CN104610182B - A kind of amorphous substance of triaizine compounds and its production and use - Google Patents
A kind of amorphous substance of triaizine compounds and its production and use Download PDFInfo
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- CN104610182B CN104610182B CN201510065736.1A CN201510065736A CN104610182B CN 104610182 B CN104610182 B CN 104610182B CN 201510065736 A CN201510065736 A CN 201510065736A CN 104610182 B CN104610182 B CN 104610182B
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- amorphous substance
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- triaizine compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of triaizine compounds amorphous substance with coccidiostat activity and its production and use.The compound amorphous substance is characterized with its X ray powder diffraction pattern and attenuated total reflectance infrared spectrogram.Preparation method be by the triaizine compounds 230 DEG C～250 DEG C heating melting after, naturally cool to room temperature, grind.The obtained compound amorphous substance can be applicable to prepare in anti-chicken coccidiosis medicine, and its dissolution faster, during use is easier to mix.
Description
Technical field
The present invention relates to compound amorphous substance and preparation method thereof and the application in chicken coccidiosis medicine is prepared.
Background technology
As the molecules align rule of solid drugs is different, molecular configuration or conformation have differences, a kind of medicine can be with shape
Into two or more solid matter existing forms, this phenomenon is referred to as the polymorphism of medicine.Amorphous (amorphous) state
A kind of special material crystal formation, be polymorph medicine a kind of existence form (Ying Jian, Lv Yang, Du Guanhua. solid drugs are without fixed
The progress of shape state. Acta Pharmaceutica Sinica, 2009,44 (5):443-448).Document (Konno T.Chem.Pharm.Bull.,
1990,38:Report in 2003-2007) compared with crystal form, amorphous (amorphous state) form in many medicines shows
Dissolution characteristics, and different biological utilisation patterns are shown in some situations.For some treatment cards, certain biological utilisation pattern
May be more favourable than another kind.It is therefore desirable to there is the method that crystalline azithromycin is changed into amorphous (amorphous state) form.
Patent of invention CN103554046A discloses a kind of triaizine compounds (formula (I) compound) with anti-chicken coccidiosis
And its production and use.
In view of formula (I) compound has the pharmacy value of higher coccidiostat activity, which is added in feedstuff applies, and is adding
Plus concentration is that its anticoccidial index is up to 189 under 10mg/kg.But the slightly solubility feature due to formula (I) compound, adds use
Dosage relatively low (5-20PPM), prepare and using when be difficult to mix, its preparation such as pre-mixing agent is difficult mixing causes uniformity of dosage units not
Ideal, is unfavorable for using and promoting for medicine.
Content of the invention
It is an object of the invention to provide the amorphous triazines chemical combination that a kind of dissolution faster, during use is easily mixed
Thing, the preparation method of the amorphous substance.
Further object is that providing application of the amorphous compound in anti-chicken coccidiosis medicine is prepared.
The object of the present invention is achieved like this：
A kind of triaizine compounds (formula (I) compound), the compound has formula：
The amorphous substance of formula (I) compound, its X-ray powder diffraction figure is as shown in Figure of description 2.Its attenuated total reflectance
The characteristic absorption that infrared spectrum shows is as follows：3044cm-1、1697cm-1、1605cm-1、1537cm-1、1490cm-1、1403cm-1、
1339cm-1、1307cm-1、1242cm-1、1218cm-1、1171cm-1、1109cm-1、819cm-1、741cm-1And 686cm-1.
For preparing formula (I) compound of amorphous formula (I) compound, " a kind of with anti-chicken coccidiosis by patent of invention
Triaizine compounds " (application number：CN201310552795 preparation method) is obtained, formula (I) the compound N of synthesis, N- bis-
Methylformamide-crystal's system, determines through high performance liquid chromatography (HPLC), and content is up to more than 98%.
The specific operation process for preparing amorphous formula (I) compound is：Take a certain amount of formula (I) compound, 230 DEG C～
After 250 DEG C of heating meltings, room temperature is naturally cooled to, grinding obtains the amorphous substance of formula (I) compound.
Feature is determined through x-ray powder diffraction and Attenuated Total Reflect ion Infrared Spectroscopy.
Unbodied formula (I) compound of the invention, discloses formula (I) change that method is obtained with patent of invention CN103554046A
Compound is compared, and increased its water solublity and stripping property, be respectively adopted the 0.1mol/L that dissolution medium pH is 1 aqueous hydrochloric acid solution,
PH is 4.5 acetate buffer and phosphate buffer that pH is 7.4, with slurry processes in 100 revs/min of rotating speed, water-bath temperature
Under conditions of spending for 37 DEG C ± 0.5 DEG C, the intrinsic dissolution test ratio of formula (I) compound and unbodied formula (I) compound is carried out
Compared with, as a result see Fig. 1, it is seen that unbodied formula (I) compound 0-24 hours intrinsic dissolution substantially than for making
Formula (I) compound of standby amorphous formula (I) compound fast.Meanwhile, the preparation side of unbodied formula (I) compound of the present invention
Method can effectively be removed the organic solvent in formula (I) compound, be significantly reduced organic solvent residual using the method for high-temperature fusion
Stay, improve Drug safety.
In addition, bean cake powder is respectively adopted is prepared into amorphous formula (I) the compound pre-mixing agent that specification is 0.5% as carrier
With formula (I) the compound pre-mixing agent for preparing amorphous formula (I) compound, 5 samples of respectively asking for respectively, using liquid chromatography
(hplc) Determination of Content Uniformity is carried out, as a result finds the relative standard deviation of the content of amorphous formula (I) compound pre-mixing agent
RSD is 3.23%, and prepares relative standard deviation RSD of the content of formula (I) the compound pre-mixing agent of amorphous formula (I) compound
For 4.67%, the pre-mixing agent prepared with amorphous formula (I) compound is described, its uniformity of dosage units is high.
The amorphous compound in triazine class dissolution of the present invention faster, during use is easier to mix.
Description of the drawings
Fig. 1 is the intrinsic stripping curve of amorphous formula (I) compound and formula (I) compound under the dissolution medium of different pH
Figure；
Powder x-ray diffraction collection of illustrative plates figures of the Fig. 2 for formula (I) compound amorphous substance；
Powder x-ray diffraction collection of illustrative plates figures of the Fig. 3 for formula (I) compound；
Attenuated total reflectance infrared spectrograms of the Fig. 4 for formula (I) compound amorphous substance；
Attenuated total reflectance infrared spectrograms of the Fig. 5 for formula (I) compound.
Specific embodiment
Following examples be in order to demonstrate the invention, but be not enough to limit the present invention be able in other common modes
Realize.
Embodiment 1
The preparation of formula (I) compound amorphous substance
10 grams of formula (I) compound, is heated to 230 DEG C, to sample fine melt, is incubated 10min, naturally cools to room temperature, uses
After grinding grinds, 60 mesh standard sieves are crossed, off-white powder is obtained.Its powder x-ray diffraction collection of illustrative plates and attenuated total reflectance infrared spectrum
See accompanying drawing 2 and accompanying drawing 4.
Embodiment 2
The preparation of formula (I) compound amorphous substance
10 grams of formula (I) compound, is heated to 240 DEG C, to sample fine melt, is incubated 10min, naturally cools to room temperature, uses
After grinding grinds, 60 mesh standard sieves are crossed, off-white powder is obtained.Its attenuated total reflectance infrared spectrum is consistent with 4 feature of accompanying drawing.
Embodiment 3
The preparation of formula (I) compound amorphous substance
10 grams of formula (I) compound, is heated to 250 DEG C, to sample fine melt, is incubated 10min, naturally cools to room temperature, uses
After grinding grinds, 60 mesh standard sieves are crossed, off-white powder is obtained.Its attenuated total reflectance infrared spectrum is consistent with 4 feature of accompanying drawing.
Embodiment 4
The preparation of formula (I) compound amorphous substance pre-mixing agent
Formula (I) compound amorphous substance 10g, plus bean cake powder 2000g is taken, the formula that obtains final product that stirs (I) compound is amorphous
Thing pre-mixing agent.Before use, take appropriate, plus chicken mixed feed stir in right amount be prepared into 10mg/kg concentration containing formula (I) chemical combination
The feedstuff of thing amorphous substance is used, and its anticoccidial index reaches 198.
Claims (4)
1. a kind of amorphous substance of formula (I) compound, its powder x-ray diffraction collection of illustrative plates is as shown in Figure of description 2：
2. a kind of amorphous substance of the formula of claim 1 (I) compound, the characteristic absorption that its attenuated total reflectance infrared spectrum shows
As follows：3044cm-1、1697cm-1、1605cm-1、1537cm-1、1490cm-1、1403cm-1、1339cm-1、1307cm-1、
1242cm-1、1218cm-1、1171cm-1、1109cm-1、819cm-1、741cm-1And 686cm-1.
3. the preparation method of formula (I) compound amorphous substance described in a kind of claim 1, it is characterised in that：By formula (I) compound
After 230 DEG C～250 DEG C heating meltings, room temperature is naturally cooled to, ground.
4. purposes of the amorphous substance of formula described in claim 1 (I) compound in anti-chicken coccidiosis medicine is prepared.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510065736.1A CN104610182B (en) | 2015-02-09 | 2015-02-09 | A kind of amorphous substance of triaizine compounds and its production and use |
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| CN201510065736.1A CN104610182B (en) | 2015-02-09 | 2015-02-09 | A kind of amorphous substance of triaizine compounds and its production and use |
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| Publication Number | Publication Date |
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| CN104610182A CN104610182A (en) | 2015-05-13 |
| CN104610182B true CN104610182B (en) | 2017-03-15 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110292561A (en) * | 2019-07-12 | 2019-10-01 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | A kind of oral pharmaceutical solutions formula and preparation with Anti-human globulin test |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050202A (en) * | 2007-05-18 | 2007-10-10 | 中国农业科学院上海兽医研究所 | Compound in triazine class for anti activity of coccidian, preparation method and application |
| CN101407499A (en) * | 2008-11-10 | 2009-04-15 | 中国农业科学院上海兽医研究所 | Triazine compounds having coccidiostat activity and preparation thereof |
| CN102285930A (en) * | 2011-08-12 | 2011-12-21 | 中国农业科学院上海兽医研究所 | Triazine compound and application thereof to chicken coccidiosis disease control |
| CN103554046A (en) * | 2013-11-08 | 2014-02-05 | 中国农业科学院上海兽医研究所 | Chicken coccidiosis preventing triazine compound |
-
2015
- 2015-02-09 CN CN201510065736.1A patent/CN104610182B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101050202A (en) * | 2007-05-18 | 2007-10-10 | 中国农业科学院上海兽医研究所 | Compound in triazine class for anti activity of coccidian, preparation method and application |
| CN101407499A (en) * | 2008-11-10 | 2009-04-15 | 中国农业科学院上海兽医研究所 | Triazine compounds having coccidiostat activity and preparation thereof |
| CN102285930A (en) * | 2011-08-12 | 2011-12-21 | 中国农业科学院上海兽医研究所 | Triazine compound and application thereof to chicken coccidiosis disease control |
| CN103554046A (en) * | 2013-11-08 | 2014-02-05 | 中国农业科学院上海兽医研究所 | Chicken coccidiosis preventing triazine compound |
Non-Patent Citations (1)
| Title |
|---|
| Identification of in vitro metabolites of a new anticoccidial drug nitromezuril using HepG2 cells, rat S9 and primary hepatocytes by liquid chromatography/tandem mass spectrometry;Keyu Zhang，等;《Rapid Communications in Mass Spectrometry》;20141231;第28卷(第15期);第1723-1734页 * |
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