CN110655543A - Novel crystal form of tulathromycin and preparation method thereof - Google Patents
Novel crystal form of tulathromycin and preparation method thereof Download PDFInfo
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- CN110655543A CN110655543A CN201810690024.2A CN201810690024A CN110655543A CN 110655543 A CN110655543 A CN 110655543A CN 201810690024 A CN201810690024 A CN 201810690024A CN 110655543 A CN110655543 A CN 110655543A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a novel tulathromycin crystal form and a preparation process thereof, wherein the XRPD pattern of the novel tulathromycin crystal form has characteristic Bragg angles at 5.9 degrees, 6.7 degrees, 8.2 degrees, 13.4 degrees, 14.5 degrees, 14.7 degrees, 16.4 degrees and 19.3 degrees. The new crystal form of telavancin has infrared absorption spectra of 1328.70, 1379.16, 1458.36 and 1735.69cm‑1There is a distinct characteristic signal. The new crystal form of tulathromycin has an endothermic peak in a temperature range of 186-200 ℃ by differential thermal analysis. The invention also provides a preparation method of the novel crystal form of tulathromycin, which comprises the steps of dissolving tulathromycin by using methanol and glacial acetic acid as dissolving solvents of tulathromycin, then crystallizing by using acetone and isopropyl ether solution as resolving solvents, filtering and drying to obtain the tulathromycin with the crystal form. The crystal form has the advantages of difficult moisture absorption, high stability and the like.
Description
Technical Field
The invention relates to a novel crystal form of tulathromycin and a preparation method thereof, belonging to the technical field of veterinary medicines.
Background
Tulathromycin (Tulathromycin), also known as Tulathromycin and tolamycin, which is sold under the trade name of Ruikacin (Draxxin), is a novel semi-synthetic erythromycin-type veterinary antibiotic developed by the American Gilles de Neuro health products company in the late century, and belongs to the third-generation endocrinic antibiotics. The tulathromycin is mainly used for treating and preventing the respiratory system diseases of pigs and cattle caused by actinobacillus pleuropneumoniae, mycoplasma, pasteurella, haemophilus parasuis, bordetella bronchiseptica and the like. The tulathromycin has the advantages of strong antibacterial activity, wide antibacterial spectrum, ultra-long half-life period, completion of the whole treatment process by single administration and the like, and becomes a first-line medicament for treating the respiratory tract infection of the livestock. The tulathromycin has a molecular formula of C41H79N3O12, a molecular weight of 806.08 and a density of 1.17, and is a mixture of 2 isomers of a 15-membered azalide ring and a 13-membered azalide ring in a ratio of 9: 1.
The tulathromycin is easy to degrade in an aqueous solution, and the color of the solution is gradually changed from colorless to brown. The tulathromycin is easy to absorb moisture in a humid environment, and then the rising speed of impurities is obviously accelerated.
Currently, tulathromycin bulk drugs on the market have a plurality of different crystal forms. Generally, the crystal forms of the tulathromycin products of different manufacturers are different. Stability test data show that different tulathromycin crystal forms have different hygroscopicity and stability.
Patent US6583274 describes three crystalline forms of tulathromycin. Wherein the XRPD of the anhydrous crystalline form is characterized by Bragg angles (2 theta) of 6.0, 8.6, 9.7, 15.4, 15.9, 17.5, 18.2, 18.8, 21.0; the XRPD of the monohydrate form characterized by bragg angles (2 θ) of 6.2, 7.6, 9.2, 9.5, 12.3, 12.9, 14.2, 14.6, 17.8, 19.5; XRPD of crystalline forms of hemihydrate (Sesquihydrate) characterized by bragg angles (2 θ) of 5.2, 7.4, 11.2, 11.7, 12.3, 12.9, 14.9, 15.4, 16.7, 17.9.
Patent CN106008622 describes a crystal form of tulathromycin. The XRPD of the crystal form is characterized by the Bragg angles (2 theta) of 5.27, 7.45, 8.32, 10.55, 11.19, 16.68 and 17.93.
The same drug with different crystal forms has obvious differences in the aspects of solubility, dissolution rate, melting point, density, hardness, appearance, biological effectiveness and the like, thereby influencing the stability, bioavailability and therapeutic effect of the drug. The study of drug polymorphism has become an essential component for the daily control of drug production and design of new drug dosage forms before definition. The research on the medicament polymorphism can find the medicament dominant crystal form which is beneficial to playing the medicament effect, and simultaneously, the preparation process is determined according to the characteristics of the crystal form, so that the medicament equivalence among batches is effectively ensured.
Disclosure of Invention
The invention provides a novel crystal form of tulathromycin and a preparation process thereof, and the crystal form has the advantages of difficult moisture absorption, high stability and the like.
The technical scheme adopted for realizing the above purpose of the invention is as follows:
a new crystal form of tulathromycin has characteristic Bragg angles at XRPD patterns of 5.9 degrees, 6.7 degrees, 8.2 degrees, 13.4 degrees, 14.5 degrees, 14.7 degrees, 16.4 degrees and 19.3 degrees.
The new crystal form of telavancin has infrared absorption spectra of 1328.70, 1379.16, 1458.36 and 1735.69cm-1There is a distinct characteristic signal.
The new crystal form of tulathromycin has an endothermic peak in a temperature range of 186-200 ℃ by differential thermal analysis.
The invention also provides a preparation method of the novel crystal form of tulathromycin, which comprises the steps of dissolving tulathromycin by using methanol and glacial acetic acid as dissolving solvents of tulathromycin, then crystallizing by using acetone and isopropyl ether solution as resolving solvents, filtering and drying to obtain the tulathromycin with the crystal form.
The volume-mass ratio of the methanol to the tulathromycin is 10: 1-8: 1 mL/g; the mass ratio of the glacial acetic acid to the tulathromycin is 0.08: 1-0.12: 1; the volume-mass ratio of the acetone to the tulathromycin is 4: 1-3: 1 mL/g; the volume-mass ratio of the isopropyl ether to the tulathromycin is 8: 1-6: 1 mL/g.
Compared with the prior art, the novel crystal form of tulathromycin provided by the invention has the advantages of difficult moisture absorption, high stability and the like.
Drawings
FIG. 1 is an XRPD pattern for a novel form of tulathromycin provided in an example of the invention;
FIG. 2 is a plot of the infrared absorption (IR) spectrum of a novel crystalline form of tulathromycin provided in an example of the present invention;
fig. 3 is a differential thermal analysis (DSC) profile of a novel crystalline form of tulathromycin provided in an example of the present invention.
Detailed Description
The present invention will be more specifically understood from the following examples, which are given by way of illustration and are not intended to limit the scope of the present invention.
Examples
10g of the crude tulathromycin is dissolved in 80mL of anhydrous methanol, the temperature is slowly increased to 35 ℃, and the system is completely dissolved and clear. A mixed solution containing 0.9g of glacial acetic acid and 10mL of anhydrous methanol was added dropwise. Then, a mixed solution of 35mL of acetone and 70mL of isopropyl ether was added dropwise. The system was slowly cooled to 10 ℃ and stirred for 2 hours. And after suction filtration by a Buchner funnel, drying the product in vacuum at 40 ℃ to obtain a white solid, namely the new crystal form of the tulathromycin.
The XRPD data of the new crystal form of the tulathromycin are measured by a SmartLab-SE type X-ray derivative instrument, and relevant test parameters are as follows: 5-50 DEG, 4 DEG/min.
The XRPD pattern of the new crystal form of tulathromycin is shown in figure 1, and the XRPD characteristic Bragg angle (2 theta) of the crystal form is 5.9 degrees, 6.7 degrees, 8.2 degrees, 13.4 degrees, 14.5 degrees, 14.7 degrees, 16.4 degrees and 19.3 degrees as shown in figure 1.
The infrared absorption (IR) spectrum of the new crystal form of tulathromycin is shown in figure 2, which can be seen in figure 2 at 1328.70, 1379.16, 1458.36 and 1735.69cm-1There is a distinct characteristic signal.
Differential thermal analysis (DSC) of the novel crystal form of tulathromycin is shown in figure 3, and an endothermic peak at 186-200 ℃ can be seen from figure 3.
Claims (5)
1. A new crystal form of tulathromycin has characteristic Bragg angles at XRPD patterns of 5.9 degrees, 6.7 degrees, 8.2 degrees, 13.4 degrees, 14.5 degrees, 14.7 degrees, 16.4 degrees and 19.3 degrees.
2. The novel crystal form of tulathromycin of claim 1, characterized in that: the infrared absorption spectrum is 1328.70, 1379.16, 1458.36 and 1735.69cm-1There is a distinct characteristic signal.
3. The novel crystal form of tulathromycin of claim 1, characterized in that: the differential thermal analysis has an endothermic peak in the range of 186-200 ℃.
4. The process for preparing a novel crystal form of tulathromycin as claimed in claim 1, wherein tulathromycin is dissolved in methanol and glacial acetic acid as the dissolution solvent for tulathromycin, followed by crystallization using acetone and isopropyl ether solution as the resolution solvent, filtration and drying to obtain said crystal form of tulathromycin.
5. A process for the preparation of a new crystalline form of tulathromycin according to claim 4, characterized in that: the volume-mass ratio of the methanol to the tulathromycin is 10: 1-8: 1 mL/g; the mass ratio of the glacial acetic acid to the tulathromycin is 0.08: 1-0.12: 1; the volume-mass ratio of the acetone to the tulathromycin is 4: 1-3: 1 mL/g; the volume-mass ratio of the isopropyl ether to the tulathromycin is 8: 1-6: 1 mL/g.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285910A (en) * | 2020-03-06 | 2020-06-16 | 浙江康牧药业有限公司 | Refining and purifying process of tulathromycin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111285910A (en) * | 2020-03-06 | 2020-06-16 | 浙江康牧药业有限公司 | Refining and purifying process of tulathromycin |
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