CN115872918A - Indobufen crystal form E and preparation method thereof - Google Patents
Indobufen crystal form E and preparation method thereof Download PDFInfo
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- CN115872918A CN115872918A CN202111134156.5A CN202111134156A CN115872918A CN 115872918 A CN115872918 A CN 115872918A CN 202111134156 A CN202111134156 A CN 202111134156A CN 115872918 A CN115872918 A CN 115872918A
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- AYDXAULLCROVIT-UHFFFAOYSA-N indobufen Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1N1C(=O)C2=CC=CC=C2C1 AYDXAULLCROVIT-UHFFFAOYSA-N 0.000 title claims abstract description 46
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Abstract
The invention discloses an indobufen crystal form E, wherein the crystal form E is an anhydrate, faSSIF, feSSIF and FaSSGF are sequentially dissolved in three biological media from large to small, the crystal form E can stably exist in the three biological media, crystal transformation does not occur, the crystallinity is good, the thermal stability is good, the hygroscopicity is poor, a solvent is not used in the preparation process, and the indobufen crystal form E is green and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of drug crystal forms, and particularly relates to an indobufen crystal form E and a preparation method thereof.
Background
Thromboembolic diseases are systemic diseases affecting heart, brain and peripheral vessels, and are classified into arterial diseases and venous diseases, high-risk patients of the diseases comprise patients suffering from ischemic cerebrovascular diseases, patients suffering from atrial fibrillation, patients suffering from long-term braking, patients suffering from intermittent claudication and the like, the prevention is focused on treatment, and antiplatelet drugs are widely applied to the prevention of the thrombotic events.
Among various anti-platelet drugs, indobufen is an anti-thrombus drug which can effectively block platelet aggregation through reversible inhibition of cyclooxygenase, reduction of thromboxane A2 generation and other mechanisms, can selectively act on circulating platelets, can block thrombus formation, can inhibit platelet factor release to play an anti-platelet aggregation role, does not change plasma parameters, does not damage platelet functions, and can restore abnormal platelet functions to normal.
The 2008 American College of Chest Physicians (ACCP) guidelines suggest that indobufen is a potent inhibitor of platelet cyclooxygenase-1, cox-1, both biochemically and clinically, comparable to standard doses of aspirin. Compared with similar medicines, the indobufen inhibits platelet factor, has the platelet aggregation inhibiting effect 2-5 times that of salicylic acid, and has slightly shorter bleeding time than the similar medicines. Compared with ticlopidine, the oral clinical curative effect has no obvious difference, but indobufen shows good tolerance.
Chinese invention patent CN 10639298B discloses three crystalline forms of indobufen compounds, wherein the crystalline form a is prepared by two methods: a) After the indobufen and a solvent (selected from a mixed solution of ethanol/water, acetonitrile/water, 1, 4-dioxane/water, ethyl acetate and butanone in any proportion) are subjected to ultrasonic dissolution and cleaning, the indobufen and the solvent are volatilized at room temperature to 60 ℃; b) The indobufen and a solvent (any one of isopropanol, dimethyl sulfoxide and ethyl acetate) are subjected to ultrasonic dissolution and are dispersed in a water-air atmosphere at room temperature to 40 ℃ to obtain the indobufen-containing water-soluble chitosan. The infrared spectra of the crystalline forms have characteristic peaks at 2942, 1682, 1610, 1467, 1446, 1381, 1305, 1269, 1218, 1156, 959, 810, and 730cm-1, and the dynamic adsorption curves show that the samples have a weight change of about 0.06% rh to 80% rh.
The crystal form B is prepared by heating indobufen to 189 ℃ at 10 ℃/min through DSC, and then cooling to 20 ℃ at 10 ℃/min. The infrared spectra of this crystalline form have characteristic peaks at 2930, 1727, 1649, 1612, 1514, 1439, 1397, 1307, 1263, 1176, 929, 833 and 739cm-1 with dynamic adsorption curves showing that the samples were weight-changed by about 0.14% rh-80% rh.
The crystal form C is obtained by ultrasonic dissolution of indobufen and dichloromethane and rapid decompression and volatilization at 40 ℃, but the crystal form B is obtained when the scale is enlarged to 100mg, which indicates that the crystal form C and the preparation process thereof are unstable and cannot be prepared in an enlarged mode temporarily.
The existing reported crystal forms and the disclosed preparation methods are limited to the hundred milligram grade. In order to meet the requirement of indobufen solid preparation on drug solubility, expand the form of raw materials selected for preparation development and simultaneously meet the reproducibility and controllability of a crystallization process in an industrial production process, the field needs to develop a new indobufen crystal form and a corresponding preparation method suitable for industrial production.
Disclosure of Invention
In the existing reported crystal forms, the inventor of the present application repeats the preparation of the crystal forms a and B according to the method provided in examples 9, 10, 13 and 14 of patent CN 10639298B, and finds that the reproducibility of the crystal forms a and B is poor, corresponding crystal forms cannot be obtained when the specification is 200mg, and the solubility in three biological media has no obvious advantage. Therefore, the indobufen crystal form E provided by the invention has the advantages of stable structure, simple and convenient preparation method, convenience for amplification and improvement of crystal form solubility.
The invention provides an indobufen crystal form E, wherein a powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2 theta, a crystal face spacing d and relative intensity, and the 2 theta error is +/-0.2 degrees; the X-ray powder diffraction pattern has diffraction peaks at one or more positions with 2 theta angles of 6.346, 15.047, 22.976, 24.598 and 26.085.
Preferably, the characteristic diffraction angle 2 θ includes 6.346, 13.479, 14.824, 15.047, 17.125, 20.060, 22.045, 22.976, 24.598 and 26.085.
More preferably, said crystalline form E has an X-ray powder diffraction pattern substantially as shown in figure 1, having characteristic peaks and their relative intensities at the following diffraction angles 2 Θ:
as a further preference, the TGA profile is shown in figure 3: the crystal form E only has 0.2 +/-0.2 percent of weight loss at the temperature of between room temperature and 100 ℃, and is decomposed at about 250 ℃.
As a further preference, the DSC pattern is shown in figure 3: the crystal form E has obvious endothermic peaks at the peak values of 167 +/-2 ℃ and 182 +/-2 ℃, and the peak values of the endothermic peaks at 167 +/-2 ℃ and 182 +/-2 ℃ respectively. According to the thermal analysis result, the crystal form E is anhydrous.
As a further preference, the DVS profile is shown in fig. 4: form E gained 0.10% weight at 95% rh and 0.04% weight loss at 0% rh, indicating that form E has poor hygroscopicity and XRPD results show that the sample after DVS testing did not undergo crystal form change.
Further, the preparation method of the crystal form E comprises the following steps:
and (3) heating the indobufen to 110-150 ℃ in an amorphous manner, and cooling to obtain a crystal form E.
Further, preferably, the heating rate is 10-30 ℃/min; preferably, the temperature rise process is to rise to 130 ℃.
Further, preferably, the temperature reduction is natural temperature reduction.
Further, preferably, the preparation method of the indobufen amorphous form comprises methods such as spray drying, rotary evaporation, rapid precipitation, thermal crystal transformation and the like.
As a specific embodiment, the preparation method of the indobufen amorphous form comprises the following steps: heating indobufen to 200-240 ℃, and then cooling to-5-5 ℃ to obtain amorphous form.
Further, preferably, the heating rate is 10-30 ℃/min; preferably, the temperature is increased to 230 ℃,
further, preferably, in the cooling process, the cooling rate is 20-50 ℃/min, and the temperature is reduced to 0 ℃.
The invention also discloses a pharmaceutical composition, which comprises one or more pharmaceutically acceptable carriers and an effective amount of indobufen crystal form E.
Further, the indobufen crystal form E is used for preparing a medicine for preventing and/or treating an antiplatelet disease, wherein the disease is ischemic cardiovascular disease, ischemic cerebrovascular disease and venous thrombosis caused by arteriosclerosis or thrombosis prevention during hemodialysis.
Compared with the existing disclosed crystal forms, the crystal form disclosed by the invention has the following advantages:
1. by comparing with the disclosed indobufen crystal form by XRPD, the crystal form E in the invention is a new crystal form with high purity (shown in figure 2 NMR), low hygroscopicity, good crystallinity and regular crystal appearance.
2. The crystal form E can realize multi-batch bench test preparation, and shows that the crystallization process has good reproducibility, stability and controllability; and the crystallization process is solvent-free and environment-friendly.
3. The crystal form E is a blocky crystal form and has good fluidity.
4. Solubility test results show that the solubility of the crystal form E in three biological media is FaSSIF, feSSIF and FaSSGF in sequence from large to small, the crystal form E can stably exist in the three biological media and cannot generate crystal transformation, and the in vitro dissolution evaluation has great significance in the development process of a preparation formula.
5. Solubility test results show that the solubility of the crystal form E in three biological media is superior to that of the disclosed crystal form A/B/I, crystal form B can be subjected to crystal transformation in the test process, and crystal form A can be subjected to melting and crystal transformation at high temperature, so that the crystal form E is relatively stable in the currently disclosed crystal form in terms of crystal form stability, and the solubility of the crystal form E in the three biological media is relatively superior in the currently disclosed crystal form.
6. The crystal form E has good stability under the conditions of high temperature, high humidity and illumination, has no crystal transformation phenomenon within 15 days, and is convenient for long-term storage and transportation.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of form E;
figure 2 is a TGA profile and a DSC profile of form E;
FIG. 3 is a DVS plot of form E;
FIG. 4 is a powder X-ray diffraction pattern of form E before and after DVS testing;
FIG. 5 is a PLM diagram of form E;
FIG. 6 is a DSC of various stages in the preparation of form E of example 2;
figure 7 is a DSC diagram during different stages of the preparation of form B in example 4;
FIG. 8 is a powder X-ray diffraction pattern of form B of example 4;
FIG. 9 is a powder X-ray diffraction pattern of a stability study of form E from example 5;
FIG. 10 is a powder X-ray diffraction pattern of the solid remaining after shaking form E in medium for 24h in example 6.
Detailed Description
The invention will be further elucidated with reference to embodiments in the following, with reference to the drawing. The examples are provided for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art can make insubstantial modifications and adaptations to the embodiments described above without departing from the scope of the present invention.
Examples
Detection apparatus and method:
1. nuclear magnetic analysis of ( 1 H NMR)
Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d 6 Nuclear magnetic analyses were performed on Bruker AVANCE-III (Bruker, GER) in solvent.
2. X-ray powder diffraction (XRPD)
The solid samples obtained from the experiments were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2 theta scan angle was from 3 deg. to 45 deg., the scan step size was 0.02 deg., and the exposure time was 0.12 seconds. The light tube voltage and current were 40kV and 40mA, respectively, for the test samples, and the sample disks were zero background sample disks.
3. Thermogravimetric analysis (TGA)
The thermogravimetric analyzer is model number TA Discovery 55 (TA, US). 2-5mg of sample was placed in an equilibrated open aluminum sample pan and automatically weighed in a TGA oven. The sample was heated to the final temperature at a rate of 10 deg.C/min with a nitrogen purge rate of 60 mL/min at the sample and 40mL/min at the balance.
4. Differential Scanning Calorimetry (DSC)
The model of the differential scanning calorimetry analyzer is TA Discovery 2500 (TA, US). 1-2mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan and heated to the final temperature at a rate of 10 deg.C/min with a nitrogen purge rate in the furnace of 50mL/min.
5. Dynamic water desorption analysis (DVS)
Dynamic water sorption desorption analysis was determined using DVS Intrinsic (SMS, UK). The test adopts a gradient mode, the humidity change is 50% -95% -0% -50%, the humidity change amount of each gradient in the range of 0% to 90% is 10%, the gradient end point is judged in a dm/dt mode, and the gradient end point is determined by maintaining the dm/dt value to be less than 0.002% for 10 minutes. After the test was completed, XRPD analysis of the sample confirmed whether the solid morphology changed.
6. Polarizing microscope analysis (PLM)
The polarizing microscope was model Nikon Ci-POL (Nikon, japan). A small amount of samples are placed on a glass slide, and proper lenses are selected to observe the appearance of the samples.
7. High Performance Liquid Chromatography (HPLC)
The HPLC model is Waters Acquity Arc (Waters, US) and the test conditions are shown in Table 1.
TABLE 1 HPLC test conditions
Example 1
Weighing an indobufen sample (305.4 mg), placing the indobufen sample in a weighing bottle, heating the indobufen sample to 230 ℃ by using a forced air drying oven at a heating speed of 10 ℃/min, keeping the temperature until the sample is completely melted, quickly taking out the weighing bottle, placing the weighing bottle at 0 ℃ for 3min at a cooling speed of 50 ℃/min, placing the weighing bottle in a forced air drying oven at 100 ℃, heating the indobufen sample to 130 ℃, heating the indobufen sample at a heating speed of 10 ℃/min, keeping the temperature for 10 min, and naturally cooling the indobufen sample to room temperature to obtain a crystal form E which is a solid with good crystallinity, wherein a powder X-diffraction spectrum of the crystal form E is shown in a figure 1;
the TGA spectrum is shown in FIG. 2: form E has only 0.2% weight loss from room temperature to 100 ℃, and may decompose above 250 ℃.
The DSC spectrum is shown in figure 2: form E exhibited a melting endotherm at 167 ℃, followed by an exotherm signal corresponding to recrystallization at 171 ℃, followed by a melting endotherm at 182 ℃ for the recrystallized solid, and according to thermal analysis results, form E was anhydrous.
The DVS spectra are shown in FIG. 3: form E gained 0.10% weight at 95% rh and 0.04% weight loss at 0% rh, indicating that form E has poor hygroscopicity; XRPD results showed no crystal transformation during the test (see figure 4 of the accompanying drawings).
PLM is shown in FIG. 5: the PLM image shows that the crystal form E is a blocky crystal, and the size of the blocky crystal is generally less than 10 mu m.
Example 2
Weighing an indobufen sample (85.6 mg), placing the indobufen sample in a weighing bottle, heating to 200 ℃ by DSC, raising the temperature at a speed of 10 ℃/min, keeping the temperature until the sample is completely melted, then reducing the temperature to 0 ℃, lowering the temperature at a speed of 50 ℃/min, raising the temperature to 125 ℃, raising the temperature at a speed of 10 ℃/min, keeping the temperature for 10 min, and naturally cooling to room temperature to obtain the crystal form E.
Heating-cooling (50 ℃/min) -heating-again processing the crystal form E by using a DSC analyzer (see attached figure 6), wherein no obvious heat flow signal exists in the process of cooling to 0 ℃ at 50 ℃/min; when the temperature is raised to 125 ℃, the glass transition is carried out at about 44 ℃, and a recrystallization exothermic peak is formed at about 100 ℃.
Example 3
Weighing an indobufen sample (95.3 mg), placing the indobufen sample in a weighing bottle, heating to 200 ℃ by using a hot table, raising the temperature at a speed of 10 ℃/min, keeping the temperature until the sample is completely melted, then reducing the temperature to 0 ℃, lowering the temperature at a speed of 50 ℃/min, raising the temperature to 125 ℃, raising the temperature at a speed of 10 ℃/min, keeping the temperature for 10 min, and naturally cooling to room temperature to obtain the crystal form E.
Example 4 comparative example
Weighing an indobufen sample (77.3 mg), placing the indobufen sample in a weighing bottle, heating to 200 ℃ by using a hot table at a heating speed of 10 ℃/min, keeping the temperature until the sample is completely melted, then cooling to 0 ℃, cooling to 10 ℃/min, heating to 115 ℃, heating to 10 ℃/min at a heating speed of 10 ℃/min, keeping the temperature for 10 min, and naturally cooling to room temperature to obtain a diffraction peak of which the solid is mostly crystal form B and contains a few other crystal forms.
Example 5 stability experiment
About 10mg of the sample was weighed into a weighing bottle, and placed under high temperature (60 ℃), high humidity (25 ℃/92.5% RH), illumination (25 ℃/4500 Lux), acceleration (40 ℃/75% RH), and XRPD characterization was performed by sampling for 7 days and 15 days. The results are shown in Table 2. The XRPD results show (see figure 9) that Form E is stable under high temperature, high humidity, light and acceleration conditions for 15 days without crystal transformation.
TABLE 2Form E stability study results
Example 6 solubility testing
The dynamic solubility of the crystal form E is determined in three biological solvent media (FaSSIF, feSSIF and FaSSGF), faSSIF (fast State complexed Intestinal Fluid simulating Intestinal Fluid in the small intestine in the hungry State before eating human), feSSIF (Fed State complexed Intestinal Fluid simulating Intestinal Fluid in the small intestine in the hungry State after eating human), faSSGF (fast State complexed Gastric Fluid simulating Gastric juice in the empty stomach State under hungry State) by adding about 30mg of sample into 4.0 mL of biological medium, shaking at constant temperature of 37 ℃ for 24h, sampling at 0.5h, 2h and 24h respectively, filtering the sampled solution with a 0.22 mu m water system filter membrane, properly diluting the sample with a diluent, measuring the signal of the solution by HPLC, and finally calculating the peak area of the compound in the solution according to the HPLC standard curve and the fold of the concentration of the compound. In addition, the supernatant was taken for 24h to test its pH and the remaining solids were subjected to XRPD testing, with the results shown in table 3.
The result shows that the 24h solubility of Form E in the biological medium is FaSSIF > FeSSIF > FaSSGF from large to small, and all the rest solid has no crystal Form transformation (see attached figure 10). Meanwhile, compared with the disclosed crystal form, the 24h solubility of the crystal form E in a three-medium biological medium has obvious advantages.
TABLE 3 dynamic solubility test in biological media
The process of configuring the biological media is shown in table 4.
TABLE 4 Process for the deployment of biological media
Claims (14)
1. An indobufen crystalline form E characterized by: the powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2 theta, a crystal face spacing d and relative intensity, and the error of the 2 theta is +/-0.2 degrees; the X-ray powder diffraction pattern has diffraction peaks at one or more positions with 2 theta angles of 6.346, 15.047, 22.976, 24.598 and 26.085.
2. Indobufen crystalline form E according to claim 1, characterized in that: the powder X-ray diffraction pattern of the crystal form E has a characteristic diffraction angle 2 theta, a crystal face spacing d and relative intensity, and the error of the 2 theta is +/-0.2 degree; the characteristic diffraction angle 2 theta comprises 6.346, 13.479, 14.824, 15.047, 17.125, 20.060, 22.045, 22.976, 24.598 and 26.085.
3. Form E according to claim 1, characterized in that: which has an XRPD pattern substantially the same as that shown in figure 1 of the drawings.
4. A process for the preparation of form E according to any one of claims 1 to 3, characterized in that: the method comprises the following steps:
and (3) heating the indobufen to 110-150 ℃ in an amorphous manner, and cooling to obtain a crystal form E.
5. The method of claim 4, wherein: the heating rate is 10-30 ℃/min; preferably, the temperature rise process is to rise to 130 ℃.
6. The method of claim 4, wherein: the temperature reduction is natural temperature reduction.
7. The method of claim 4, wherein: the preparation method of the indobufen amorphous form comprises the following steps:
heating indobufen to 200-240 ℃, and then cooling to-5-5 ℃ to obtain amorphous form.
8. The method of claim 6, wherein: the heating rate is 10-30 ℃/min; preferably, the temperature is raised to 230 ℃.
9. The method of claim 6, wherein: in the cooling process, the cooling rate is 20-50 ℃/min and the temperature is reduced to 0 ℃.
10. Form E according to any one of claims 1 to 3, characterized in that: the crystal form E has the weight loss of 0.2 +/-0.2 percent at the temperature of between room temperature and 100 ℃, and starts to decompose at about 250 ℃.
11. Form E according to any one of claims 1 to 3, characterized in that: the DSC spectrum of the crystal form E has obvious endothermic peaks at the peak values of 167 plus or minus 2 ℃ and 182 plus or minus 2 ℃.
12. Form E according to any one of claims 1 to 3, characterized in that: the crystalline form E has a DSC-TGA profile substantially in accordance with figure 3.
13. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and an effective amount of indobufen crystalline form E as claimed in any one of claims 1 to 3.
14. Use of indobufen crystal form E according to any one of claims 1 to 3 in the preparation of a medicament for preventing and/or treating an antiplatelet disease, wherein the disease is ischemic cardiovascular disease caused by arteriosclerosis, ischemic cerebrovascular disease, venous thrombosis or thrombosis prevention in hemodialysis.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH650252A5 (en) * | 1981-10-08 | 1985-07-15 | Lisapharma Spa | Indoprofen derivative, process for its preparation and therapeutic compositions containing it as active principle |
| JPH11199482A (en) * | 1998-01-07 | 1999-07-27 | Taisho Pharmaceut Co Ltd | Preparation composition for external use |
| KR20110005974A (en) * | 2009-07-13 | 2011-01-20 | 일동제약주식회사 | A sustained release preparation of indobufen and stereo isomer and isolating method of stereo isomer thereof |
| CN106397298A (en) * | 2016-08-11 | 2017-02-15 | 杭州中美华东制药有限公司 | A pharmaceutical composition containing indobufen and uses thereof |
| CN109651229A (en) * | 2018-12-05 | 2019-04-19 | 济南康和医药科技有限公司 | A kind of preparation method of Indobufen crystal form |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH650252A5 (en) * | 1981-10-08 | 1985-07-15 | Lisapharma Spa | Indoprofen derivative, process for its preparation and therapeutic compositions containing it as active principle |
| JPH11199482A (en) * | 1998-01-07 | 1999-07-27 | Taisho Pharmaceut Co Ltd | Preparation composition for external use |
| KR20110005974A (en) * | 2009-07-13 | 2011-01-20 | 일동제약주식회사 | A sustained release preparation of indobufen and stereo isomer and isolating method of stereo isomer thereof |
| CN106397298A (en) * | 2016-08-11 | 2017-02-15 | 杭州中美华东制药有限公司 | A pharmaceutical composition containing indobufen and uses thereof |
| CN109651229A (en) * | 2018-12-05 | 2019-04-19 | 济南康和医药科技有限公司 | A kind of preparation method of Indobufen crystal form |
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