CN112625047B - Crystal form of fangchinoline-7-propionate and preparation method thereof - Google Patents
Crystal form of fangchinoline-7-propionate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a fangchinoline-7-propionate crystal form I, which uses Cu-Ka radiation, and has characteristic peaks at 9.96, 12.42, 13.72, 14.18, 19.61, 20.06 and 25.02 +/-0.2 in X-ray powder diffraction represented by a 2 theta angle. The crystal form has the advantages of high stability, high bioavailability and easy preparation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a new crystal form of fangchinoline-7-propionate and a preparation method thereof.
Background
The dibenzylisoquinoline alkaloid Tetrandrine (see the structural formula below) is the main active ingredient of the root of Tetrandrine of Menispermaceae. A great deal of research reports that the tetrandrine and the 5-bromo-derivative thereof can reverse Pgp overexpression and apoptosis deficiency mediated tumor multidrug resistance in vivo and in vitro and increase the sensitivity of chemotherapeutic drugs (Jin, J, etc., Cancer Chemother Pharmacol,2005.55(2): 179-88; Liu XD, etc., Cancer Lett,2010, 292(1): 24-31.). The 7-position of tetrandrine is transformed and modified thickly to obtain fangchinoline-7-propionate (compound with the formula W6) (see chemical structural formula below), which has high-efficiency multidrug resistance reversal activity and chemotherapy sensitization activity in vitro research (Sun H et al, J Asian Nat Res,2015,17(6): 638-48.).
Patent CN1293196 discloses a synthesis method of compound W6, and an amorphous sample is obtained, but the crystal form of the compound is not referred to, and no other literature reports exist. The crystal form of the medicine has important significance and influence on the physicochemical property, the stability, the quality and the process of the preparation, especially on the bioavailability of the medicine. Generally, the same drug has better stability in a crystalline form than in an amorphous form, is convenient for long-term stable storage and prolongs the quality guarantee period of the drug, and the crystalline form also has better particle fluidity. In the production process of the preparation, the better fluidity can reduce the difference of tablet weight of tablets or the difference of the loading amount of capsules, and better ensure the medication safety. Therefore, it is necessary to study the crystal form of W6.
Disclosure of Invention
The invention aims to provide a new crystal form of fangchinoline-7-propionate.
Another object of the present invention is to provide a method for preparing a novel crystalline form.
The novel crystalline forms of fangchinoline-7-propionate of the present invention may be referred to herein as "fangchinoline-7-propionate form I" or "fangchinoline-7-propionate form I".
In one embodiment, the fangchinoline-7-propionate crystal form I has characteristic peaks at 9.96 ± 0.2, 12.42 ± 0.2, 13.72 ± 0.2, 14.18 ± 0.2, 19.61 ± 0.2, 20.06 ± 0.2 and 25.02 ± 0.2 of the 2 θ angle of X-ray powder diffraction.
In a preferred embodiment, the fangchinoline-7-propionate I crystal form of the invention has characteristic peaks in X-ray powder diffraction at 9.96 +/-0.2, 12.42 +/-0.2, 13.72 +/-0.2, 14.18 +/-0.2, 18.82 +/-0.2, 19.40 +/-0.2, 19.61 +/-0.2, 20.06 +/-0.2, 23.82 +/-0.2, 25.02 +/-0.2, 25.58 +/-0.2, 27.00 +/-0.2 and 30.51 +/-0.2.
In a more preferred embodiment, the fangchinoline-7-propionic acid ester of the invention has crystal form I, and the X-ray powder diffraction of the crystal form I has characteristic peaks as shown in figure 1.
In another embodiment, the preparation method of fangchinoline-7-propionate crystal form I comprises the steps of dissolving fangchinoline-7-propionate in a polar solvent, adding an ester solvent, heating and stirring until boiling, and cooling for crystallization to obtain crystal form I. Wherein the mass (g)/volume (ml) ratio of the fangchinoline-7-propionate to the polar solvent is 1 (10-30), preferably 1 (15-20); the volume ratio of the polar solvent to the ester solvent is (2-8): 1, preferably (3-6) 1; the drying temperature is 30-50 ℃, and the drying time is 4-8 h.
In another embodiment of the above, the method for preparing fangchinoline-7-propionate as crystal form I of the present invention comprises the steps of extracting fangchinoline-7-propionate as a polar solvent, wherein the polar solvent is selected from one or more of methanol, ethanol, acetone, N-propanol, isopropanol, tert-butanol and N, N-dimethylformamide, preferably from one or more of methanol, ethanol and N-propanol, and most preferably from methanol or ethanol; the ester solvent is selected from one or more of ethyl formate, ethyl acetate and propyl acetate, and preferably, ethyl acetate.
In a specific embodiment, the preparation method of the fangchinoline-7-propionate crystal form I comprises the steps of dissolving fangchinoline-7-propionate in a polar solvent, heating to 25-35 ℃, adding an ester solvent, heating and stirring to boil, cooling to 0-20 ℃ for crystallization, filtering, and drying a filter cake to obtain the fangchinoline-7-propionate crystal form I, wherein the mass/volume ratio of fangchinoline-7-propionate to the polar solvent is 1 (10-30), and preferably 1 (15-20); the volume ratio of the polar solvent to the ester solvent is (2-8): 1, preferably (3-6):1, wherein the polar solvent is selected from one or more of methanol, ethanol, acetone, N-propanol, isopropanol, tert-butanol and N, N-dimethylformamide, preferably, is selected from one or more of methanol, ethanol and N-propanol, and most preferably, is methanol or ethanol; the ester solvent is selected from one or more of ethyl formate, ethyl acetate and propyl acetate, and preferably, ethyl acetate; the drying temperature is 30-50 ℃, and the drying time is 4-8 h.
The invention also provides application of the crystal form I of fangchinoline-7-propionate in preparation of a tumor treatment drug.
The invention also provides a pharmaceutical composition, which comprises the fangchinoline-7-propionate crystal form I and a pharmaceutical adjuvant.
In embodiments, fangchinoline-7-propionate of the present invention has crystalline form I with characteristic peaks at 9.96(8.87), 12.42(7.12), 13.72(6.44), 14.18(6.24), 19.61(4.52), 20.06(4.42), 25.02(3.55) ± 0.2 by X-ray powder diffraction at 2 θ angle and interplanar spacing (d) using Cu-Ka radiation.
In embodiments, the fangchinoline-7-propionate of the present invention has a characteristic peak at 9.96(8.87), 12.42(7.12), 13.72(6.44), 14.18(6.24), 18.821(4.68), 19.40(4.57), 19.61(4.52), 20.06(4.42), 23.82(3.73), 25.02(3.55), 25.58(3.47), 27.00(3.29), 30.51(2.92) ± 0.2 by X-ray powder diffraction expressed in terms of 2 θ angle and interplanar spacing (d) using Cu-Ka radiation, as shown in fig. 1.
In a preferred embodiment, the method for preparing fangchinoline-7-propionate I crystal form comprises the following steps: dissolving fangchinoline-7-propionate in a polar solvent, heating to 25-35 ℃, then adding an ester solvent, heating and stirring to boil, cooling to 0-20 ℃ for crystallization, filtering, and drying a filter cake to obtain a fangchinoline-7-propionate I crystal form, wherein the mass/volume ratio of fangchinoline-7-propionate to the polar solvent is 1 (15-20), the volume ratio of the polar solvent to the ester solvent is (3-6) to 1, the polar solvent is selected from methanol, ethanol and n-propanol, and the ester solvent is ethyl formate or ethyl acetate; the drying temperature is 30-50 ℃, and the drying time is 4-8 h.
In a more preferred embodiment, the process for preparing fangchinoline-7-propanoate form I of the present invention comprises: amorphous fangchinoline-7-propionate is dissolved in a polar solvent (1, 15-20) (mass (g)/volume (ml)), the temperature is heated to 25-35 ℃, then an ester solvent is added, the mixture is heated and stirred to boil, the mixture is cooled to 0-20 ℃ for crystallization, the filtration is carried out, a filter cake is dried for 4-8 hours at the temperature of 30-50 ℃, and the I crystal form of fangchinoline-7-propionate is obtained, wherein the volume ratio of the polar solvent to ethyl acetate is 3-6:1, the polar solvent is selected from methanol and ethanol, and the ester solvent is ethyl acetate.
The invention also provides a pharmaceutical composition, which comprises the fangchinoline-7-propionate I crystal form and pharmaceutic adjuvant. The pharmaceutical composition is tablets, capsules, granules, injection and the like, and the pharmaceutic adjuvant is selected from conventional pharmaceutic adjuvants in the field, such as lactose, microcrystalline cellulose, crospovidone, low-substituted hypromellose, magnesium stearate, talcum powder and the like. The dosage forms may be prepared using excipients and manufacturing techniques well known in the art.
The invention provides application of fangchinoline-7-propionate crystal form I in preparing medicines for treating tumors, tumor resistance and tumor sensitization.
The crystal form I of the fangchinoline-7-propionate has the advantages of higher stability, high bioavailability and suitability for preparation manufacture.
Drawings
Figure 1, X-ray powder diffraction pattern of the crystal form I of fangchinoline-7-propionate obtained in example 1.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
Weighing amorphous fangchinoline-7-propionate (obtained according to patent CN1293196, the same below) 500mg in a round-bottom flask, adding 10ml of methanol, stirring and heating to 30 ℃, adding 2ml of ethyl acetate, heating to reflux, cooling to 10-15 ℃, separating out crystals, filtering, and drying the obtained filter cake at 40 ℃ for 4h to obtain the fangchinoline-7-propionate I crystal form 482mg, wherein the yield is 96.4%, and the purity is 99.80%. At room temperature, 50mg of crystal form I sample is taken to be subjected to X-ray powder diffraction (RINT 2100Ultima X-ray diffractometer, Cu target, graphite crystal monochromator filter, working voltage: 40kV, current: 150mA, receiving slit: 0.3nm, 2 theta angle of 3-50 degrees and step length: 0.02 degree) test, and the XRPD of the obtained crystal form I is shown in figure 1.
Example 2
Weighing 500mg of fangchinoline-7-propionate amorphous form into a round-bottom flask, adding 10ml of methanol, stirring and heating to 30 ℃, adding 2.5ml of ethyl formate, heating to reflux, cooling to 15-20 ℃, separating out crystals, filtering, drying the obtained filter cake at 35 ℃ for 5h, and obtaining fangchinoline-7-propionate I crystal form 476mg, wherein the yield is 95.2%, and the purity is 99.65%.
Example 3
Weighing 500mg of fangchinoline-7-propionate amorphous form in a round-bottom flask, adding 9.0ml of ethanol, stirring and heating to 30 ℃, adding 2ml of ethyl acetate, heating to reflux, cooling to 10-15 ℃, separating out crystals, filtering, and drying the obtained filter cake for 5 hours at 40 ℃ to obtain 486mg of fangchinoline-7-propionate I crystal form, wherein the yield is 97.2%, and the purity is 99.86%.
Example 4
Weighing 500mg of fangchinoline-7-propionate amorphous product into a round-bottom flask, adding 10ml of isopropanol, stirring and heating to 30 ℃, adding 2ml of ethyl acetate, heating to reflux, cooling to 10-15 ℃, precipitating crystals, filtering, and drying the obtained filter cake at 40 ℃ for 5 hours to obtain 470mg of fangchinoline-7-propionate I crystal form, wherein the yield is 94.0%, and the purity is 99.05%.
Example 5
Weighing 600mg of fangchinoline-7-propionate amorphous form in a round-bottom flask, adding 10ml of methanol, stirring and heating to 30 ℃, adding 3ml of ethyl acetate, heating to reflux, cooling to 10-15 ℃, precipitating crystals, filtering, and drying the obtained filter cake at 40 ℃ for 4 hours to obtain the fangchinoline-7-propionate I crystal form of 572mg, wherein the yield is 95.3%, and the purity is 99.75%.
Example 6
Weighing 300mg of fangchinoline-7-propionate amorphous product into a round-bottom flask, adding 4.5ml of ethanol, stirring and heating to 30 ℃, adding 1.5ml of ethyl formate, heating to reflux, cooling to 10-15 ℃, precipitating crystals, filtering, and drying the obtained filter cake at 40 ℃ for 4 hours to obtain 280mg of fangchinoline-7-propionate I crystal form, wherein the yield is 93.3%, and the purity is 99.70%.
Form I obtained from examples 2-6 was tested for XDPD using the test method of example 1 and the results showed that the characteristic XRPD peaks for each form I were substantially the same within the error range as the characteristic XRPD peaks for form I of example 1. Indicating that the crystalline forms obtained in examples 1-6 are all the same form I.
Example 7
Stability study of fangchinoline-7-propionate (W6) form i:
taking W6 amorphous and I crystal as samples, respectively placing in a constant temperature and humidity box at 40 deg.C and humidity of 75% for accelerated experiment, respectively measuring content after 0, 1, and 3 months, and calculating total impurity growth (impurity amount)3/1 monthAmount of impurities0 month) The results are shown in the table 1, the total impurity growth of the W6 crystal form I is obviously less than that of the W6 amorphous sample (P is less than 0.05, P is less than 0.01) in 1 month and 3 months, and crystal transformation and moisture absorption phenomena are not seen, which indicates that the W6 crystal form I has better stability.
Table 1 results of stability studies of form i of W6
Note: compared with the total impurity increment of amorphous 1 month,*p is less than 0.05, compared with the total impurity increment of amorphous 3 months,#P＜0.05,##P＜0.01。
example 8
Oral bioavailability pharmacokinetic study of fangchinoline-7-propionate (W6) form i:
18 SD male rats are randomly divided into 3 groups, 6 rats are not eaten for 12 hours, 100m g kg is adopted, W6 solution is injected into the tail vein of the first group, W6 amorphous sample is orally administered (intragastrically) in the second group, W6 crystal form I sample is orally administered (intragastrically) in the third group, blood is taken from the inner canthus at the time points of 5min, 10min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h and 24h after administration, the blood is placed in a heparinized centrifugal plastic tube for testing, the supernatant is centrifugally taken for 150 mu L, the blood concentration of the rats at different times is detected by a reversed phase high performance liquid chromatography (RP-HPLC) method, and the measured blood concentration data pharmacokinetic parameters (Mean +/-SD) are calculated by using a non-atrioventricular model by using pharmacokinetic processing analysis software (DAS 3.0.7), and the results are shown in Table 2.
TABLE 2 SD rats administered form I W6 and the pharmacokinetic parameters of amorphous form
The results in table 2 above show that the oral bioavailability of the sample of form i is 59.5% (F ═ AUC)po./AUCiv.X 100%), the amorphous bioavailability is 37.2%, the oral bioavailability of the sample of the crystal form I is obviously higher than that of the amorphous form (P is less than 0.05), and the results show that the crystal form I of the W6 has better oral bioavailability and stability and can be usedSuitable pharmaceutical preparations include tablets, capsules, orally disintegrating tablets, dispersible tablets and the like during manufacture and storage of the preparation.
Claims (8)
1. A fangchinoline-7-propionate crystal form I has X-ray powder diffraction pattern shown in figure 1.
2. A method for preparing fangchinoline-7-propionate crystal form I as claimed in claim 1, comprising dissolving fangchinoline-7-propionate in polar solvent, heating to 25-35 deg.C, adding ester solvent, heating and stirring to boil, cooling to 0-20 deg.C for crystallization, filtering, and drying filter cake at 30-50 deg.C for 4-8 hr to obtain fangchinoline-7-propionate crystal form I.
3. The method according to claim 2, wherein the polar solvent is selected from one or more of methanol, ethanol and isopropanol.
4. The method according to claim 2, wherein the ester solvent is one or more selected from the group consisting of ethyl formate and ethyl acetate.
5. The preparation method of claim 2, wherein the mass/volume ratio of fangchinoline-7-propionate to polar solvent is 1 (10-30), the mass unit is g, and the volume unit is ml.
6. The preparation method according to claim 2, wherein the volume ratio of the polar solvent to the ester solvent is (2-8): 1.
7. use of the crystalline form I of fangchinoline-7-propionate according to claim 1 for the preparation of a medicament for the treatment of tumors or tumor sensitization.
8. A pharmaceutical composition comprising the crystalline form I of fangchinoline-7-propionate of claim 1 and a pharmaceutically acceptable adjuvant.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293196A (en) * | 2000-09-08 | 2001-05-02 | 华西医科大学药物研究所 | Dibenzylisoquinoline alkaloids and its preparing process and medicinal composition |
| US6617335B1 (en) * | 2002-05-02 | 2003-09-09 | Kanghong Usa, Inc. | Preparation and drug composition of bis-benzyl-isoquinoline class alkaloids |
| CN103923092A (en) * | 2014-03-26 | 2014-07-16 | 山东师范大学 | Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine |
| CN109908145A (en) * | 2019-04-28 | 2019-06-21 | 重庆医药高等专科学校 | The pharmaceutical composition of the root of fangji Nuo Lin -7- propionic ester and tyrosine kinase inhibitor |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293196A (en) * | 2000-09-08 | 2001-05-02 | 华西医科大学药物研究所 | Dibenzylisoquinoline alkaloids and its preparing process and medicinal composition |
| US6617335B1 (en) * | 2002-05-02 | 2003-09-09 | Kanghong Usa, Inc. | Preparation and drug composition of bis-benzyl-isoquinoline class alkaloids |
| CN103923092A (en) * | 2014-03-26 | 2014-07-16 | 山东师范大学 | Tetrandrine derivatives and preparation method and application thereof in preparation of antitumor medicine |
| CN109908145A (en) * | 2019-04-28 | 2019-06-21 | 重庆医药高等专科学校 | The pharmaceutical composition of the root of fangji Nuo Lin -7- propionic ester and tyrosine kinase inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| Partial synthesis and biological evaluation of bisbenzylisoquinoline alkaloids derivatives. Potential modulators of multidrug resistance in cancer;Ping He等;《Journal of Asian Natural Products Research》;20120515;第564-576页 * |
| Reversal of P-Glycoprotein-Dependent Resistance to Vinblastine by Newly Synthesized Bisbenzylisoquinoline Alkaloids in Mouse Leukemia P388 Cells;Feng-Peng WANG等;《Biol. Pharm. Bull.》;20051230;第1979-1982页 * |
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