Iodopyracet form ii and a process for its preparation

Abstract

This invention provides an iodopyridine compound crystal form II and its preparation method. Compared with existing crystal forms, the iodopyridine crystal form II of this invention has advantages such as low hygroscopicity, high purity, high tap density, and good stability. The preparation process of the crystal form of this invention is simple and has a high yield, which is beneficial to the production and storage of pharmaceuticals.

Description

Technical Field

[0001] This invention relates to a compound crystal form and its crystallization method, and more specifically to an X-ray contrast agent, iodine-based crystal form II, and its preparation method. Background Technology

[0002] Iobitridol is a non-ionic iodine-containing contrast agent developed by Guerbet in France in the 1990s. Iobitridol (structural formula I) has the advantages of high water solubility, low viscosity and low osmotic pressure, and is therefore widely used in urinary venography, arteriography, digital subtraction angiography of veins, etc., to assist in the diagnosis of target tissues or organs.

[0003]

[0004] Currently, no data on the crystal form of iodopyridine has been reported in domestic or international patents or literature. Patents EP0437144, CN110903275A, and CN109134289A report methods for synthesizing iodopyridine, but do not directly describe any information related to its crystal form.

[0005] For pharmaceuticals, different crystal forms can possess different physical and chemical properties, such as melting point, stability, apparent solubility, and dissolution rate. These properties directly affect the stability, solubility, hygroscopicity, and bioavailability of drug formulations, and even the final clinical efficacy. Therefore, the preparation and research of iodine crystal forms are of great significance. Summary of the Invention

[0006] The inventors prepared iodide using existing methods for preparing iodide (according to patents CN109134289A and CN110903275A), and all of these crystal forms were identified as the same. This crystal form is defined as iodide crystal form I. During the research, another new crystal form of iodide was discovered, which was identified as a new crystal form. This is defined as iodide crystal form II.

[0007] Specifically, this invention provides an iodopylene crystal form II, and the X-ray powder diffraction pattern obtained by Cu Ka radiation includes at least 2θ characteristic peaks located at 7.40±0.2°, 12.50±0.2°, 18.48±0.2°, 19.12±0.2°, and 20.32±0.2°.

[0008] Furthermore, the X-ray powder diffraction pattern also includes characteristic peaks of 2θ at 17.10±0.2°, 22.26±0.2°, 25.24±0.2°, 27.08±0.2°, 27.54±0.2°, and 29.52±0.2°.

[0009] The X-ray powder diffraction pattern peaks of the iodopylene crystal form II are as follows:

[0010]

[0011]

[0012] Furthermore, the X-ray powder diffraction pattern of crystal form II is as follows: Figure 1 As shown.

[0013] The differential scanning calorimetry spectrum of crystal form II shows a melting endothermic peak at 296.15–302.97 °C and a maximum absorption peak at 299.21 °C.

[0014] This invention also provides a method for preparing iodopylene crystal form II, comprising the following steps:

[0015] (1) Mix iodine with water and heat to the first temperature to dissolve;

[0016] (2) Add ether solvent, maintain the first temperature in step (1) and stir for more than 5 hours, then reduce to the second temperature;

[0017] (3) Maintain the second temperature in step (2) until the crystals are completely precipitated, then filter and dry.

[0018] In one embodiment, the ether solvent is selected from one or more combinations of ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and propylene glycol dimethyl ether.

[0019] In one embodiment, the first temperature is 70–80°C and the second temperature is 25–35°C.

[0020] In one embodiment, the first temperature is 75°C and the second temperature is 30°C.

[0021] In one embodiment, the mass-volume ratio of iodopyrrol to water in step (1) is 1g:0.1ml to 1.0mL; in another embodiment, it is selected from 1g:0.5mL; the mass-volume ratio of iodopyrrol to ether solvent in step (2) is 1g:3.0ml to 6.0mL; in another embodiment, it is selected from 1g:4.0mL.

[0022] In one embodiment, in step (2), the mixture is stirred for more than 8 hours.

[0023] In one embodiment, in step (3), the drying conditions are vacuum drying at 60-70°C for 10-14 hours, with the preferred drying temperature being 65°C.

[0024] In one embodiment, in step (3), vacuum drying is performed for 12 hours.

[0025] In this invention, during the filtration process, unsuitable solvents can also be used for rinsing, such as isopropanol.

[0026] The stability of iodide polymorph II provided by this invention is significantly better than that of iodide polymorph I, which provides the possibility of improving the bioavailability and safety of the drug; the lower hygroscopicity of polymorph II facilitates dispensing and storage during the production process in the workshop; in addition, the preparation process of the polymorph of this invention is simple, has a high yield, and is suitable for industrial production.

[0027] In this invention, "crystal" or "polymorphic" refers to a solid confirmed by X-ray powder diffraction (XPD) characterization. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray powder diffraction patterns typically vary with different instrument conditions. It should be particularly noted that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystal. The diffraction peak intensities shown in this invention are illustrative rather than for absolute comparison. Furthermore, experimental errors in diffraction peak positions are typically 5% or less, and these positional errors should also be taken into account, generally allowing for ±0.2%. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in diffraction peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention need not be completely identical to the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern with the same or similar characteristic peaks as those in these patterns is within the scope of the present invention. Attached Figure Description

[0028] Figure 1 The image shown is the X-ray powder diffraction (XRPD) pattern of iodopylene crystal form II obtained in Example 1.

[0029] Figure 2 The image shown is a differential scanning calorimetry (DSC) spectrum of iodopylene crystal form II obtained in Example 1.

[0030] Figure 3 The image shown is the X-ray powder diffraction (XRPD) pattern of iodopylene crystal form II obtained in Example 2.

[0031] Figure 4 The image shown is the X-ray powder diffraction (XRPD) pattern of iodopylene crystal form I obtained in Example 6.

[0032] Figure 5The image shown is a differential scanning calorimetry (DSC) spectrum of iodopylene crystal form I obtained in Example 6. Detailed Implementation

[0033] To make the technical problems solved, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to embodiments, but this is not intended to limit the invention. Any equivalent substitutions made in the art based on the disclosure of this invention are within the protection scope of this invention.

[0034] The abbreviations used in this invention are explained as follows:

[0035] XRPD: X-ray powder diffraction

[0036] DSC: Differential Scan Calorimetry

[0037] Analytical methods

[0038] Instruments and methods used for XRPD data acquisition :

[0039] X-ray source: Cu Ka

[0040] Testing instrument: DX-2700BH X-ray diffractometer

[0041] Test method: Pipe voltage 40KV, pipe current 30mA

[0042] Acquisition time: 0.02° / 0.5s

[0043] Test angle: 3-40°

[0044] Instruments and methods used for DSC data acquisition :

[0045] The differential scanning calorimetry (DSC) graph described in this invention was acquired on a Mettler DSC3, and the DSC analysis method parameters are as follows:

[0046] Heating rate: 10℃ / min

[0047] Protective gas: Nitrogen

[0048] Instruments and methods used for tap density data acquisition :

[0049] The tap density data described in this invention were collected using a GJ03-09 powder comprehensive characteristic tester. The analysis method parameters for tap density are as follows:

[0050] Amplitude: 14mm

[0051] Vibration time: 1 minute

[0052] Test method: Accurately measure 20g of sample and place it into the pre-installed graduated cylinder. Start the timer to begin the test. After vibration ends, read and record the volume of the sample in the graduated cylinder. After removing all the powder from the graduated cylinder, repeat the test three times and take the average value.

[0053] To make the technical problems solved, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to embodiments, but this is not intended to limit the invention. Any equivalent substitutions made in the art based on the disclosure of this invention are within the protection scope of this invention.

[0054] Iodopyrol can be obtained by purchasing commercially available products or by preparing it according to existing techniques. The raw material iodopyrol used in this invention is obtained by referring to the methods reported in patents EP0437144, CN110903275A, and CN109134289A.

[0055] Example 1: Preparation of Iodopyl II crystal form

[0056] Add 250 ml of purified water to the reaction flask, then add 500 g of iodopyrrolizol. Stir and heat to 75 °C to dissolve. Then add 2.0 L of ethylene glycol dimethyl ether dropwise, maintain the temperature at 75 °C and stir for 8 hours. Allow to cool naturally to 30 °C, filter, wash the filter cake with a small amount of isopropanol and dry under vacuum. Transfer to a drying oven and dry under vacuum at 65 °C for 12 hours to obtain 443 g of white solid. The yield of iodopyrrolizol is 88.6%, the moisture content is 0.10%, the maximum single impurity is 0.03%, the total impurities are 0.08%, and the hygroscopicity is 0.06%. The X-ray powder diffraction pattern, expressed in 2θ angles, obtained using Cu-Ka radiation is shown in the appendix. Figure 1 Characteristic peaks are observed at approximately 7.40±0.2°, 12.50±0.2°, 17.10±0.2°, 18.48±0.2°, 19.14±0.2°, 20.32±0.2°, 22.26±0.2°, 25.24±0.2°, 27.08±0.2°, 27.54±0.2°, and 29.52±0.2°. The DSC spectrum is attached. Figure 2 It has a characteristic absorption peak near 299.37℃, and this crystal form is defined as iodide-based crystal form II.

[0057] Example 2: Preparation of Iodipulol II crystal form

[0058] 25 L of purified water was added to the reaction vessel, followed by 50 kg of iodopyrrolizol. The mixture was stirred and heated to 75 °C to dissolve the iodopyrrolizol. Then, 200 L of ethylene glycol dimethyl ether was added dropwise. The mixture was kept at 75 °C and stirred for 8 hours, then allowed to cool naturally to 30 °C. After centrifugation, the filter cake was washed with an appropriate amount of isopropanol. The cake was then transferred to a double-cone desiccator and vacuum dried at 65 °C for 12 hours to obtain 43.73 kg of white solid. The yield of iodopyrrolizol was 87.5%, the moisture content was 0.08%, and the related substances were: maximum single impurity 0.02%, total impurities 0.07%, and hygroscopicity 0.08%. The X-ray powder diffraction pattern, expressed in 2θ angles, was obtained using Cu-Ka radiation and is shown in the appendix. Figure 3 Characteristic peaks are observed at approximately 7.42°, 12.52°, 17.10°, 18.48°, 19.14°, 20.30°, 22.18°, 25.22°, 27.12°, 27.60°, and 29.56°.

[0059] Example 3: Preparation of Iodipulol II crystal form

[0060] Add 400 ml of purified water to the reaction flask, then add 500 g of iodopyrrolizol. Stir and heat to 75 °C to dissolve. Then add 2.5 L of ethylene glycol dimethyl ether dropwise, maintain the temperature at 75 °C and stir for 8 hours. Allow to cool naturally to 30 °C, filter, wash the filter cake with a small amount of isopropanol and dry under vacuum. Transfer to a drying oven and dry under vacuum at 65 °C for 12 hours to obtain 438 g of white solid. The yield of iodopyrrolizol is 87.6%, the moisture content is 0.11%, the maximum single impurity is 0.02%, the total impurities are 0.06%, and the hygroscopicity is 0.07%.

[0061] Example 4: Preparation of Iodipulol II crystal form

[0062] Add 200 ml of purified water to the reaction flask, then add 500 g of iodopyrrolizol. Stir and heat to 75 °C to dissolve. Then add 2.0 L of propylene glycol dimethyl ether dropwise, maintain the temperature at 75 °C and stir for 8 hours. Allow to cool naturally to 30 °C, filter, wash the filter cake with a small amount of isopropanol and dry under vacuum. Transfer to a drying oven and dry under vacuum at 65 °C for 12 hours to obtain 448 g of white solid. The yield of iodopyrrolizol is 89.6%, the moisture content is 0.08%, the maximum single impurity is 0.03%, the total impurities are 0.07%, and the hygroscopicity is 0.07%.

[0063] Example 5: Preparation of Iodipulol II crystal form

[0064] Add 250 ml of purified water to the reaction flask, then add 500 g of iodopyrrolizol. Stir and heat to 75 °C to dissolve. Then add 2.0 L of ethylene glycol diethyl ether dropwise, maintain the temperature at 75 °C and stir for 8 hours. Allow to cool naturally to 30 °C, filter, wash the filter cake with a small amount of isopropanol and dry under vacuum. Transfer to a drying oven and dry under vacuum at 65 °C for 12 hours to obtain 451 g of white solid. The yield of iodopyrrolizol is 90.2%, the water content is 0.08%, the maximum single impurity is 0.02%, the total impurities are 0.07%, and the hygroscopicity is 0.08%.

[0065] Example 6: Comparative Example. The preparation method of the prior art product is based on Chinese Patent CN109134289A, yielding iodopylene crystal form I with a hygroscopicity of 0.6%. X-ray powder diffraction patterns expressed in 2θ angles were obtained using Cu-Ka radiation (see attached figure). Figure 4 Characteristic peaks are observed at approximately 6.92, 8.50, 8.70, 9.44, 14.24, 18.20, 20.46, 20.76, 21.08, 21.72, 23.44, 25.74, 25.94, 26.92, 27.37, and 28.64. See the attached DSC spectrum. Figure 5 .

[0066] (Synthesis of iodopyrol in Example 3 of Patent CN109134289A:)

[0067] Compound (III) (146.6 g, 200 mmol) was added to a 1 L three-necked flask, along with 290 mL of ethyl acetate, 45 mL of N,N-dimethylacetamide, acetic anhydride (91.8 g, 0.9 mol), and 4-dimethylaminopyridine (2.44 g, 20 mmol). The mixture was magnetically stirred and reacted overnight at room temperature. The reaction was monitored by TLC until the starting material and intermediate states disappeared, yielding compound 53. The resulting reaction solution was then directly used for the next reaction step.

[0068] 2-Isopropyl-5-carboxy-1,3-dioxane (69.7 g, 400 mmol) and 200 mL of ethyl acetate were added to a reaction flask. Thionyl chloride (95.2 g, 800 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was refluxed for 7 h. Ethyl acetate and thionyl chloride were then removed by vacuum distillation. The residue was dissolved in 100 mL of ethyl acetate and added dropwise to the reaction solution of compound 53 under ice bath conditions. After the addition was complete, the mixture was stirred at 60–70 °C for 2–8 h. TLC monitoring was performed until the starting material spot disappeared. After the reaction was complete, the mixture was cooled to room temperature, and 200 mL of purified water was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL * 2). The combined organic phases were washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 193.1 g of a white solid, compound 54, with a yield of 91.3% and an HPLC purity of 97.3%.

[0069] Compound 54 (105.7 g, 100 mmol) was added to a reaction flask, followed by 200 mL of methanol. Sodium hydroxide (18.0 g, 450 mmol) was dissolved in 200 mL of water. After cooling to room temperature, the sodium hydroxide solution was added to the methanol solution of compound 54. The mixture was stirred at room temperature for 3-4 h. TLC was used to monitor the reaction until the starting material and intermediates disappeared. Then, concentrated hydrochloric acid (75 mL, 900 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was reacted at room temperature for 6-8 h. TLC was used to monitor the reaction until the starting material disappeared. The pH was adjusted to 7-8 with 10% sodium hydroxide under ice bath conditions. After desalination with ion exchange resin, the water was concentrated to dryness. The residue was recrystallized from isopropanol to give 68.1 g of white iodopyrrolidone solid.

[0070] Example 7: Comparative Example. The preparation method of the prior art product is based on Chinese Patent CN110903275A, which yields iodopyrine crystal form I, with characteristic peaks at approximately 6.92, 8.50, 8.70, 14.24, 18.20, 20.76, 23.44, 25.74, 25.94, 26.92, 27.37, and 28.64.

[0071] (Example 5 in patent CN110903275A:)

[0072] Preparation of iodopyrol: M3-A (174.49 g) obtained in Example 4, a strong acid ion exchange resin (150.00 g, Dow Chemical AMBERLYST 40), ethanol (350 ml), and water (350 ml) were added to a reaction flask and reacted at 70°C for 60 hours. After the reaction was complete, the reaction solution was cooled to room temperature and then filtered sequentially using filter paper and a 0.45 μm filter membrane. The reaction solution was concentrated to dryness, and the resulting solid was dissolved in methanol (350 ml). Dichloromethane (700 ml) was added dropwise to the above methanol solution to crystallize. The mixture was filtered, and the filter cake was collected. The filter cake was washed twice with dichloromethane (200 ml) and then dried under vacuum at 35°C to obtain the target product, iodopyrol (120.36 g).

[0073] Example 8: Preparation of Iodine-based amorphous form

[0074] 20 kg of the iodopyridine sample obtained in Example 2 was diluted with purified water to a 20% aqueous solution. The heating system of the spray drying tower was turned on, and when the inlet air temperature reached 180°C, the feed and spray drying process began. The inlet air temperature was maintained at 180–210°C during the spray drying process. 16.23 kg of white solid was obtained. Moisture content was 1.8%, and related substances: maximum single impurity 0.02%, total impurities 0.07%.

[0075] Example 9: Purity and stability of iodopyridine I and II crystalline and amorphous samples

[0076] Samples of iodopyridine I (Example 6) and iodopyridine II (Example 1) were laid flat in the open and their stability was tested under heating (60°C), light irradiation (4500 lux), and high humidity (RH 75%, RH 92.5%) conditions. Sampling times were 10 days and 30 days, and the purity determined by HPLC is shown in Table 1.

[0077] Table 1. Detection of crystal form and amorphous purity of iodopyridine I and II under different conditions.

[0078]

[0079]

[0080] The results above show that the stability of iodide-II crystal form is superior to that of iodide-I crystal form and amorphous form under high temperature (60℃), light (4500 lux), and high humidity (RH75%, RH92.5%) conditions. In particular, under high humidity (RH75%, RH92.5%) or high temperature (60℃) conditions, no significant degradation impurities were observed in iodide-II crystal form after 10 days and 30 days, respectively, and its stability is much better than that of iodide-I crystal form and amorphous form, which provides a possibility for improving drug safety. In addition, the preparation process of the crystal form of the present invention is simple, has a high yield, and is suitable for industrial production.

[0081] Example 10: Comparison of hygroscopicity and hygroscopic rate of iodopylene I and II crystalline and amorphous samples

[0082] The hygroscopicity of iodine I and II crystal forms and amorphous form was compared according to the 2020 edition of the Chinese Pharmacopoeia (9103). The specific results are shown in Table 2.

[0083] Table 2 Comparison of the hygroscopic properties of iodide I and II crystal forms and amorphous forms under different conditions.

[0084]

[0085] As can be seen from the table above, the hygroscopicity of crystal form II of the present invention is lower than that of the other two solid forms, and its average hygroscopic rate is significantly lower than that of the other solid forms. Based on this favorable property, crystal form II of the present invention can be produced and packaged using conventional equipment and environmental control, which is beneficial to the production and packaging of pharmaceuticals.

[0086] Example 11: Comparison of tap density of iodopylene I and II crystal and amorphous samples

[0087] The tap density of iodopyridine I and II crystal forms and amorphous form was compared according to the 2020 edition of the Chinese Pharmacopoeia (0993). The specific results are shown in Table 3.

[0088] Table 3 Comparison of the hygroscopic properties of iodide I and II crystal forms and amorphous forms under different conditions.

[0089]

[0090]

[0091] As can be seen from the table above, the tap density of crystal form II of this invention is significantly greater than that of the other two solid forms. Since this product is a dosage form for injection, the solid active pharmaceutical ingredient needs to be dissolved in water during the formulation production process. Solids with lower tap densities tend to float more during the preparation process, which is inconvenient for formulation production. Crystal form II, with its higher tap density, settles faster and almost never floats on the water surface, making it more advantageous for formulation production operations.

Claims

1. Iodopyracet Form II, characterized in that, The X-ray powder diffraction pattern of the crystal form II is shown in Figure 1.

2. Iobitridol crystalline form II according to claim 1, characterized by, The differential scanning calorimetric spectrum of the crystal form II has a melting endothermic peak at 296.15-302.97℃, and the maximum absorption peak is at 299.21℃.

3. A preparation method of iodobuthalol crystal form II, comprising the following steps: (1) mixing iodobuthalol with water, and heating to a first temperature for dissolution; the first temperature is 75℃; the mass / volume ratio of iodobuthalol to water in step (1) is 1g:0.5mL; (2) adding an ether solvent, keeping the first temperature in step (1) for stirring for 5h or more, and then reducing to a second temperature; the second temperature is 30℃; the ether solvent is selected from the group consisting of one or more of ethylene glycol dimethyl ether, ethylene glycol, diethyl ether, and propylene glycol dimethyl ether; the mass / volume ratio of iodobuthalol to ether solvent in step (2) is 1g:4.0mL; (3) keeping the second temperature in step (2), and filtering and drying after the crystal is completely precipitated; in step (3), the drying condition is vacuum drying at 65℃ for 10-14h.

4. The method of claim 3, wherein, in step (2), the stirring time is 8h or more.

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