CN113999274A - Tilmicosin-saccharin eutectic and preparation method thereof - Google Patents
Tilmicosin-saccharin eutectic and preparation method thereof Download PDFInfo
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- CN113999274A CN113999274A CN202111367728.4A CN202111367728A CN113999274A CN 113999274 A CN113999274 A CN 113999274A CN 202111367728 A CN202111367728 A CN 202111367728A CN 113999274 A CN113999274 A CN 113999274A
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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- 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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Abstract
The invention discloses a tilmicosin-saccharin eutectic and a preparation method thereof, wherein the tilmicosin-saccharin eutectic forms saccharin, the tilmicosin and the saccharin form an eutectic I or an eutectic II, and the eutectic I is prepared by mixing tilmicosin and saccharin 1: 1 eutectic crystal, wherein the eutectic compound II is tilmicosin and saccharin 1: 2, eutectic crystal, namely adding tilmicosin and saccharin into an organic solvent, adding the solution to 40-80 ℃ for dissolving, stirring for 0.5-5 hours to form the eutectic crystal, and carrying out solid-liquid separation and drying on the obtained product to obtain the tilmicosin-saccharin eutectic crystal. The invention adopts a crystallization mode, avoids dust pollution of the medicament, reduces the physical harm of operators, reduces the pollution to the environment, has a melting point and an initial decomposition temperature higher than tilmicosin and tilmicosin phosphate, improves the thermal stability of the medicament, and is beneficial to the smooth production, storage and transportation processes of the tilmicosin.
Description
Technical Field
The invention belongs to the field of industrial crystallization, and particularly relates to a tilmicosin-saccharin eutectic and a preparation method thereof.
Background
Tilmicosin (Timicosin) is a special semi-synthetic macrolide antibiotic for livestock and poultry developed in the 80 th generation of the 20 th century, and has a molecular formula as follows: c46H80N2O13The chemical structural formula is shown as follows:
tilmicosin is one of macrolide antibiotics which are relatively effective in clinical use, and the unique lung targeting distribution characteristic of tilmicosin enables tilmicosin to become a first-choice medicine for controlling respiratory diseases of livestock. The preparation comprises tilmicosin (alkali) and phosphate tilmicosin, and is coated or uncoated, and can be prepared into premix, solution and injection. However, the use of the composition is affected by the disadvantages of bitter taste, poor fluidity, low dispersibility and the like. At present, the production process of tilmicosin and tilmicosin phosphate mostly adopts a spray drying mode, and a large amount of dust pollution is easily generated in the production and packaging processes, so that certain harm is caused to the bodies of operators; in the using process, the tilmicosin or the tilmicosin phosphate is added into beverage or drinking water of animals, and the powder floats on the water surface due to small specific gravity, and is slowly dissolved, so that the normal use is influenced. Some enterprises make tilmicosin phosphate into premix or granules for sale, but the content of tilmicosin phosphate can be reduced in the preparation process, so that the drug effect is reduced. Tilmicosin phosphate is more acidic than tilmicosin, and has improved solubility but greater irritation to the gastrointestinal tract.
Chinese patent CN 103288904A discloses a method for preparing tilmicosin phosphate crystals, which uses crystal particles to replace powder to avoid dust pollution of drugs, and adopts an anti-solvent method for crystallization, i.e. dissolving tilmicosin in ethyl acetate, adding isopropyl ether with the dosage of 1-2 times of that of the ethyl acetate, and separating out crystalline tilmicosin phosphate. The disadvantages are that a mixed solvent system is adopted, the solvent consumption is large, the solvent needs to be recovered by distillation, the post-treatment process is complicated, and the cost is high.
The eutectic is a novel solid form, wherein the active ingredient and a eutectic ligand (or called a eutectic former) are combined in a hydrogen bond or other non-covalent bond mode on the basis of not destroying the original molecular covalent bond to form a new crystal, and a fixed stoichiometric ratio exists among the components. On the basis of ensuring that the active components of the medicine are not changed, the pharmaceutical cocrystal can improve the physicochemical property of the medicine, effectively improve the stability, the solubility, the dissolution rate, the bioavailability and the like of the medicine, improve the hygroscopicity, the mouthfeel and the like of the medicine, and has wide development space in the pharmaceutical industry, particularly for some insoluble medicines. From the pharmaceutical point of view, the choice of the co-crystal former is one of the key factors for the successful implementation of the co-crystallization process. Saccharin is white crystalline powder, is easy to dissolve in water, has sweetness 300-500 times that of cane sugar, and can improve appetite of people.
Disclosure of Invention
Aiming at the problems, the invention discloses a tilmicosin-saccharin eutectic and a preparation method thereof, which are realized by adopting the following technical scheme:
the invention discloses a tilmicosin-saccharin eutectic, which comprises tilmicosin and an eutectic composition saccharin.
As a further improvement, the tilmicosin and the saccharin form a eutectic compound I or a eutectic compound II, wherein the eutectic compound I is the mixture of the tilmicosin and the saccharin 1: 1, the eutectic compound II is tilmicosin and saccharin 1: 2 eutectic crystal.
As a further improvement, the eutectic compound I according to the present invention contains characteristic diffraction peaks at positions of 5.49, 8.24, 9.30, 9.58, 11.02, 12.02, 12.88, 13.26, 13.96, 14.46, 14.92, 15.16, 15.84, 16.12, 16.74, 18.48, 21.00, and 21.24 in X-ray powder diffraction at a diffraction angle of 2 θ ± 0.2 °.
As a further improvement, the eutectic compound I of the invention melts at the peak top value of 178.1 +/-2 ℃ without weight loss, and the initial decomposition temperature is 258.3 +/-2 ℃.
As a further improvement, the eutectic compound II comprises characteristic diffraction peaks at 4.41, 5.10, 8.82, 9.12, 11.06, 11.32, 13.22, 14.00, 14.38, 16.14, 17.76, 18.44, 19.64, 20.44 and 23.22 in X-ray powder diffraction at a diffraction angle of 2 theta +/-0.2 degrees.
As a further improvement, the eutectic compound II of the invention melts at a peak top value of 138.7 +/-2 ℃ and has an initial decomposition temperature of 243.8 +/-2 ℃.
The invention also discloses a preparation method of the tilmicosin-saccharin eutectic, which comprises the steps of adding tilmicosin and saccharin into an organic solvent, adding the solution to 40-80 ℃ for dissolving, stirring for 0.5-5 hours, forming an eutectic crystal, carrying out solid-liquid separation on the obtained product, and drying to obtain the tilmicosin-saccharin eutectic crystal.
As a further improvement, the invention takes tilmicosin and saccharin as raw materials, and the molar ratio of the raw materials is 1: 1 obtaining an eutectic compound I, wherein the molar ratio of tilmicosin to saccharin serving as raw materials is 1: 2 to obtain the eutectic compound II.
As a further improvement, the ratio of the weight g of tilmicosin to the volume ml of the organic solvent is 1: 3 to 8.
As a further improvement, the organic solvent is any one of methyl acetate, ethyl acetate and isopropyl acetate, the drying temperature under normal pressure is 40-60 ℃, and the drying time is 2-8 hours.
Compared with the prior art, the tilmicosin drying agent improves the dispersibility, the flowability and the bitter taste of tilmicosin, increases the solubility, solves the problem of difficult tilmicosin drying, replaces the original spray drying with the common blast drying, not only saves the energy consumption, but also shortens the drying time, greatly reduces the production cost, and particularly has the following beneficial effects:
(1) the invention adopts a crystallization mode, avoids dust pollution of the medicine, reduces the physical harm of operators and reduces the pollution to the environment.
(2) The tilmicosin-saccharin eutectic compound I is an acicular crystal, and the eutectic compound II is a rod-shaped crystal in shape, as shown in figures 9 and 10, the tilmicosin-saccharin eutectic compound I is good in dispersity, not easy to agglomerate and convenient to use.
(3) The melting point and the initial decomposition temperature of the tilmicosin-saccharin eutectic compound I and the eutectic compound II are higher than that of tilmicosin and tilmicosin phosphate, so that the thermal stability of the medicament is improved, and the smooth production, storage and transportation processes of tilmicosin are facilitated.
(4) According to the tilmicosin-saccharin eutectic compound I and the tilmicosin-saccharin eutectic compound II, saccharin is selected as an eutectic forming substance, and the solubility and the bitterness of tilmicosin are obviously improved by utilizing the water-solubility and the sweet taste of the saccharin.
Drawings
Fig. 1 is an X-ray diffraction pattern of tilmicosin-saccharin cocrystal I;
fig. 2 is a TG diagram of tilmicosin-saccharin co-crystal I;
figure 3 DSC diagram of tilmicosin-saccharin co-crystal I;
FIG. 4 is an X-ray diffraction pattern of tilmicosin-saccharin cocrystal II;
FIG. 5 is a TG plot of tilmicosin-saccharin co-crystal II;
FIG. 6 is a DSC of tilmicosin-saccharin co-crystal II;
FIG. 7 is a crystal structure diagram ORTEP of tilmicosin-saccharin eutectic II;
wherein a is one tilmicosin molecule and two saccharin molecules; b is the ORTEP plot of the eutectic molecules in the smallest asymmetric unit (4 tilmicosin molecules and 8 saccharin molecules);
fig. 8 is a three-dimensional stack of the tilmicosin-saccharin eutectic ii;
fig. 9 is a crystal morphology of tilmicosin-saccharin cocrystal I;
fig. 10 is the crystal morphology of tilmicosin-saccharin cocrystal ii.
Detailed Description
The invention discloses a tilmicosin-saccharin eutectic and a preparation method thereof.
The tilmicosin and the crystal form of the sugar form a eutectic compound I or II: the co-crystal I is tilmicosin-saccharin 1: 1 eutectic crystal, wherein the eutectic compound II is tilmicosin-saccharin 1: 2 eutectic crystal.
The preparation method of the tilmicosin and eutectic composition saccharin comprises the following steps: adding tilmicosin and saccharin into an organic solvent, then adding the solution to 40-80 ℃ for dissolving, stirring for 0.5-5 hours, forming an eutectic crystal, carrying out solid-liquid separation (such as suction filtration) on the obtained product, and drying to obtain a tilmicosin-saccharin eutectic crystal, wherein the tilmicosin and saccharin are used as raw materials in a molar ratio of 1: 1 to obtain a eutectic compound I, wherein the molar ratio of raw materials is 1: 2 preparation of a cocrystal II with a ratio of tilmicosin to organic solvent (g: ml) of 1 g: 3-8 ml; the organic solvent is any one of methyl acetate, ethyl acetate and isopropyl acetate, preferably ethyl acetate; the drying temperature under normal pressure is 40-60 ℃, and the drying time is 2-8 hours.
Tilmicosin-saccharin eutectic compound I has an X-ray powder diffraction pattern shown in figure 1, and has characteristic diffraction peaks at diffraction angles 2 theta (DEG C, + -0.2) of 5.49, 8.24, 9.30, 9.58, 11.02, 12.02, 12.88, 13.26, 13.96, 14.46, 14.92, 15.16, 15.84, 16.12, 16.74, 18.48, 21.00,21.24 and the like; the tilmicosin-saccharin eutectic compound I is melted at 178.1 +/-2 ℃ without weight loss, and the initial decomposition temperature is 258.3 +/-2 ℃, as shown in figures 2 and 3.
The tilmicosin-saccharin eutectic compound II has an X-ray powder diffraction pattern shown in figure 4, and has characteristic diffraction peaks at diffraction angles 2 theta (DEG C, + -0.2) of 4.41, 5.10, 8.82, 9.12, 11.06, 11.32, 13.22, 14.00, 14.38, 16.14, 17.76, 18.44, 19.64, 20.44, 23.22 and the like; tilmicosin-saccharin co-crystal ii melted at 138.7 ± 2 ℃ with about 3.1% weight loss, indicating that there was also a small amount of ethyl acetate in the structure with an initial decomposition temperature of 243.8 ± 2 ℃, as shown in fig. 5 and 6.
The crystal structure analysis of the tilmicosin-saccharin eutectic compound II shows that the tilmicosin-saccharin eutectic compound II belongs to a monoclinic system, P21The space group has crystallographic parameters shown in Table 1, and the minimum asymmetric unit contains four tilmicosin molecules, eight saccharin molecules and about 2-4 disordered solvent (ethyl acetate) molecules, i.e. tilmicosin and saccharin in eutectic compound IIIn a molar ratio of 1: 2, fig. 7 is a crystal structure diagram ORTEP of tilmicosin-saccharin eutectic compound II; wherein a is one tilmicosin molecule and two saccharin molecules; b is the ORTEP plot of the eutectic molecules in the smallest asymmetric unit (4 tilmicosin molecules and 8 saccharin molecules); fig. 8 is a three-dimensional stack of the tilmicosin-saccharin co-crystal ii. As shown, the solvent ethyl acetate molecules fill the cavities disorderly, and there are no hydrogen bonds or other intermolecular forces with the eutectic molecules, and thus are very easily removed upon drying.
TABLE 1 crystallographic parameters of tilmicosin-saccharin cocrystal II
The present invention will be further described below by way of specific embodiments, but the present invention is not limited to only the following examples.
Example 1
Respectively weighing 1.74 g (2mmol) of tilmicosin and 0.37 g (2mmol) of saccharin, adding into a 100ml round-bottom flask, adding 5.5ml of ethyl acetate, heating to 60-65 ℃, refluxing, stirring until the tilmicosin and the saccharin are completely dissolved, continuously stirring for 30-60 min, gradually separating out a solid, stopping stirring after a large amount of the solid is separated out, cooling to room temperature, carrying out solid-liquid separation (suction filtration), and drying at 50 ℃ for 1-2 hours to obtain a white solid, namely tilmicosin-saccharin eutectic compound I, wherein an X-ray diffraction spectrum of the white solid is shown in figure 1.
Example 2
Respectively weighing 1.74 g (2mmol) of tilmicosin and 0.37 g (2mmol) of saccharin, adding into a 100ml round-bottom flask, adding 6ml of ethyl acetate, heating to 40 ℃, refluxing, stirring until the mixture is completely dissolved, continuously stirring for 1-2 hours, gradually separating out a solid, stopping stirring after a large amount of the solid is separated out, cooling to room temperature, carrying out solid-liquid separation (suction filtration), and drying at 60 ℃ for 1 hour to obtain a white solid, namely tilmicosin-saccharin eutectic compound I.
Example 3
Respectively weighing 3.48 g (4mmol) of tilmicosin and 0.74 g (4mmol) of saccharin, adding into a 100ml round-bottom flask, adding 20ml of ethyl acetate, heating to 80 ℃, refluxing, stirring until the mixture is completely dissolved, continuously stirring for 30min, gradually separating out a solid, stopping stirring after a large amount of the solid is separated out, cooling to room temperature, carrying out solid-liquid separation (suction filtration), and drying at 40 ℃ for 5 hours to obtain a white solid, namely the tilmicosin-saccharin eutectic compound I.
Example 4
Respectively weighing 0.87 g (1mmol) of tilmicosin and 0.18 g (1mmol) of saccharin, adding the tilmicosin and the saccharin into a 100ml round-bottom flask, adding 7ml of isopropyl acetate, heating to 70 ℃, refluxing, stirring until the mixture is completely dissolved, continuously stirring for 30-60 min, gradually separating out a solid, stopping stirring after a large amount of the solid is separated out, cooling to room temperature, carrying out solid-liquid separation (suction filtration), and drying at 50 ℃ for 2 hours to obtain a white solid, namely tilmicosin-saccharin eutectic compound I.
Example 5
Respectively weighing 0.87 g (1mmol) of tilmicosin and 0.36 g (2mmol) of saccharin, adding the weighed tilmicosin and the saccharin into a 100ml round-bottom flask, adding 4ml of methyl acetate, heating to 70 ℃, refluxing, stirring until the mixture is completely dissolved, continuously stirring for 30-60 min, gradually separating out a solid, stopping stirring after a large amount of the solid is separated out, cooling to room temperature, carrying out solid-liquid separation (suction filtration), and drying at 50 ℃ for 2 hours to obtain a white solid, namely tilmicosin-saccharin eutectic compound II, wherein an X-ray diffraction spectrum of the tilmicosin-saccharin eutectic compound II is shown in figure 4.
Example 6
Respectively weighing 3.48 g (4mmol) of tilmicosin and 1.46 g (8mmol) of saccharin, respectively dissolving in 15ml and 10ml of ethyl acetate, mixing the two, heating to 65 ℃, refluxing, stirring for 30-90 min to gradually separate out solids, stopping stirring after a large amount of the solids are separated out, cooling to room temperature, performing solid-liquid separation (suction filtration), and drying at 50 ℃ for 2 hours to obtain a white solid, namely the tilmicosin-saccharin eutectic compound II.
Example 7
Weighing 0.2 g of tilmicosin-saccharin eutectic compound II, placing the tilmicosin-saccharin eutectic compound II in a 50ml small beaker, adding 7ml of ethyl acetate, heating to 50 ℃ until the tilmicosin-saccharin eutectic compound II is completely dissolved, standing, placing the mixture in an ice water bath for cooling and crystallization, and obtaining a rod-shaped crystal after a plurality of hours, namely the tilmicosin-saccharin eutectic compound II, wherein the crystallographic parameters are shown in Table 1, and the crystal structure is shown in figures 7-8.
While only a few specific embodiments of the present invention have been shown and described, it will be obvious that the invention is not limited thereto, but may be embodied in many different forms and that all changes and modifications that can be derived from the disclosure set forth herein by one of ordinary skill in the art are deemed to be within the scope of the present invention.
Claims (10)
1. A tilmicosin-saccharin eutectic is characterized by comprising tilmicosin and saccharin as an eutectic formation.
2. The tilmicosin-saccharin cocrystal of claim 1, wherein tilmicosin forms a cocrystal I or a cocrystal ii with saccharin, wherein cocrystal I is a mixture of tilmicosin and saccharin 1: 1, the eutectic compound II is tilmicosin and saccharin 1: 2 eutectic crystal.
3. Tilmicosin-saccharin cocrystal according to claim 2, wherein the cocrystal I comprises characteristic diffraction peaks at 5.49, 8.24, 9.30, 9.58, 11.02, 12.02, 12.88, 13.26, 13.96, 14.46, 14.92, 15.16, 15.84, 16.12, 16.74, 18.48, 21.00,21.24 by X-ray powder diffraction at diffraction angles 2 Θ ± 0.2 °.
4. Tilmicosin-saccharin cocrystals as claimed in claim 2, wherein the cocrystal I melts at peak top 178.1 ± 2 ℃ without weight loss and has an onset decomposition temperature of 258.3 ± 2 ℃.
5. Tilmicosin-saccharin cocrystal as claimed in claim 1 or 2 or 3 or 4, wherein the cocrystal II comprises characteristic diffraction peaks at 4.41, 5.10, 8.82, 9.12, 11.06, 11.32, 13.22, 14.00, 14.38, 16.14, 17.76, 18.44, 19.64, 20.44, 23.22 by X-ray powder diffraction at diffraction angles 2 θ ± 0.2 °.
6. Tilmicosin-saccharin cocrystals as claimed in claim 5, wherein the cocrystal ii melts at a peak top value of 138.7 ± 2 ℃ and has an onset decomposition temperature of 243.8 ± 2 ℃.
7. A preparation method of tilmicosin-saccharin cocrystal as claimed in claim 1, 2, 3, 4 or 6, characterized in that tilmicosin and saccharin are added into an organic solvent, then the solution is added to 40-80 ℃ to be dissolved, stirred for 0.5-5 hours, eutectic is formed, and the obtained product is subjected to solid-liquid separation and drying to obtain tilmicosin-saccharin cocrystal.
8. The method of claim 7, wherein the molar ratio of tilmicosin to saccharin as starting materials is 1: 1 obtaining an eutectic compound I, wherein the molar ratio of tilmicosin to saccharin serving as raw materials is 1: 2 to obtain the eutectic compound II.
9. The method of preparing a tilmicosin-saccharin cocrystal of claim 7, wherein the ratio of the weight g of tilmicosin to the volume ml of organic solvent is 1: 3 to 8.
10. The method for preparing tilmicosin-saccharin co-crystal according to claim 7, wherein the organic solvent is any one of methyl acetate, ethyl acetate and isopropyl acetate, the drying temperature under normal pressure is 40-60 ℃, and the drying time is 2-8 hours.
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| CN103054808A (en) * | 2012-12-27 | 2013-04-24 | 成都乾坤动物药业有限公司 | Tilmicosin dry suspension, method for preparing dry suspension and uses thereof |
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2021
- 2021-11-18 CN CN202111367728.4A patent/CN113999274A/en active Pending
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| CN103054808A (en) * | 2012-12-27 | 2013-04-24 | 成都乾坤动物药业有限公司 | Tilmicosin dry suspension, method for preparing dry suspension and uses thereof |
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