CN105259286B - The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound - Google Patents
The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound Download PDFInfo
- Publication number
- CN105259286B CN105259286B CN201510700788.1A CN201510700788A CN105259286B CN 105259286 B CN105259286 B CN 105259286B CN 201510700788 A CN201510700788 A CN 201510700788A CN 105259286 B CN105259286 B CN 105259286B
- Authority
- CN
- China
- Prior art keywords
- compound
- creatine phosphate
- impurity
- water
- liquid
- 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.)
- Active
Links
Abstract
The invention belongs to pharmaceutical technology field, specifically related to a kind of high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound, the impurity compound has the structure as shown in following formula (Ia), to the condition detected by impurity compound Ia is：With octadecylsilane chemically bonded silica as filler, in mobile phase with acetonitrile or methanol as organic faciess, with the aqueous solution of buffer salt and ion-pairing agent as water phase, detector is UV-detector.The high-efficiency liquid chromatography method for detecting of the impurity in disodium creatine phosphate compound of the present invention, to the content for controlling compound Ia in Creatine Phosphate Sodium crude product and finished product, can strengthen the effective control to Creatine Phosphate Sodium quality.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of efficient liquid of impurity in disodium creatine phosphate compound
Phase chromatographic detection method.
Background technology
Phosphagen is a kind of containing energy-rich phosphate key compound, and important work is played in the energy metabolism of muscle contraction
With.It is the chemical energy store of cardiac muscle and skeletal muscle, and for the resynthesis of ATP.Intramuscular injection or vein are adopted clinically
Injection of exogenous disodium creatine phosphate treating the myocardial metabolism exception under ischemic state, and in operation on heart by phosphoric acid
Creatine disodium salt adds protection cardiac muscle in cardioplegic solution.Disodium creatine phosphate as myocardial protective agent medicine at home
It is outer to be listed using for many years.
The preparation method of exogenous phosphocreatine has chemical synthesiss, biological extraction method and enzyme process at present.Biological extraction method
With enzyme process due to high cost, the more low reason of relative efficiency, its application is limited to a certain extent.Phosphorus is prepared with chemical synthesiss
Creatine acid is a main path of currently acquired exogenous phosphocreatine, wherein with creatinine as the side of Material synthesis phosphagen
Method (patent 200710038838.X) is one of method most widely used at present.When with creatinine as raw material production phosphagen,
Side reaction is had in creatinine and phosphorus oxychloride condensation reaction, the side reaction product with follow-up technical process, ultimately form with
The approximate aqueous by-product of Creatine Phosphate Sodium polarity, it is easy to affect finished product quality in mixing product, at present side reaction is produced
The detection of thing there are no document report.
The current clinically topmost purposes of phosphagen, is formed into Creatine Phosphate Sodium for Injection.Injection compares which
Its dosage form, the quality and safety to product have higher requirement.To in Creatine Phosphate Sodium crude product and finished product because side reaction produce
Impurity compound detected, and it is achieved effective control in finished product, be favorably improved drug quality stability and
Clinical application safety.
The content of the invention
Invention broadly provides a kind of high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound,
To control the content of compound Ia in Creatine Phosphate Sodium crude product and finished product, the effective control to Creatine Phosphate Sodium quality can be strengthened
System.Its technical scheme is as follows：
A kind of high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound, the impurity compound tool
Just like the structure shown in following formula (Ia)：
With creatinine as raw material production Creatine Phosphate Sodium, it is one of production technology of current main-stream.We are ground in increased quality
During studying carefully, it was found that compound Ia, it is a main by-product in technical process.The structure of the compound, from having no
Document report is crossed, is inferred and is generated via following approach：
The physicochemical property and Creatine Phosphate Sodium of the compound is close to, it is easy to product quality is affected in being mixed in finished product, therefore
Be necessary content detection to be carried out to the compound Ia in crude product and finished product, control the content of the composition to ensure product quality.
Concrete testing conditions and detection method are：
Testing conditions are as follows
With octadecylsilane chemically bonded silica as filler, in mobile phase with acetonitrile or methanol as organic faciess, with buffer salt
And the aqueous solution of ion-pairing agent is water phase, detector is UV-detector.
Wherein, organic faciess and the volume ratio of water phase are 0-40:60-100, it is preferred that for 20:80.
Preferably, organic faciess are acetonitrile.
Preferably, in water phase, buffer salt is sodium dihydrogen phosphate or potassium dihydrogen phosphate, and ion-pairing agent is tetrabutylammonium hydroxide
Ammonium or tetrabutyl ammonium bromide or Dodecyl trimethyl ammonium chloride, pH is 4-8；It is furthermore preferred that buffer salt content is in water phase
0.2wt%, ion-pairing agent content are 0.1wt%, and pH is 6.3-6.8.
Ultraviolet detection wavelength is 210nm.
Detection method is as follows：
Reference substance：With Ia, Ib, Ic or Id as reference substance, Ib, Ic, Id have the general structure shown in formula I：
Wherein, for Ib, M1 is Na, and M2 is H；For Ic, M1 is K, and M2 is K；For Id, M1 is K, and M2 is H；
The preparation method of Ia, Ib, Ic and Id is as follows：
(1) preparation of Ia
The disodium creatine phosphate crude product of enrichment by-product, plus methanol supersound process is twice, upper strata of inclining, precipitation adds water and makes
Dissolving, adds methanol or ethanol, stirs, and filters, and filtrate places crystallization in 0～10 DEG C, then with water-methanol or water-second
Alcohol recrystallization once, is leached, and is dried, you can obtain compound Ia sterlings, and purity is more than 98%；
(2) preparation of Ib
Taking compound Ia to be dissolved in water, PH to 3～4 being adjusted with 1M HCl, add ethanol to stir, sucking filtration obtains final product compound Ib；
(3) preparation of Ic
The creatinine phosphoryl chloride phosphorus oxychloride that will be obtained by creatinine and phosphorus oxychloride condensation reaction, is slowly added into mass concentration while stirring
In for 20% KOH solution, being stirred overnight, PH to 7～8 being adjusted with hydrochloric acid, the lower ethanol for adding 4 times of amounts of liquor capacity of stirring is quiet
After putting a few hours, sucking filtration obtains phosphagen potassium crude product, and after enrichment by-product, plus methanol supersound process is twice, upper strata of inclining,
Precipitation adds water and makes dissolving, adds methanol or ethanol, stirs, and filters, and filtrate places crystallization in 0～10 DEG C, then with water-first
Alcohol or water-ethanol recrystallization once, are leached, and are dried, that is, are obtained compound Ic sterlings；
(4) preparation of Id
Take compound Ic to be dissolved in water, PH to 3～4 is adjusted with 1M HCl, add ethanol stirring, sucking filtration to obtain final product compound Id.
Specifically detecting step is：
Ia, Ib, Ic or Id sterling is taken, is dissolved in mobile phase, be respectively prepared the comparison liquid 1 and 5 μ g/ml of 50 μ g/ml
Comparison liquid 2；Take testing sample to be dissolved in mobile phase, be configured to the prepare liquid of 5mg/ml；Prepare liquid is Creatine Phosphate Sodium crude product
When use comparison liquid 1, draw respectively 20 μ l comparison liquid 1 and prepare liquid injection chromatograph of liquid, determine Creatine Phosphate Sodium crude product
The content of middle Ia；Comparison liquid 2 is used when prepare liquid is Creatine Phosphate Sodium highly finished product, the comparison liquid 2 of 20 μ l and to be measured is drawn respectively
Liquid injects chromatograph of liquid, determines the content of Ia in Creatine Phosphate Sodium highly finished product.
Using the high-efficiency liquid chromatography method for detecting of above-mentioned impurity in disodium creatine phosphate compound, the present invention with
Lower advantage：
The invention provides a kind of efficient liquid phase detection method of detection Creatine Phosphate Sodium by-product impurities Ia, controls thick
The content of compound Ia in product and finished product, can strengthen the effective control to Creatine Phosphate Sodium quality, be favorably improved clinical use
The safety of medicine and effectiveness.
Description of the drawings
Structure charts of the Fig. 1 and Fig. 2 for compound Ia；
Fig. 3 is the HPLC chromatogram for determining impurity Ia in Creatine Phosphate Sodium crude product；
Fig. 4 is the HPLC chromatogram for determining impurity Ia in Creatine Phosphate Sodium highly finished product.
Specific embodiment
Specific embodiment
Embodiment 1
The preparation of compound Ia
Learn from else's experience enrichment by-product Creatine Phosphate Sodium crude product 60g, add 200ml methanol ultrasound about 5min, placement, incline on
Layer liquid, precipitation is same again to be processed once, and incline supernatant liquid, and precipitation adds 140ml water to make dissolving, adds 420ml methanol,
Stir, filter, filtrate places crystallization in 10 DEG C, next day filters, obtains crystal 11.0g, plus 30ml water and 100ml methanol are tied again
Brilliant once to leach crystal, room temperature forced air drying 2 hours obtains 7.6 grams, with the HPLC methods detection purity in embodiment 8, pure
Spend for 98.6% (area normalization method).
Embodiment 2
The structural identification of compound Ia
Sample source：
The compound Ia sterlings that embodiment 1 is obtained.X diffraction test monocrystalline used is in 1 recrystallization process of embodiment
The monocrystalline picked out.
Test content：
1H NMR；31P NMR；ESI mass spectrums；ESI high resolution mass spectrums；X single crystal diffractions；Karr-Fei Xiushi methods determine moisture.
Test result：
A：1H NMR(D2O,400M),δ3.82(2H,s,CH2),2.82(3H,s,CH3)。
B：31P NMR (D2O, 400M), δ -0.15, δ -9.69, (unused phosphoric acid does reference), two unimodal integration ratios are 1：
1。
C：, there are 361.8 [M+Na] in ESI mass spectrums (cation)+Quasi-molecular ions and 700.8 [2M+Na]+Quasi-molecular ions.
D：ESI (cation) high resolution mass spectrum
1 result of table
| Mass | Calc.Mass | mDa | PPM | [M+Na]+Molecular formula |
| 361.9266 | 361.9272 | -0.6 | -1.6 | C4H6N3O7Na4P2 |
E：The structure that X single crystal diffraction results show, is shown in Fig. 1 and Fig. 2, and monocrystalline crystal data is shown in Table 2：
The crystal data of the 8 hydrate monocrystalline of 2 compound Ia of table
F：Karr-Fei Xiushi methods determine moisture result：30.06%.
Parsing：1CH is shown in H H NMR spectroscopies2[3.82,2 H of δ, unimodal] and CH3The signal of [2.82,3 H of δ, unimodal], its
Chemical displacement value chemical displacement value corresponding with phosphagen is close to, and shows containing creatine or creatinine structure fragment.In phosphorus spectrum,
Show two 1：1 it is unimodal, show containing the different phosphate groups of two chemical environments.ESI mass spectrums show that molecule adds sodium
Quasi-molecular ions and corresponding 2 times of quasi-molecular ions, the result that the molecular formula that ESI high resolution mass spectrums show is obtained with X single crystal diffractions are consistent completely.
X single crystal diffractions are shown containing 8 water of crystallization, during containing 8 water of crystallization, moisture theoretical value 29.81%, and this and karr-Fei Xiu
Family name's method determines the result of moisture closely, and both results mutually can be confirmed.Therefore the stereochemical structure of 8 hydrates of compound Ia
It is as shown in accompanying drawing 1, Fig. 2.
Embodiment 3
The different drying conditions of compound Ia and crystal water content
2 parts of the crystal obtained in Example 1,0.5 gram per part, it is accurately weighed after, be dried according to the methods below：
1st, 40 DEG C of forced air dryings 3 hours；2nd, 60 DEG C of forced air dryings 2 hours.After room temperature is cooled in exsiccator, accurately weighed weight,
Purity is determined according to the HPLC conditions in embodiment 8, crystal water content n after calculating weightlessness and being dried.As a result such as following table：
The crystal water content of 3 compound Ia of table
| Baking temperature (DEG C) | Drying time (h) | Weightless (%) | Purity (HPLC) | n(H2O) |
| Room temperature | 2 | 0 | 98.6 | 8 |
| 40 | 3 | 0.32 | 98.6 | 8 |
| 60 | 2 | 14.58 | 98.5 | 4 |
Embodiment 4
The preparation of compound Ib
0.5 gram of compound Ia is taken, 2ml water dissolutioies are added, PH to 3～4 is adjusted with 1M HCl, add 10ml ethanol, stirring 1
Hour, sucking filtration obtains compound Ib, 40 DEG C of forced air dryings 3 hours, obtains 0.45 gram.
With the HPLC methods detection purity in embodiment 8,98.7% (area normalization method).ESI mass spectrums (cation):
340.3[M+Na]+.Karr-Fei Xiushi methods determine moisture：10.94%.
Embodiment 5
The preparation of compound Ic
The creatinine phosphoryl chloride phosphorus oxychloride that will be obtained by creatinine and phosphorus oxychloride condensation reaction, is added slowly with stirring volumetric concentration
In 20%KOH solution, it is stirred overnight, adjusts PH7～8, the lower ethanol for adding 4 times of amounts of liquor capacity of stirring to stand number little with hydrochloric acid
Shi Hou, sucking filtration obtain phosphagen potassium crude product, after enrichment by-product, then are processed with the method similar to embodiment 1, obtained
Compound Ic sterlings.
With the HPLC methods detection purity in embodiment 8,99.1% (area normalization method).ESI mass spectrums (cation):
410.5[M+Na]+.Karr-Fei Xiushi methods determine moisture：16.21%.
Embodiment 6
The preparation of compound Id
0.5 gram of compound Ic is taken, 2ml water dissolutioies are added, PH to 3～4 is adjusted with 1M HCl, add 10ml ethanol, stirring 1
Hour, sucking filtration obtains compound Id, 40 DEG C of forced air dryings 3 hours, obtains 0.45 gram.
With the HPLC methods detection purity in embodiment 8,98.8% (area normalization method).ESI mass spectrums (cation):
372.4[M+Na]+.Karr-Fei Xiushi methods determine moisture：10.07%.
Embodiment 7
The preparation of 2 water things of compound Ia, 2 water things of compound Ic
The each 500mg of compound Ia, Ic is taken respectively, is made into 10% solution with distilled water, the quick freezing at -20 DEG C, so
Lyophilization afterwards.After end, moisture is determined respectively with karr-Fei Xiushi methods, it is as a result as follows：
4 moisture of table
| Compound | Moisture (%) | Purity (HPLC) is (%) |
| 2 water things of compound Ia | 10.41 | 98.5 |
| 2 water things of compound Ic | 9.15 | 98.9 |
Embodiment 8
The content of compound Ia in liquid chromatography detection phosphagen sodium sample
1 material
1.1 instruments and material
Agilent 1100Series highly effective liquid phase chromatographic systems；DAD detectors.
1.2 medicines and reagent
Acetonitrile is chromatographically pure；Water is purified water；Sodium dihydrogen phosphate, TBAH aqueous solution (10%) are analysis
It is pure.
Reference substance：8 hydrates of compound Ia, purity 98.6%, moisture (karr-Fei Xiushi methods) 30.06%.
Test sample：The Creatine Phosphate Sodium that Creatine Phosphate Sodium crude product, Jing are refined repeatedly.
2 methods
2.1 chromatographic condition
Chromatographic column：Megres C18 posts (4.6 × 150mm)
Mobile phase：Acetonitrile：Water (contains 0.2% sodium dihydrogen phosphate, 0.1% TBAH, is adjusted with phosphoric acid or ammonia solution
PH value is saved to 6.6)=20：80
Wavelength：210nm
Flow velocity：1ml/min
Sample size：20μl
Column temperature：Room temperature
2.2 the range of linearity
Compound Ia is configured to into the right of 2.5 μ g/ml, 5 μ g/ml, 25 μ g/ml, 50 μ g/ml and 100 μ g/ml with mobile phase
According to product solution, concentration is based on anhydride.20 μ l sample introductions under condition determination are taken respectively, the absolute sample size of reference substance is respectively
50ng, 0.1 μ g, 0.5 μ g, 1.0 μ g and 2.0 μ g.Determine under the chromatographic condition described in 2.1.With peak area as vertical coordinate (Y),
Compound Ia sample sizes are abscissa (X), carry out linear regression, obtain regression equation：Y=32926X+4714.1, R2=
0.9999
2.3 precision
The reference substance solution that concentration is 25 μ g/ml is taken respectively, and 20 μ l of each sample introduction, continuous sample introduction 6 times record peak area,
Calculate precision.
2.4 stability
It is 50 μ g/ml, the reference substance solution of 5 μ g/ml to take concentration respectively, each comfortable 0h, 2h, 4h, 6h sample introduction, records peak face
Product, investigates stability.
Precision weighs Creatine Phosphate Sodium crude product and highly finished product sample is appropriate, with flowing phased soln, is made into the solution of 5mg/ml,
Respectively in 0h, 2h, 4h, 6h sample introduction, impurity Ia peak areas are recorded, investigate stability.
2.5 repeatability
Taking Creatine Phosphate Sodium crude product and refining repeatedly sample carries out 6 parallel assays respectively, calculates relative standard deviation
(RSD%), investigate repeatability.
2.6 average recovery
Precision weighs Creatine Phosphate Sodium crude product 1g and totally 6 parts and refines repeatedly totally 6 parts of sample 1g, the former per part be separately added into
10mg reference substances, per part of the latter are separately added into the reference substance solution that 1ml concentration is 1mg/ml, and reference substance is flowed based on anhydride
Dynamic phased soln is simultaneously diluted to 5mg/ml, determines under the chromatographic condition described in 2.1, calculates the response rate of compound Ia.
2.7 test samples are determined
Precision weighs Creatine Phosphate Sodium associated sample in right amount, is made into the solution of 5mg/ml with mobile phase, accurate respectively to draw
Reference substance solution and each 20 μ l of need testing solution, inject chromatograph of liquid, determine, obtain final product.Make when determining Creatine Phosphate Sodium crude product
With the reference substance solution (reference substance solution 1) of 50 μ g/ml, determine molten using the reference substance of 5 μ g/ml during Creatine Phosphate Sodium highly finished product
Liquid (reference substance solution 2).
3 results
In test sample, compound Ia is separated with other peak bases, and preferably, theoretical cam curve is up to more than 3500 for peak shape；Compound
The detection of Ia is limited to 10ng, and analysis of the Creatine Phosphate Sodium to compound Ia is noiseless；The range of linearity of compound Ia is 50ng～2
μg；Precision is good, and RSD is 0.25%；50 μ g/ml of reference substance, 5 μ g/ml are stable in 6 hours, and RSD is respectively 0.78%,
0.89%, the Ia in the test sample of Creatine Phosphate Sodium crude product and highly finished product are stable in 6 hours, and RSD is respectively 0.81%,
0.90%；This assay method has good repeatability, and Creatine Phosphate Sodium crude product RSD is 0.87%, and highly finished product RSD is
0.92%；Compound Ia average recoveries, Creatine Phosphate Sodium crude product is 1.03% for 99.85%, RSD, and highly finished product are
99.47%, RSD are 1.35%.
Determine 6 batches of Creatine Phosphate Sodium crude products in compound Ia content be respectively 1.03%, 1.01%, 0.78%,
1.56%th, 2.01% and 1.05%；In the Creatine Phosphate Sodium that the 6 crowdes of Jing are refined repeatedly the content of compound Ia be respectively 0,
0.05%th, 0,0,0.02% and 0.08%.The Creatine Phosphate Sodium HPLC chromatogram that Creatine Phosphate Sodium crude product, Jing are refined repeatedly is shown in figure
3 and Fig. 4, Fig. 3 in, peak 1 be Creatine Phosphate Sodium, peak 2 be compound Ia.
Embodiment 9
The content of compound Ia in liquid chromatography detection phosphagen sodium sample
Compound in following table detects the content of compound Ia in phosphagen sodium sample for reference substance.The side of measure
Method and condition are same as Example 8.Reference substance solution concentration, according to anhydride meter.
5 different reference substance test results of table
| Numbering | Reference substance | Purity (%) | Moisture (%) | Source |
| 1 | Compound Ia (4 hydrate) | 98.5 | 18.05 | Embodiment 3 |
| 2 | Compound Ia (2 water thing) | 98.5 | 10.41 | Embodiment 7 |
| 3 | Compound Ib (2 hydrate) | 98.7 | 10.94 | Embodiment 4 |
| 4 | Compound Ic (4 water thing) | 99.1 | 16.21 | Embodiment 5 |
| 5 | Compound Ic (2 water thing) | 98.9 | 9.15 | Embodiment 7 |
| 6 | Compound Id (2 water thing) | 98.8 | 10.07 | Embodiment 6 |
Embodiment 10
The content of compound Ia in liquid chromatography detection phosphagen sodium sample
8 hydrates with compound Ia are as reference substance.Condition in following table is mobile phase, remaining condition and embodiment 8
It is identical, detect the content of chemical combination Ia in phosphagen sodium sample.
6 different mobile phase test results of table
It will be apparent to those skilled in the art that technical scheme that can be as described above and design, make other various
It is corresponding to change and deformation, and all these change and deformation should all belong to the protection domain of the claims in the present invention
Within.
Claims (7)
1. a kind of high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound, it is characterised in that：It is described miscellaneous
Matter compound has the structure as shown in following formula (Ia)：
To the condition detected by impurity compound Ia it is：With octadecylsilane chemically bonded silica as filler, in mobile phase with
Acetonitrile or methanol is organic faciess, with the aqueous solution of buffer salt and ion-pairing agent as water phase, detector is UV-detector；
Wherein, organic faciess and the volume ratio of water phase are 0-40:60-100, in water phase, buffer salt is sodium dihydrogen phosphate or biphosphate
Potassium, ion-pairing agent are TBAH or tetrabutyl ammonium bromide or Dodecyl trimethyl ammonium chloride, and the pH of water phase is
4-8。
2. the high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound according to claim 1, its
It is characterised by：With Ia, Ib, Ic or Id as reference substance, Ib, Ic, Id have the general structure shown in formula I to the detection method：
Wherein, for Ib, M1 is Na, and M2 is H；For Ic, M1 is K, and M2 is K；For Id, M1 is K, and M2 is H；
The preparation method of Ia, Ib, Ic and Id is as follows：
(1) preparation of Ia
The disodium creatine phosphate crude product of enrichment by-product, plus methanol supersound process is twice, upper strata of inclining, precipitation add water make it is molten
Solution, adds methanol or ethanol, stirs, and filters, and filtrate places crystallization in 0～10 DEG C, then with water-methanol or water-ethanol
Recrystallization once, is leached, and is dried, you can obtain compound Ia sterlings, and purity is more than 98%；
(2) preparation of Ib
Take compound Ia to be dissolved in water, PH to 3～4 is adjusted with 1M HCl, add ethanol stirring, sucking filtration to obtain final product compound Ib；
(3) preparation of Ic
The creatinine phosphoryl chloride phosphorus oxychloride that will be obtained by creatinine and phosphorus oxychloride condensation reaction, being slowly added into mass concentration while stirring is
In 20% KOH solution, it is stirred overnight, adjusts PH to 7～8, the lower ethanol for adding 4 times of amounts of liquor capacity of stirring to stand with hydrochloric acid
After a few hours, sucking filtration obtains phosphagen potassium crude product, and after enrichment by-product, plus methanol supersound process is twice, upper strata of inclining, and sinks
Shallow lake adds water makes dissolving, adds methanol or ethanol, stirs, and filters, and filtrate places crystallization in 0～10 DEG C, then uses water-methanol
Or water-ethanol recrystallization is once, leaches, it is dried, that is, obtains compound Ic sterlings；
(4) preparation of Id
Take compound Ic to be dissolved in water, PH to 3～4 is adjusted with 1M HCl, add ethanol stirring, sucking filtration to obtain final product compound Id.
3. the high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound according to claim 2, its
It is characterised by：Ia, Ib, Ic or Id sterling is taken, is dissolved in mobile phase, be respectively prepared the comparison liquid 1 and 5 μ g/ml of 50 μ g/ml
Comparison liquid 2；Take testing sample to be dissolved in mobile phase, be configured to the prepare liquid of 5mg/ml；Prepare liquid is Creatine Phosphate Sodium crude product
When use comparison liquid 1, respectively the comparison liquid 1 and prepare liquid injection chromatograph of liquid of draws equal amounts, determines Creatine Phosphate Sodium crude product
The content of middle Ia；Comparison liquid 2 is used when prepare liquid is Creatine Phosphate Sodium highly finished product, respectively the comparison liquid 2 of draws equal amounts and to be measured
Liquid injects chromatograph of liquid, determines the content of Ia in Creatine Phosphate Sodium highly finished product.
4. the high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound according to claim 3, its
It is characterised by：Organic faciess are 20 with the volume ratio of water phase:80.
5. the high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound according to claim 1, its
It is characterised by：Organic faciess are acetonitrile.
6. the high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound according to claim 1, its
It is characterised by：In water phase, buffer salt content is 0.2wt%, and ion-pairing agent content is 0.1wt%, and pH is 6.3-6.8.
7. the high performance liquid chromatography detection of the impurity in disodium creatine phosphate compound according to any one of claim 1-6
Method, it is characterised in that：Ultraviolet detection wavelength is 210nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510700788.1A CN105259286B (en) | 2015-10-26 | 2015-10-26 | The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510700788.1A CN105259286B (en) | 2015-10-26 | 2015-10-26 | The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105259286A CN105259286A (en) | 2016-01-20 |
| CN105259286B true CN105259286B (en) | 2017-03-29 |
Family
ID=55099053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510700788.1A Active CN105259286B (en) | 2015-10-26 | 2015-10-26 | The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105259286B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006138243A2 (en) * | 2005-06-13 | 2006-12-28 | University Of Vermont And State Agricultural College | Inhibition of creatine uptake to promote weight loss |
| CN101034086A (en) * | 2007-03-30 | 2007-09-12 | 上海华拓医药科技发展股份有限公司 | Method for detecting impurity in disodium creatine phosphate |
| CN103760267A (en) * | 2014-01-16 | 2014-04-30 | 中山百灵生物技术有限公司 | High performance liquid chromatography detection method for creatine phosphate sodium disodium salt content and impurities |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005073247A1 (en) * | 2004-01-23 | 2005-08-11 | The Regents Of The University Of California | Amino acid and peptide conjugates of amiloride and methods of use thereof |
| US20050282781A1 (en) * | 2004-06-18 | 2005-12-22 | Shibnath Ghosal | Compositions of stable bioactive metabolites of docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids |
-
2015
- 2015-10-26 CN CN201510700788.1A patent/CN105259286B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006138243A2 (en) * | 2005-06-13 | 2006-12-28 | University Of Vermont And State Agricultural College | Inhibition of creatine uptake to promote weight loss |
| CN101034086A (en) * | 2007-03-30 | 2007-09-12 | 上海华拓医药科技发展股份有限公司 | Method for detecting impurity in disodium creatine phosphate |
| CN103760267A (en) * | 2014-01-16 | 2014-04-30 | 中山百灵生物技术有限公司 | High performance liquid chromatography detection method for creatine phosphate sodium disodium salt content and impurities |
Non-Patent Citations (5)
| Title |
|---|
| Simultaneous determination of myocardial nucleotides, nucleosides, purine bases and creatine phosphate by ion-pair high-performance liquid chromatography;Walter Furst et al;《Journal of Chromatography》;19921231;第578卷;39-44 * |
| Specific Detection of Nucleotides, Creatine Phosphate, and their Derivatives from Tissue Samples in a Simple, Isocratic, Recycling, Low-Volume System;J.H. Fischer;《LC-GC International - The magazine of Separation Science》;19950531;第8卷;254-264 * |
| 注射用磷酸肌酸钠有关物质检查方法的改进;石蓓佳 等;《中国药品标准》;20090430;第10卷(第4期);280-281 * |
| 离子对色谱法测定磷酸肌酸钠的稳定性;祁广建 等;《中国医院药学杂志》;20040131;第24卷(第1期);11-12 * |
| 高效液相色谱法测定磷酸肌酸二钠盐含量及应用;张晓平 等;《天津药学》;20030228;第15卷(第1期);18-20 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105259286A (en) | 2016-01-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Arpalahti et al. | Coordination of aquated cis-platinum (II) diamines to purine nucleosides. Kinetics of complex formation | |
| EP1975150A1 (en) | Cinacalcet salts | |
| CN111562322B (en) | Enrichment detection method and application of five anti-tumor drugs in blood sample | |
| Çiftçi et al. | Synthesis and characterization of new cyclotriphosphazene compounds | |
| CN105067742B (en) | Method for simultaneous determination of content of all components in composite phospholipid liposome by HPLC-ELSD | |
| CN104558090A (en) | Abiraterone acetate impurity and determination method thereof | |
| CN108982695A (en) | The method that derivatization HPLC method measures azido compound in drug or in which mesosome | |
| CN114264745A (en) | Imatinib mesylate related substance and detection method of preparation related substance thereof | |
| CN112098549B (en) | Method for determining impurity content in arbidol hydrochloride solution | |
| CN105259286B (en) | The high-efficiency liquid chromatography method for detecting of impurity in disodium creatine phosphate compound | |
| CN102757391A (en) | Phenobarbital derivative and preparation method and application thereof | |
| CN105294768B (en) | Phosphocreatine class compound and its application | |
| CN112213424A (en) | Method for simultaneously determining coexisting impurities in atorvastatin calcium intermediate | |
| CN113049687A (en) | Method for detecting related substances of ambroxol hydrochloride raw material and injection | |
| CN110346493A (en) | The method for detecting Midkine antisense oligonucleotides acid content in Macaque Plasma | |
| CN110606846A (en) | Tofacitinib citrate impurity and analysis method and application thereof | |
| CN110174482B (en) | UPLC analysis method for simultaneously determining citicoline sodium and nine related substances | |
| CN101865894A (en) | Method for detecting impurities in freeze-dried powder injection of nedaplatin | |
| CN109096327A (en) | A kind of preparation method of high-purity yolk phospholipid acyl ethanol amine | |
| CN102841155A (en) | Method for detecting related substances in fosfomycin sodium by high-performance liquid chromatography | |
| CN109001342B (en) | High performance liquid chromatography method for detecting N-2, 3-dimethoxybenzyl piperonylethylamine and salt content thereof | |
| CN104422738B (en) | A kind of method separating analysis milrinone | |
| CN103226142B (en) | The detection method of leucogen concentration in a kind of blood plasma | |
| BR112018010634B1 (en) | ANALYTICAL METHOD | |
| Attiyat et al. | Synthesis and potentiometric selectivity study of 14-cyclic dioxadiamides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170608 Address after: 226221, Jiangsu Road, Qidong, Jiangsu, Nantong fine chemical industry park, No. 88 Patentee after: QIDONG HUATUO PHARMACEUTICAL CO., LTD. Address before: 200433 room, Lane 2005, Huang Xing Road, Shanghai, Yangpu District, China, 411-5 Patentee before: Shanghai Huatuo Medicine Sci-Tech Development Co., Ltd. |
|
| TR01 | Transfer of patent right |