CN107778185A - A kind of melitracen hydrochloride crystal formation A and preparation method thereof - Google Patents
A kind of melitracen hydrochloride crystal formation A and preparation method thereof Download PDFInfo
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- CN107778185A CN107778185A CN201610738945.2A CN201610738945A CN107778185A CN 107778185 A CN107778185 A CN 107778185A CN 201610738945 A CN201610738945 A CN 201610738945A CN 107778185 A CN107778185 A CN 107778185A
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- crystal formation
- melitracen hydrochloride
- melitracen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/31—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by at least three rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
Abstract
The present invention provides a kind of novel crystal forms A of melitracen hydrochloride, and the X ray powder diffractograms that crystal formation A is represented with the 2 θ ± 0.2 ° angles of diffraction are 10.467,11.361,11.812,13.895,15.785,16.602,17.419, characteristic peak is shown at 18.696,21.133,21.691,24.370.
Description
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to a kind of melitracen hydrochloride crystal formation A and preparation method thereof.
Background technology：
Melitracen hydrochloride (Melitracen hydrochloride) its chemical name is 3- [10,10- dimethyl -9
(10H)-anthracene subunit]-N, N- dimethyl propylene amine hydrochlorates；3- [10,10- dimethyl -9 (10H)-anthrylene]-N, N- dimethyl
Propylamin hydrochloride, No. CAS：10563-70-9.Melitracen hydrochloride can suppress reuptake of the presynaptic membrane to norepinephrine,
Improve the content of the monoamine transmitterses of cynapse.This product lists in nineteen sixty-eight, is shared with Flupentixol, has synergic adjustment maincenter
The function of nervous system, antidepression, antianxiety and firing properties are played, suitable for acute and chronic schizophrenia, depression.
Structural formula is as follows：
Melitracen hydrochloride belongs to tricyclic antidepressant, and antidepressant effect is stronger, and psychosis effect is weaker, mainly
Treatment for depression.This product toxicity is relatively low, and without carcinogenic, teratogenesis, mutagenic report, its preparation is clinically bad anti-
Should be light less, the income in clinical practice is more than risk.
Melitracen hydrochloride has a variety of crystal formations, wherein, Chinese patent application CN105218383A discloses a kind of hydrochloric acid
Melitracen crystal formation and preparation method thereof；Hoong-Kun Fun etc. report salt in Acta Cryst. (2011) .E67, o1725
The single crystal data of sour melitracen.
Polymorph medicine is generally believed, because crystal formation difference, its fusing point, solubility, stability etc. are possible to different, this
The effect of absorption and release of medicine in vivo can be influenceed, and then influence medicine and security.Therefore, for melitracen hydrochloride
Polymorphism, it is necessary to study its polymorphic situation.
The content of the invention：
The present invention provides a kind of melitracen novel crystal forms A and preparation method thereof.
On the one hand, the present invention provides a kind of melitracen hydrochloride crystal formation A, and described crystal formation A is with 2 θ ± 0.2 ° angle of diffraction tables
The X-ray powder diffraction spectrogram shown 10.467,11.361,11.812,13.895,15.785,16.602,17.419,
Characteristic peak is shown at 18.696,21.133,21.691,24.370；The X- that described crystal formation A is represented with the 2 θ ± 0.2 ° angles of diffraction is penetrated
Line powder diffractogram also shows characteristic peak at 17.077,2.918,23.327；Described crystal formation A X-ray powder diffraction
Spectrogram is as shown in Figure 1.
Further, the decomposition endothermic peak of described melitracen hydrochloride crystal formation A differential scanning calorimeteries (DSC) is
244.9 DEG C, DSC figures are as shown in Figure 2.
Further, described melitracen hydrochloride crystal formation A Raman shift is in 1637.89cm-1, 1595.29cm-1,
1041.46cm-1,1161.54cm-1,677.31cm-1,3059.25±2cm-1Place shows characteristic peak, Raman spectrogram such as Fig. 3 institutes
Show, wherein " ± 2 " the measurement error scope to allow.
Further, described melitracen hydrochloride crystal formation A infrared spectrogram (IR) is as shown in Figure 4.
On the other hand, the present invention provides a kind of crystal formation A of melitracen hydrochloride method, comprises the following steps：By hydrochloric acid
Melitracen adds 95%~98% ethanol, and at 45~60 DEG C, vacuum rotary steam removes solvent, collects solid, 40~60 DEG C of dryings,
Obtain melitracen hydrochloride crystal formation A.
Preparation method more specifically, by melitracen hydrochloride adds the ethanol of 10ml 95%, in vacuum 0.09MPa and 45
Vacuum rotary steam removes solvent under the conditions of DEG C, collects solid, 50~60 DEG C of dryings, obtains melitracen hydrochloride crystal formation A.
The present invention relates to a kind of new crystal formation A of melitracen hydrochloride, the stability and dissolubility that the crystal formation has had, have
Good druggability.Method for preparing melitracen hydrochloride crystal formation A is simple to operate controllable, suitable industrialized production.
Brief description of the drawings
Fig. 1 is melitracen hydrochloride crystal formation A of the present invention X-ray powder diffraction spectrogram
Fig. 2 is melitracen hydrochloride crystal formation A of the present invention differential scanning calorimetery (DSC) analysis chart
Fig. 3 is melitracen hydrochloride crystal formation A of the present invention Raman spectrum (RM) spectrogram
Fig. 4 is melitracen hydrochloride crystal formation A of the present invention infrared chromatography (IR) spectrogram
Fig. 5 is melitracen hydrochloride crystal formation A high humiditys of the present invention 5 days, the X-ray powder of 10 days factors affecting stabilities spreads out
Penetrate spectrogram
Fig. 6 is melitracen hydrochloride crystal formation A high temperature of the present invention 5 days, the X-ray powder of 10 days factors affecting stabilities spreads out
Penetrate spectrogram
Fig. 7 is IV illumination of Cariliprazine hydrochloride Form of the present invention 5 days, the X-ray powder of 10 days factors affecting stabilities
Diffraction spectrogram
Fig. 8 is the X-ray powder diffraction spectrogram that melitracen hydrochloride crystal formation A of the present invention accelerates June
Embodiment：
The present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment below.
Those skilled in the art can make improvement to preparation method and using instrument within the scope of the claims, and these improvement also should be regarded as
Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
In following embodiments, unless otherwise indicated, described experimental method is generally built according to normal condition or manufacturer
The condition of view is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
X-ray powder diffraction figure of the present invention gathers on Bruker D8Focus X-ray powder diffraction instrument.
The method parameter of X-ray powder diffraction of the present invention is as follows：
X-ray parameter：
Voltage：40 KVs (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 60 degree
Sampling step length：0.02 degree
Sample leg speed：0.5 second/step
Means of differential scanning calorimetry (DSC) analysis chart of the present invention is by the resistance to DSC 200F3 detections of speeding of Germany, temperature range
35~180 DEG C, heating rate 10K/min；Hole is pricked in aluminium crucible, sealing, and purge gass are nitrogen (60ml/min), and protection gas is nitrogen
(40ml/min)。
Thermogravimetric analysis (TG) of the present invention is by the resistance to TG 209F3 detections of speeding of Germany, and balance, temperature are kept at 25 DEG C
40~250 DEG C, heating rate 10K/min of scope, be open aluminium crucible, and purge gass are nitrogen (40ml/min), and protection gas is nitrogen
(20ml/min)。
Fourier's Raman spectrum (FT-RM) of the present invention is by Thermo SCIENTIFIC DXR SmartRaman light
Spectrometer detects.Sample is placed on quartz slide, Raman spectroscopy is gathered through quartz slide.
HPLC content measurings in the present invention：
Instrument：The liquid chromatographs of Agilent 1200
Foundation：Chinese Pharmacopoeia the 4th high performance liquid chromatography of general rule 0512 of version in 2015
Test condition：
Chromatographic column：Agilent XDB C18 posts (150*4.6mm, 5 μm)
Mobile phase A：0.025M potassium dihydrogen phosphates (containing 0.2% triethylamine)-acetonitrile (80:20)
Mobile phase B：Acetonitrile-water (80:20)
Diluent：Acetonitrile-water (80:20)
Detection wavelength：281nm
Column temperature：40℃
Flow velocity：1.2ml/min
Gradient condition：
Embodiment 1
Weigh melitracen hydrochloride sample 1g, add eggplant-shape bottle, add the ethanol of 10ml 95%, vacuum 0.09MPa with
Vacuum rotary steam removes solvent under the conditions of 45 DEG C, collects solid, 60 DEG C are dried overnight, and obtain melitracen hydrochloride crystal formation A.Purity is
99.8%, X-ray powder diffraction is as shown in Figure 1.
Embodiment 2
Weigh melitracen hydrochloride sample 1g, add eggplant-shape bottle, add the ethanol of 10ml 90%, vacuum 0.09MPa with
Vacuum rotary steam removes solvent under the conditions of 60 DEG C, collects solid, 50 DEG C are dried overnight, and obtain melitracen hydrochloride crystal formation A.
Test example 1
The crystal formation A for the melitracen hydrochloride that embodiment 1 obtains stability is investigated.
Carry out high humidity (RH 92%), high temperature (60 DEG C), illumination (4500 ± 500lx) respectively to melitracen hydrochloride crystal formation A
Under the conditions of factors affecting stability experiment.PXRD detections are carried out respectively at 5 days, sampling in 10 days, and are carried out pair with the result of 0 day
According to, and carry out HPLC assays；PXRD detections are carried out after accelerated test terminates within 6 months.It the results are shown in Table 1.
The melitracen hydrochloride crystal formation A factors affecting stabilities of table 1. are tested
Learnt from the data of table 1, crystal formation can be very under the conditions of high humidity 10 days, high temperature 10 days and illumination 10 days by crystal formation A
Good holding is stable (see accompanying drawing 5,6,7), and chemical property is stable, and content did not change with 0 day, and content can reach
More than 99.70.Other 6 months accelerated tests, the x-ray diffraction patterns of melitracen hydrochloride A crystal formations it is consistent with primary data (see
Accompanying drawing 8), also without crystal phenomenon occurs, show that crystal stability provided by the invention is good, beneficial to the storage of preparation.
Test example 2:Melitracen hydrochloride crystal formation A solubility experiment
Solubility of the melitracen crystal formation A in water
Take test sample appropriate, grind into powder, add certain volume pure water, it is strong every 5min under the conditions of 25 DEG C ± 2 DEG C
Strong shaking 30 seconds, observes the dissolubility situation in 30min.Melitracen hydrochloride crystal formation A dissolubility the results are shown in Table 2.
The melitracen hydrochloride dissolubility test of table 2
Claims (6)
1. a kind of melitracen hydrochloride crystal formation A, it is characterised in that described melitracen hydrochloride crystal formation A is with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction spectrogram that angle represents 10.467,11.361,11.812,13.895,15.785,16.602,17.419,
Characteristic peak is shown at 18.696,21.133,21.691,24.370.
2. melitracen hydrochloride crystal formation A according to claim 1, it is characterised in that described melitracen hydrochloride crystal formation A
Characteristic peak is also shown at 17.077,2.918,23.327 with the X-ray powder diffraction spectrogram that the 2 θ ± 0.2 ° angles of diffraction represent.
3. melitracen hydrochloride crystal formation A according to claim 1, it is characterised in that described melitracen hydrochloride crystal formation A
X-ray powder diffraction spectrogram it is as shown in Figure 1.
4. according to any described melitracen hydrochloride crystal formation A of claim 1-3, it is characterised in that the U.S. profit of described hydrochloric acid is bent
It is 244.9 DEG C that pungent crystal formation A DSC, which decomposes endothermic peak,.
5. according to any described melitracen hydrochloride crystal formation A of claim 1-3, it is characterised in that the U.S. profit of described hydrochloric acid is bent
Pungent crystal formation A Raman shift is in 1637.89cm-1, 1595.29cm-1,1041.46cm-1,1161.54cm-1,677.31cm-1,
3059.25±2cm-1Place shows characteristic peak.
A kind of 6. method for the crystal formation A for preparing the melitracen hydrochloride described in claim 1, it is characterised in that include following step
Suddenly：
Melitracen hydrochloride is added into 95%~98% ethanol, at 45~60 DEG C, vacuum rotary steam removes solvent, collects solid, and 40
~60 DEG C of dryings, obtain melitracen hydrochloride crystal formation A.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610738945.2A CN107778185A (en) | 2016-08-26 | 2016-08-26 | A kind of melitracen hydrochloride crystal formation A and preparation method thereof |
| CN202111463830.4A CN114057586A (en) | 2016-08-26 | 2016-08-26 | Melletoxin hydrochloride crystal form A and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610738945.2A CN107778185A (en) | 2016-08-26 | 2016-08-26 | A kind of melitracen hydrochloride crystal formation A and preparation method thereof |
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| CN202111463830.4A Division CN114057586A (en) | 2016-08-26 | 2016-08-26 | Melletoxin hydrochloride crystal form A and preparation method thereof |
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| CN107778185A true CN107778185A (en) | 2018-03-09 |
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| CN201610738945.2A Pending CN107778185A (en) | 2016-08-26 | 2016-08-26 | A kind of melitracen hydrochloride crystal formation A and preparation method thereof |
| CN202111463830.4A Pending CN114057586A (en) | 2016-08-26 | 2016-08-26 | Melletoxin hydrochloride crystal form A and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3177209A (en) * | 1960-09-16 | 1965-04-06 | Kefalas As | Dihydroanthracene compounds |
| US3190893A (en) * | 1961-02-17 | 1965-06-22 | Kefalas As | Method of producing 9, 10-dihydroanthracenes |
| CN105218383A (en) * | 2014-06-03 | 2016-01-06 | 四川海思科制药有限公司 | A kind of U-24973A compound |
| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
-
2016
- 2016-08-26 CN CN201610738945.2A patent/CN107778185A/en active Pending
- 2016-08-26 CN CN202111463830.4A patent/CN114057586A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3177209A (en) * | 1960-09-16 | 1965-04-06 | Kefalas As | Dihydroanthracene compounds |
| US3190893A (en) * | 1961-02-17 | 1965-06-22 | Kefalas As | Method of producing 9, 10-dihydroanthracenes |
| CN105218383A (en) * | 2014-06-03 | 2016-01-06 | 四川海思科制药有限公司 | A kind of U-24973A compound |
| CN105481774A (en) * | 2016-01-26 | 2016-04-13 | 江苏恩华药业股份有限公司 | Dexmedetomidine hydrochloride crystal form C and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| HOONG-KUN FUN等: "Melitracenium chloride", 《ACTA CRYSTALLOGRAPHICA SECTION E》 * |
| 张立颖 等: "盐酸美利曲辛合成工艺研究", 《山东化工》 * |
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| Publication number | Publication date |
|---|---|
| CN114057586A (en) | 2022-02-18 |
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Application publication date: 20180309 |