An indobufen crystalline form and a method for preparing the same

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to an indobufen crystal form, a preparation method and application thereof. The preparation method is simple, only needs to add indobufen into a mixed solvent, heat and stir to dissolve, and then concentrate and dry under reduced pressure to obtain the crystal form. The anhydrous crystal form of indobufen provided by the present application has good chemical stability in solid state or solution state, and has good solubility.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to the crystal form of indobufen, its preparation method, and its application. Background Technology

[0002] Indobufen is a multi-target antiplatelet drug developed by Erba. It effectively blocks platelet aggregation through mechanisms such as reversible inhibition of cyclooxygenase and reduction of thromboxane A2 production. It selectively acts on circulating platelets, blocking thrombus formation and inhibiting the release of platelet factors to exert its antiplatelet aggregation effect. Furthermore, it does not alter plasma parameters, does not impair platelet function, and restores abnormal platelet function to normal. Its structure is as follows: .

[0003] Chinese invention patent CN106397298B discloses three crystalline forms of indobufen, but the preparation processes for these three crystal forms are unstable and cannot be scaled up. Chinese patent CN11463440A reports crystal forms X and D of indobufen and their preparation methods. Chinese patent CN109651229A reports a preparation method for crystal form C. Some literature reports indicate that crystal form C reported by Jinan Kanghe Medical Patent and crystal forms D and X reported by Hangzhou Zhongmei Patent are the same crystal form as crystal form I reported by the earlier patent PL172906B1.

[0004] Different crystal forms of drugs are essentially different solid forms of the same substance, with different molecular arrangements (crystal structures). This directly leads to differences in their physicochemical properties, ultimately affecting the quality, safety, and efficacy of the drugs.

[0005] To meet the requirements for drug solubility in indobufen solid dosage forms, expand the range of raw material forms used in formulation development, and simultaneously satisfy the requirements of industrial production processes, this invention provides a product with good chemical stability and solubility, providing a better basis for the application of indobufen in drug therapy, thereby more efficiently leveraging the medicinal value of indobufen. Summary of the Invention

[0006] In view of the shortcomings of existing crystal forms, one object of the present invention is to provide an indobufen crystal form that is free of water and other crystallization solvents.

[0007] The specific technical content of this invention is as follows:

[0008] In a first aspect, the present invention provides an indobufen crystal form free of water and other crystallizing solvents.

[0009] Preferably, the indobufen crystal form is obtained by Cu-Kα radiation with a 2 θThe X-ray diffraction pattern shown has characteristic peaks at least at 5.04±0.2°, 10.18±0.2°, 18.78±0.2°, 19.87±0.2°, 23.31±0.2°, 23.99±0.2°, 25.70±0.2°, and 27.79±0.2°.

[0010] Preferably, the indobufen crystal form is obtained by Cu-Kα radiation with a 2 θ The X-ray diffraction pattern shown has characteristic peaks at least at 5.04±0.2°, 9.36±0.2°, 10.18±0.2°, 12.70±0.2°, 15.07±0.2°, 16.03±0.2°, 17.05±0.2°, 17.38±0.2°, 18.78±0.2°, 19.87±0.2°, 20.19±0.2°, 23.31±0.2°, 23.99±0.2°, 25.70±0.2°, 27.79±0.2°, 26.29±0.2°, and 28.53±0.2°.

[0011] Preferably, the indobufen crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks that conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] Preferably, the indobufen crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks that conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown in Table 1, and the XRD peaks are shown in Table 1.

[0013] Preferably, the indobufen crystal form has an endothermic peak at 182 °C in the differential scanning calorimetry (DSC) curve, and the crystal form exhibits the following characteristics: Figure 2 The DSC-TGA spectrum shown.

[0014] In a second aspect, a method for preparing indobufen crystal form is provided, characterized in that the specific preparation steps include: adding indobufen to a good solvent, heating and stirring to dissolve, and after the solution becomes clear, concentrating and drying under reduced pressure to obtain the crystal form.

[0015] Preferably, the benign solvent is a mixture of methanol, isopropanol, n-propanol, ethanol, tetrahydrofuran, and dichloromethane.

[0016] Preferably, the mass-to-volume ratio of indobufen to the benign solvent is 1:20-50, g / ml, and the volume ratio of dichloromethane to another solvent in the benign solvent is 1.0:0.8-2.0.

[0017] Preferably, the heating temperature is 30 °C to 60 °C.

[0018] Preferably, the drying method is vacuum drying, the drying temperature is 50℃, and the drying time is 6-8 hours.

[0019] In another aspect of the present invention, any of the indobufen crystal forms defined in the present invention is used as an active ingredient in the preparation of asthma-treating drugs.

[0020] In another aspect of the present invention, a pharmaceutical composition is characterized in that the composition contains any of the indobufen crystal forms described in the present invention and is mixed with other components.

[0021] Preferably, the pharmaceutical composition of the present invention is prepared as follows: using standard and conventional techniques, the compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with pharmaceutically acceptable excipients and formulations to prepare a usable dosage form.

[0022] Preferably, the other components include other active ingredients, excipients, fillers, etc., that can be used in combination.

[0023] Preferably, the pharmaceutical composition is a spray, tablet, capsule, powder for injection, liquid for injection, etc.

[0024] Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 1.

[0025] Table 1. Main XRD peaks of indobufen crystal form

[0026] All samples prepared in the examples had the same X-ray powder diffraction pattern.

[0027] The DSC-TGA test results of the indobufen crystal form prepared by the method of the present invention are as follows: Figure 2 As shown, the DSC detection results show an endothermic peak at 162.89℃ followed by an exothermic peak, indicating crystal transformation, and another endothermic peak at 181.86℃. The TGA detection results show the absence of a weight loss step, indicating that this indobufen crystal form does not contain water or other solvents. Combined with the DSC-TGA results, the crystal form prepared in this invention is the indobufen amorphous form.

[0028] Compared with the prior art, the method for preparing indobufen crystal form provided by the present invention is simple to operate, the prepared crystal form has high purity, and the indobufen crystal form provided by the present invention has good chemical stability and good solubility in both solid and solution states. Attached Figure Description

[0029] Figure 1X-ray powder diffraction pattern of indobufen crystal form.

[0030] Figure 2 DSC-TGA diagram of indobufen crystal form. Detailed Implementation

[0031] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0032] Example 1

[0033] 1 g of indobufen powder sample was added to 15 ml of ethanol and 15 ml of dichloromethane, heated to 40 °C and stirred to dissolve, and a clear solution was obtained. The solution was concentrated under reduced pressure and dried under vacuum, with a yield of 97.33% and a purity of 99.95%.

[0034] Example 2

[0035] 1 g of indobufen powder sample was added to 10 ml of methanol and 10 ml of dichloromethane, heated to 30°C and stirred to dissolve, resulting in a clear solution. The solution was concentrated under reduced pressure and dried under vacuum, with a yield of 94.3% and a purity of 99.66%.

[0036] Example 3

[0037] 1 g of indobufen powder sample was added to 20 ml of isopropanol and 30 ml of dichloromethane, heated to 60°C and stirred to dissolve, and a clear solution was obtained. The solution was concentrated under reduced pressure and dried under vacuum, with a yield of 96.2% and a purity of 99.58%.

[0038] Example 4

[0039] 1 g of indobufen powder sample was added to 9 ml of n-butanol and 7 ml of dichloromethane, heated to 25°C and stirred to dissolve, and a clear solution was obtained. The solution was concentrated under reduced pressure and dried under vacuum, with a yield of 89.6% and a purity of 98.96%.

[0040] Example 5

[0041] 1 g of indobufen powder sample was added to 45 ml of tetrahydrofuran and 20 ml of dichloromethane, heated to 55°C and stirred to dissolve, and a clear solution was obtained. The solution was concentrated under reduced pressure and dried under vacuum, with a yield of 90.2% and a purity of 98.21%.

[0042] Verification test

[0043] 1.1 Stability Test

[0044] The crystal form obtained in Example 1 was placed in an open environment for 10 days under high temperature test (60℃), high humidity test (25℃, relative humidity 90%±5%) and strong light irradiation test (illuminance 4500±500lx). The results are shown in Table 2 below.

[0045] Table 2 Results of the photostability test of indobufen crystal form

[0046] Experiments showed that the new indobufen crystal forms (Examples 1-5) prepared by this invention did not exhibit significant changes in purity or appearance under light, high temperature, and high humidity conditions, indicating that the crystal forms prepared by this invention have good chemical stability.

[0047] 1.2 Accelerated Stability Experiment

[0048] The new indobufen crystal form obtained in Example 1 was sealed in a polyethylene film plastic bag and placed in a constant temperature and humidity incubator at 40±2℃ and 75±5% relative humidity for six months. The results of the tests at the end of 1, 2, 3 and 6 months are shown in Table 3.

[0049] Table 3 Results of accelerated stability experiments

[0050] 2. In vitro dissolution test

[0051] 1. Experimental Materials: The indobufen crystal form obtained in the examples and crystal form A and crystal form B prepared by the method given in the prior art CN201610663448.0 were prepared into tablets using the same conventional wet granulation process in the art. In vitro dissolution was tested. The formulation is as follows:

[0052] Table 4 Indobufen Prescriptions

[0053] 2. Preparation method:

[0054] Step 1: Add indobufen, ground lactose, and magnesium dodecyl sulfate into the hopper of a mixer and mix at 10 rpm for 20 minutes. Then add it to a hammer mill and set the frequency to 30 Hz. Grind the mixture until D90 = 13.6 μm to obtain the co-pulverized material.

[0055] Step 2: Add the above co-pulverized material, microcrystalline cellulose, added carboxymethyl cellulose calcium, and spray-dried lactose into the hopper of a mixer and mix at 10 rpm for 20 minutes. Then, add it to a dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After granulation, use a 20-mesh sieve for dry granulation to obtain granules.

[0056] Step 3: Add calcium carboxymethyl cellulose to the above granules and mix at 10 prm for 20 min in a mixer. Then add magnesium stearate and continue mixing for 8 min. Compress the tablets using a high-speed tablet press to obtain indobufen tablets with a weight difference of ±5%, a core disintegration time of 3-8 min, and a hardness of 100-220 N.

[0057] 3. Dissolution conditions:

[0058] According to the standard provisions of the national drug standard for indobufen tablets (WS1-(X-072)-2006Z-2021) under the dissolution test item, the standard medium pH 7.6 phosphate buffer was selected, and the basket method was used with a rotation speed of 75 r / min. The dissolution curves of the tablets prepared according to the formulation and process in Table 5 for the new crystal forms prepared in Examples 1 to 5 above, and the tablets prepared according to crystal form A and crystal form B prepared according to the method given in the prior art CN201610663448.0 were investigated. The results are shown in Table 5. The sampling time points were 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min.

[0059] Table 5. Tablet dissolution rates using the API crystal form of each embodiment.

[0060] The novel crystal form of this application card exhibits excellent solubility and in vitro dissolution, providing a new option for the development of indobufen formulations.

[0061] In summary, the indobufen crystal form prepared by this invention has better solubility, stability, and dissolution rate, and is better suited for use in indobufen formulations.

Claims

1. A novel crystal form of indobufen, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in terms of angle, has characteristic diffraction peaks at 5.04±0.2°, 10.18±0.2°, 18.78±0.2°, 19.87±0.2°, 23.31±0.2°, 23.99±0.2°, 25.70±0.2°, and 27.79±0.2°.

2. The new crystal form of indobufen according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in angles, exhibits characteristic diffraction peaks at 5.04±0.2°, 9.36±0.2°, 10.18±0.2°, 12.70±0.2°, 15.07±0.2°, 16.03±0.2°, 17.05±0.2°, 17.38±0.2°, 18.78±0.2°, 19.87±0.2°, 20.19±0.2°, 23.31±0.2°, 23.99±0.2°, 25.70±0.2°, 27.79±0.2°, 26.29±0.2°, and 28.53±0.2°.

3. The new crystal form of indobufen according to claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

4. A method for preparing the indobufen crystal form according to any one of claims 1-3, characterized in that, The preparation method includes the following steps: adding indobufen to a mixed solvent, heating and stirring to dissolve, and after the solution becomes clear, concentrating and drying under reduced pressure to obtain the crystal form.

5. The preparation method according to claim 4, characterized in that, The mixed solvent is a mixture of one or more of methanol, isopropanol, n-propanol, ethanol, tetrahydrofuran, and dichloromethane.

6. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of indobufen to the benign solvent is 1:20-50, g / ml, and the volume ratio of dichloromethane to another solvent in the benign solvent is 1.0:0.8-2.

0.

7. The preparation method according to claim 4, characterized in that, The heating temperature is 30 °C to 60 °C.

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