CN105859573B - A kind of Agomelatine sulfuric acid composition polymorph b and its preparation method and application - Google Patents
A kind of Agomelatine sulfuric acid composition polymorph b and its preparation method and application Download PDFInfo
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- CN105859573B CN105859573B CN201510029936.1A CN201510029936A CN105859573B CN 105859573 B CN105859573 B CN 105859573B CN 201510029936 A CN201510029936 A CN 201510029936A CN 105859573 B CN105859573 B CN 105859573B
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Abstract
The invention provides a kind of Agomelatine sulfuric acid composition novel crystal forms B and its preparation method.The crystal formation compares published Agomelatine sulfuric acid composition crystal formation, has higher fusing point.Present invention also offers the pharmaceutical composition of the crystal formation, the disease related for preventing and treating depression simultaneously.
Description
Technical field
The present invention relates to a kind of Agomelatine sulfuric acid composition novel crystal forms and its preparation method, and include its medicine
Compositions, the disease related for preventing and treating depression, belong to technical field of medicine synthesis.
Background technology
Agomelatine, the entitled Agomelatine of its English, it is that the melatonin of French Servier companies research and development is exciting
Agent, have antagonism 5HT concurrently2CThe effect of acceptor, trade name Valdoxan.It is first melatonin class antidepressants, can be had
Effect treatment depression, improves sleep parameters and does not influence sexual function, less sexual function badness reaction.
In view of agomelatine has higher pharmacy value, have become study hotspot in recent years, EP0447285,
CN200510071611.6、CN200610108396.7、CN200610108394.8、CN200610108395.2、
Have in the patents such as CN200910047399.2, CN201010126254.x, CN201010126263.9 open beautiful on algebraic oriented language
Draw the crystal formation in spit of fland and the report of acid group compound.
Our company makes public for the first time Agomelatine sulfuric acid composition and preparation method thereof in CN201210178635.1, report
(hereinafter referred to as sulfuric acid algebraic oriented language is beautiful draws for a kind of stability in road and the water-soluble sulfuric acid compound for being significantly better than agomelatine
Spit of fland).As shown in Equation 1.It is applied to pharmaceutical composition, achieves drug effect more more preferable than agomelatine, can be used for treating
Or prevention one or more are selected from following kind of disease：Including epiphysin energy systemic disease, sleep-disorder, anxiety, anxiety
Disease, seasonal Emotional Disorders, angiocardiopathy, disease of digestive system, the caused insomnia of jet lag or fatigue, schizophrenia
The diseases such as disease, neurosis, depression.
During drug research, it is often necessary to select medicine according to the requirement of the property of medicine and target formulation
Solid forms.The difference of medical solid form can cause physicochemical property, such as solubility, dissolution rate, stability, draw it is moist not
Together, and then its drug effect and Pharmacology are influenceed.More drug crystal forms species are provided to provide more for pharmaceutical preparation research
More selections, and then the preparation technology and quality of its product may be influenceed, or even clinical efficacy.From it is above-mentioned it is published on Ah
Ge Meilating result of study is visible, obtains that product stability is good, purity is high, has and determines crystal formation and favorable reproducibility, is adapted into
The agomelatine compound that product pharmaceutical preparation uses is considerable, therefore further to sulfuric acid agomelatine polymorphic
Research, contribute to people to have a better understanding for the compound, and one kind can be looked for be more suitable for preparation and make
Sulfuric acid agomelatine crystal form.
The content of the invention：
The present invention is intended to provide a kind of novel crystal forms of sulfuric acid agomelatine, if applicant is existed
Sulfuric acid agomelatine crystal form is named as crystal formation A disclosed in CN201210178635.1, then the novel crystal forms of the present patent application are sulphur
Sour agomelatine crystal form B.Crystal formation B has higher fusing point and stability.
Present invention also offers above-mentioned sulfuric acid agomelatine crystal form B preparation method and include crystal formation B medicine
Composition.
Applicant has carried out the polymorphic research of a variety of methods, including grinding, solvent, temperature for sulfuric acid agomelatine
The multifactor investigation with mixing speed etc., finally obtain a kind of sulfuric acid New crystal form of agomelatine B, it is characterised in that the crystalline substance
2 θ angles (± 0.2 °) in type B X-ray powder diffraction figure are 8.9,15.4,17.3,20.0,21.9,24.1,25.4,25.8
There is characteristic peak with 26.9 °, its X-ray powder diffraction figure is as shown in Figure 1.
Described sulfuric acid agomelatine crystal form B, its maximum absorption band is detected as 167 ± 2 through differential scanning calorimetric analysis
DEG C, the DSC figures of representative sample are as shown in Figure 2.With we the patent CN201210178635.1 crystal formation A announced DSC
Figure is compared (shown in CN201210178635.1 Figure of description 2), and the crystal formation DSC maximum absorption bands that the present invention is announced substantially rise
High (increasing about 9 DEG C), display crystal formation B have higher fusing point, illustrate its stability also more preferably.
The second object of the present invention there is provided above-mentioned sulfuric acid agomelatine crystal form B preparation method.Applicant is directed to
The polymorphic that sulfuric acid agomelatine has carried out a variety of methods is studied, including grinding, solvent, temperature and mixing speed etc. are multifactor
Investigation, finally found that the system that can be able to easily realize sulfuric acid agomelatine crystal form B by following two technical schemes
It is standby.One of method is to dissolve by heating sulfuric acid agomelatine in alcohols, esters, ketones solvent or their in the mixed solvent,
Sulfuric acid agomelatine crystal form B is separated out after cooling；The two of method are that agomelatine is dissolved in into alcohols, esters, ketones solvent
Or their in the mixed solvent, sulfuric acid is added, less than 10 DEG C is subsequently cooled to and separates out sulfuric acid agomelatine crystal form B.
The alcohols solvent that above two prepares used in sulfuric acid agomelatine crystal form B method refers to C1-C4Alcohol or it
Mixed solvent；Esters solvent refers to C2-C6Ester or their mixed solvent；Ketone refers to C3-C6Ketone or their mixing
Solvent.Further, alcohols solvent nail alcohol, ethanol, isopropanol or their mixed solvent；Esters solvent refer to ethyl acetate,
Isopropyl acetate or their mixed solvent；Ketone refers to acetone, butanone, methyl iso-butyl ketone (MIBK) or their mixed solvent.
Part it is multifactor investigate sulfuric acid agomelatine polymorphic result of study it is as shown in table 1 below, wherein alcohols solvent with
Exemplified by methanol, ethanol and isopropanol, esters solvent is by taking ethyl acetate and isopropyl acetate as an example, and ketones solvent is with acetone and methyl
Exemplified by isobutyl ketone.
Table 1：The research of the sulfuric acid agomelatine crystalline polymorph method of method one
Table 2：The sulfuric acid agomelatine polymorphic of method two is studied
During drug research, it is often necessary to select medicine according to the requirement of the property of medicine and target formulation
Solid forms.The difference of medical solid form can cause physicochemical property, such as solubility, dissolution rate, stability, draw it is moist not
Together, and then its drug effect and Pharmacology are influenceed.More drug crystal forms species are provided to provide more for pharmaceutical preparation research
More selections, and then the preparation technology and quality of its product may be influenceed, or even clinical efficacy.Described sulfuric acid agomelatine
Crystal formation B, compared with we are in the crystal formation A that patent CN201210178635.1 is announced, there is higher fusing point, illustrate that it is stable
More preferably, this provides a kind of more stable medical solid form to property for preparation research, so as to influence its curative effect of medication.With institute
The sulfuric acid agomelatine crystal form B stated is active component, can be with any pharmaceutically acceptable carrier, diluent or figuration
Agent, form pharmaceutical composition.
Described sulfuric acid agomelatine crystal form B and its pharmaceutical composition can prepare a kind of or more for treating or preventing
Application in kind of the medicine selected from following disease type, the disease type include epiphysin energy systemic disease, sleep-disorder, tight
Open, insomnia caused by anxiety disorder, seasonal Emotional Disorders, angiocardiopathy, disease of digestive system, jet lag or tired, smart
Refreshing Split disease, neurosis, depressive illness.
Figure of description
In order to become apparent from understanding purpose, feature and advantage of the present invention, the preferable reality below with reference to accompanying drawing to the present invention
Example is applied to be described in detail, wherein：
Fig. 1 is sulfuric acid agomelatine crystal form B X-ray powder diffraction (XRD) figure；
Fig. 2 is sulfuric acid agomelatine crystal form B differential scanning calorimeter (DSC) collection of illustrative plates.
Embodiment
Below by specific embodiments and the drawings, technical scheme is described in further detail, but this
Invention is not limited to these embodiments.Sulfuric acid agomelatine refers to use patent in example below
CN201210178635.1 preparation method is prepared.
Embodiment 1
Sulfuric acid agomelatine crystal form B preparation：
10.0g sulfuric acid agomelatine is added in appropriate solvent methanol, is heated to being completely dissolved, then cools down, is separated out
Crystal, continuing insulated and stirred makes crystallization complete in 1 hour, filters, and solid is washed 2 times with methanol 10mL, and vacuum drying obtains white
Solid 9.3g；Purity 99.8%, yield：93.0%.mp：164.0-167.0℃.KF：0.411%.Product passes through powder diffraction
Determine XRD results as shown in Figure 1, DSC results are as shown in Figure 2.
Embodiment 2-14 sulfuric acid agomelatine crystal forms B preparation, operated with embodiment 1 it is identical, it is but used molten
Agent is different, and obtained sulfuric acid agomelatine crystal form determines by XRD and DSC, and its result is consistent with crystal formation B.
| Embodiment | Solvent | The type of cooling | Product crystal formation |
| 2 | Ethanol | Ice-water bath cools | Crystal formation B |
| 3 | Methanol+ethanol | Ice salt bath cools | Crystal formation B |
| 4 | Isopropanol | Water-bath cools | Crystal formation B |
| 5 | Acetone | Ice salt bath cools | Crystal formation B |
| 6 | Butanone | Water-bath cools | Crystal formation B |
| 7 | Ethyl acetate | Ice salt bath cools | Crystal formation B |
| 8 | Isopropyl acetate | Ice salt bath cools | Crystal formation B |
| 9 | Methyl iso-butyl ketone (MIBK) | Water-bath cools | Crystal formation B |
| 10 | Sucrose Acetate base ester | Ice salt bath cools | Crystal formation B |
| 11 | Acetone+butanone | Ice salt bath cools | Crystal formation B |
| 12 | Ethyl acetate+isopropyl acetate | Ice salt bath cools | Crystal formation B |
| 13 | Methanol+acetone | Ice-water bath cools | Crystal formation B |
| 14 | Ethanol+acetone | Water-bath cools | Crystal formation B |
Embodiment 15
Sulfuric acid agomelatine crystal form B preparation：
By 10.0g agomelatines add solvent acetone in, be heated to 50 DEG C dissolving, be added dropwise 1-3eq the concentrated sulfuric acid (or
The concentrated sulfuric acid is diluted with acetone), less than 10 DEG C are cooled to ice salt bath or other types of cooling after adding, separates out crystal, is continued
Insulated and stirred makes crystallization complete in 1 hour, and filtering, solid is washed 2 times with acetone in proper, and vacuum drying obtains white solid 13.4g；
Purity 99.7%, yield：95.6%.mp：164.0-167.0℃.KF：0.481%.XRD with DSC results are consistent with embodiment 1.
Embodiment 16-29 operates identical with embodiment 15, but used solvent is different, and obtained sulfuric acid algebraic oriented language is beautiful to be drawn
Spit of fland crystal formation determines by XRD and DSC, consistent with crystal formation B.
| Embodiment | Solvent | The type of cooling | Product crystal formation |
| 16 | Methanol | Ice-water bath cools | Crystal formation B |
| 17 | Ethanol | Ice salt bath cools | Crystal formation B |
| 18 | Isopropanol | Ice-water bath cools | Crystal formation B |
| 19 | Methanol+ethanol | Ice salt bath cools | Crystal formation B |
| 20 | Butanone | Ice salt bath cools | Crystal formation B |
| 21 | Methyl iso-butyl ketone (MIBK) | Ice salt bath cools | Crystal formation B |
| 22 | Acetone+butanone | Ice-water bath cools | Crystal formation B |
| 23 | Ethyl acetate | Ice salt bath cools | Crystal formation B |
| 24 | Isopropyl acetate | Ice salt bath cools | Crystal formation B |
| 25 | Sucrose Acetate base ester | Ice salt bath cools | Crystal formation B |
| 26 | Ethyl acetate+isopropyl acetate | Ice salt bath cools | Crystal formation B |
| 27 | Ethanol+acetone | Ice salt bath cools | Crystal formation B |
| 28 | Ethyl acetate+acetone | Ice salt bath cools | Crystal formation B |
| 29 | Ethanol+ethyl acetate | Ice-water bath cools | Crystal formation B |
Embodiment 30
Sulfuric acid agomelatine crystal form B drug regimens
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvement and optimization can also be made, these are improved and optimization also should
It is considered as protection scope of the present invention.
Claims (5)
- A kind of 1. Agomelatine sulfuric acid composition crystal formation B method, it is characterised in that by agomelatine be dissolved in alcohols, Esters, ketones solvent or their in the mixed solvent, sulfuric acid is added, then using ice salt bath or frozen water water-bath cooling down to 10 Agomelatine sulfuric acid composition crystal formation B is separated out below DEG C；2 θ angles (± 0.2 °) in the X-ray powder diffraction figure of the crystal formation B are 8.9,15.4,17.3,20.0,21.9, 24.1st, 25.4,25.8 and 26.9 ° have characteristic peak.
- 2. Agomelatine sulfuric acid composition crystal formation B according to claim 1 method, it is characterised in that described alcohol Class solvent refers to C1-C4Alcohol or their mixed solvent；Esters solvent refers to C2-C6Ester or their mixed solvent；Ketone refers to C3- C6Ketone or their mixed solvent.
- 3. Agomelatine sulfuric acid composition crystal formation B according to claim 2 method, it is characterised in that described alcohol Class solvent nail alcohol, ethanol, isopropanol or their mixed solvent；Esters solvent refer to ethyl acetate, isopropyl acetate or they Mixed solvent；Ketone refers to acetone, butanone, methyl iso-butyl ketone (MIBK) or their mixed solvent.
- 4. Agomelatine sulfuric acid composition crystal formation B according to claim 1 method, it is characterised in that the crystal formation B X-ray powder diffraction figure it is as shown in Figure 1.
- 5. Agomelatine sulfuric acid composition crystal formation B according to claim 1 method, it is characterised in that the crystal formation B DSC figures it is as shown in Figure 2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718676A (en) * | 2012-06-26 | 2012-10-10 | 福建广生堂药业股份有限公司 | Agomelatine sulfate and preparation method thereof |
| CN102911075A (en) * | 2012-09-29 | 2013-02-06 | 福建广生堂药业股份有限公司 | New crystal form I of agomelatine sulfate and preparation method thereof |
| JP2013515751A (en) * | 2009-12-29 | 2013-05-09 | 上海中西制薬有限公司 | Method for producing solid preparation and solid preparation produced by the method |
| WO2014096373A1 (en) * | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005102342A1 (en) * | 2004-04-22 | 2005-11-03 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions for the treatment of sexual disorders ii |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013515751A (en) * | 2009-12-29 | 2013-05-09 | 上海中西制薬有限公司 | Method for producing solid preparation and solid preparation produced by the method |
| CN102718676A (en) * | 2012-06-26 | 2012-10-10 | 福建广生堂药业股份有限公司 | Agomelatine sulfate and preparation method thereof |
| CN102911075A (en) * | 2012-09-29 | 2013-02-06 | 福建广生堂药业股份有限公司 | New crystal form I of agomelatine sulfate and preparation method thereof |
| WO2014096373A1 (en) * | 2012-12-21 | 2014-06-26 | Laboratorios Lesvi, S. L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
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