Iopamidol amorphous and process for its preparation
Iopamidol amorphous compounds were prepared by heating and refluxing in solvents such as ethanol and spray drying, which solved the technical barrier to the study of iopamidol crystal form and achieved the preparation of amorphous compounds with good stability, suitable for industrial production.
Patent Information
- Application Number
- CN202311094126.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Priority Date
- 2023-07-06
- Filing Date
- 2023-08-29
- Publication Date
- 2025-11-18
- Estimated Expiration
- 2043-08-29
AI Technical Summary
There are no reports on the crystal form of iopamidol in the existing technology, and there are technical barriers to the process development and quality research of its active pharmaceutical ingredient. There is a large market demand, but there is a lack of stable methods for preparing amorphous products.
Using ethanol, methanol, isopropanol, or n-butanol as primary solvents, iopamidol is completely dissolved by heating and reflux with stirring, then cooled to crystallize, and finally stirred in water and spray-dried to prepare a stable iopamidol amorphous product.
The prepared iopamidol amorphous compound exhibits good stability under accelerated conditions, making it suitable for industrial production with a high yield, thus facilitating industrial applications.
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Figure CN117164476B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of drug synthesis, and in particular to an iopamidol amorphous substance and a preparation method thereof. BACKGROUND
[0002] Iopamidol, chemical name: (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5[(2-hydroxy-1-propionyl)amino]-2,4,6-triiodo-1,3-benzene dicarboxamide, was officially launched in 1974. Trade name: Iopamiro (Dianbile) or Isovue (Isovue), English name: Iopamidol. It is a non-ionic, water-soluble, triiodinated X-ray contrast agent for intravascular administration. Intravascular injection of the product can make the blood vessels in the contrast agent flow path turbid, and the internal structure can be shown by imaging before the blood concentration is significantly diluted. The structural formula is as follows:
[0003]
[0004] Iopamidol is a new type of triiodine-containing low-osmolar non-ionic contrast agent developed by Italy Boleke Company, which was officially launched in 1981. PMDA public information shows [3] The product is in the form of injection, and the specifications are 150mgI / ml, 300mgI / ml and 370mgI / ml. The product is a white crystalline powder and has little hygroscopicity. The product is easily soluble in water, not easily soluble in methanol, and very difficultly soluble in ethanol (99.5). The long-term test condition is 25℃, and the observation period is 24 months. The accelerated test condition is 40℃, and the observation period is 6 months.
[0005] According to the drug registration information disclosed by the State Food and Drug Administration, Italy Boleke obtained approval to export iopamidol to China as early as 2007. Globally, the iopamidol market is still dominated by the original research drug. In July 2022, the seventh round of national procurement, the only contrast agent selected was the variety. The iopamidol winning bidder is Boleke Xinyi Pharmaceutical, Beilu Pharmaceutical, Steril and Zhengda Tianqing. The market demand is large and the future development prospect is broad, and the technical barriers for the process development, pilot production and quality research of its raw material drug are high, and cost reduction and efficiency increase are imminent. So far, no literature has reported the existence of iopamidol raw material drug polymorphism, including crystal form.
[0006] In view of the crystal form of iopamidol and its medicinal value, it is very necessary to develop an iopamidol amorphous substance and a preparation method thereof. SUMMARY
[0007] In view of the above problems, the present application aims to provide an iopamidol amorphous substance with good stability and suitable for industrial production and a preparation method thereof.
[0008] To achieve the above object, the technical scheme adopted by the present application is as follows: an iodipam amorphous substance, wherein the amorphous substance has an X-ray powder diffraction pattern and diffraction peaks as shown in Figure 1
[0009] A preparation method of the iodipam amorphous substance comprises the following steps:
[0010] 1) adding a crude product of iodipam in any crystal form into a primary solvent, heating and refluxing to stir until completely dissolved, refluxing, cooling and crystallizing, and filtering to obtain a wet product of iodipam;
[0011] 2) adding the wet product of iodipam obtained in step 1) into a secondary solvent, stirring until completely dissolved, and performing spray drying at a certain temperature to obtain the iodipam amorphous substance.
[0012] In the preparation method of the present application, the primary solvent is selected from any one of ethanol, methanol, isopropanol, n-butanol or ethyl acetate; preferably, the primary solvent is ethanol.
[0013] In the preparation method of the present application, the time for heating and refluxing to stir until completely dissolved in step 1) is ≤180 min. By controlling the time for completely dissolving, the rapid crystallization of the wet product of iodipam is facilitated, and finally the yield of the iodipam amorphous substance is improved.
[0014] In the preparation method of the present application, the secondary solvent in step 2) is water.
[0015] In the preparation method of the present application, the concentration of the iodipam after being dissolved in water in step 2) is 0.005 g / ml-50 g / ml; preferably, the concentration is 0.4 g / ml.
[0016] In the preparation method of the present application, the stirring time in step 2) is 1 h-120 h, and preferably, the stirring time is 10 h-16 h.
[0017] In the preparation method of the present application, the spray drying inlet temperature in step 2) is 210℃-230℃, and the outlet temperature is 105℃-125℃.
[0018] The present application has the advantages that: the present application proposes an iodipam amorphous substance and a preparation method thereof, and the amorphous crystal obtained by the production method has good stability; the crystal form of the sample does not change after being placed under accelerated conditions (40℃±2℃, 75%±5%RH) for six months, has high application value, and the overall process is suitable for industrial and industrial production. BRIEF DESCRIPTION OF DRAWINGS
[0019] Figure 1 X-ray powder diffraction pattern of the iodipam amorphous substance in Example 1 of the present application;
[0020] The above table is the test condition of the X-ray powder diffraction pattern, and the following table is the detailed pattern of the X-ray powder diffraction pattern.
[0021] Figure 2 The X-ray powder diffraction pattern of the iopamidol amorphous substance accelerated for 12 months in Example 4 of the present application is shown in the following table.
[0022] The above table is the test condition of the X-ray powder diffraction pattern, and the following table is the detailed pattern of the X-ray powder diffraction pattern. DETAILED DESCRIPTION
[0023] The present application will be further described in detail below in conjunction with the description and specific embodiments of the drawings.
[0024] The model numbers and test conditions of the test instruments used in the experiments in the examples of the present application are as follows:
[0025] X-ray diffraction spectrum
[0026] Instrument model: SmartLab·SE·X-ray powder diffractometer
[0027] X-ray: monochromatic Cu-Kα ray
[0028] Scanning mode: θ / 2θ, scanning range: 3-40°
[0029] Example 1:
[0030] Add 150.0 g of iopamidol crude product of any crystal form to 600 ml of ethanol, stir and reflux for 60 min, the reaction solution is clear, stir and reflux for 12 hours, cool the iopamidol solution to 10℃, crystallize for 2 hours, and extract the iopamidol wet product by filtration to obtain 159.6 g of iopamidol wet product.
[0031] Add the obtained iopamidol wet product 159.6 g to 300 ml of water to obtain an iopamidol aqueous solution, and spray dry the iopamidol aqueous solution after passing through a 0.22 μm filter core, with an inlet air temperature of 220℃ and an outlet air temperature of 110℃.
[0032] Collect 143.7 g of iopamidol amorphous substance, with a yield of 95.8%; the X-ray powder diffraction pattern of the iopamidol amorphous substance is shown in the following table (test date: August 19, 2022). Figure 1
[0033] Example 2:
[0034] Add 150.0 g of iopamidol of any crystal form to 600 ml of isopropanol, stir and reflux for 12 hours, cool the iopamidol solution to 10℃, crystallize for 2 hours, and extract the iopamidol wet product by filtration to obtain 95.1 g of iopamidol wet product.
[0035] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0036] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0037] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃. Figure 1 The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0038] Example 3:
[0039] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0040] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0041] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0042] The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃. Figure 1 The obtained iopamidol wet product 95.1 g was added to 300 ml of water to obtain an iopamidol aqueous solution. After the iopamidol aqueous solution was filtered through a 0.22 μm filter, it was spray dried at an inlet air temperature of 220 ℃ and an outlet air temperature of 110 ℃.
[0043] Example 4: Stability comparison example
[0044] The iopamidol amorphous crystal produced in August 2022 was placed under accelerated conditions (40 ℃ ± 2 ℃, 75% ± 5% RH) to investigate the stability of the iopamidol sample. The sampling time for investigation was 12 months.
[0045] The stability investigation results showed that after the iopamidol amorphous crystal was stored under accelerated conditions of 40 ℃ ± 2 ℃ and 75% ± 5% RH for 12 months, the crystal form of the sample did not change. This indicates that the iopamidol amorphous crystal is stable during the accelerated (40 ℃ ± 2 ℃, 75% ± 5% RH) storage process.
[0046] The X-ray powder diffraction pattern of the iopamidol amorphous crystal after 12 months of acceleration is shown in Figure 2 The X-ray powder diffraction pattern of the iopamidol amorphous crystal after 12 months of acceleration is shown in
[0047] It should be noted that the above are only preferred embodiments of the present application and are not intended to limit the protection scope of the present application. Any combination or equivalent transformation made on the basis of the above embodiments is within the protection scope of the present application.
Claims
1. A method for preparing an amorphous form of iopamidol, characterized in that, The preparation method includes the following steps: 1) Add crude iopamidol of any crystal form to a primary solvent, heat under reflux and stir until completely dissolved in ≤180 min, reflux reaction, cool to crystallize, filter to obtain wet iopamidol; the primary solvent is ethanol; 2) Add the wet iopamidol obtained in step 1) to a secondary solvent, which is water, and stir until completely dissolved. The stirring time is 1 h to 120 h. The concentration of iopamidol in water after dissolution is 0.005 g / ml to 50 g / ml. Spray dry at a certain temperature to obtain iopamidol amorphous product. The amorphous product has the X-ray powder diffraction pattern and diffraction peaks shown in Figure 1.
2. The preparation method according to claim 1, characterized in that, In step 2), the concentration of the dissolved iopamidol in water is 0.4 g / ml.
3. The preparation method according to claim 1, characterized in that, In step 2), the stirring time is 10h to 18h.
4. The preparation method according to claim 1, characterized in that, In step 2), the inlet air temperature for spray drying is 210℃~230℃, and the outlet air temperature is 105℃~125℃.