CN104058992A - Crystal form of levomilnacipran hydrochloride - Google Patents
Crystal form of levomilnacipran hydrochloride Download PDFInfo
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- CN104058992A CN104058992A CN201410265089.4A CN201410265089A CN104058992A CN 104058992 A CN104058992 A CN 104058992A CN 201410265089 A CN201410265089 A CN 201410265089A CN 104058992 A CN104058992 A CN 104058992A
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Abstract
The invention provides a crystal form of levomilnacipran hydrochloride. In the powder X-ray diffractogram of the crystal form, the crystal form has major characteristic peaks at diffraction angles 2theta, namely 5.94 degrees, 11.90 degrees and 13.60 degrees. The invention also provides a preparation method of the crystal form, a pharmaceutical composition containing the crystal form and an application of the crystal form in medicine preparation.
Description
Technical field
The present invention relates to chemicals field, be specifically related to crystal formation of a kind of antidepressant drug-left-handed Milnacipran hydrochloride and its preparation method and application.
Background technology
Left-handed Midalcipran (levominacipran), its chemistry (1S, 2R)-2-(aminomethyl)-N by name, N-diethyl-1-phenyl cyclopropane carboxamide, the chemical structure of its hydrochloride is as follows:
On July 26th, 2013, the left-handed Milnacipran hydrochloride of New type of S NRI class medicine (trade name is Fetzima) in U.S. food and FAD (FDA) approval forest laboratory is used for the treatment of Adult Severe depressive disorder, and this is also the 4th kind of serotonin and NRI in U.S.'s listing through FDA approval.According to the instruction in production firm forest laboratory, under external environment, left-handed Midalcipran is better than the similar effect to serotonin to the reuptake inhibition of norepinephrine, and this medicine does not directly affect the re-uptake of Dopamine HCL and other neurotransmitters in the process of performance pharmacological action.
In view of the pharmacy value of this medicine, the favorable reproducibility obtaining in good, the stable crystal form of purity and preparation method is vital, thereby the crystal formation obtaining has advantage aspect preparation: enough stablizing can prolonged storage, and temperature, light, humidity or oxygen level are not had to particular requirement.
13 kinds of XRPD data of different crystal forms are disclosed in world patent WO2011/057176 specification sheets, wherein " crystal form A " is to make from the crystallization of ethanol/ether, other 12 kinds of XRPD data are data that the crystallization that makes from deionized water, methyl alcohol, ethanol, Virahol, n-butyl alcohol, N,N-dimethylacetamide, water/acetonitrile, water/methyl alcohol (80:20), water/methyl alcohol (20:80), methylene dichloride and Iso Butyl Acetate/ethanol respectively records.
Summary of the invention
On the one hand, the invention provides a kind of crystal formation of new left-handed Milnacipran hydrochloride, this crystal formation has advantage aspect preparation.
The new crystal of left-handed Milnacipran hydrochloride, in its x-ray diffractogram of powder, diffraction angle 2 θ be 5.94,11.90,13.60 degree (°) located principal character peak.
The new crystal of left-handed Milnacipran hydrochloride, in its x-ray diffractogram of powder, diffraction angle 2 θ be 5.94,11.90,13.60 degree (°) located principal character peak; 21.61,24.31,26.67,27.40,38.80,41.59 degree (°) located accidental quality peak.
The crystal formation of left-handed Milnacipran hydrochloride, in its x-ray diffractogram of powder, diffraction angle 2 θ have peak at following place, and corresponding following relative intensity:
| 2θ(°) | Relative intensity |
| 5.94 | 100 |
| 11.90 | 27.1 |
| 13.60 | 21.7 |
| 21.61 | 2.2 |
| 24.31 | 1.8 |
| 26.67 | 2.9 |
| 27.40 | 3.4 |
| 38.80 | 1.8 |
| 41.59 | 1.4 |
The X-diffraction powder diagram of the crystal formation sample of left-handed Milnacipran hydrochloride of the present invention as shown in Figure 1.It may be noted that routine techniques personnel of the present invention understand, between a machine and another and between sample and another, X-diffraction powder diffraction spectrum may slightly change in 2 θ values, and therefore given numerical value can not be considered as definitely.The relative intensity that should also be understood that peak value can change along with the Time-orientation of tested sample, and it is exemplary obtaining intensity shown in XRD curve (or describing stitching) here, does not intend being used as absolute comparison.
On the other hand, the invention provides the preparation method of above-mentioned left-handed Milnacipran hydrochloride crystal formation, this preparation method is simple to operate, favorable reproducibility.
The preparation method of above-mentioned left-handed Milnacipran hydrochloride crystal formation, the method is first by water-soluble left-handed Milnacipran hydrochloride-toluene, is heated to reflux, utilize component distillation to divide the method for water, remove the water in reaction system, progressively except in the process of anhydrating, crystallization.
The preparation method of above-mentioned left-handed Milnacipran hydrochloride crystal formation, the addition of solvent is left-handed Milnacipran hydrochloride: water: toluene is 1g:7mL:100mL.
The preparation method of above-mentioned left-handed Milnacipran hydrochloride new crystal, the water yield that azeotropic is removed is the 50%-100% that adds the water yield.
Another reverse side, left-handed Milnacipran hydrochloride new crystal provided by the present invention can make various pharmaceutical compositions together with various auxiliary materials pharmaceutically or vehicle, for oral or injection.
Another reverse side, left-handed Milnacipran hydrochloride new crystal provided by the present invention, it is applied to preparation treatment adult severe depression obstacle medicine.
For the illness of hope treatment, can use composition of the present invention with standard manner, for example, and by oral, part, parenteral road, nose, vagina or rectal administration or use by suction.For with these mode administrations, can this promoting agent be mixed with to formulation by known in the art, for example tablet, capsule, water or oil solution, suspension, emulsion, creme, ointment, gelifying agent.Nasal spray, suppository, finely divided pulvis or suction aerosol, and parenteral canal drug administration sterilized water or oil solution or suspension agent or the aseptic emulsion of (comprising intravenous injection, intramuscularly or infusion).Preferred route of administration is oral.
Brief description of the drawings
Fig. 1 is the X ray diffracting spectrum of the embodiment of the present invention 1 gained crystal formation.Adopt Bruker D8Advance x-ray diffractometer to measure, condition determination is as follows: Cu-K a40Kv40mA is light source, 0.05 ° of step-length, and sweep velocity: 8 °/minute, sweep limit: 3 °～50 °.In Fig. 1, X-coordinate is diffraction angle (θ) value, the intensity that ordinate zou is absorption peak.
Fig. 2 is the DSC collection of illustrative plates of the embodiment of the present invention 1 gained crystal formation.Adopt P-E means of differential scanning calorimetry thermal analyzer.Test condition: Range:30/10.0 (k/min)/300, Crucible:Pan Al, pierced lid, Atmosphere:N2,20.0ml/min N2,60.0ml/min, Corr/m.range:300/5000 μ V.In Fig. 2, Peak represents absorption peak temperature value, and Onset represents starting temperature value.In the DSC collection of illustrative plates of gained crystal formation, 95.8 ° of starting temperatures, and peak temperature is 96.9 °; And 151.4 ° of starting temperatures, and peak temperature is 155.5 ° and 175.2 °.
By the following examples further to illustrate the present invention; It should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise, can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Embodiment
Embodiment 1
Left-handed 1.0g Milnacipran hydrochloride is dissolved in 7.0g water, then adds 100.0ml toluene, be heated to reflux, progressively remove the water in reaction system with water trap, along with steaming of water, crystallization, when the water yield steaming reaches 6.3g, stop azeotropic water removing, stirring is cooled to room temperature, and insulated and stirred 3-5 hour is cooled to 5-10 DEG C, insulated and stirred 2 hours, filters.50-55 DEG C of vacuum-drying, to constant weight, obtains white solid, and 0.81g weighs.
Embodiment 2
Left-handed 1.0g Milnacipran hydrochloride is dissolved in 7.0g water, then adds 100.0ml toluene, be heated to reflux, progressively remove the water in reaction system with water trap, along with steaming of water, crystallization, when the water yield steaming reaches 5.6g, stop azeotropic water removing, stirring is cooled to room temperature, and insulated and stirred 3-5 hour is cooled to 5-10 DEG C, insulated and stirred 2 hours, filters.50-55 DEG C of vacuum-drying, to constant weight, obtains white solid, and 0.70g weighs.
Embodiment 3
Left-handed 1.0g Milnacipran hydrochloride is dissolved in 7.0g water, then adds 100.0ml toluene, be heated to reflux, progressively remove the water in reaction system with water trap, along with steaming of water, crystallization, when the water yield steaming reaches 4.2g, stop azeotropic water removing, stirring is cooled to room temperature, and insulated and stirred 3-5 hour is cooled to 5-10 DEG C, insulated and stirred 2 hours, filters.50-55 DEG C of vacuum-drying, to constant weight, obtains white solid, and 0.30g weighs.
The left-handed Milnacipran hydrochloride crystal formation of gained in embodiment 2, in its actual measurement X ray diffracting spectrum, minute surface spacing d, 2 θ and relative intensity value are:
| 2θ(°) | d(A) | Relative intensity |
| 5.94 | 14.73 | 100 |
| 11.90 | 7.39 | 20.6 |
| 13.65 | 6.47 | 14.2 |
| 24.00 | 3.70 | 0.7 |
| 27.45 | 3.24 | 1.4 |
| 38.82 | 2.31 | 0.5 |
| 42.67 | 2.11 | 0.4 |
The left-handed Milnacipran hydrochloride crystal formation of gained in embodiment 3, in its actual measurement X ray diffracting spectrum, minute surface spacing d, 2 θ and relative intensity value are:
| 2θ(°) | d(A) | Relative intensity |
| 5.98 | 14.77 | 100 |
| 11.94 | 7.40 | 22.1 |
| 13.64 | 6.49 | 15.0 |
| 23.95 | 3.71 | 0.4 |
| 26.72 | 3.33 | 1.2 |
| 27.42 | 3.25 | 1.6 |
| 38.83 | 2.31 | 0.8 |
Claims (8)
1. the crystal formation of left-handed Milnacipran hydrochloride, in its x-ray diffractogram of powder, diffraction angle 2 θ be 5.94,11.90,13.60 degree (°) located principal character peak.
2. crystal formation as claimed in claim 1, in its x-ray diffractogram of powder, diffraction angle 2 θ be 21.61,24.31,26.67,27.40,38.80 and 41.59 degree (°) located accidental quality peak.
3. crystal formation as claimed in claim 2, in its x-ray diffractogram of powder, diffraction angle 2 θ have peak at following place, and corresponding following relative intensity:
4. the preparation method of crystal formation as described in claim 1-3 any one, comprises step: by water-soluble left-handed Milnacipran hydrochloride-toluene, be heated to reflux, utilize azeotropic to remove the water in reaction system, progressively except in the process of anhydrating, crystallization.
5. the preparation method of left-handed Milnacipran hydrochloride crystal formation as claimed in claim 4, is characterized in that: in the method, the addition of solvent is left-handed Milnacipran hydrochloride: water: toluene is 1g:7mL:100mL.
6. the preparation method of the left-handed Milnacipran hydrochloride crystal formation as described in claim 4 or 5, is characterized in that: the water yield that azeotropic is removed is to add 50% to 100% of the water yield.
7. a pharmaceutical composition, is made up of left-handed Milnacipran hydrochloride crystal formation and pharmaceutically acceptable auxiliary material described in claim 1-3 any one.
8. the application of the crystal formation of the left-handed Milnacipran hydrochloride described in claim 1-3 any one in treatment adult severe depression obstacle medicine.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5634386A (en) * | 1985-04-25 | 1986-10-30 | Medicament, P.F. | Process for preparing (z)-1-phenyl-1-diethylaminocarbonyl-2- aminomethylcyclopropane hydrochloride |
| WO2008067752A1 (en) * | 2006-12-04 | 2008-06-12 | Lin Ai | A process for preparing optical pure milnacipran and its pharmaceutically accepted salts |
| US20110112197A1 (en) * | 2009-11-06 | 2011-05-12 | Forest Laboratories Holdings Ltd. | Novel crystalline forms of (1s,2r)-2-(amino methyl)-n,n-diethyl-1-phenyl cyclopropane carboxamide |
| CN102300840A (en) * | 2009-01-29 | 2011-12-28 | 皮埃尔法布雷医药公司 | Method for synthesis of (1S, 2R)-milnacipran |
| WO2012059933A1 (en) * | 2010-11-03 | 2012-05-10 | Arch Pharmalabs Limited | A new process for preparing optically pure milnacipran and its pharmaceutically acceptable salts. |
| WO2014009767A1 (en) * | 2012-07-07 | 2014-01-16 | Micro Labs Limited | An improved process for the preparation of 1-aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers and salts |
| CN103601652A (en) * | 2013-12-09 | 2014-02-26 | 上海现代制药股份有限公司 | Preparation method of milnacipran hydrochloride |
-
2014
- 2014-06-13 CN CN201410265089.4A patent/CN104058992A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5634386A (en) * | 1985-04-25 | 1986-10-30 | Medicament, P.F. | Process for preparing (z)-1-phenyl-1-diethylaminocarbonyl-2- aminomethylcyclopropane hydrochloride |
| WO2008067752A1 (en) * | 2006-12-04 | 2008-06-12 | Lin Ai | A process for preparing optical pure milnacipran and its pharmaceutically accepted salts |
| CN102300840A (en) * | 2009-01-29 | 2011-12-28 | 皮埃尔法布雷医药公司 | Method for synthesis of (1S, 2R)-milnacipran |
| US20110112197A1 (en) * | 2009-11-06 | 2011-05-12 | Forest Laboratories Holdings Ltd. | Novel crystalline forms of (1s,2r)-2-(amino methyl)-n,n-diethyl-1-phenyl cyclopropane carboxamide |
| WO2012059933A1 (en) * | 2010-11-03 | 2012-05-10 | Arch Pharmalabs Limited | A new process for preparing optically pure milnacipran and its pharmaceutically acceptable salts. |
| WO2014009767A1 (en) * | 2012-07-07 | 2014-01-16 | Micro Labs Limited | An improved process for the preparation of 1-aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers and salts |
| CN103601652A (en) * | 2013-12-09 | 2014-02-26 | 上海现代制药股份有限公司 | Preparation method of milnacipran hydrochloride |
Non-Patent Citations (7)
| Title |
|---|
| HEIDI ROGGEN 等: "Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine,serotonin,and norepinephrine transporters", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTER》 * |
| JULIEN ALLIOT 等: "Enantioselective synthesis of levomilnacipran", 《CHEM.COMMUN.》 * |
| MICHAEL P.DOYLE 等: "A New Enantioselective Synthesis of milnacipran and an Analogue by Catalytic Asymmetric Cyclopropanation", 《ADV.SYNTH.CATAL.》 * |
| SATOSHI SHUTO 等: "Synthesis of (+)- and (-)-milnaciprans and their conformationally restricted analogs", 《TETRAHEDRON LETTERS》 * |
| 刘啸 等: "组合拆分法制备米那普仑(1S,2R)对映体", 《中国抗生素杂志》 * |
| 卞红平 等: "盐酸米那普仑反式异构体的合成及结构确证", 《中国医药工业杂志》 * |
| 王晓琴 等: "盐酸米那普仑右旋异构体的合成", 《中国医药工业杂志》 * |
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Application publication date: 20140924 |