CN105891377B - A kind of HPLC analytical method of istradefylline about material - Google Patents
A kind of HPLC analytical method of istradefylline about material Download PDFInfo
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- CN105891377B CN105891377B CN201610475927.XA CN201610475927A CN105891377B CN 105891377 B CN105891377 B CN 105891377B CN 201610475927 A CN201610475927 A CN 201610475927A CN 105891377 B CN105891377 B CN 105891377B
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01N2030/027—Liquid chromatography
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Abstract
The invention discloses a kind of HPLC analytical method of istradefylline about material, and this method uses reverse-phase chromatographic column and UV-detector, using acetonitrile phosphate buffer as mobile phase, carries out isocratic elution.This method can analyze all known impurities in istradefylline raw material and its preparation simultaneously, and each known impurity level can effectively be controlled by the principal component Self-control method of the correction up factor, separating degree between each impurity peaks and main peak is more than 1.5, and main peak and each impurity peaks peak purity are 1.0.The present invention provides analysis method simple, that specificity is strong for the Quality Control Analysis of istradefylline raw material and its preparation.
Description
First, technical field
The present invention relates to a kind of analysis method of chemicals purity, the relevant material of specifically a kind of istradefylline
HPLC analytical method.
2nd, background technology
Istradefylline (Istradefylline), entitled (E) -8- (3,4- dimethoxy-styryl) -1, the 3- bis- of chemistry
Ethyl -7- methyl -3,7- dihydro -1H- purine -2,6- diketone, chemical structural formula are as follows：
Istradefylline is a kind of selective adenosine A 2 A receptor antagonists, is opened by Japanese Kyowa Hakko Kirin companies
Hair.Istradefylline piece (trade name Nouriast, specification 20mg) obtains Japanese PMDA approvals listing in March, 2013, is clinically used for
Treat Parkinson's and improve the dyskinesia at parkinsonism initial stage, the improvement that is particularly suitable for use in is because levodopa treatment causes
Agent end phenomenon.
Istradefylline impurity is more, and from structure, impurity is mainly derived from the change of substituted purin mother nucleus structure and its side
Base styryl structures isomerization is relevant, and impurity is respectively provided with styryl structures, and the close impurity of polarity is many；In terms of source, Yi Qucha
The impurity of alkali raw material is mainly derived from the reaction raw materials (impurity H) introduced in building-up process, synthetic intermediate (impurity D), reaction
Accessory substance (impurity E, impurity F, impurity G) and degradation impurity (impurity A, impurity B, impurity C), the impurity source of istradefylline preparation
Impurity (impurity D, impurity E, impurity F, impurity G, impurity H), process contaminants (impurity B) and degradation impurity (impurity are introduced in raw material
A, impurity B, impurity C).
The istradefylline raw material and its analysis method of preparation established at present on comprehensive impurity spectrum analysis foundation do not have also
Related document report.
3rd, the content of the invention
Missing of the present invention for existing literature to istradefylline raw material and its preparation impurity identification research, it is desirable to provide one
Kind HPLC analytical method of the istradefylline about material.The present invention is by process trial, forced degradation experiment to her
Bent theophylline impurity is enriched with, separating-purifying, identifies 8 main known impurities, and has carried out ownership of tracing to the source to impurity, bag
It is (impurity E, impurity F, miscellaneous to include istradefylline reaction raw materials (impurity H), synthetic intermediate (impurity D), istradefylline synthesising by-product
Matter G) and degradation impurity (impurity A, impurity B, impurity C).
Inventor is attempted to by C18 (150 × 4.6mm, 5 μm) each known impurities of chromatogram post separation, but each impurity and master
Composition can not reach baseline separation, improper.Therefore, the chromatographic column for using C18 (250 × 4.6mm, 5 μm) instead is separated, through pair
The optimal screening of phase composition and ratio is flowed, it is determined that the analysis method of the present invention.It is simultaneously logical by Chinese Pharmacopoeia version four in 2015
Then<0512>(high performance liquid chromatography) and general rule<9101>The definition of (drug standard analysis method verification guide principle)
And verification method, carry out specificity checking, the results showed that this method can analyze the institute in istradefylline raw material and its preparation simultaneously
There are known impurities, and each known impurity level can effectively be controlled by the main composition Self-control method of the correction up factor, it is each miscellaneous
Separating degree between mass peak and main peak is more than 1.5, and main peak and each impurity peaks peak purity are 1.0.
The peak purity refers to use the photodiode array detector equipped with corresponding analysis software, collection, record, analysis
Spectroscopic data through chromatogram post separation component, spectral signature uniformity corresponding to the sign particular separation component automatically generated add
Weights.
HPLC analytical method of the istradefylline of the present invention about material, using reverse-phase chromatographic column and ultraviolet detection
Device, it is using the mixed solution of acetonitrile-phosphate buffer as mobile phase, carries out isocratic elution, comprise the following steps：
(1) sample preparation：Istradefylline raw material or powder formulation are taken, with the mixed liquor of acetonitrile and phosphate buffer ultrasound
Dissolving, filtering or centrifugation, it is configured to the istradefylline solution that concentration is 0.1-1.5mg/ml；
(2) chromatographic condition is set：Using anti-phase C18 posts, column temperature is arranged on 20-50 DEG C；With acetonitrile and phosphate buffer
Mixed liquor be mobile phase, carry out isocratic elution；Flow velocity is 0.5-2.0ml/min；Detection wavelength is 210-270nm；
(3) detect：The istradefylline solution for taking step (1) to prepare, sample introduction 10-50 μ l, record chromatogram.
Anti-phase C18 posts are selected from Grace Smart C18 (250 × 4.6mm, 5 μm), Agilent C18 (250 in step (2)
× 4.6mm, 5 μm) or Diamonsil C18 (250 × 4.6mm, 5 μm), preferably Diamonsil C18 (250 × 4.6mm, 5 μ
m)。
The volume ratio of acetonitrile and phosphate buffer is 1: 1 in the mixed liquor of step (1) acetonitrile and phosphate buffer.
The volume ratio of acetonitrile and phosphate buffer is 50: 49-54, preferably 50: 50 in step (2) mobile phase.
In step (1) or step (2) phosphate buffer used be potassium dihydrogen phosphate the aqueous solution, potassium dihydrogen phosphate it is dense
Spend for 0.01-0.5mol/L, preferably 0.05mol/L, pH value is adjusted to 5.0-7.0, preferably 5.9-6.3 with potassium hydroxide.
Flow velocity is 0.8-1.2ml/min, Detection wavelength 225-235nm in step (2).
Sample size is 20 μ l in step (3).
The relevant material in istradefylline raw material and preparation, 8 known impurities can be efficiently controlled using the inventive method
It can analyze and on a collection of illustrative plates, the separating degree between each impurity peaks and main peak is more than 1.5, and main peak and each impurity peaks peak are pure
Degree is 1.0.Analysis process is shown in embodiment 1, and typical chromatogram is shown in Fig. 1, and result of calculation is shown in Table 1.
The istradefylline of table 1 and each known impurities chromatographic isolation parametric results
| Title | Relative retention time | Separating degree | The peak purity factor |
| Impurity H | 0.19 | / | 1.0 |
| Impurity G | 0.23 | 3.329 | 1.0 |
| Impurity F | 0.36 | 4.813 | 1.0 |
| Impurity C | 0.39 | 2.095 | 1.0 |
| Impurity D | 0.51 | 7.765 | 1.0 |
| Impurity E | 0.52 | 0.715 | 1.0 |
| Impurity A | 0.68 | 8.233 | 1.0 |
| Istradefylline | 1.00 | 13.223 | 1.0 |
| Impurity B | 1.21 | 6.281 | 1.0 |
Degradation impurity of the istradefylline under various complex environments, method specificity can be analyzed using the inventive method
By force.By Chinese Pharmacopoeia four general rules of version in 2015<0512>(high performance liquid chromatography) and general rule<9101>(drug standard
Analysis method verification guide principle) definition and verification method, by istradefylline raw material or powder formulation respectively with acid, alkali, height
Temperature, oxidation, illumination are destroyed, and are made and destroy sample, gather each destruction sample chromatogram figure respectively by the inventive method, and analysis process is shown in
Embodiment 2, typical chromatogram are shown in Fig. 2-7.As a result show that this method can be analyzed to destroy through acid, alkali, high temperature, oxidation, illumination
Sample, main peak can reach baseline separation with each impurity peaks, and main peak purity is 1.0.
Quantitative analysis can be carried out to each known impurities using the inventive method.By Chinese Pharmacopoeia four general rules of version in 2015
The definition and checking of 0512 (high performance liquid chromatography) and general rule 9101 (drug standard analysis method verification guide principle)
Method, test limit, the quantitative limit of 8 known impurities of istradefylline are detected using impurity counter point, the results showed that the party
Method is high to the response of each impurity, can effectively control each known impurities, the results are shown in Table 2.
The istradefylline of table 2 and its known impurities quantitative analysis certificate parameter result
The present invention carries out ownership of tracing to the source to istradefylline raw material and its preparation impurity first, identifies 8 known impurities, is
Istradefylline raw material and its relevant material research of preparation provide reliable impurity spectrum reference, have larger positive effect
And actual application value.
4th, illustrate
Fig. 1 is the istradefylline of embodiment 1 and the mixed chromatogram of known impurities.
Fig. 2 is that the acid of embodiment 2 destroys chromatogram.
Fig. 3 is that the alkali of embodiment 2 destroys chromatogram.
Fig. 4 is the high temperature chromatogram of embodiment 2.
Fig. 5 is the Oxidative demage chromatogram of embodiment 2.
Fig. 6 is that the illumination of embodiment 2 destroys chromatogram.
Fig. 7 is that the istradefylline piece of embodiment 2 does not destroy sample chromatogram figure.
Fig. 8 is the relevant material chromatogram of the istradefylline of embodiment 3.
Using analysis method of the present invention positioning known impurities (impurity A-H, Fig. 1), main peak can reach base with each impurity peaks
Line separates.Using analysis method istradefylline of the present invention and its relevant material of tablet, as a result istradefylline raw material only detects micro
Impurity B (retention time：14.160min, Fig. 8), istradefylline piece then detects trace impurity B and 1 unknown impuritie (retention time
It is followed successively by：13.935min, 7.073min, Fig. 7).Using analysis method of the present invention investigate istradefylline formulation samples acid, alkali,
Catabolite under the influence of the factors such as high temperature, illumination, oxidation, compared with sample before degraded, the results showed that this product to acid, high temperature compared with
Stable, acid destroys only detection trace impurity A and impurity B, and (retention time is followed successively by：7.898min, 13.949min, Fig. 2), high temperature
Destroying only detection trace impurity B and 1 unknown impuritie, (retention time is followed successively by：13.896min, 7.027min, Fig. 4)；This product
Unstable under alkali, light, oxidizing condition, wherein alkali destroys detection impurity A (retention time：7.909min), impurity B is (during reservation
Between：13.962min), impurity C (retention times：4.560min) (retain with 1 unknown impuritie (Fig. 3), photo damage detection impurity A
Time：7.889min), impurity B (retention time：13.915min), impurity C (retention times：4.564min) and 1 unknown miscellaneous
Matter (Fig. 3), Oxidative demage detection impurity B (retention time：13.984min), impurity C (retention times：4.563min) with 3 not
Know impurity (Fig. 5).
5th, embodiment
Embodiment 1：
Detecting instrument and chromatographic condition：
High performance liquid chromatograph：Agilent PUMP, Agilent DAD detectors
Chromatographic column：Diamonsil C18 chromatographic columns (250 × 4.6mm, 5 μm)；Mobile phase：The second that volume ratio is 50: 50
Nitrile -0.05mol/L phosphate buffers (potassium hydroxide adjusts pH value to 6.1)；Detection wavelength：230nm；Flow velocity：1.0ml/min；
Sample size：20μl.
Experimental procedure：
(1) sample preparation：
Take istradefylline, known impurities A-H each appropriate, (di(2-ethylhexyl)phosphate is taken with acetonitrile-phosphate buffer of volume ratio 1: 1
Hydrogen potassium 6.8g, adds water 1000ml to make dissolving, and adjusting pH value to 6.1) ultrasonic dissolution and dilution with potassium hydroxide is made containing Yi Qucha
Alkali is about 0.5mg/ml, impurity A-H is each about 5 μ g/ml solution, as sample solution.
(2) detect：Above-mentioned sample solution is taken, the μ l of sample introduction 20, records chromatogram.
Typical chromatogram is shown in Fig. 1.
Embodiment 2：
Detecting instrument and chromatographic condition：
High performance liquid chromatograph：Agilent PUMP, Agilent DAD detectors
Chromatographic column：Diamonsil C18 chromatographic columns (250 × 4.6mm, 5 μm)；Mobile phase：With embodiment 1；Detection wavelength：
230nm；Flow velocity：1.0ml/min.
(1) sample preparation：
Acid destroys：Istradefylline piece is taken, it is finely ground, take fine powder appropriate (being approximately equivalent to contain istradefylline 10mg), put 20ml palm fibres
In colo(u)r specification bottle, add 1mol/L hydrochloric acid solution 2ml, put 60 DEG C of water-baths 2 hours, take out, let cool, add 1mol/L sodium hydroxide solutions
2ml, with acetonitrile-phosphate buffer of volume ratio 1: 1 (potassium dihydrogen phosphate 6.8g is taken, adds water 1000ml to make dissolving, uses hydroxide
Potassium adjusts pH value to 6.1) dissolving and being diluted to scale, shakes up, filters, sample is destroyed as acid.
Alkali destroys：Istradefylline piece is taken, it is finely ground, take fine powder appropriate (being approximately equivalent to contain istradefylline 10mg), put 20ml palm fibres
In colo(u)r specification bottle, add 1mol/L sodium hydroxide solution 2ml, put 60 DEG C of water-baths 2 hours, take out, let cool, add 1mol/L hydrochloric acid solutions
2ml, with acetonitrile-phosphate buffer of volume ratio 1: 1 (potassium dihydrogen phosphate 6.8g is taken, adds water 1000ml to make dissolving, uses hydroxide
Potassium adjusts pH value to 6.1) dissolving and being diluted to scale, shakes up, filters, sample is destroyed as alkali.
High temperature：Istradefylline piece is taken, it is finely ground, heated 3 hours in 150 DEG C, take fine powder (to be approximately equivalent to contain Yi Qu in right amount
Theophylline 10mg), put in 20ml brown measuring bottles, (taken potassium dihydrogen phosphate 6.8g with acetonitrile-phosphate buffer of volume ratio 1: 1, added
Water 1000ml makes dissolving, adjusts pH value to 6.1) dissolving and being diluted to scale with potassium hydroxide, shakes up, filter, broken as high temperature
Bad sample.
Oxidative demage：Istradefylline piece is taken, it is finely ground, take fine powder appropriate (being approximately equivalent to contain istradefylline 10mg), put 20ml
In brown measuring bottle, add 30% hydrogenperoxide steam generator 2ml, put 60 DEG C of water-baths 2 hours, take out, let cool, with the acetonitrile of volume ratio 1: 1-
Phosphate buffer (takes potassium dihydrogen phosphate 6.8g, adds water 1000ml to make dissolving, with potassium hydroxide regulation pH value to 6.1) dissolving simultaneously
Scale is diluted to, is shaken up, is filtered, as Oxidative demage sample.
Photo damage：Istradefylline piece is taken, it is finely ground, take fine powder appropriate (being approximately equivalent to contain istradefylline 10mg), put 20ml palm fibres
In colo(u)r specification bottle, with acetonitrile-phosphate buffer of volume ratio 1: 1 (potassium dihydrogen phosphate 6.8g is taken, adds water 1000ml to make dissolving, is used
Potassium hydroxide adjusts pH value to 6.1) dissolving and being diluted to scale, puts and is irradiated 72 hours under strong light (10000Lx), shaken up, is filtered,
As photo damage sample.
Do not destroy：Istradefylline piece is taken, it is finely ground, take fine powder appropriate (being approximately equivalent to contain istradefylline 10mg), put 20ml palm fibres
In colo(u)r specification bottle, with acetonitrile-phosphate buffer of volume ratio 1: 1 (potassium dihydrogen phosphate 6.8g is taken, adds water 1000ml to make dissolving, is used
Potassium hydroxide adjusts pH value to 6.1) dissolving and being diluted to scale, shakes up, filters, as not destroying sample.
(2) detect：Above-mentioned each sample solution is taken, the μ l of sample introduction 20, record chromatogram respectively respectively.
Typical chromatogram is shown in Fig. 2-7.
Embodiment 3：
Detecting instrument and chromatographic condition：
High performance liquid chromatograph：Agilent PUMP, Agilent DAD detectors
Chromatographic column：Diamonsil C18 chromatographic columns (250 × 4.6mm, 5 μm)；Mobile phase：The second that volume ratio is 50: 50
Nitrile -0.05mol/L phosphate buffers (potassium hydroxide adjusts pH value to 6.1)；Detection wavelength：230nm；Flow velocity：1.0ml/min；
Sample size：20μl.
Experimental procedure：
(1) sample preparation：Take istradefylline appropriate, with the acetonitrile -0.05mol/L phosphate buffer (hydrogen of volume ratio 1: 1
Potassium oxide adjusts pH value that solution in every 1ml containing about 0.5mg is made to 6.1) dissolving and dilute, and shakes up, as sample solution.
(2) detect：Above-mentioned sample solution is taken, the μ l of sample introduction 20, records chromatogram.
Typical chromatogram is shown in Fig. 8.
Claims (8)
1. HPLC analytical method of a kind of istradefylline about material, it is characterised in that comprise the following steps：
(1) sample preparation：Istradefylline raw material or powder formulation are taken, the mixed liquor ultrasound with acetonitrile and phosphate buffer is molten
Solution, filtering or centrifugation, it is configured to the istradefylline solution that concentration is 0.1-1.5mg/ml；
(2) chromatographic condition is set：Using anti-phase C18 posts, column temperature is arranged on 20-50 DEG C；With the mixed of acetonitrile and phosphate buffer
Conjunction liquid is mobile phase, carries out isocratic elution；Flow velocity is 0.5-2.0ml/min；Detection wavelength is 210-270nm；
(3) detect：The istradefylline solution for taking step (1) to prepare, sample introduction 10-50 μ l, record chromatogram；
The volume ratio of acetonitrile and phosphate buffer is 50: 49-54 in step (2) mobile phase；
The phosphate buffer is the aqueous solution of potassium dihydrogen phosphate, and the concentration of potassium dihydrogen phosphate is 0.01-0.5mol/L, uses hydrogen
Potassium oxide adjusts pH value to 5.0-7.0；
The relevant material of the istradefylline refers to eight main known impurities, including istradefylline reaction raw materials-impurity H, synthesis
It is intermediate-impurity D, istradefylline synthesising by-product-impurity E, impurity F, impurity G and degradation impurity-impurity A, impurity B, miscellaneous
Matter C：
2. HPLC analytical method according to claim 1, it is characterised in that：
In step (2) anti-phase C18 posts be selected from 250 × 4.6mm, 5 μm of Grace Smart C18,250 × 4.6mm, 5 μm
Agilent C18 or 250 × 4.6mm, 5 μm of Diamonsil C18.
3. HPLC analytical method according to claim 1 or 2, it is characterised in that：
Anti-phase C18 posts are 250 × 4.6mm, 5 μm of Diamonsil C18 in step (2).
4. HPLC analytical method according to claim 1, it is characterised in that：
The volume ratio of acetonitrile and phosphate buffer is 1: 1 in the mixed liquor of step (1) acetonitrile and phosphate buffer.
5. HPLC analytical method according to claim 1, it is characterised in that：
The volume ratio of acetonitrile and phosphate buffer is 50: 50 in step (2) mobile phase.
6. HPLC analytical method according to claim 1, it is characterised in that：
The concentration of potassium dihydrogen phosphate is 0.05mol/L in the phosphate buffer, and pH value is adjusted to 5.9-6.3 with potassium hydroxide.
7. HPLC analytical method according to claim 1, it is characterised in that：
Flow velocity is 0.8-1.2ml/min, Detection wavelength 225-235nm in step (2).
8. HPLC analytical method according to claim 1, it is characterised in that：
Sample size is 20 μ l in step (3).
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