CN106543164A - Stable Su Wolei raw compounds - Google Patents
Stable Su Wolei raw compounds Download PDFInfo
- Publication number
- CN106543164A CN106543164A CN201510601620.5A CN201510601620A CN106543164A CN 106543164 A CN106543164 A CN 106543164A CN 201510601620 A CN201510601620 A CN 201510601620A CN 106543164 A CN106543164 A CN 106543164A
- Authority
- CN
- China
- Prior art keywords
- wolei
- woleisheng
- composition
- unboiled water
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to mono- hydrated compounds of Su Woleisheng, the Su Wolei unboiled water compounds that the present invention is obtained, containing a crystallization water, have the advantage that：Purity is high, good stability, even if moisture absorption weightening is not also obvious under high humidity conditions.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to Su Wolei unboiled water compounds and preparation method thereof.
Background technology
MSD Corp. develop insomnia drug Su Woleisheng (suvorexant,
Trade name:Belsomra) in the U.S. of in 8Yue13Huo, 2014 food and FAD（FDA）Ratify to fall asleep and dyscoimesis for treating（Insomnia）Patient, is a kind of high selectivity orexin receptor antagonists, is the medicine that first gets the Green Light in such medicine.Orexin（orexin）It is a kind of neurotransmitter for being present in brain privileged site, a people can be helped to keep clear-headed, Belsomra usually promotes sleep by blocking appetite.Four kinds for the treatment of intensity of FDA approveds suvorexant, respectively 5mg, 10mg, 15mg and 20mg；Medication total amount is not to be exceeded 20mg daily.Chloro- 2- [(5R) -5- methyl -4- [5- methyl -2- (2H-1,2,3- triazole -2- bases) benzoyl]-Isosorbide-5-Nitrae-Diazesuberane -1- bases] -1, the 3- benzoxazoles of the entitled 5- of chemistry, its structural formula are as follows：
Su Woleisheng structural formulas
Through studying to Su Woleisheng, a kind of new Su Wolei unboiled water solvate crystals of the present invention have the advantage that the present inventor：Purity is high, and maximum contaminant is less than 1 ‰；Good stability, even if moisture absorption weightening is not also obvious under high humidity conditions.
The content of the invention
One object of the present invention, discloses a kind of Su Woleisheng monohydrates.
Another object of the present invention, discloses the preparation method of Su Woleisheng monohydrates.
A further object of the present invention, discloses the pharmaceutical composition comprising Su Woleisheng monohydrates.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of Su Woleisheng monohydrates（Shown in formula I）,
（Ⅰ）
Karl_Fischer method（Karl Fischer methods）In being a kind of all kinds of chemical methodes for determining moisture in material, method the most single-minded to water, the most accurate has been listed in the standard method of determination of moisture in many materials, especially organic compound, reliable results.6 batches of Jing are determined, and the moisture that described invention compound contains is between 2.97% -4.56% (percentage by weight).In Su Woleisheng times of semihydrate, the theoretical content of water is 3.84%, it can be assumed that invention compound contains a crystallization water.
The Su Woleisheng monohydrate crystals, are determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values.
In the present invention, the measure of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational error range, and its error range is ± 0.2 °.
Another object of the present invention, discloses the preparation method of Su Wolei unboiled water solvate crystals, by Su Woleisheng in the dissolving of acetone-heated in water solution, to naturally cool to room temperature, then is incubated a period of time and obtains.
Specifically include the following steps：Su Woleisheng adds 4-5 times（Weight or measurement (WM) ratio）Acetone-water=7-8：In the mixed liquor of 2-1,70 DEG C -75 DEG C are heated to, are filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hours, separate out crystallization, filtered, drying is obtained.
Su Woleisheng used can be readily obtained by commercial sources.
A further object of the present invention, there is provided the composition comprising Su Wolei unboiled water solvate crystal and the Su Wolei unboiled water compounds of one or more pharmaceutically acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.
The active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount can be specifically applied according to the situation of the state of an illness of patient, diagnosis, the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is the 1%～40% of composition（Weight）.
Stability test
Inventor is studied to the chemical stability of the crystal formation of the present invention, and investigation condition is high temperature（60℃±2℃）, strong illumination（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under high light, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, and illustrate that chemical stability is good, are adapted to the manufacture and long term storage of pharmaceutical preparation.
At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, the measure of moisture in hydrate crystal of the present invention：
As a result：At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, water tariff collection is constant, and explanation has good stability, and is adapted to the manufacture and long term storage of pharmaceutical preparation.
At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, the measure of moisture in Su Woleisheng：
As a result：At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, Su Woleisheng has moisture absorption to increase weight, to moist lability.
Specific embodiment：
With reference to embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from the present invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
In the present invention, Su Woleisheng used is obtained from commercial channels, purity 99.1% (HPLC normalization methods), its chemical constitution Jing proton nmr spectra, elementary analysis confirmation, it was demonstrated that chemical constitution is correct.
It is 0.16% with the moisture that Karl_Fischer method is measured.
Embodiment
1
In equipped with stirring, thermometer, the 2000ml reaction bulbs of condenser, the acetone-water of 200 Ke Suwoleisheng and 1000ml is added（8：2）Mixed liquor, starts stirring, is heated to 70 DEG C -75 DEG C, treats all molten clear, filters while hot.Filtrate naturally cools to room temperature, then is incubated 8 hours, separates out crystallization, filters, Jing indoor seasonings, obtains 181.6 grams of Su Woleisheng white crystals, and fusing point is 183.1 DEG C -184.6 DEG C, content 99.86%.Jing Karl_Fischer methods are determined, the moisture containing 3.84% (percentage by weight).
INSTRUMENT MODEL and condition determination：2500 type diffractometers of Rigaku D/max； CuKa
40Kv 100mA;2 θ sweep limits：0-50°。
Using standard and conventional technique, the compounds of this invention is combined with acceptable solid or liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.Said composition is used to prepare oral formulations, injection.Only citing is illustrated, and is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
2
Tablet containing Su Woleisheng monohydrates
Prescription：40 grams of Su Woleisheng monohydrates, 100 grams of lactose, 25 grams of PEG-4000,6 grams of magnesium stearate, 30 grams of PVP K30s, 33 grams of Ac-Di-Sol distill appropriate amount of water, make 1000.
Technique：PEG-4000 and Su Woleisheng monohydrates are crushed jointly, cross 80 mesh sieves, and with distilled water softwood after mixing with other materials, the pelleting of 16 mesh sieves is mixed in adding dry particl in 40-45 DEG C of drying, 16 mesh sieve whole grains, magnesium stearate in putting drying box, compressing tablet.
Claims (5)
1. Su Wolei raw compounds shown in formula I,
（Ⅰ）
Determined with Karl_Fischer method, the hydrate contains the moisture of 2.97% -4.56% (percentage by weight)；
The crystal of the Su Wolei unboiled water compound, in being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction and D values,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of Su Wolei unboiled water solvate crystal described in claim 1, by Su Woleisheng in acetone-heated in water solution dissolving, to naturally cool to room temperature, then is incubated a period of time and obtains.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Su Woleisheng adds 4-5 times of weight/volume acetone-water=7-8：In the mixed liquor of 2-1,70 DEG C -75 DEG C are heated to, are filtered while hot, filtrate naturally cools to room temperature, then is incubated 5-10 hours, separate out crystallization, filtered, drying is obtained.
4. the composition of the Su Wolei unboiled water compounds of a kind of Su Wolei unboiled water solvate crystal containing described in claim 1 and one or more pharmaceutically acceptable carrier composition.
5. 4 required by right described in Su Wolei unboiled water compounds composition, it is characterised in that said composition be used for prepare oral formulations.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510601620.5A CN106543164A (en) | 2015-09-21 | 2015-09-21 | Stable Su Wolei raw compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510601620.5A CN106543164A (en) | 2015-09-21 | 2015-09-21 | Stable Su Wolei raw compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106543164A true CN106543164A (en) | 2017-03-29 |
Family
ID=58362321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510601620.5A Pending CN106543164A (en) | 2015-09-21 | 2015-09-21 | Stable Su Wolei raw compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106543164A (en) |
-
2015
- 2015-09-21 CN CN201510601620.5A patent/CN106543164A/en active Pending
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170329 |