CN102212014B - Crystal form of O-demethyl-venlafaxine glutamate, preparation method and medicinal application thereof - Google Patents
Crystal form of O-demethyl-venlafaxine glutamate, preparation method and medicinal application thereof Download PDFInfo
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- CN102212014B CN102212014B CN2010101475349A CN201010147534A CN102212014B CN 102212014 B CN102212014 B CN 102212014B CN 2010101475349 A CN2010101475349 A CN 2010101475349A CN 201010147534 A CN201010147534 A CN 201010147534A CN 102212014 B CN102212014 B CN 102212014B
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- Prior art keywords
- venlafaxine
- demethyl
- crystal formation
- glutaminate
- preparation
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- 229960004688 venlafaxine Drugs 0.000 title claims abstract description 22
- 239000013078 crystal Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 title abstract description 4
- 229930195712 glutamate Natural products 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 claims abstract 2
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 2
- 238000010009 beating Methods 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 8
- 150000003839 salts Chemical class 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- 239000002250 absorbent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229920001684 low density polyethylene Polymers 0.000 description 2
- 239000004702 low-density polyethylene Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical group C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a crystal form of O-demethyl-venlafaxine glutamate, a preparation method and medicinal application thereof, in particular to application in preparation of an anti-depression medicament. The invention also relates to a medicinal composition containing therapeutically effective amount of crystal form and application thereof in preparation of an anti-depression medicament.
Description
Technical field
The present invention relates to the O-demethyl-crystal formation of Venlafaxine glutaminate, its preparation method, and the pharmaceutical composition that contains this crystal formation for the treatment of significant quantity, and the purposes in preparing antidepressant drug.
Background technology
O-demethyl-Venlafaxine is the major metabolite of Venlafaxine, is serotonin and NRI, is used for the treatment of various dysthymia disorders, and its chemical name is 4-[2-dimethylamino-1-(1-hydroxy-cyclohexyl) ethyl] phenol.U.S. Patent No. 4,535,186 have enumerated its fumarate; U.S. Patent No. 2004044241 discloses its succinate; U.S. Patent No. 2003236309 discloses its formate.
Suitable salt can be on the basis that does not change basic chemical structure by the physico-chemical property that changes medicine and then affect its appropriateness as medicine.The formation of salt provides the means that change physical and chemical properties of drugs and biological characteristics and do not change its chemical structure.Salt form can produce on the character of medicine violent impact.The selection part of suitable salt is by the decision of yield, speed and the output of crystalline texture.In addition, the water-absorbent of salt form, stability, solvability and processing characteristics are important aspects.The evaluation of salt form with proper combination of many-sided character may be difficult.
Solvability is a key property of salt form, and it may affect its appropriateness as medicine.When water-soluble low, while being less than 10mg/ml, decomposition rate during vivo medicine-feeding may limit the speed of absorption process, causes bioavailability poor.Water-absorbent is also an important characteristic.The compound that water-absorbent is low more stable and be easy to processing.
Summary of the invention
The object of the present invention is to provide the crystal formation of O-demethyl-Venlafaxine glutaminate, the characteristic peak of the excellent X-ray powder diffraction figure of this crystal formation means to be positioned at 10.160 with 2 θ (± 0.2 ° of 2 θ), 12.980,16.120,21.980,26.060,30.920,33.600,35.520,40.400, with 43.940, more preferably there is the crystalline structure shown in accompanying drawing 1.
The object of the present invention is to provide and using the crystal formation of described O-demethyl-Venlafaxine glutaminate as the pharmaceutical composition of activeconstituents and pharmaceutically acceptable carrier.
The present invention also aims to provide the method for the crystal formation for preparing described O-demethyl-Venlafaxine glutaminate, the method comprises the following steps:
(1) stoichiometric L-glutamic acid is contacted with O-demethyl-Venlafaxine free alkali, wherein said contact is carried out in ethanol, acetone, water.；
(2) process to obtain product with organic solvent, wherein said organic solvent is toluene.
Further, the invention provides crystal formation or the purposes of described pharmaceutical composition in preparing antidepressant drug of described O-demethyl-Venlafaxine glutaminate.
The crystal formation of O-demethyl provided by the invention-Venlafaxine glutaminate has the suitable character be particularly suitable for as medicine, comprises and is difficult for water suction to facilitate preparation, good solubility, stability, perviousness and bioavailability.
The accompanying drawing explanation
The X-ray powder diffraction pattern that Fig. 1 is embodiment 1 product.
Embodiment
Can prepare by the following examples by the crystal formation of O-demethyl-Venlafaxine glutaminate, but be not limited to following method.
Embodiment 1
By desmethylvenlafaxine (20.2g, 76.7mmol), Pidolidone (10.1g, 69.0mmol, 0.9 times of amount), ethanol 200ml, deionized water 125ml adds, be heated to 85 ℃, stir until solid all dissolves 80 ℃ of pressure reducing and steaming solvents, obtain oily matter, add toluene 300ml, be warmed up to 135 ℃, normal pressure steams except 150ml toluene (now having a large amount of solid products to generate).Be cooled to normal temperature, stir 2 hours, filter, with ethyl acetate (150ml * 2) making beating washing, drain, 70 ℃ of vacuum-drying 6 hours, obtain O-demethyl-Venlafaxine-Pidolidone salt 26.5g.
1HNMR(400MHz，DMSO-d
6)：δ＝9.2～8.8(bs，2H)，7.00～6.97(d，2H)，6.67～6.64(d，2H)，3.27～3.24(t，1H)，3.05～2.99(dd，1H)，2.75～2.71(t，2H)，2.43～2.33(m，2H)，2.17(s，6H)，1.6～0.8(m，12H)。
Through X-ray diffraction test, its crystalline structure has and is positioned at 10.160,12.980, and the characteristic peak at 16.120,21.980,26.060,30.920,33.600,35.520,40.400 and 43.940 degree 2 θ angles, refer to accompanying drawing 1.
Test example
Crystal formation to O-demethyl of the present invention-Venlafaxine glutaminate carries out solvability, Stability Determination, contrasts O-demethyl-Venlafaxine succinate (according to the CN1501909 preparation) simultaneously and detects relevant nature.
1, solubleness
Press two note on the use tests of Chinese Pharmacopoeia version in 2005.
Take the trial-product that is ground into fine powder, be placed in the solvent of 25 ℃ ± 2 ℃ of certain capacities, every 5 minutes, powerful jolting was 30 seconds; Observe the dissolving situation in 30 minutes, as while cannot see particles of solute, be considered as dissolving fully.The results are shown in following table 1.
Table 1: solvability detected result
| The name of an article | O-demethyl-Venlafaxine succinate | Embodiment 1 product |
| Water (solute: solvent) | Dissolve (1: 29) | Yi Rong (1: 9) |
Conclusion: the crystal formation of O-demethyl-Venlafaxine of the present invention-Pidolidone salt is better than the solvability of O-demethyl-Venlafaxine succinate.
Test example 2, stability test
Accelerated test
This product is placed in to the particular envelope material, and (two-layer medicinal Low Density Polyethylene bag, distinguish heat sealing, adds siccative, the outer SP of using compound membrane bag seals to be packed) in, in (40 ℃ RH75%) are placed 1 month under the condition, detect its related substance, measurement result is in Table 2.
Test of long duration
This product is placed in to the particular envelope material, and (two-layer medicinal Low Density Polyethylene bag, distinguish heat sealing, adds siccative, the outer SP of using compound membrane bag seals to be packed) in, in (25 ℃, RH60%) the long-term placement, 1 month, detect its related substance, measurement result is in Table 2.
Table 2: stability test result
Conclusion: 1 month data of acceleration, long-term stable experiment show that the crystal formation of O-demethyl-Venlafaxine of the present invention-Pidolidone salt is highly stable, substantially without degraded.
Claims (4)
1. the crystal formation of the glutaminate of an O-demethyl-Venlafaxine, is characterized in that the X-ray powder diffraction figure of described crystal formation as shown in Figure 1.
2. a pharmaceutical composition, the crystal formation of the glutaminate that said composition contains O-demethyl-Venlafaxine as claimed in claim 1 is as activeconstituents and pharmaceutically acceptable carrier.
3. the method for the crystal formation of a glutaminate for preparing O-demethyl-Venlafaxine as claimed in claim 1, the method comprises the following steps:
By desmethylvenlafaxine 20.2g, Pidolidone 10.1g, ethanol 200ml, deionized water 125m1 adds, and is heated to 85 ℃, stir until solid all dissolves, 80 ℃ of pressure reducing and steaming solvents, obtain oily matter, adds toluene 300ml, be warmed up to 135 ℃, normal pressure steams except 150ml toluene, now has a large amount of solid products to generate, and is cooled to normal temperature, stir 2 hours, filter, with ethyl acetate 150ml * 2 making beating washings, drain, 70 ℃ of vacuum-drying 6 hours, obtain O-demethyl-Venlafaxine-Pidolidone salt 26.5g.
4. the crystal formation of the glutaminate of O-demethyl-Venlafaxine as claimed in claim 1 or the purposes of pharmaceutical composition as claimed in claim 2 in preparing antidepressant drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101475349A CN102212014B (en) | 2010-04-09 | 2010-04-09 | Crystal form of O-demethyl-venlafaxine glutamate, preparation method and medicinal application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101475349A CN102212014B (en) | 2010-04-09 | 2010-04-09 | Crystal form of O-demethyl-venlafaxine glutamate, preparation method and medicinal application thereof |
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| Publication Number | Publication Date |
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| CN102212014A CN102212014A (en) | 2011-10-12 |
| CN102212014B true CN102212014B (en) | 2013-12-25 |
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| CN2010101475349A Expired - Fee Related CN102212014B (en) | 2010-04-09 | 2010-04-09 | Crystal form of O-demethyl-venlafaxine glutamate, preparation method and medicinal application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003082806A1 (en) * | 2002-03-28 | 2003-10-09 | Synthon B.V. | Venlafaxine base |
| CN1501909A (en) * | 2001-02-12 | 2004-06-02 | Novel succinate salt of o-desmethyl-venlafaxine | |
| CN101092366A (en) * | 2000-10-19 | 2007-12-26 | 特瓦制药工业有限公司 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
| EP2085377A1 (en) * | 2008-01-29 | 2009-08-05 | LEK Pharmaceuticals D.D. | Novel salts of O-desmethyl-venlafaxine |
| WO2010008735A2 (en) * | 2008-06-16 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Solid states of o-desmethylvenlaf axine salts |
-
2010
- 2010-04-09 CN CN2010101475349A patent/CN102212014B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092366A (en) * | 2000-10-19 | 2007-12-26 | 特瓦制药工业有限公司 | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
| CN1501909A (en) * | 2001-02-12 | 2004-06-02 | Novel succinate salt of o-desmethyl-venlafaxine | |
| WO2003082806A1 (en) * | 2002-03-28 | 2003-10-09 | Synthon B.V. | Venlafaxine base |
| EP2085377A1 (en) * | 2008-01-29 | 2009-08-05 | LEK Pharmaceuticals D.D. | Novel salts of O-desmethyl-venlafaxine |
| WO2010008735A2 (en) * | 2008-06-16 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Solid states of o-desmethylvenlaf axine salts |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸文拉法辛多晶型现象的研究;葛继龙 等;《中国医药工业杂志》;20090531;第40卷(第5期);第361-374页 * |
| 葛继龙 等.盐酸文拉法辛多晶型现象的研究.《中国医药工业杂志》.2009,第40卷(第5期), |
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| CN102212014A (en) | 2011-10-12 |
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