CN104130207B - Acotiamide hydrobromide hydrate and the preparation method of crystal formation thereof - Google Patents
Acotiamide hydrobromide hydrate and the preparation method of crystal formation thereof Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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Abstract
nullThe present invention relates to I crystal formation of a kind of Acotiamide hydrobromide hydrate and preparation method thereof，Specifically，The present invention relates to the preparation method of a kind of Acotiamide hydrobromide hydrate I crystal formation，Characterized by X powder diffraction，Described Acotiamide I crystal formation is at 6.26 ° ± 0.2 °、9.64±0.2°、10.94°±0.2°、12.51°±0.2°、14.22°±0.2°、15.05°±0.2°、16.36°±0.2°、16.77°±0.2°、17.84°±0.2°、19.30°±0.2°、20.33°±0.2°、20.60°±0.2°、22.91°±0.2°、23.75°±0.2°、There is X-ray diffraction peak in 24.46 ° ± 0.2 ° and 26.08 ° ± 0.2 ° (2 θ).I crystal formation of the Acotiamide hydrobromide hydrate of the present invention can be used in treating the diseases such as functional dyspepsia.
Description
Technical field
The invention belongs to the field of chemical synthesis, specifically, the present invention relates to Acotiamide hydrobromide hydrate and crystal formation thereof
Preparation method.
Background technology
Acotiamide (compound shown in Formulas I) is first the functional dyspepsia medicine for treatment in the whole world, by Japan Ze Lixin
Medicine Co., Ltd. develops, and lists in Japan's approval in February, 2013.Being applicable to feeling of repletion after the meal, functional digestive is not
Good, epigastrium is glutted, the treatment of early satiety.
But, the method preparing Acotiamide crystal formation at present, still have much room for improvement.
Summary of the invention
It is contemplated that solve one of above-mentioned technical problem the most to a certain extent or provide at a kind of useful business choosing
Select.To this end, it is an object of the present invention to propose a kind of Acotiamide hydrobromide hydrate and I crystal formation thereof and for treating
Functional dyspepsia and be used for improving gastric motility disorder, delayed gastric emptying, thus improve FD symptom, including post-prandial fullness,
Big belly, the purposes such as early satiety provides space.
In the first aspect of the invention, powder x-ray diffraction research is widely used in and illustrates molecular structure, crystallization and polycrystalline
Type phenomenon, with the Philips APD3720 of the detector that shines equipped with 3KW x-ray generator (CuK α 1 radiates) and NaI (Ti)
Type powder diffractometer record powder X-ray (XRD), is measured from 3～45 ° (2 θ).Sample is maintained at ambient temperature.
According to embodiments of the invention, the X-ray powder diffraction figure of described Acotiamide hydrobromide hydrate I crystal formation exists
6.26°±0.2°、9.64±0.2°、10.94°±0.2°、12.51°±0.2°、14.22°±0.2°、15.05°±0.2°、16.36°±0.2°、
16.77°±0.2°、17.84°±0.2°、19.30°±0.2°、20.33°±0.2°、20.60°±0.2°、22.91°±0.2°、23.75°±0.2°、
There is X-ray diffraction peak in 24.46 ° ± 0.2 ° and 26.08 ° ± 0.2 ° (2 θ).Thus can improve Acotiamide hydrobromide hydrate
The purity of I crystal formation.
It addition, according to embodiments of the invention, I crystal formation of described Acotiamide hydrobromide hydrate can also have as follows
Additional technical characteristic:
According to embodiments of the invention, described Acotiamide hydrobromic acid hydrate sample is at DSC (TGA) (STA449F3
Synchronous solving Germany Nai Chi instrument manufacturing company limited) figure showing, its about 74.8 DEG C have an endothermic peak, weightless 3.11%,
For a part water, about 184.9 DEG C fusings.By through may determine that in this sample containing a water of crystallization, and purity is higher.
According to embodiments of the invention, I crystal formation of above-mentioned Acotiamide hydrobromide hydrate contains at least 99.5% weight
Acotiamide hydrobromide hydrate, thus can improve the purity of Acotiamide hydrobromide hydrate I crystal formation further.
Optionally, containing compound shown in 0.5% weight below formula I
Thus, it is possible to improve the purity of Acotiamide hydrobromide hydrate I crystal formation further.
According to embodiments of the invention, I crystal formation of above-mentioned Acotiamide hydrobromide hydrate is controlled as functional dyspepsia
Treat medication.Thus can improve the therapeutic effect of Acotiamide.
In a second aspect of the present invention, the present invention proposes a kind of Acotiamide hydrobromide hydrate preparing above-described embodiment
The method of I crystal formation, the method includes: Acotiamide mixed with organic solvent, in order to obtain containing Acotiamide and organic
First mixture of solvent；Salt-forming reaction is carried out, in order to obtain and replace containing Ah examining by described first mixture adds into salt solvent
Second mixture of amine hydrobromate；Described second mixture is filtered, filter cake organic solvent washing, be dried, in order to obtain
The 3rd mixture containing Acotiamide hydrobromate crude product；Described 3rd mixture is dissolved in aqueous organic solvent, adds
Slow cooling crystallize after heat of solution, in order to obtain the 4th mixture of Acotiamide hydrobromide hydrate crystal；And from described
4th mixture separates described crystal, and heats at 20～90 DEG C of crystal to being separated, in order to obtain Acotiamide hydrogen
Bromate monohydrate I crystal formation.
It addition, method according to the above embodiment of the present invention can also have a following additional technical characteristic:
According to embodiments of the invention, described organic solvent be selected from methanol, ethanol, isopropanol, ethyl acetate, oxolane, third
Ketone, t-butyl methyl ether, methyltetrahydrofuran at least one, preferably methanol, ethanol, isopropanol, ethyl acetate, tetrahydrochysene furan
Mutter, at least one in acetone, t-butyl methyl ether, most preferably methanol, ethanol, isopropanol at least one.
According to embodiments of the invention, described one-tenth salt solvent is hydrobromic acid aqueous solution.
According to embodiments of the invention, gross weight based on described hydrobromic acid aqueous solution, described hydrobromic content be 10%～
40% weight, hydrobromic content is preferably 30%～40% weight.
According to embodiments of the invention, described salt-forming reaction temperature is 30～100 DEG C, preferably 50～80 DEG C, most preferably 70～
80℃。
According to embodiments of the invention, solvent selected from methanol, ethanol, isopropanol, tetrahydrochysene furan in described aqueous organic solvent
Mutter, in acetone at least one, preferably methanol, ethanol, isopropanol, oxolane, most preferably methanol, ethanol, isopropanol
At least one.In described organic solvent, organic solvent volume ratio is 10%～90% volume, preferably 40%～90% volume,
Most preferably 60%～90% volume.
According to a particular embodiment of the invention, after separating described crystal from described 4th mixture, preferably right at 20～70 DEG C
The crystal separated heats, and most preferably heats at 30～60 DEG C of crystal to being separated.Thus can obtain further
High-purity Acotiamide hydrobromide hydrate I crystal formation.
Compared with prior art, it is an advantage of the current invention that: prepare a kind of Acotiamide hydrobromate one not having document to report
Hydrate, and show that it is the crystal-form compound not having document to report through XRD data, this compound can stable existence,
Therefore can be as a kind of medicinal hydrochlorate of new Acotiamide.
Additional aspect of the present invention and advantage will part be given in the following description, and part will become bright from the following description
Aobvious, or recognized by the practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or the additional aspect of the present invention and advantage will be apparent from from combining the accompanying drawings below description to embodiment
With easy to understand, wherein:
Fig. 1 is the HPLC-UV detection of the Acotiamide hydrobromide monohydrate according to the embodiment of the present invention；
Fig. 2 is the DSC figure of the Acotiamide hydrobromide monohydrate (I crystal formation) according to the embodiment of the present invention；
Fig. 3 is the hydrogen spectrum of the Acotiamide hydrobromide monohydrate according to the embodiment of the present invention；
Fig. 4 is the X-ray diffractogram of the Acotiamide hydrobromide monohydrate (I crystal formation) according to the embodiment of the present invention；
Fig. 5 is the DSC figure of the Acotiamide hydrochlorate trihydrate (I crystal formation) according to the embodiment of the present invention.
Detailed description of the invention
Embodiments of the invention are described below in detail, it should be noted that the embodiments described below is exemplary, be only used for
Explain the present invention, and be not considered as limiting the invention.It addition, without clearly stating, in the following embodiments
The all reagent used are on market commercially available, or can synthesize according to text or known method, for not having
There is the reaction condition listed, be also what those skilled in the art were readily available.
Conventional method
With reference to following formula, in the examples below that, the method for preparation Acotiamide hydrobromide hydrate mainly comprises the steps that
(1) weigh free state Acotiamide, after adding organic solvent heating for dissolving, add into salt solvent, stirring, natural cooling；
(2) filter, filter cake organic solvent washing, dry, obtain Acotiamide hydrobromate crude product；
(3) by Acotiamide dissolving crude product in aqueous organic solvent, slow cooling crystallize after heating for dissolving, stirring, filter,
In the range of 20～90 DEG C, the crystal separated is heated, obtain I crystal formation of Acotiamide hydrobromide monohydrate.
The specific embodiment of patent of the present invention is as follows:
The synthesis of embodiment 1 Acotiamide hydrobromide hydrate
The preparation of step (1) Acotiamide hydrobromate crude product
Take 3.0g free state Acotiamide, add 30ml isopropanol, be heated to 50 DEG C of dissolvings.At this temperature, add 4g,
35% hydrobromic acid aqueous solution, stirs 5h, naturally cools to 15 DEG C.Filtering, filter cake 20ml isopropanol washs.At 50 DEG C of bars
Dry under part.Finally give 2.7g Acotiamide hydrobromate crude product.
Refining of step (2) Acotiamide hydrobromate
Taking the Acotiamide hydrobromic acid crude product 2.6g of above-mentioned preparation, adding 25ml volume ratio is 60% isopropanol water solution, adds
Heat is to 70 DEG C of dissolvings.Stirring 4h.Filtering, filter cake 10ml isopropanol washs.Then under the conditions of 40 DEG C, it is dried 4h.Finally
Obtain 2.4g Acotiamide hydrobromic acid hydrate.HPLC purity assay is 99.5%, and HPLC collection of illustrative plates is as shown in Figure 1.Moisture
KF value 3.33%, through DSC-TGA atlas analysis, it has an endothermic peak at about 74.8 DEG C, and weightless 3.11%, for a part water,
About 184.9 DEG C fusings, as shown in Figure 2.
Preparation for Acotiamide hydrobromic acid monohydrate.
Target product1H-NMR (400MHz DMSO-d6): δ 1.30-1.33 (m, 12H), 3.20-3.25 (m, 2H),
3.56-3.61 (m, 2H), 3.67-3.70 (t, 2H), 3.77-3.84 (ss, 6H), 6.69-6.70 (s, 1H), 7.51-7.52 (s,
1H), 7.91-7.95 (s, 1H), 8.63-8.68 (m, 2H), 11.68-11.69 (s, 1H), 11.74-11.76 (s, 1H), such as figure
Shown in 3.
Through XRD analysis, prepared sample about 6.26 ± 0.2,9.64 ± 0.2,10.94 ± 0.2,12.51 ± 0.2,14.22 ± 0.2,
15.05±0.2、16.36±0.2、16.77±0.2、17.84±0.2、19.30±0.2、20.33±0.2、20.60±0.2、22.91±0.2、
There is the absworption peak of key at 23.75 ± 0.2,24.46 ± 0.2 and 26.08 ± 0.2 (2 θ) place.It is I crystal formation, as shown in Figure 4.
The synthesis of embodiment 2 Acotiamide hydrobromide hydrate
The preparation of step (1) Acotiamide hydrobromate
Take 30g free state Acotiamide, add 300ml isopropanol, be heated to 70 DEG C of dissolvings.At this temperature, add
35g40% hydrobromic acid aqueous solution, stirs 5h, naturally cools to 15 DEG C.Filtering, filter cake 100ml isopropanol washs.At 70 DEG C
Under the conditions of dry.Finally give 28.8g Acotiamide hydrobromate crude product.
The preparation of step (2) Acotiamide hydrobromide hydrate
Taking the Acotiamide hydrobromic acid crude product 28.8g of above-mentioned preparation, adding 300ml volume ratio is 80% isopropanol water solution,
It is heated to 70 DEG C of dissolvings.Stirring 4h.Filtering, filter cake 100ml isopropanol washs.Then under the conditions of 40 DEG C, it is dried 4h.
Finally give 24g Acotiamide hydrobromic acid hydrate.Purity 99.5%, moisture KF value 3.33%, divide through DSC-TGA collection of illustrative plates
Analysis, preparation for Acotiamide hydrobromic acid monohydrate.Through XRD analysis, prepared sample is I crystal formation.
Embodiment 3 Acotiamide hydrobromide hydrate physicochemical property
In embodiment 2, gained Acotiamide hydrobromide monohydrate surveys fusing point.Measuring instrument is VRR type melting point apparatus, surveys
Definite value is 182.6-186.6 DEG C.
The sample obtained in embodiment 2 is done DSC-TGA detection, spectrogram such as accompanying drawing 4: Acotiamide hydrochloric acid acid hydrate
Sample shows that in DSC (TGA) figure its about 74.8 DEG C have endothermic peak, and weightlessness 3.11%, for a part water, 184.9 DEG C of left sides
Right fusing.By through may determine that in this sample containing 1 water of crystallization, and purity is higher.
Embodiment 4 Acotiamide hydrobromic acid monohydrate stability under high humidity and hot conditions and and Acotiamide salt
The stability contrast under high humidity and hot conditions of hydrochloride-hydrate, trihydrate
In embodiment 2, gained Acotiamide hydrobromic acid hydrate is determined to monohydrate.Then this sample is individually positioned in
Investigating its stability under high temperature and super-humid conditions, in this embodiment, high humidity environment is the exsiccator being placed with saturated sodium-chloride water solution.
Hot environment is 60 DEG C of air dry ovens.
Table 1 Acotiamide hydrobromic acid monohydrate is the change of water content under high humidity environment (25 DEG C, humidity 75%)
| Standing time | Moisture KF value | Hydrate type |
| 0day | 3.33% | Monohydrate |
| 2day | 3.58% | Monohydrate |
| 7day | 3.30% | Monohydrate |
| 14day | 3.47% | Monohydrate |
Table 2 Acotiamide hydrobromic acid monohydrate is the change of water content under hot environment (60 DEG C, humidity ＜ 40%)
| Standing time | Moisture KF value | Hydrate type |
| 0h | 3.47% | Monohydrate |
| 5h | 3.56% | Monohydrate |
| 18h | 3.23% | Monohydrate |
| 20h | 3.35% | Monohydrate |
It is known that prepared Acotiamide hydrobromic acid monohydrate all can be stablized under high temperature and super-humid conditions from table
Exist.
Acotiamide hydrochloride monohydrate and trihydrate are in the stability under high humidity and hot conditions
According to the process conditions indicated in technique patent CN101006040B that Ze Li new drug Co., Ltd. of Japan announces, we
Preparing Acotiamide hydrochloride monohydrate and Acotiamide hydrochlorate trihydrate, in this embodiment, high humidity environment is for being placed with
The exsiccator of saturated sodium-chloride water solution.Hot environment is 60 DEG C of air dry ovens.
The change of water content under high humidity environment of table 3 Acotiamide hydrochloride monohydrate
| Standing time | Moisture KF value | Hydrate type |
| 0day | 3.6% | Monohydrate |
| 4day | 9.70% | Monohydrate |
| 15day | 9.85% | Monohydrate |
| 30day | 10.03% | Monohydrate |
The change of table 4 Acotiamide hydrochlorate trihydrate water content in high temperature environments
| Standing time | Moisture KF value | Hydrate type |
| 0h | 10.03% | Trihydrate |
| 5h | 6.54% | Trihydrate |
| 18h | 4.30% | Trihydrate |
| 20h | 3.30% | Trihydrate |
It is known that prepared Acotiamide hydrochlorate exists monohydrate, dihydrate and trihydrate from table, and
Trihydrate is stable under conditions of high humidity, but unstable under the high temperature conditions, therefore, prepares stable Acotiamide hydrochlorate three
Hydrate will strengthen the requirement of production technology and eqUipment.And Acotiamide hydrobromic acid monohydrate energy under high temperature and super-humid conditions
Enough stable existences.Comparatively speaking, Acotiamide hydrobromic acid monohydrate more has advantage.
Embodiment 5 Acotiamide hydrobromide monohydrate and Acotiamide hydrochlorate trihydrate heat differential thermogravimetric analysis
The sample obtained in embodiment 1 is DSC-TGA detect, spectrogram such as accompanying drawing 4: from collection of illustrative plates, prepared
Sample be monohydrate, it has an endothermic peak at about 74.8 DEG C, weightless 3.11%, follow-up do not have weightless change substantially, shows
It contains a part water, about 184.9 DEG C fusings.
The sample obtained in embodiment 4 is DSC-TGA detect, spectrogram such as accompanying drawing 5: from collection of illustrative plates, prepared
Sample be trihydrate, it has an endothermic peak at about 70 DEG C, weightless 6.48%, show that it contains two molecular waters,
122.1-143.6 DEG C has endothermic peak, weightlessness 3.27%, shows that it contains a part water, 152.6-167.0 DEG C of fusing.
The pharmacokinetics of embodiment 6 Oral Administration in Rats Acotiamide hydrobromate
Tested raw material: the Acotiamide hydrobromide monohydrate of embodiment 1 synthesis and acotiamide hydrochloride hydrate three water of our synthesis
Compound
Packet is administered
Select Wistar rat 40, be divided into 4 groups by body weight, often group 10, male and female dual-purpose, fasting 16h, each component
Other oral administration gavage Acotiamide hydrobromide hydrate and acotiamide hydrochloride trihydrate, dosage is 20mg/kg.Respectively, give respectively
After medicine 0.5,1,2,4,6,8,12,18,24,36,48,60h eye frame take blood, separate serum ,-20 DEG C of preservations are to be measured
Chromatographic condition
Fixing phase: DiamonsilTM C18 post, 10 μm, 250 × 4.6mm (I.D.), column temperature 30 DEG C.
Flowing phase: methanol: water=70: 30, flow velocity: 1ml/min.
Detection wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
Blood sample treatments
Take rat blood serum 200 μ l, add internal standard (Acotiamide 200 μ g/ml) 10 μ l, after mixing, add DMF (N, N-diformazan
Base Methanamide) 200 μ l, vibrate 10min, places 30 minutes, with the centrifugation 10min of 10000 turns/min, takes supernatant
20 μ l sample introductions.
Determination of plasma concentration
After bioassay standard curve, draw linear regression equation (y=ax+b).Measure blood sample gained peak area after rat is administered
Ratio, calculates blood drug level according to linear regression equation, and calculates medicine for parameter through 3P97 medicine for calculation procedure.
Instrument
HPLC tests system: Shimadzu SPD-10AUv detector, Hi-Tech P4000 high-pressure pump, Lab Alliance-
AS1000 automatic sampler, ANASTAR chromatographic work station.
HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai manufactures.
WX-80A miniature vortex mixed instrument: Shanghai Hu Xi analytical tool factory produces.
Result of study
Note: in table, data are average ± standard deviation (n=6).
Conclusion: the pharmacokinetic after Oral Administration in Rats Acotiamide hydrobromide monohydrate raw material shows, Oral Administration in Rats
Examining for amine hydrobromide monohydrate of gavage 20mg/kg, from medicine for parameter, between parameters, there is some difference,
But the most all in the range of the same order of magnitude, may be used for developing into new medicine, and this Stability Analysis of Structures, in animal body
Absorption, eliminate basically identical.
Therefore, the Acotiamide hydrobromate that the embodiment of the present invention 1 prepares is at preparation treatment functional dyspepsia medicine
Aspect shows higher biological activity, provides broad space for Subsequent pharmacological exploitation.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " concrete example "
Or specific features, structure, material or the feature that the description of " some examples " etc. means to combine this embodiment or example describes comprises
In at least one embodiment or example of the present invention.In this manual, the schematic representation to above-mentioned term not necessarily refers to
It is identical embodiment or example.And, the specific features of description, structure, material or feature can at any one or
Multiple embodiments or example combine in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is exemplary,
Being not considered as limiting the invention, those of ordinary skill in the art is in the case of without departing from the principle of the present invention and objective
Above-described embodiment can be changed within the scope of the invention, revise, replace and modification.
Claims (19)
1. I crystal formation of an Acotiamide hydrobromide hydrate, it is characterised in that the X-ray powder diffraction figure of described I crystal formation exists
6.26°±0.2°、9.64±0.2°、10.94°±0.2°、12.51°±0.2°、14.22°±0.2°、15.05°±0.2°、16.36°±0.2°、
16.77°±0.2°、17.84°±0.2°、19.30°±0.2°、20.33°±0.2°、20.60°±0.2°、22.91°±0.2°、23.75°±0.2°、
There is X-ray diffraction peak in 24.46 ° ± 0.2 ° and 26.08 ° ± 0.2 ° (2 θ)；
Described I crystal formation is Acotiamide hydrobromide monohydrate, and described Acotiamide hydrobromide monohydrate has at about 74.8 DEG C
Endothermic peak, weightless 3.11%, for a part water, about 184.9 DEG C fusings.
I crystal formation of Acotiamide hydrobromide hydrate the most according to claim 1, it is characterised in that containing at least 99.5%
The Acotiamide hydrobromide hydrate of weight,
I crystal formation of Acotiamide hydrobromide hydrate the most according to claim 2, it is characterised in that containing 0.5% weight with
Under Formulas I shown in compound
Formulas I.
4. I crystal formation of the Acotiamide hydrobromide hydrate described in claim 1 or 2 purposes in preparing medicine, described medicine
For treating functional dyspepsia.
5. the method for I crystal formation of the Acotiamide hydrobromide hydrate that a kind is prepared described in claim 1 or 2, it is characterised in that
Including:
Acotiamide is mixed with organic solvent, in order to obtain containing Acotiamide and the first mixture of organic solvent；
Salt-forming reaction is carried out, in order to obtain the containing Acotiamide hydrobromate by described first mixture adds hydrobromic acid aqueous solution
Two mixture；
Described second mixture is filtered, filter cake organic solvent washing, be dried, in order to obtain containing Acotiamide hydrobromate crude product
The 3rd mixture；
Described 3rd mixture is dissolved in aqueous organic solvent, slow cooling crystallize after heating for dissolving, in order to obtain Acotiamide
4th mixture of hydrobromide hydrate crystal；And separate described crystal from described 4th mixture, and at 20～90 DEG C
The crystal separated is heated, in order to obtain I crystal formation of described Acotiamide hydrobromide hydrate,
I crystal formation of described Acotiamide hydrobromide hydrate is Acotiamide hydrobromide monohydrate.
Method the most according to claim 5, it is characterised in that described organic solvent is selected from methanol, ethanol, isopropanol, second
Acetoacetic ester, oxolane, acetone, t-butyl methyl ether, methyltetrahydrofuran at least one.
Method the most according to claim 6, it is characterised in that described organic solvent is selected from methanol, ethanol, isopropanol, second
At least one in acetoacetic ester, oxolane, acetone, t-butyl methyl ether.
Method the most according to claim 6, it is characterised in that described organic solvent is selected from methanol, ethanol, isopropanol extremely
Few one.
Method the most according to claim 5, it is characterised in that the concentration of described hydrobromic acid aqueous solution is 10%～40% weight.
Method the most according to claim 9, it is characterised in that the concentration of described hydrobromic acid aqueous solution is 30%～40% weight.
11. methods according to claim 5, it is characterised in that the temperature of described salt-forming reaction is 30～100 DEG C.
12. methods according to claim 11, it is characterised in that the temperature of described salt-forming reaction is 50～80 DEG C.
13. methods according to claim 11, it is characterised in that the temperature of described salt-forming reaction is 70～80 DEG C.
14. methods according to claim 5, it is characterised in that in described aqueous organic solvent organic solvent selected from methanol,
In ethanol, isopropanol, oxolane, acetone at least one.
15. methods according to claim 14, it is characterised in that in described aqueous organic solvent organic solvent selected from methanol,
Ethanol, isopropanol, oxolane at least one.
16. methods according to claim 14, it is characterised in that in described aqueous organic solvent organic solvent selected from methanol,
Ethanol, isopropanol at least one.
17. methods according to claim 5, it is characterised in that in described aqueous organic solvent organic solvent account for 10%～
90% volume.
18. methods according to claim 17, it is characterised in that in described aqueous organic solvent organic solvent account for 40%～
90% volume.
19. methods according to claim 17, it is characterised in that in described aqueous organic solvent organic solvent account for 60%～
90% volume.
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| CN104698106B (en) * | 2015-03-21 | 2016-06-29 | 石家庄四药有限公司 | A kind of chemicals acotiamide hydrochloride hydrate has the detection method of related substance |
| CN105481791B (en) * | 2015-12-09 | 2017-10-24 | 北京科莱博医药开发有限责任公司 | A kind of crystal formation of acotiamide hydrochloride amine dihydrate and preparation method and application |
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