CN110483597A - Pseudo-polymorphic, preparation method and its application of Arbekacin hydrochloride - Google Patents
Pseudo-polymorphic, preparation method and its application of Arbekacin hydrochloride Download PDFInfo
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- CN110483597A CN110483597A CN201910840067.9A CN201910840067A CN110483597A CN 110483597 A CN110483597 A CN 110483597A CN 201910840067 A CN201910840067 A CN 201910840067A CN 110483597 A CN110483597 A CN 110483597A
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- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
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Abstract
The invention discloses pseudo-polymorphic, preparation method and its applications of a kind of Arbekacin hydrochloride.Its described polymorphs show have 2 θ ° be 7.6 ± 0.2, 9.6 ± 0.2, 10.2 ± 0.2, 11.5 ± 0.2, 14.0 ± 0.2, 14.5 ± 0.2, 15.1 ± 0.2, 16.3 ± 0.2, 17.3 ± 0.2, 19.3 ± 0.2, 19.7 ± 0.2, 20.0 ± 0.2, 23.0 ± 0.2, 23.4 ± 0.2, 25.0 ± 0.2, 25.3 ± 0.2, 26.1 ± 0.2, 27.0 ± 0.2, 28.1 ± 0.2, 28.9 ± 0.2, 33.2 ± 0.2, 35.6 ± 0.2, 37.2 ± 0.2, 38.6 ± 0.2, 39.0 ± 0.2, 40.0 ± 0.2, 41.0 ± 0.2, The X-ray powder diffraction pattern of 42.3 ± 0.2,43.3 ± 0.2,45.5 ± 0.2 characteristic peaks indicated.
Description
Technical field
The present invention relates to the pseudo-polymorphic II of novel Arbekacin hydrochloride, preparation method and its produce it is high-purity
Application in terms of the Arbekacin free alkali of degree.
Background technique
Arbekacin (free alkali) is the compound with following structures, its sulfate is used for golden yellow by methicillin-resistant
The treatment of pneumonia caused by color staphylococcus, septicemia.
In general, Arbekacin sulfate is by using according to Japanese public clear 52-33629 bulletin (patent document 1) etc.
The Arbekacin free alkali of the method synthesis of record, sulfuric acid is added into the aqueous solution of the Arbekacin free alkali, is then carried out
Freeze-drying, thus obtain in solid form.In this case, synthesized Arbekacin free alkali by chromatography into
Row purification.However, in order to improve refining effect, it usually needs a large amount of resin, the concentration for needing the stage to sexually revise eluent are come
It removes similar substance, need a large amount of eluent, and operate and need long-time etc., institute is inefficent in this way.In addition, by
The Arbekacin sulfate that this method obtains contains the similar substances such as 1 ~ 2% or so dibekacin.
Arbekacin can also be not transitioning to the pharmaceutical salt as sulfate, and make as Arbekacin free alkali
With.In addition, Arbekacin free alkali can also be changed into the pharmaceutical salt other than sulfuric acid and utilize.However, Arbekacin
Free alkali is easy to decompose, and generates dibekacin.Therefore cryo-conservation is needed, is industrially unfavorable.
In addition, a kind of method that CN105246907A manufactures Arbekacin free alkali with disclosing high-purity, that is, pass through to
Carbon dioxide, carbonate or bicarbonate are added in liquid containing Arbekacin free alkali, make the carbamic acid of Arbekacin
Derivative and Arbekacin carbonate are formed in a liquid together, it is made to be precipitated and separate, obtain include as solid form
The carbamic acid derivative of the Arbekacin of Arbekacin carbonate.But the method is inconvenient, refining effect is limited, and solid
Crystal form is very poor.
CN103826611A refers to Arbekacin hydrochloride, but does not refer to preparation method and crystal form, does not also refer to it
Application in terms of the Arbekacin free alkali of production high-purity.Other domestic and international patents do not find that this compound is polymorphous yet
Report.
Summary of the invention
The first purpose of this invention is to provide a kind of pseudo-polymorphic II of novel Arbekacin hydrochloride.Its feature
Be, the polymorphs show have 2 θ ° for 7.6 ± 0.2,9.6 ± 0.2,10.2 ± 0.2,11.5 ± 0.2,14.0 ±
0.2、14.5±0.2、15.1±0.2、16.3±0.2、17.3±0.2、19.3±0.2、19.7±0.2、20.0±0.2、
23.0±0.2、23.4±0.2、25.0±0.2、25.3±0.2、26.1±0.2、27.0±0.2、28.1±0.2、28.9±
0.2、33.2±0.2、35.6±0.2、37.2±0.2、38.6±0.2、39.0±0.2、40.0±0.2、41.0±0.2、
The X-ray powder diffraction pattern of 42.3 ± 0.2,43.3 ± 0.2,45.5 ± 0.2 characteristic peaks indicated.
Wherein " ± 0.2 " is the measurement error range allowed.
" pseudo-polymorphic " of the present invention refers to drug in crystallization, and solvent molecule is incorporated in lattice with stoichiometric ratio
In and constitute molecular complex；Also it can refer to solvate, when solvent is water, refer in particular to water solvates or crystal of hydrate.
It is above-mentioned that the pseudo-polymorphic II of Arbekacin hydrochloride of the present invention is characterized in that its X-ray powder diffraction pattern has
The characteristic peaks of 2 θ ° of expression, relative intensity is close to following numerical value:
Term " close " herein refers to the uncertainty of relative intensity measure value.Those skilled in the art understand relative intensity
Uncertainty is highly dependent on measuring condition.Relative intensity value can for example change in ± 50% range or preferably in ± 20% model
Enclose interior change.
Above-mentioned crystal pseudo-polymorphic II has X-ray powder diffraction pattern shown in FIG. 1, differential thermal analysis shown in Fig. 2
(DSC) map and thermogravimetric analysis shown in Fig. 3 (TGA) map.
Above-mentioned crystal pseudo-polymorphic II can use thermogravimetric analysis (TGA) Expressive Features.So Arbekacin salt of the invention
The pseudo-polymorphic II of hydrochlorate, it is characterised in that when being heated to 120 DEG C ~ 170 DEG C, in stepped weightless, weightless ratio is 5% ~
20%。
Another feature of this pseudo-polymorphic II be weightless object be water, therefore its be Arbekacin hydrochloride hydrate or
Water solvates.Its skeleton symbol is C22H44N6O10·nHCl·(H2O)m, n=3 ~ 5, m=2 ~ 10.Due to the hydration formed every time
Object enhydrous amount is not fixed, thus it is speculated that one molecule hydrochloride should contain 2 ~ 10 hydrones.
A second object of the present invention is to provide a kind of method for preparing above-mentioned pseudo-polymorphic II, the manufacturing method includes
Following processes:
Process (a): it is modulated by adding aqueous hydrochloric acid solution into the liquid containing Arbekacin free alkali containing Arbekacin
The liquid of hydrochloride.
Process (b): salt out the Arbekacin hydrochloric acid in liquid.
Process (c): make the Arbekacin hydrochloride being precipitated separation.
In process (a), as long as used solvent can dissolve Arbekacin free alkali, can be used water or
The mixing of water and methanol, ethyl alcohol, propyl alcohol, dimethyl sulfoxide, acetonitrile, pyridine, tetrahydrofuran, acetone or N,N-dimethylformamide
Solvent.Preferably water.As for the usage amount of solvent, as long as the amount of the Arbekacin free alkali as raw material can be dissolved, just
It is not particularly limited, is preferably ~ 200 times of amounts of 1.5 times of amounts relative to Arbekacin free alkali.To the liquid containing Arbekacin free alkali
Temperature when aqueous hydrochloric acid solution is added in body is not particularly limited, and can be implemented at ambient temperature, preferably 0 ~ 30 DEG C.The hydrochloric acid
The concentration of aqueous solution any concentration between 1 ~ 12mol/L, preferably 4 ~ 8mol/L.The final pH value of mother liquor is added dropwise to 1.0 ~ 7.0
Between.
In process (a), in the case where using the mixed liquor of water and organic solvent as solvent, by adding hydrochloric acid water
Arbekacin hydrochloride can be precipitated in liquid in solution, the addition without further organic solvent.In this case, process (a) with
Process (b) is integrally formed inseparable process.
In the case where using water as solvent in process (a), even if addition aqueous hydrochloric acid solution, Ah is not also precipitated in liquid
Bekaa star hydrochloride.So by that will be mixed by the liquid that process (a) is modulated with organic solvent, making Abbe in process (b)
Card star hydrochloric acid salts out.The organic solvent used in this case, without spy as long as Arbekacin hydrochloric acid can be made to salt out
It does not limit, is preferably selected from methanol, ethyl alcohol, propyl alcohol, dimethyl sulfoxide, acetonitrile, pyridine, tetrahydrofuran, acetone and N, N- diformazan
Single or mixed solvent in base formamide, further preferably methanol or ethyl alcohol.As for the usage amount of solvent, as long as can
The amount for salting out Arbekacin hydrochloric acid is just not particularly limited.
In process (c), preferably the Arbekacin hydrochloride of precipitation is divided by common method, such as filtering
From being then dried in vacuo.
When preparing by the above method, the pseudo-polymorphic II of above-mentioned crystal will be obtained.
Third object of the present invention is to provide the Arbekacin hydrochloride pseudo-polymorphic II production high-purity Ah
Application in terms of Bekaa star free alkali.
Arbekacin hydrochloride pseudo-polymorphic II of the present invention, with CN105246907A announce include Arbekacin
The carbamic acid derivative of the Arbekacin of carbonate is compared, and crystal form is more preferable, refining effect more preferably, and thermodynamically more
Stablize.
Detailed description of the invention
Fig. 1 is X-ray powder diffraction (PXRD) map of 1 gained pseudo-polymorphic II of the embodiment of the present invention；
Fig. 2 is differential thermal analysis (DSC) map of 1 gained pseudo-polymorphic II of the embodiment of the present invention；
Fig. 3 is thermogravimetric analysis (TGA) map of 1 gained pseudo-polymorphic II of the embodiment of the present invention；
Fig. 4 is X-ray powder diffraction (PXRD) map of 2 gained Arbekacin carbonate of experimental example of the present invention；
Fig. 5 is differential thermal analysis (DSC) map of 2 gained Arbekacin carbonate of experimental example of the present invention；
Fig. 6 is thermogravimetric analysis (TGA) map of 2 gained Arbekacin carbonate of experimental example of the present invention.
Specific embodiment
The specific determination condition of X-ray powder diffraction in following embodiment are as follows: measured using BrukerD8ADVANCE instrument.
Determination condition is as follows: CuKa 40Kv 40mA be light source, 0.02 ° of step-length, scanning speed: 8 °/min, scanning range: 3 °-
80 °, room temperature.
The specific determination condition of DSC are as follows: measured using DSC204F1 instrument, 20 DEG C of initial temperature, 230 DEG C of outlet temperature, heating
10 DEG C/min of speed.
The specific determination condition of TGA are as follows: measured using SDTQ600 instrument, initial temperature room temperature, 300 DEG C of outlet temperature, heating speed
Spend 10 DEG C/min.
The specific determination condition that the chromatography of ions detects chloride ion content are as follows: sample solution: 19.92mg/
1000mL；Contrast solution: 3 Cl-1.04 μ g/mL, Cl-2.08 μ g/mL and Cl-5.21 μ g/mL(calibration curves)；Detection
Device: conductivity detection；Tubing string: Dionex IonpacTM AS17-C(4 × 250mm)；Tubing string temperature: about 30 DEG C of steady temperature；
Mobile phase: Dionex KOH leacheate；The volume injected of solution: 25 μ L.
Embodiment 1
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 3.0, under stiring maintain 30 DEG C of temperature.Then it is added into reaction kettle
100mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 5.8g.Desciccate X-ray powder diffraction (Fig. 1),
DSC map (Fig. 2) and TGA map (Fig. 3) are determined as pseudo-polymorphic II.The polymorphic show with 2 θ ° be about 7.6,9.6,
10.2、11.5、14.0、14.5、15.1、16.3、17.3、19.3、19.7、20.0、23.0、23.4、25.0、25.3、26.1、
27.0,28.1,28.9,33.2,35.6,37.2,38.6,39.0,40.0,41.0,42.3,43.3 and 45.5 characteristic peak indicated
X-ray powder diffraction pattern, as shown in Figure 1.The fusing point for measuring the pseudo-polymorphic II is 80 ~ 100 DEG C.
Embodiment 2
The Arbekacin free alkali of 5g is dissolved in 10mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 4.0, under stiring maintain 30 DEG C of temperature.Then it is added into reaction kettle
70mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 6.0g.Desciccate X-ray powder diffraction, DSC map
And TGA map is determined as pseudo-polymorphic II.
Embodiment 3
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 4.5, under stiring maintain 30 DEG C of temperature.Then it is added into reaction kettle
100mL methanol.Stirring is filtered after 3 hours, obtains drying solid powder 5.7g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 4
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.4mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
100mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 5.2g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 5
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.5, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
100mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 6.1g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 6
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 2.5, under stiring maintain 5 DEG C of temperature.Then it is added into reaction kettle
100mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 6.3g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 7
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 2.0, under stiring maintain 10 DEG C of temperature.Then it is added into reaction kettle
40mL methanol and 60mL ethyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 5.9g.Desciccate is spread out with x-ray powder
It penetrates, DSC map and TGA map are determined as pseudo-polymorphic II.
Embodiment 8
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 3.5, under stiring maintain 10 DEG C of temperature.Then it is added into reaction kettle
60mL ethyl alcohol and 40mL dimethyl sulfoxide.Stirring is filtered after 3 hours, obtains drying solid powder 5.3g.Desciccate X-ray powder
Last diffraction, DSC map and TGA map are determined as pseudo-polymorphic II.
Embodiment 9
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 6.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
100mL dimethyl sulfoxide.Stirring is filtered after 3 hours, obtains drying solid powder 5.1g.Desciccate X-ray powder diffraction,
DSC map and TGA map are determined as pseudo-polymorphic II.
Embodiment 10
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
100mL acetone.Stirring is filtered after 3 hours, obtains drying solid powder 4.9g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 11
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.5, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
120mL acetonitrile.Stirring is filtered after 3 hours, obtains drying solid powder 5.0g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 12
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.5, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
95mL tetrahydrofuran.Stirring is filtered after 3 hours, obtains drying solid powder 4.4g.Desciccate X-ray powder diffraction, DSC
Map and TGA map are determined as pseudo-polymorphic II.
Embodiment 13
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 5.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
110mL pyridine.Stirring is filtered after 3 hours, obtains drying solid powder 4.7g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 14
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 6.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
110mL propyl alcohol.Stirring is filtered after 3 hours, obtains drying solid powder 4.3g.Desciccate X-ray powder diffraction, DSC figure
Spectrum and TGA map are determined as pseudo-polymorphic II.
Embodiment 15
The Arbekacin free alkali of 5g is dissolved in 15mL water, and is added in reaction kettle.6mol/L is added dropwise into reaction kettle
Aqueous hydrochloric acid solution, be adjusted to the final PH of mother liquor be 6.0, under stiring maintain 20 DEG C of temperature.Then it is added into reaction kettle
105mL N,N-dimethylformamide.Stirring is filtered after 3 hours, obtains drying solid powder 3.8g.Desciccate X-ray powder
Last diffraction, DSC map and TGA map are determined as pseudo-polymorphic II.
Embodiment 16
The Arbekacin free alkali of 5g is dissolved in the in the mixed solvent of 15mL water Yu 90mL ethyl alcohol, and is added in reaction kettle.
The aqueous hydrochloric acid solution of 6mol/L is added dropwise into reaction kettle, being adjusted to the final PH of mother liquor is 3.0, under stiring 20 DEG C of temperature of maintenance, 3
It is filtered after hour, obtains drying solid powder 5.2g.Desciccate X-ray powder diffraction, DSC map and TGA map determine
For pseudo-polymorphic II.
Embodiment 17
The Arbekacin free alkali of 5g is dissolved in the in the mixed solvent of 15mL water Yu 90mL methanol, and is added in reaction kettle.
The aqueous hydrochloric acid solution of 6mol/L is added dropwise into reaction kettle, being adjusted to the final PH of mother liquor is 5.0,20 DEG C of temperature are maintained under stiring,
Stirring is filtered after 3 hours, obtains drying solid powder 5.0g.Desciccate X-ray powder diffraction, DSC map and TGA map
It is determined as pseudo-polymorphic II.
Experimental example 1: chloride ion content in Arbekacin hydrochloride pseudo-polymorphic II is detected
Chloride ion is detected by the chromatography of ions under the following conditions: sample solution: 19.92mg/1000mL；It compares molten
Liquid: 3 Cl-1.04 μ g/mL, Cl-2.08 μ g/mL and Cl-5.21 μ g/mL(calibration curves)；Detector: conductivity detection；
Tubing string: Dionex IonpacTM AS17-C(4 × 250mm)；Tubing string temperature: about 30 DEG C of steady temperature；Mobile phase: Dionex
KOH leacheate；The volume injected of solution: 25 μ L.As a result it is shown in Table 1.Chloride ion content is 20.05%.
Table 1
Based on the calculated result in table 2, it is believed that the quantity of hydrochloride unit is 3.5 to 4.0 in Arbekacin hydrochloride.
Table 2
Experimental example 2: compare the refining effect of Arbekacin hydrochloride pseudo-polymorphic II Yu Arbekacin carbonate
1. taking Arbekacin free alkali 10g, initial purity 98.2%.2 parts are divided into, every part of 5g.Implemented respectively using the present invention
The method of example 1 obtains II 5.8g of Arbekacin hydrochloride pseudo-polymorphic, measures purity 99.6%.It is invented using CN105246907A
The method of patent obtains Arbekacin carbonate 5.1g, measures purity 98.8%.Arbekacin carbonate desciccate X-ray
Powder diffraction (Fig. 4), DSC map (Fig. 5) and TGA map (Fig. 6) confirm that crystal form is poor.
2. taking Arbekacin free alkali 10g, initial purity 87.8%.2 parts are divided into, every part of 5g.Respectively using the present invention
The method of embodiment 1 obtains II 5.2g of Arbekacin hydrochloride pseudo-polymorphic, measures purity 98.5%.Use CN105246907A
Grease is precipitated in the method for patent of invention, does not obtain Arbekacin carbonate solid.
These results suggest that Arbekacin hydrochloride pseudo-polymorphic II of the present invention, is announced with CN105246907A
The carbamic acid derivative of the Arbekacin comprising Arbekacin carbonate compare, more preferably, crystal form is more preferable for refining effect.
Experimental example 3: compare Arbekacin hydrochloride pseudo-polymorphic II and Arbekacin carbonate, Arbekacin free alkali
Stability.(table 3)
Table 3
These results suggest that Arbekacin hydrochloride polymorph of the present invention, with CN105246907A announce comprising Ah
Carbamic acid derivative, the Arbekacin free alkali of the Arbekacin of Bekaa star carbonate are compared, more stable.
Experimental example 4: compare the hygroscopicity of Arbekacin hydrochloride and Arbekacin carbonate, Arbekacin free alkali.(table
4)
Table 4
These results suggest that Arbekacin hydrochloride pseudo-polymorphic II of the present invention, the packet announced with CN105246907A
Carbamic acid derivative, the Arbekacin free alkali of the Arbekacin of the carbonate containing Arbekacin are compared, more steady at room temperature
It is fixed, it is not easy to moisture absorption.
It is strong that the Arbekacin hydrochloride pseudo-polymorphic II can improve Arbekacin bulk pharmaceutical chemicals hygroscopicity, unstable at room temperature
The shortcomings that.
Claims (8)
1. a kind of pseudo-polymorphic of Arbekacin hydrochloride, skeleton symbol C22H44N6O10·nHCl·(H2O)m, n=2-10,
M=1-50, wherein m value is not fixed.
2. the pseudo-polymorphic of Arbekacin hydrochloride as described in claim 1, which is characterized in that its X-ray powder diffraction figure
Spectrum display has the 2 θ ° of characteristic peaks indicated for 5-50, relative intensity value 5-100, and not specification variation tendency is presented.
3. the pseudo-polymorphic of Arbekacin hydrochloride as described in claim 1, which is characterized in that it is heated to 120-170 DEG C
When, crystal is water in stepped weightlessness, weightless ratio 5%-20%, weightless object.
4. the pseudo-polymorphic of Arbekacin hydrochloride as described in claim 1, which is characterized in that its fusing point is 80-100 DEG C.
5. the preparation method of any Arbekacin hydrochloride pseudo-polymorphic as described in claim 1-4, it is characterised in that the party
Method the following steps are included:
A) Arbekacin free alkali is dissolved in reaction dissolvent, and aqueous hydrochloric acid solution is added dropwise to reaction under certain reaction temperature
In solution, the final pH value of reaction solution is 1.0-7.0；
B) solvent for salting out Arbekacin hydrochloric acid is added in reaction solution, it includes but is not limited to methanol, second that solvent, which is precipitated,
Alcohol, propyl alcohol, dimethyl sulfoxide, acetonitrile, pyridine, tetrahydrofuran, acetone or n,N-Dimethylformamide, preferably methanol or second
Alcohol；
C) the Arbekacin hydrochloride of precipitation is separated by conventional method, preferably room temperature filtering, vacuum drying.
6. preparation method as claimed in claim 5, it is characterised in that reaction dissolvent includes but is not limited to water, methanol, ethyl alcohol, third
The amount of alcohol, dimethyl sulfoxide, acetonitrile, pyridine, tetrahydrofuran, acetone or n,N-Dimethylformamide, preferably water, solvent is unlimited
1.5-200 times of the free alkali number of system, preferably Arbekacin.
7. preparation method as claimed in claim 5, it is characterised in that reaction temperature is without limitation, preferably 0 ~ 30 DEG C, hydrochloric acid water
The concentration of solution is 1-12mol/L, preferably 4-8mol/L.
8. the pseudo-polymorphic of any Arbekacin hydrochloride as described in claim 1-4, which is characterized in that 40 DEG C, it is 40% wet
Spend, save it is trimestral under the conditions of, the incrementss in relation to substance are no more than 0.2%, 25 DEG C, 75% humidity, save three hours
Under the conditions of, the incrementss of moisture are no more than 2.5%, and when separating precipitation, the pseudo-polymorphic of Arbekacin hydrochloride is crystal precipitation.
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