Jasamycin propionate crystal form I as well as preparation method and application thereof
The preparation of crosamycin propionate crystal form I was solved by solvent cooling crystallization method, which solved its stability and purity problems, and achieved a high purity and stability drug crystal form, which was suitable for drug applications, and the preparation method was environmentally friendly and economical.
Patent Information
- Application Number
- CN202311841137.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-28
- Publication Date
- 2025-07-08
AI Technical Summary
The lack of crystal form research on the crosamycin propionate in the prior art makes it difficult to guarantee its stability and purity, and cannot meet the requirements of finished pharmaceutical products.
By mixing essamycin propionate with a specific solvent and cooling and crystallizing, crystallization is prepared with characteristic X-ray powder diffraction patterns. A green and environmentally friendly preparation method is provided using conventional compounds and mild conditions.
The prepared crosamycin propionate crystal form I has high purity, good stability and reproducibility, is suitable for drug applications, and the preparation method is environmentally friendly and low cost, and is suitable for industrial production.
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Figure CN120271643A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to polymorphic form I of josamycin propionate, its preparation method and application. Background Art
[0002] Josamycin propionate is a macrolide antibiotic, which is used for pharyngitis and tonsillitis caused by Streptococcus pyogenes, sinusitis, otitis media, acute bronchitis and oral abscess caused by sensitive bacteria, pneumonia caused by Mycoplasma pneumoniae, skin and soft tissue infections caused by sensitive bacteria, and can also be used for Staphylococcus infections resistant to penicillin and erythromycin. The chemical name of josamycin propionate is [6-[6-[[(11Z,13E)-4-acetoxy-10-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-7-(2-oxoethyl)-1-oxacyclohexadec-11,13-dien-6-yl]oxy]-4-dimethylamino-2-methyl-5-propionyloxytetrahydropyran-3-yl]oxy-4-hydroxy-2,4-dimethyltetrahydropyran-3-yl] 3-methylbutyrate. The structure of josamycin propionate is shown as follows:
[0003]
[0004] The synthesis of josamycin propionate has been reported in Patent USP4001399, and the synthesis route is shown as follows. Josamycin reacts with propionic anhydride under the catalysis of pyridine to obtain an intermediate; the intermediate is hydrolyzed in 70% methanol to obtain the crude product of josamycin propionate, and the crude product is recrystallized to obtain josamycin propionate.
[0005]
[0006] Currently, there is no report on the polymorphic form of josamycin propionate. Summary of the Invention
[0007] One object of the present invention is to provide polymorphic form I of josamycin propionate, which has good stability;
[0008] Another object of the present invention is to provide a preparation method of polymorphic form I of josamycin propionate;
[0009] Another object of the present invention is to provide the application of polymorphic form I of josamycin propionate.
[0010] Specifically, the present invention provides:
[0011] Josamycin propionate polymorph I, the X-ray powder diffraction pattern of this polymorph has characteristic peaks at the following diffraction angles 2θ: 4.81° ± 0.2, 5.93° ± 0.2, 7.27° ± 0.2, 8.98° ± 0.2, 9.60° ± 0.2, 10.11° ± 0.2, 10.92° ± 0.2, 12.18° ± 0.2, 14.82° ± 0.2, 15.40° ± 0.2.
[0012] Furthermore, the X-ray powder diffraction pattern of the crystal of josamycin propionate has characteristic peaks and their relative intensities at the following diffraction angles 2θ,
[0013] 2θ ± 0.2° Interplanar spacing d (Å) Relative intensity I% 4.81 18.341 100.0 5.93 14.888 23.4 7.27 12.156 40.7 8.98 9.837 38.3 9.60 9.210 22.8 10.11 8.746 22.1 10.92 8.096 74.7 11.44 7.277 17.1 11.85 7.461 16.9 12.18 7.262 23.4 13.20 6.700 21.8 14.82 5.974 42.9 15.40 5.750 23.5 16.36 5.414 12.5 16.98 5.216 18.6 17.64 5.022 16.9 19.04 4.658 14.9 20.50 4.328 19.2 21.74 4.084 13.8 .
[0014] In a second aspect, the present invention provides a method for preparing the josamycin propionate polymorph I, comprising the following steps:
[0015] 1) Mix josamycin propionate with a solvent, dissolve it to obtain a josamycin propionate solution;
[0016] 2) Cool the josamycin propionate solution in step 1) to crystallize, obtaining josamycin propionate polymorph I.
[0017] Furthermore, the solvent is selected from any one or more of water, dichloromethane, acetone, methanol, ethanol, toluene, n-propanol, isopropanol, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, n-heptane.
[0018] Preferably, the solvent is selected from any one or more of water, methyl tert-butyl ether, ethanol, acetone, isopropanol, n-propanol, toluene, n-heptane, dichloromethane.
[0019] Furthermore, the dissolution temperature in step 1) is 10 - 80°C, preferably, the dissolution temperature is 30 - 80°C.
[0020] Furthermore, the temperature for cooling and crystallizing in step 2) is 0 - 30°C. Preferably, the temperature for cooling and crystallizing in step 2) is 0 - 20°C.
[0021] The weight ratio of the solvent to josamycin propionate in step 1) is 2 - 50:1. Preferably, the weight ratio of the solvent to josamycin propionate in step 1) is 3 - 9:1
[0022] After cooling and crystallizing in step 2), it further includes filtration and drying. It can be understood that washing can be carried out after filtration, and the solvent for washing is the same as the solvent in step 1).
[0023] The drying is carried out under reduced pressure at 50 - 80°C.
[0024] A pharmaceutical composition comprising at least one of the above-mentioned josamycin propionate polymorph I and at least one pharmaceutically acceptable carrier. "Pharmaceutical composition" refers to a composition that can be used as a drug, which contains a drug active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to pharmaceutical excipients that are compatible with the drug active ingredient and harmless to the subject, including (but not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH regulators, solvents, cosolvents, surfactants, etc.
[0025] The application of josamycin propionate polymorph I provided by the present invention in the preparation of drugs for treating pharyngitis and tonsillitis caused by Streptococcus pyogenes, sinusitis, otitis media, acute bronchitis and oral abscess caused by sensitive bacteria, pneumonia caused by Mycoplasma pneumoniae, and skin and soft tissue infections caused by sensitive bacteria.
[0026] The application of josamycin propionate polymorph I of the present invention in the preparation of drugs for treating staphylococcal infections resistant to penicillin and erythromycin.
[0027] The beneficial effect of the present invention is to provide polymorph I of josamycin propionate, which has high purity and yield, good stability and reproducibility, and the hygroscopicity can meet the requirements of drug formation.
[0028] The present invention provides a green and environmentally friendly preparation method of josamycin propionate polymorph I. The chemical reagents used in this preparation method are all conventional agents and are inexpensive and easily available. The reaction conditions are mild, the environmental pollution is less, the cost is low, and the post-treatment method is simple, which is suitable for industrial production. Specific implementation plan
[0029] In the present invention, "crystal form" is characterized by the X-ray powder diffraction pattern shown. Those skilled in the art can understand that the experimental error therein depends on the instrument conditions, sample preparation and sample purity.
[0030] In the present invention, the X-ray powder diffraction pattern is measured by the following method: Test instrument: DX-2700SSC type. Test conditions: 40 kV / 30 mA; scanning 3.0 / 53.0 / 0.05 / 1 (seconds).
[0031] It should be noted that in the X-ray powder diffraction pattern, the diffraction pattern obtained from a crystalline compound is often characteristic of a specific crystal form. The relative intensity of the spectral bands (especially at low angles) may vary due to the preferred orientation effect caused by differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of the targeted crystal form. When determining whether it is the same as a known crystal form, more attention should be paid to the relative positions of the peaks rather than their relative intensities. In addition, for any given crystal form, there may be slight errors in the peak positions, which is also well-known in the field of crystallography. For example, due to changes in temperature during sample analysis, sample movement, or instrument calibration, etc., the peak positions can shift, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining the crystal structure of each form. In the X-ray powder diffraction pattern, the peak position is usually represented by the 2θ angle or the interplanar spacing d, and there is a simple conversion relationship between them: d = λ / 2sinθ, where d represents the interplanar spacing, λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same crystal form of the same compound, the peak positions of its X-ray powder diffraction pattern are generally similar, and the relative intensity error may be relatively large. It should also be noted that in the identification of mixtures, due to factors such as decreased content, some diffraction lines may be missing. At this time, it is not necessary to rely on all the spectral bands observed in a high-purity sample, and even a single spectral band may be characteristic of a given crystal.
[0032] The stability and hygroscopicity of josamycin propionate polymorph I of the present invention were tested by conventional test methods. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Figure 1 is the XRD pattern of josamycin propionate polymorph I in Example 1.
[0034] Figure 2 is the infrared absorption spectrum of josamycin propionate polymorph I.
[0035] Figure 3 is the high-resolution mass spectrum of josamycin propionate polymorph I.
[0036] Figure 4 is the 1H NMR spectrum of josamycin propionate polymorph I.
[0037] Figure 5 is the 13C NMR spectrum of josamycin propionate polymorph I.
[0038] Figure 6 is the liquid chromatography spectrum of josamycin propionate with a purity of 96.15% in the example.
[0039] Figure 7 is the liquid chromatography spectrum of josamycin propionate polymorph I crystallized in Example 1. Specific Embodiments
[0041] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight. The josamycin propionate used in the present invention can be obtained by conventional methods in the art or through commercial channels.
[0042] Example 1 Preparation of Josamycin Propionate Polymorph I
[0043] 1) Weigh 5.0 g of josamycin propionate (purity 96.15%, see the liquid chromatography spectrum in Figure 6 ) and add it to a 100 ml three-necked flask. Add 30 g of methyl tert-butyl ether, start stirring and heat up to 50 - 60 °C. Stir until the solid dissolves completely. Filter while it is hot to obtain a methyl tert-butyl ether solution of josamycin propionate;
[0044] 2) Cool down. Crystals gradually precipitate during the cooling process. Then stir at 0 - 10 °C for 0.5 h, filter and wash with 5 g of methyl tert-butyl ether. The obtained filter cake is dried under reduced pressure at 60 - 70 °C to obtain 3.87 g of josamycin propionate polymorph I, with a purity of 98.30% and a yield of 77.4%. The XRD pattern of josamycin propionate polymorph I is as shown in Figure 1 , and the liquid chromatography spectrum is shown in Figure 7 ; the infrared absorption spectrum, high-resolution mass spectrum, nuclear magnetic resonance hydrogen spectrum, and nuclear magnetic resonance carbon spectrum are respectively shown in Figures 2 - 5 .
[0045] Example 2 Preparation of Josamycin Propionate Polymorph I
[0046] 1) Weigh 5.0 g of josamycin propionate (purity 96.15%) and add it to a 100 ml three-necked flask. Add 20 g of n-propanol and stir at 70 - 80 °C until the solid dissolves completely. Filter to obtain an n-propanol solution of josamycin propionate;
[0047] 2) Cool down. Crystals gradually precipitate during the cooling process. Then stir at 0 - 10 °C for 0.5 h; filter and wash with 5 g of n-propanol. The obtained filter cake is dried under reduced pressure at 60 - 70 °C to obtain 3.96 g of josamycin propionate polymorph I, with a purity of 98.13% and a yield of 79.2%. The XRD pattern of josamycin propionate is the same as that in Example 1.
[0048] Example 3 Preparation of Josamycin Propionate Polymorph I
[0049] 1) Weigh 100.0 g of josamycin propionate and add it to a 1-L three-necked flask. Add 300 g of isopropanol, start stirring, and heat up to 70 - 80 °C. Stir until the solid dissolves completely, then filter while it is hot to obtain an isopropanol solution of josamycin propionate;
[0050] 2) Cool down. Crystals gradually precipitate during the cooling process. Stir the solution at 0 - 10 °C for 0.5 h, filter, and wash with 100 g of isopropanol. The obtained filter cake is dried under reduced pressure at 70 - 80 °C to obtain 80.8 g of josamycin propionate polymorph I, with a purity of 98.10% and a yield of 80.8%. The XRD pattern of josamycin propionate is the same as that in Example 1.
[0051] Example 4 Preparation of josamycin propionate polymorph I
[0052] 1) Weigh 25 g of josamycin propionate and add it to a 1-L three-necked flask. Add 75 g of dichloromethane and 150 g of n-heptane, start stirring, and maintain the temperature at 30 - 40 °C; Stir until the solid dissolves completely, then filter to obtain a dichloromethane / n-heptane solution of josamycin propionate;
[0053] 2) Cool down. Crystals gradually precipitate during the cooling process. Stir the solution at 10 - 20 °C for 0.5 h, filter, and dry the obtained filter cake under reduced pressure at 50 - 60 °C to obtain 15.5 g of josamycin propionate polymorph I, with a purity of 97.74% and a yield of 62.0%. The XRD pattern of josamycin propionate is the same as that in Example 1.
[0054] Example 5 Preparation of josamycin propionate polymorph I
[0055] 1) Weigh 5 g of josamycin propionate and add it to a 100-ml three-necked flask. Add 15 g of toluene, start stirring, and heat up to 70 - 80 °C. Stir until the solid dissolves completely, then filter while it is hot to obtain a toluene solution of josamycin propionate;
[0056] 2) Cool down. Crystals gradually precipitate during the cooling process. Stir the solution at 0 - 10 °C for 0.5 h, filter, and wash with 5 g of toluene. The obtained filter cake is dried under reduced pressure at 60 - 70 °C to obtain 3.65 g of josamycin propionate polymorph I, with a purity of 98.42% and a yield of 73.0%. The XRD pattern of josamycin propionate is the same as that in Example 1.
[0057] Example 6 Preparation of josamycin propionate polymorph I
[0058] 1) Weigh 50 g of josamycin propionate and add it to a 2-L three-necked flask. Add 150 g of isopropanol and 50 g of n-heptane, start stirring, and heat up to 70 - 80 °C. Stir until the solid dissolves completely, then filter while it is hot to obtain an isopropanol aqueous solution of josamycin propionate;
[0059] 2) Cooling: During the cooling process, crystals gradually precipitate. The solution is stirred at 0 - 10 °C for 0.5 h, filtered, and the obtained filter cake is dried under reduced pressure at 60 - 70 °C to obtain 43.3 g of josamycin propionate with a purity of 97.92% and a yield of 86.6%. The XRD pattern of josamycin propionate is the same as that in Example 1.
[0060] Experimental Example
[0061] The crystalline form I obtained in Example 1 was subjected to an accelerated stability test, and the experimental data are shown in Table 1:
[0062] Packaging: Sealed with a double-layer low-density polyethylene plastic bag and then placed in a polyester / aluminum / polyethylene composite pharmaceutical packaging bag and sealed. Investigation conditions: 40 °C ± 2 °C / RH 75% ± 5%
[0063] Table 1 Experimental data of the stability of the crystalline form in Example 1
[0064]
[0065] It can be seen from the data in Table 1 that for the crystalline form I of josamycin propionate provided by the present invention, there are no obvious changes in impurities and specific rotation after being placed for 6 months under the accelerated conditions of 40 °C ± 2 °C / RH 75% ± 5%. The crystalline form I of josamycin propionate provided by the present invention has good stability.
[0066] Although the present invention has been described with reference to several illustrative embodiments of the present invention, it should be understood that those skilled in the art can make many other modifications and implementations, and these modifications and implementations will fall within the scope and spirit of the principles disclosed in this application. For those skilled in the art, these modifications or improvements are obvious.
Claims
1. A josamycin propionate polymorphic form I, characterized in that, The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at the following diffraction angles 2θ: 4.81° ± 0.2, 5.93° ± 0.2, 7.27° ± 0.2, 8.98° ± 0.2, 9.60° ± 0.2, 10.11° ± 0.2, 10.92° ± 0.2, 12.18° ± 0.2, 14.82° ± 0.2, 15.40° ± 0.
2.
2. The josamycin propionate polymorphic form I according to claim 1, wherein, The X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 。 3. The josamycin propionate polymorph I as described in claim 1, wherein The X-ray powder diffraction pattern is shown in Figure 1.
4. The preparation method of josamycin propionate polymorph I according to any one of claims 1-3, characterized in that, Comprising the following steps: 1) Mix josamycin propionate with a solvent and dissolve to obtain a josamycin propionate solution; 2) Cool the josamycin propionate solution in step 1) for crystallization to obtain josamycin propionate crystalline form I.
5. The preparation method according to claim 4, wherein The solvent is selected from any one or more of water, dichloromethane, acetone, methanol, ethanol, toluene, n-propanol, isopropanol, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and n-heptane; preferably, the solvent is selected from any one or more of water, methyl tert-butyl ether, ethanol, acetone, isopropanol, n-propanol, toluene, n-heptane, and dichloromethane.
6. The preparation method according to claim 4, characterized in that, The dissolution temperature in step 1) is 10 - 80°C, and the temperature for cooling crystallization in step 2) is 0 - 30°C.
7. The preparation method according to claim 4, wherein The weight ratio of the solvent to josamycin propionate in step 1) is 2 - 50:1; preferably, the weight ratio of the solvent to josamycin propionate in step 1) is 3 - 9:
1.
8. A pharmaceutical composition comprising at least one josamycin propionate crystalline form I according to any one of claims 1 - 3, and at least one pharmaceutically acceptable carrier.
9. Use of the josamycin propionate crystalline form I according to any one of claims 1 - 3 in the preparation of a drug for treating pharyngitis and tonsillitis caused by Streptococcus pyogenes, sinusitis, otitis media, acute bronchitis, and oral abscess caused by sensitive bacteria, pneumonia caused by Mycoplasma pneumoniae, and skin and soft tissue infections caused by sensitive bacteria.
10. Use of the josamycin propionate crystalline form I according to any one of claims 1 - 3 in the preparation of a drug for treating Staphylococcus infections resistant to penicillin and erythromycin.