodiments, in step (2), solvent II is an antisolvent, and solvent II is added either all at once or at a certain dropping rate, with the added amount being 15 times the volume of solvent I. Preferably, the dropping rate is 0.2 ml / min.

[0018] In any of the above-mentioned preferred embodiments, the crystal growth time in step (3) is 3 to 4 hours.

[0019] In any of the above-mentioned preferred embodiments, the crystal growth temperature in step (3) is 25°C.

[0020] In any of the above-mentioned preferred embodiments, in step (4), the drying temperature is 45-55°C and the drying time is 3-4 hours.

[0021] The X-ray powder diffraction pattern of the tilmicosin phosphate trihydrate crystal of this invention shows characteristic peaks at diffraction angles 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. Figure 1 As shown.

[0022] The tilmicosin phosphate trihydrate crystals described in this invention exhibit TGA analysis showing dehydration at 60°C, as shown in the attached figure. Figure 2 As shown.

[0023] In a preferred embodiment of the present invention, the method for preparing tilmicosin phosphate trihydrate is as follows:

[0024] (1) At room temperature, more preferably at 25°C, a certain amount of tilmicosin phosphate solid is dissolved in solvent I and magnetically stirred until it becomes clear;

[0025] (2) Add solvent II and maintain a constant temperature of 25°C;

[0026] (3) Then, crystal growth was carried out at the same temperature for 4 hours;

[0027] (4) Filter the product and use vacuum filtration;

[0028] (5) Dry the obtained crystals in a drying oven at 45-55℃;

[0029] (6) After drying, grind to obtain the final tilmicosin phosphate trihydrate product.

[0030] In step (1) of the method, the initial temperature is 25°C, solvent I is deionized water or / or methanol, and the ratio of solute to solvent in step 1 is 0.6g / ml-1g / ml;

[0031] In step (2) of the method, solvent II is one of acetone, butyl acetate, etc. The drop rate of solvent II is either added at once or at a certain drop rate, preferably 0.2 ml / min, and the solution temperature is 25°C.

[0032] In step (3) of the method, the crystal growth time is 4 hours; the crystal growth temperature is preferably 25°C.

[0033] In step (5) of the method, the drying temperature is 45-55℃, more preferably 50℃, and the drying time is 3-4h;

[0034] In the method described, the crystallization method is dissolution crystallization.

[0035] The chemical stability of the prepared tilmicosin phosphate trihydrate crystals was investigated. During storage at 30℃±5℃ and RH40±5% for 30 days, the color, purity, and morphology of the product remained unchanged, indicating good chemical stability of the crystal form. The results are shown in Table 1.

[0036] Table 1. Chemical stability study of tilmicosin phosphate trihydrate

[0037] Properties White powder White powder White powder White powder White powder White powder purity 99.8％ 99.8％ 99.7％ 99.7％ 99.7％ 99.7％

[0038] The results of the chemical stability study of tilmicosin phosphate amorphous form are shown in Table 2.

[0039] Table 2. Chemical stability study of tilmicosin phosphate trihydrate

[0040] Properties pale yellow powder pale yellow powder The main body is pale yellow, with yellow powder appearing at the edges. Increase the yellow edge purity 99.2％ 99.0％ 98.5％ 98.2％

[0041] The average particle size of tilmicosin phosphate trihydrate was also investigated, and the results are shown in Table 3.

[0042] Table 3. Average Particle Size Assessment Table

[0043] Average particle size (μm) 115

[0044] The novel crystalline form of tilmicosin phosphate of the present invention is simple to operate, has a stable process, consumes little energy, is highly economical, and the product has excellent chemical stability, with a yield of over 75% and a purity of over 99%. Moreover, the preparation process is stable, highly reproducible, and has a short production cycle, which improves production efficiency and is suitable for the manufacture and long-term storage of pharmaceutical preparations. Attached Figure Description

[0045] Figure 1 X-ray powder diffraction pattern of the tilmicosin phosphate trihydrate crystal of the present invention.

[0046] Figure 2 DSC-TG analysis chromatogram of tilmicosin phosphate trihydrate crystals described in this invention.

[0047] Figure 3 Microscopic image of tilmicosin phosphate trihydrate crystal of the present invention.

[0048] Figure 4 The particle size distribution of the trihydrate crystals of tilmicosin phosphate described in this invention.

[0049] Figure 5 X-ray powder diffraction pattern of tilmicosin phosphate solvate product obtained by the prior art method in Comparative Example 1. Detailed Implementation

[0050] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0051] The X-ray powder diffraction pattern of the tilmicosin phosphate trihydrate crystal of this invention shows characteristic peaks at diffraction angles 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. Figure 1 The image shown is an X-ray powder diffraction pattern of the tilmicosin phosphate trihydrate crystal described in this invention.

[0052] The TGA analysis of the described tilmicosin phosphate trihydrate crystals showed dehydration at 60°C, as... Figure 2 The image shown is a DSC-TG analysis diagram of the tilmicosin phosphate trihydrate crystal described in this invention.

[0053] Figure 3 The image shown is a crystal microscope image of tilmicosin phosphate trihydrate described in this invention.

[0054] Figure 4 The image shows the crystal size distribution of tilmicosin phosphate trihydrate, as described in this invention.

[0055] Example 1

[0056] 0.6021 g of tilmicosin phosphate solid was dissolved in 1 ml of deionized water at 25 °C. The solution was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 15 ml of the antisolvent acetone was added at once, and the solution was stirred at a constant temperature of 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The resulting crystals were dried in a 50 °C drying oven. After drying, the crystals were ground to obtain the final tilmicosin phosphate trihydrate product.

[0057] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 75%.

[0058] Example 2

[0059] 1.002 g of tilmicosin phosphate solid was dissolved in 1 ml of deionized water at 25 °C. The mixture was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 15 ml of the antisolvent acetone was added at once, and the mixture was stirred at a constant temperature of 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The obtained crystals were dried in a drying oven at 50 °C. After drying, the crystals were ground to obtain the final tilmicosin phosphate trihydrate product.

[0060] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 74%.

[0061] Example 3

[0062] 1.002 g of tilmicosin phosphate solid was dissolved in 1 ml of deionized water at 25 °C, and the mixture was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 15 ml of the anti-solvent acetone was added at a feeding rate of 0.2 ml / min, and the mixture was stirred at a constant temperature of 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The obtained crystals were dried in a drying oven at 50 °C. After drying, the crystals were ground to obtain the final tilmicosin phosphate trihydrate product.

[0063] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 78%.

[0064] Example 4

[0065] 1.2356 g of tilmicosin phosphate solid was dissolved in 2 ml of methanol at 25 °C, and the solution was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 30 ml of the anti-solvent butyl acetate was added at a feeding rate of 0.2 ml / min, and the solution was kept at a constant temperature of 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The resulting crystals were dried in a drying oven at 50 °C. The final tilmicosin phosphate trihydrate product was obtained after drying.

[0066] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 79%.

[0067] Example 5

[0068] 2.0211 g of tilmicosin phosphate solid was dissolved in 2 ml of methanol at 25 °C, and the solution was magnetically stirred and kept at the same temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 30 ml of the anti-solvent butyl acetate was added at a feeding rate of 0.2 ml / min and kept at the same temperature for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The obtained crystals were dried in a drying oven at 50 °C. The final tilmicosin phosphate trihydrate product was obtained after drying.

[0069] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 79%.

[0070] Example 6

[0071] 2.0211 g of tilmicosin phosphate solid was dissolved in 2 ml of methanol at 25 °C, and the solution was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 30 ml of the anti-solvent butyl acetate was added at once, and the solution was kept at a constant temperature of 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The obtained crystals were dried in a drying oven at 50 °C. The final tilmicosin phosphate trihydrate product was obtained after drying.

[0072] The X-ray powder diffraction pattern of the product shows characteristic peaks at diffraction angles of 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. TGA-DSC results indicate a dehydration temperature of 60℃. The product is a white powder with a purity of 99.8% and a process yield of 72%.

[0073] The product obtained by the preparation method provided by this invention, tilmicosin phosphate trihydrate, i.e., the tilmicosin phosphate trihydrate crystal of this invention, is fundamentally different from the tilmicosin phosphate solvate product prepared by known methods in the prior art. The following is an example of Comparative Example 1:

[0074] Comparative Example 1

[0075] 1.0211 g of tilmicosin phosphate solid was dissolved in 1 ml of water at 25 °C, and the solution was magnetically stirred and kept at a constant temperature for 15 min to ensure complete dissolution and uniform dispersion of the solid in the solvent. 20 ml of the antisolvent acetonitrile was added at once, and the solution was kept at 25 °C for 2 h. Crystallization was then carried out at the same temperature for 4 h. The product was filtered and vacuum filtered. The resulting crystals were dried in a 50 °C drying oven. The final tilmicosin phosphate solvate product was obtained after drying.

[0076] X-ray powder diffraction pattern of the product (see) Figure 5 Characteristic peaks are observed at diffraction angles 2θ = 3.511 ± 0.2°, 7.099 ± 0.2°, 9.990 ± 0.2°, 13.250 ± 0.2°, 16.480 ± 0.2°, 18.600 ± 0.2°, and 20.250 ± 0.2°.

[0077] The crystal form of tilmicosin phosphate trihydrate and its preparation method disclosed in this invention can be implemented by those skilled in the art by appropriately modifying the raw materials, process parameters, and other aspects, based on the content of this document. The methods and products of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this invention to achieve the technical results of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.

Claims

1. A trihydrate crystal of tilmicosin phosphate, characterized in that, The X-ray powder diffraction pattern of the crystal shows characteristic peaks at diffraction angles 2θ = 3.520 ± 0.2°, 6.780 ± 0.2°, 7.400 ± 0.2°, 8.360 ± 0.2°, 10.890 ± 0.2°, 15.420 ± 0.2°, and 19.680 ± 0.2°. Step 1: Dissolve tilmicosin phosphate solid in solvent I and stir until clear; solvent I is methanol; Step 2: Heat the solution obtained in Step 1 to 25°C and maintain this temperature, then add solvent II; the solvent II is butyl acetate; the drop rate of solvent II is 0.2 ml / min, and the solution temperature is 25°C; Step 3: Constant temperature crystal growth; crystal growth temperature is 25℃; crystal growth time is 4 hours; Step 4: Filter the product and dry it to obtain tilmicosin phosphate trihydrate crystals.

2. The tilmicosin phosphate trihydrate crystal as described in claim 1, characterized in that, The crystal has the molecular formula C. 46 H 80 N2O 13 ·H3PO4·3H2O.

3. The tilmicosin phosphate trihydrate crystal as described in claim 1 or 2, characterized in that, The TGA analysis of the crystal showed dehydration at 60°C.

4. A method for preparing tilmicosin phosphate trihydrate crystals according to any one of claims 1-3, comprising the following steps: Step 1: Dissolve tilmicosin phosphate solid in solvent I and stir until clear; solvent I is methanol; Step 2: Heat the solution obtained in Step 1 to 25°C and maintain this temperature, then add solvent II; the solvent II is butyl acetate; the drop rate of solvent II is 0.2 ml / min, and the solution temperature is 25°C; Step 3: Constant temperature crystal growth; crystal growth temperature is 25℃; crystal growth time is 4 hours; Step 4: Filter the product and dry it to obtain tilmicosin phosphate trihydrate crystals.

5. The preparation method according to claim 4, characterized in that, In step 1, the initial temperature is 25°C.

6. The preparation method according to claim 4, characterized in that, In step 2, the amount of solvent II added is 15 times the volume of solvent I.

7. The preparation method according to claim 4, characterized in that, In step 4, the drying temperature is 45~55℃ and the drying time is 3~4h.

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