CN106908531A - A kind of Gradient High Performance Liquid Chromatography simultaneously determine Nabumetone for Buddhist nun's Photodegradation Products and other about material method - Google Patents
A kind of Gradient High Performance Liquid Chromatography simultaneously determine Nabumetone for Buddhist nun's Photodegradation Products and other about material method Download PDFInfo
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- CN106908531A CN106908531A CN201710096465.5A CN201710096465A CN106908531A CN 106908531 A CN106908531 A CN 106908531A CN 201710096465 A CN201710096465 A CN 201710096465A CN 106908531 A CN106908531 A CN 106908531A
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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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
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Abstract
The invention discloses the high efficiency liquid phase chromatographic analysis method that a kind of Nabumetone replaces Buddhist nun, specifically chromatographic column is octadecylsilane chemically bonded silica post (100 × 4.6mm, 3.5 μm), with phosphate buffer methyl alcohol (82: 18) as mobile phase A, with phosphate buffer methyl alcohol (40：60) it is Mobile phase B, gradient elution, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm；Take Nabumetone and be made the solution that concentration is 0.5mg/ml for Buddhist nun's preparation, plus mobile phase A for Buddhist nun or Nabumetone, as need testing solution；Take Nabumetone and be made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, as reference substance solution.Sample introduction respectively, by external standard method with calculated by peak area, in the chromatogram of need testing solution each impurity peak area and must not exceed 1.0%.First Determination of the present invention Nabumetone for Buddhist nun Photodegradation Products and other about the content of material, have no that pertinent literature is reported.Photodegradation Products and other impurity of the Nabumetone for Buddhist nun can be fast and accurately detected, simple to operate, favorable reproducibility, sensitivity is high, can preferably control Nabumetone for Buddhist nun's product quality, be that synthesis and preparation process optimization provide guarantee.
Description
Technical field
The present invention relates to Nabumetone for Buddhist nun's raw material and its analysis method of related preparations, and in particular to one kind high-efficient liquid phase color
The method that the method for spectral gradient is measured, belongs to Pharmaceutical Analysis detection field.
Background technology
Nabumetone is a kind of aniline quinazoline class PTS for Buddhist nun, and clinic is envisaged for the treatment of advanced Non-small cell lung.
Its chemical name is (E)-N- [4- (the chloro- 4- fluorophenyls of 3-) amino) -7- ethoxyquin oxazoline -6- bases] -4- (dimethylamino)
But-2-enamides xylenesulfonate crystalline hydrate, molecular formula is C22H23ClFN5O2·(C7H8O3S)2, its chemical structural formula
It is as follows：
Nabumetone easily produces cis-isomer in synthesis and storage for Buddhist nun in 2 double bonds, another to be likely to simultaneously
There is each intermediate, accessory substance and catabolite, it is different with its optics for Buddhist nun to be difficult to separate Nabumetone using general analysis method
Structure body, herein by adjusting different flowing phase compositions, ratio, different types of elution, different pH value and different inorganic
Salinity realizes determine simultaneously Nabumetone for Buddhist nun's Photodegradation Products and other related purposes about material first, ensures well
Nabumetone is quality controllable for Buddhist nun raw material, with realistic meaning.
The content of the invention
Nabumetone is determined simultaneously it is an object of the invention to provide a kind of Gradient High Performance Liquid Chromatography for Buddhist nun's Photodegradation Products and
Other can be used for quality control of the Nabumetone for Buddhist nun's preparation process and final products about the method for material.
The technical scheme is that：
A kind of Gradient High Performance Liquid Chromatography determines Nabumetone for Buddhist nun's Photodegradation Products and other correlations about materials simultaneously
Method, it is characterised in that the detection method is comprised the following steps：
(1) standard solution is prepared
System suitability is carried out under following chromatographic conditions with the standard solution, detecting system is edited：
Chromatographic condition：Chromatographic column is octadecylsilane chemically bonded silica post, is with phosphate buffer-methyl alcohol (82: 18)
Mobile phase A, with phosphate buffer-methyl alcohol (40: 60) as Mobile phase B, gradient elution, the concentration of phosphate buffer is 0.04
~0.1mol/L, pH value is 7.0~7.8, and column temperature is 25~35 DEG C, and flow velocity is 0.9~1.1ml/min, and Detection wavelength is
247nm；
It is prepared by standard solution：Initiation material, intermediate 1, intermediate 2, intermediate 3, impurity A, illumination product are taken respectively
(impurity B) and Nabumetone add mobile phase A to be made in every 1ml the mixed solution containing about 0.0025~0.5mg for Buddhist nun's reference substance；
Precision measures mixed solution injection liquid chromatograph described in 10 μ l, records chromatogram, edits detecting system to Nabumetone
Separating degree for Buddhist nun's main peak and the peak of other impurities B should be greater than 1.5, and number of theoretical plate and tailing factor are pressed Nabumetone and calculated for Buddhist nun's main peak
10000 and no more than 1.5 should be not less than；
(2) need testing solution and reference substance solution are prepared
Take Nabumetone and be made the solution that concentration is 0.5mg/ml for Buddhist nun's testing sample, plus mobile phase A, as need testing solution；
Take Nabumetone and be made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, as reference substance solution.
(3) by impurity B and the related content about material in high performance liquid chromatography measure testing sample
Liquid chromatograph after being edited through above-mentioned steps (1) with reference substance solution injection, adjusts detection sensitivity, then will be for
Test sample solution injects liquid chromatograph, and high performance liquid chromatography measure is carried out under the chromatographic condition described in step (1), records chromatogram
Figure replaces 3~4 times of Buddhist nun's main peak retention time to Nabumetone.
(4) content of each impurity in testing sample is calculated
By external standard method with calculated by peak area, each impurity peak area sum must not cross 1.0%.
Wherein, in above-mentioned gradient elution, the excursion of mobile phase A ratio is that linear gradient was washed in 0~10 minute
De-, the ratio of mobile phase A turns to 55% from 75% change, and the ratio of Mobile phase B turns to 45% from 25% change；In 10~20 minutes,
Isocratic elution, the ratio holding 55% of mobile phase A is constant, and the ratio holding 45% of Mobile phase B is constant；In 20~30 minutes, line
Property gradient elution, the ratio of mobile phase A becomes from 55% and turns to 0%, and the ratio of Mobile phase B becomes from 45% and turns to 100%；In 30~
40 minutes, isocratic elution, the ratio holding 0% of mobile phase A was constant, and the ratio holding 100% of Mobile phase B is constant, in 40~45
Minute, mobile phase A and B return to initial proportion, and chromatographic column is rebalanced.
It is highly preferred that above-mentioned phosphate is selected from sodium dihydrogen phosphate, concentration is 0.05mol/L, and pH value is 7.5.
Above-mentioned chromatographic condition is：Chromatographic column is octadecylsilane chemically bonded silica post (100 × 4.6mm, 3.5 μm), with body
Product is mobile phase A than the phosphate buffer-methyl alcohol for 82: 18, is 40 with volume ratio：60 phosphate buffer-methyl alcohol is
Mobile phase B, gradient elution, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm.
It is highly preferred that above-mentioned chromatographic column is Waters XBridge C18Chromatographic column.
Above-mentioned Nabumetone includes that Nabumetone replaces Buddhist nun for Buddhist nun's intermediate, Nabumetone for Buddhist nun's raw material, Nabumetone for Buddhist nun's piece and Nabumetone for Buddhist nun's sample
Capsule.
By the present invention in that with Gradient High Performance Liquid Chromatography simultaneously determine Nabumetone for Buddhist nun Photodegradation Products and other have
Material is closed, by the exploration to chromatographic condition, it is determined that Nabumetone can be efficiently separated for Buddhist nun and the chromatographic condition about material, this
Method specificity is good, separating degree is good, sensitivity is high, favorable reproducibility, to evaluating synthesis and the good and bad of preparation process, finished product quality
Control and stability sample detection have great importance, First Determination of the present invention Nabumetone for Buddhist nun Photodegradation Products and other have
The content of material is closed, has no that pertinent literature is reported.
In the present invention, " about the material " refers to that in medicine preparation and storage process, may generate and degraded is produced
Impurity (including the organic impurities such as intermediate, accessory substance).Wherein, Nabumetone includes for the relevant material of Buddhist nun：Impurity A, impurity B,
Intermediate 1, intermediate 2, intermediate 3, initiation material.
The inventive method is applied to the related preparations that Nabumetone replaces Buddhist nun for Buddhist nun's intermediate, Nabumetone for Buddhist nun's raw material and containing Nabumetone, such as
Solid pharmaceutical preparation includes tablet and capsule etc..Detection method is accurate, simple to operate, and the time is rapid, can fully meet
The requirement that Related substances separation is determined with catabolite, preferably controls the specific impurities and nonspecific impurity in sample, it is ensured that
Product quality, it is practical in actual mass control work.
Brief description of the drawings
Fig. 1 is system suitability typical case's HPLC collection of illustrative plates, and 1 is impurity A, and 2 is illumination product (impurity B), and 3 is that Nabumetone replaces Buddhist nun, 4
It is that intermediate 2,5 is that intermediate 3,6 is initiation material, 7 is intermediate 1；
Fig. 2 is chromatogram (lot number of the Nabumetone for Buddhist nun's raw material need testing solution：20141201)；
Fig. 3 is chromatogram (lot number of the Nabumetone for Buddhist nun's crude product need testing solution：20141201)；
Fig. 4 is chromatogram (lot number of the Nabumetone for Buddhist nun's tablet need testing solution：20150204)；
Fig. 5 is chromatogram (lot number of the Nabumetone for Buddhist nun's capsule need testing solution：20150301)；
Specific embodiment
Instrument：The series of high efficiency liquid chromatographs of Agilent 1260；
Reagent：Sodium dihydrogen phosphate (analysis is pure), NaOH (analysis is pure), methyl alcohol (chromatographically pure, Merk companies)；
Chromatographic column：Waters XBridge C18Chromatographic column (100 × 4.6mm, 3.5 μm)；
The chemical name of standard items, structural formula and source：
Nabumetone replaces Buddhist nun：Self-control, purity：97.6%, lot number：20141001；Nabumetone is taken to be tied again through methanol-water for Buddhist nun's raw material
Crystalline substance, dries, and obtains final product；
Impurity A：
Chemical name：1- [4- (the chloro- 4- Fluorophenylaminos of 3-) -7- ethoxyquin oxazoline -6- bases] -5- hydroxyl pyrrolidines -2-
Ketone
Structural formula：
Source：Self-control, purity：98.6%, lot number：20141105, take Nabumetone and be dissolved in methanol-water, 60 DEG C of drops for Buddhist nun's raw material
Solution 2 hours, is collected through preparative liquid chromatography, and concentration, freeze-drying is obtained final product；
Impurity B：
Chemical name：(Z)-N- [4- (the chloro- 4- fluorophenyls of 3-) amino) -7- ethoxyquin oxazoline -6- bases] -4- (diformazan ammonia
Base) but-2-enamides
Structural formula：
Source：Self-control, purity：98.2%, lot number：20141117, take Nabumetone and be dissolved in methanol-water for Buddhist nun's raw material, put illumination
Placed 5 days under the conditions of (5000 ± 500lx), taken out, collected through preparative liquid chromatography, concentration, freeze-drying is obtained final product；
Initiation material：Chemical name：N- (the chloro- 4- fluorophenyls of 3-) fluoro- 6- nitros -4- quinazoline amine of -7-, lot number：BM-
20140410, it is commercially available；
Intermediate 1：
Chemical name：N- (the chloro- 4- fluorophenyls of 3-) -7- ethyoxyl -6- nitro -4- quinazoline amine
Structural formula：
Source：Self-control, purity：95.0%, lot number：20140501, with reference to Publication No. CN 103755688A, entitled
《A kind of preparation method of afatinib compound》In method be obtained；
Intermediate 2：
Chemical name：N- (the chloro- 4- fluorophenyls of 3-) -7- ethyoxyl -4,6- quinazoline diamines
Structural formula：
Source：Self-control, purity：95.4%, lot number：20140501, with reference to Publication No. CN 103755688A, entitled
《A kind of preparation method of afatinib compound》In method be obtained；
Intermediate 3：
Chemical name：Diethyl-[4- (the chloro- 4- Fluorophenylaminos of 3-) -7- ethoxyquin oxazoline -6- amino] -2- oxygen ethyls
Phosphate
Structural formula：
Source：Self-control, purity：97.7%, lot number：20140501, with reference to Publication No. CN 103755688A, entitled
《A kind of preparation method of afatinib compound》In method be obtained；
Nabumetone replaces Buddhist nun's raw material and crude product：With reference to Patent No. ZL201410822395.3, entitled《Nabumetone is for Buddhist nun to toluene
The alpha-crystal form and preparation method and the pharmaceutical composition containing it of sulfonate》In method be obtained；
CN105777655A discloses Nabumetone for Buddhist nun with N- (the chloro- 4- fluorophenyls of 3-) the fluoro- 6- nitros -4- quinazoline amine of -7-
It is initiation material, prepared by referenced patent WO2007085638 similar method, salification process referenced patent WO2012121764
Preparation method.
Nabumetone replaces Buddhist nun's tablet and capsule：With reference to our company's patent《A kind of (4- ((the chloro- 4- fluorophenyls of 3-) ammonia containing (E)-N-
Base) -7- ethoxyquin oxazoline -6- bases) -4- (dimethylamino) but-2-enamides or its salt preparation compositions and its impurity control
Method processed》In method be obtained.
Nabumetone is as follows for the preparation method of Buddhist nun's tablet and capsule：
1st, capsule of the xylene monosulfonic acid Nabumetone for Buddhist nun is prepared
Table 1 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the capsule of Buddhist nun
Preparation method：Component and amount according to table 1,60-100 mesh is crossed by active component xylene monosulfonic acid Nabumetone for Buddhist nun
Sieve treatment, then crosses 40-60 mesh sieves once and always mixes with mannitol, colloidal silica, Compritol 888 ATO, total mixed completion
Afterwards, be placed directly within capsule automatic filling machine, according to content weight be filled in No. 4, No. 3, in No. 2 gelatin hollow capsules i.e.
Can.
2nd, tablet of the xylene monosulfonic acid Nabumetone for Buddhist nun is prepared
2.1
Table 2 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：Component and amount according to table 2,60-100 mesh is crossed by active component xylene monosulfonic acid Nabumetone for Buddhist nun
Sieve treatment, other auxiliary materials cross 40-60 mesh sieves, then carry out compressing tablet after always being mixed together, according to specification 1~4 be respectively adopted 6mm,
6mm, 7mm and 9mm circle shallow concave punch are pressed into plain piece.Coating material (HPMC, glyceryl triacetate or dioxy are sprayed to plain piece
Change titanium), control sheet surface heating temperature is between 40-55 DEG C during coating.
2.2
Table 3 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：It is identical with 2.1.
2.3
Table 4 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：It is identical with 2.1.
2.4
Table 5 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：It is identical with 2.1.
2.5 prepare tablet of the xylene monosulfonic acid Nabumetone containing stabilizer for Buddhist nun
Table 6 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：Active component xylene monosulfonic acid Nabumetone is crossed into the treatment of 60-100 mesh sieves, mistake after tartaric acid crushing for Buddhist nun
The treatment of 80-120 mesh sieves, the xylene monosulfonic acid Nabumetone after screening is pre-mixed for Buddhist nun, tartaric acid and colloidal silica, then
Always mixed with other auxiliary materials, then carry out compressing tablet, 6mm, 6mm, 7mm and 9mm circle scrobicula are respectively adopted respectively according to specification 1~4
Punch die is pressed into plain piece.Coating material (HPMC, glyceryl triacetate or titanium dioxide), control sheet table during coating are sprayed to plain piece
Face heating temperature is between 40-55 DEG C.
2.6 prepare tablet of the xylene monosulfonic acid Nabumetone containing stabilizer for Buddhist nun
Table 7 prepares raw material and proportion of the xylene monosulfonic acid Nabumetone for the tablet of Buddhist nun
Preparation method：It is identical with 2.5.
【Embodiment 1】The conditional filtering of Gradient High Performance Liquid Chromatography
1 chromatographic condition and system suitability
The selection of 1.1 mobile phases
With Nabumetone for Buddhist nun and the separating degree of impurity B (illumination product), main peak number of theoretical plate and symmetrical factor refer to as evaluation
Mark, gradient elution is carried out according to table 8 below, screens optimal phosphate buffering liquid concentration, and the pH value of optimal flow phase finally determines phosphoric acid
Sodium dihydrogen buffer solution optium concentration is 0.05mol/L, and the optimal pH of mobile phase is 7.5 or so.Phosphate buffering liquid concentration and
PH value selection result see the table below 9~10.
The mobile phase of table 8. and elution time
The phosphate concn selection result of table 9.
Table 10.pH value selection results
The selection of 1.2 chromatographic columns
With Nabumetone for Buddhist nun and the separating degree of impurity B (illumination product), main peak number of theoretical plate and symmetrical factor refer to as evaluation
Mark, attempts, with different brands, the chromatographic column of different model, finally determining using Waters XBridge C18Post (100 ×
4.6mm, 3.5 μm), chromatographic column selection result is shown in Table 11.
The chromatographic column selection result of table 11.
The selection of 1.3 column temperatures
With Nabumetone for Buddhist nun and the separating degree of impurity B (illumination product), main peak number of theoretical plate and symmetrical factor refer to as evaluation
Mark, selection column temperature is investigated for 25 DEG C, 28 DEG C, 30 DEG C, 32 DEG C and 35 DEG C, finally determines that column temperature is 30 DEG C, column temperature selection knot
Fruit is shown in Table 12.
The column temperature selection result of table 12.
1.4 instruments and flow velocity
The series of Agilent 1260, DAD detectors；Flow velocity is 1.0ml/min.
Under above-mentioned chromatographic condition, Nabumetone is moderate for Buddhist nun's main peak retention time, and number of theoretical plate is high, and peak shape is symmetrical, main peak with
The separating degree of adjacent miscellaneous peak meets the requirements.
The measure of 1.5 sensitivity
Appropriate Nabumetone is taken for Buddhist nun's reference substance, solution of every 1ml Nabumetones containing 0.5mg for Buddhist nun is configured to mobile phase A, as confession
Test sample solution.It is diluted to a series of solution of various concentrations with mobile phase A respectively again, the μ l of sample introduction 10, are allowed to produce main peak respectively
It is the signal of baseline noise three times.Through experiment, detectability is 0.6ng, (S/N >=3), if dense during with Related substances separation
Degree 0.5mg/ml is calculated, and its limit of detection is 0.01%.
1.6 stabilities of solution
Take with portion need testing solution, determined respectively at 0,0.5,1,2,4,6,8,10,12 hours difference sample introductions, its main peak
Area and relevant substance-measuring result are basicly stable in 12 hours.
Above test result indicate that, the method simple and sensitive, favorable reproducibility can be carried out to Nabumetone in sample for the quality of Buddhist nun
Preferably control.
The determination of chromatographic condition：Through above-mentioned Selection experiment, it is determined that chromatographic condition be：With octadecylsilane chemically bonded silica
(100 × 4.6mm, 3.5 μm) is filler, with phosphate buffer-methyl alcohol (82: 18) as mobile phase A, with phosphate-buffered
Liquid-methyl alcohol (40：60) it is Mobile phase B, gradient elution, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm；
In wherein described gradient elution, the excursion of mobile phase A ratio is in 0~10 minute, linear gradient elution, mobile phase A
Ratio become from 75% and turn to 55%, the ratio of Mobile phase B becomes from 25% and turns to 45%；In 10~20 minutes, isocratic elution, stream
The ratio holding 55% of dynamic phase A is constant, and the ratio holding 45% of Mobile phase B is constant；In 20~30 minutes, linear gradient elution,
The ratio of mobile phase A turns to 0% from 55% change, and the ratio of Mobile phase B turns to 100% from 45% change；It is isocratic in 30~40 minutes
Wash-out, the ratio holding 0% of mobile phase A is constant, and the ratio holding 100% of Mobile phase B was constant, in 40~45 minutes, mobile phase A
Initial proportion is returned to B, chromatographic column is rebalanced.
1.7 system suitabilities：
Initiation material, intermediate 1, intermediate 2, intermediate 3, impurity A, illumination product (impurity B) and Nabumetone is taken respectively to replace
Buddhist nun's reference substance adds mobile phase A to be made in every 1ml the mixed solution containing about 0.0025~0.5mg；Precision measured and mix described in 10 μ l
Solution injects liquid chromatograph, records chromatogram, edits detecting system to Nabumetone and is separated with the peak of other impurities B for Buddhist nun's main peak
Degree should be greater than 1.5, and number of theoretical plate and tailing factor are calculated for Buddhist nun's main peak by Nabumetone and should be not less than 10000 and no more than 1.5；Collection of illustrative plates
As shown in Figure 1, Nabumetone is 2.84 with the separating degree of illumination product for Buddhist nun, and Nabumetone replaces the number of theoretical plate and tailing factor of Buddhist nun's main peak
Respectively 26395 and 1.00, separating degree, theoretical cam curve, tailing factor meet above-mentioned requirements, accordingly, it is determined that chromatographic condition
Can be used for Nabumetone and replace Buddhist nun's capsule about the measure of material for Buddhist nun's tablet, Nabumetone for Buddhist nun's crude product, Nabumetone for Buddhist nun's raw material, Nabumetone.
The preparation of 2 need testing solutions
Take Nabumetone and be made the solution that concentration is 0.5mg/ml for Buddhist nun's testing sample, plus mobile phase A, as need testing solution；
The preparation of 3 reference substance solutions
Take Nabumetone and be made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, as reference substance solution.
4 determination methods
Precision measures the μ l of reference substance solution 10 injection liquid chromatographs, adjusts detection sensitivity, makes principal component chromatogram peak height
About the 10~20% of full scale, then precision measure the μ l of need testing solution 10 injection liquid chromatographs, record chromatogram to Nabumetone
For 3~4 times of Buddhist nun's main peak retention time, if any impurity peaks in need testing solution chromatogram, the sum of each impurity peak area is measured, pressed
With calculated by peak area, each impurity peak area sum must not cross 1.0% to external standard method.
【Embodiment 2】Nabumetone replaces Buddhist nun's raw material about the measure of material
Taking Nabumetone replaces Buddhist nun's raw material appropriate, accurately weighed, plus mobile phase A is made the solution of concentration 0.5mg/ml, used as trying
Product solution.The another Nabumetone that takes dilutes and is made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, used as control
Product solution.Under following selected chromatographic condition：Waters XbridgeC18Post (100 × 4.6mm, 3.5 μm), it is slow with phosphate
Fliud flushing-methyl alcohol (82: 18) is mobile phase A, with phosphate buffer-methyl alcohol (40: 60) as Mobile phase B, ladder is carried out according to table 13 below
Degree wash-out, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm；Number of theoretical plate is pressed Nabumetone and is calculated for Buddhist nun's main peak
10000 should be not less than, main peak should be greater than 1.5 with the separating degree at other impurities peak.Precision measures the μ l of reference substance solution 10 injection liquid
Chromatography, adjusts detection sensitivity, the 10~20% of principal component chromatogram peak height about full scale, then precision is measured test sample
The μ l of solution 10 inject liquid chromatograph, and record chromatogram to Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time, need testing solution color
If any impurity peaks in spectrogram, the sum of each impurity peak area is calculated, must not calculate 1.0%) by external standard method.Respectively to three batches
The Nabumetone of (20141001,20141101,20141201) is measured for Buddhist nun's raw material, wherein, Nabumetone replaces the relevant material of Buddhist nun's raw material
Measurement result it is as shown in table 15 below, collection of illustrative plates is as shown in Figure 2.
The mobile phase of table 13. and elution time
The Nabumetone of table 14. replaces the relevant substance-measuring result of Buddhist nun's raw material
【Embodiment 3】Nabumetone replaces Buddhist nun's crude product about the measure of material
Taking Nabumetone replaces Buddhist nun's crude product appropriate, accurately weighed, plus mobile phase A is made the solution of concentration 0.5mg/ml, used as trying
Product solution.The another Nabumetone that takes dilutes and is made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, used as control
Product solution.Under following selected chromatographic condition：Waters Xbridge C18Post (100 × 4.6mm, 3.5 μm), with phosphate
Buffer solution-methyl alcohol (82: 18) is mobile phase A, with phosphate buffer-methyl alcohol (40: 60) as Mobile phase B, is carried out according to table 15 below
Gradient elution, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm；Number of theoretical plate is by Nabumetone for based on Buddhist nun's main peak
Calculation should be not less than 10000, and main peak should be greater than 1.5 with the separating degree at other impurities peak.Precision measures the μ l of reference substance solution 10 injections
Liquid chromatograph, adjusts detection sensitivity, the 10~20% of principal component chromatogram peak height about full scale, then precision is measured for examination
The μ l of product solution 10 inject liquid chromatograph, and record chromatogram to Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time, need testing solution
If any impurity peaks in chromatogram, the sum of each impurity peak area is calculated, must not calculate 1.0%) by external standard method.Respectively to three batches
The Nabumetone of secondary (20141001,20141101,20141201) is measured for Buddhist nun's crude product, wherein, Nabumetone replaces the relevant thing of Buddhist nun's crude product
The measurement result of matter is as shown in table 16 below.Collection of illustrative plates is as shown in Figure 3.
The mobile phase of table 15. and elution time
The Nabumetone of table 16. replaces the relevant substance-measuring result of Buddhist nun's crude product
【Embodiment 4】Nabumetone replaces Buddhist nun's tablet about the measure of material
Take Nabumetone appropriate for Buddhist nun's piece fine powder, precision is weighed and (is approximately equivalent to Nabumetone for Buddhist nun 25mg) in right amount, plus mobile phase A is made
The solution of concentration 0.5mg/ml, as need testing solution.The another Nabumetone that takes dilutes and is made concentration for Buddhist nun's reference substance, plus mobile phase A
It is the solution of 0.005mg/ml, as reference substance solution.Under following selected chromatographic condition：Waters Xbridge C18Post
(100 × 4.6mm, 3.5 μm), with phosphate buffer-methyl alcohol (82: 18) as mobile phase A, with phosphate buffer-methyl alcohol (40
: it is 60) Mobile phase B, gradient elution is carried out according to table 17 below, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is
247nm；Number of theoretical plate is calculated for Buddhist nun's main peak by Nabumetone and should be not less than 10000, and main peak should be greater than with the separating degree at other impurities peak
1.5.Precision measures the μ l of reference substance solution 10 injection liquid chromatographs, adjusts detection sensitivity, is about principal component chromatogram peak height
The 10~20% of full scale, then precision measures the μ l of need testing solution 10 injection liquid chromatographs, and record chromatogram to Nabumetone replaces Buddhist nun
3~4 times of main peak retention time, if any impurity peaks in need testing solution chromatogram, measure the sum of each impurity peak area, by external standard
Method must not calculate 1.0%.The Nabumetone to three batches (20150202,20150203,20150204) enters for Buddhist nun's tablet respectively
Row is determined, wherein, Nabumetone is as shown in table 18 below about the measurement result of material for Buddhist nun's piece.Collection of illustrative plates is as shown in Figure 4.
The mobile phase of table 17. and elution time
The Nabumetone of table 18 replaces the relevant substance-measuring result of Buddhist nun's piece
【Embodiment 5】Nabumetone replaces Buddhist nun's capsule about the measure of material
Take Nabumetone to be mixed for Buddhist nun's capsule powders, precision is weighed and (is approximately equivalent to Nabumetone for Buddhist nun 25mg) in right amount, plus mobile phase A system
Into the solution of concentration 0.5mg/ml, as need testing solution.The another Nabumetone that takes dilutes and is made dense for Buddhist nun's reference substance, plus mobile phase A
The solution for 0.005mg/ml is spent, as reference substance solution.Under following selected chromatographic condition：Waters Xbridge C18
Post (100 × 4.6mm, 3.5 μm), with phosphate buffer-methyl alcohol (82: 18) as mobile phase A, with phosphate buffer-methyl alcohol
(40: 60) are Mobile phase B, and gradient elution is carried out according to table 19 below, and column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is
247nm；Number of theoretical plate is calculated for Buddhist nun's main peak by Nabumetone and should be not less than 10000, and main peak should be greater than with the separating degree at other impurities peak
1.5.Precision measures the μ l of reference substance solution 10 injection liquid chromatographs, adjusts detection sensitivity, is about principal component chromatogram peak height
The 10~20% of full scale, then precision measures the μ l of need testing solution 10 injection liquid chromatographs, and record chromatogram to Nabumetone replaces Buddhist nun
3~4 times of main peak retention time, if any impurity peaks in need testing solution chromatogram, measure the sum of each impurity peak area, by external standard
Method must not calculate 1.0%.The Nabumetone to three batches (20150301,20150302,20150303) enters for Buddhist nun's capsule respectively
Row is determined, wherein, Nabumetone is as shown in table 20 below about the measurement result of material for Buddhist nun's capsule.Collection of illustrative plates is as shown in Figure 5.
The mobile phase of table 19. and elution time
The Nabumetone of table 20. replaces the relevant substance-measuring result of Buddhist nun's capsule
Claims (7)
1. a kind of Gradient High Performance Liquid Chromatography simultaneously determine Nabumetone for Buddhist nun's Photodegradation Products and other about material method, its
It is characterised by, the detection method is comprised the following steps：
(1) standard solution is prepared, system suitability is carried out under following chromatographic conditions with the standard solution, edited
Detecting system；
Chromatographic condition：Chromatographic column is octadecylsilane chemically bonded silica post, the phosphate buffer-first with volume ratio as 82: 18
Alcohol is mobile phase A, the phosphate buffer-methyl alcohol with volume ratio as 40: 60 as Mobile phase B, gradient elution, phosphate buffer
Concentration be 0.04~0.1mol/L, pH value be 7.0~7.8, column temperature be 25~35 DEG C, flow velocity be 0.9~1.1ml/min, inspection
Survey wavelength is 247nm；
It is prepared by standard solution：Initiation material, intermediate 1, intermediate 2, intermediate 3, impurity A, impurity B and Nabumetone is taken respectively to replace
Buddhist nun's reference substance adds mobile phase A to be made the mixed solution containing 0.0025~0.5mg in every 1ml；
Precision measures mixed solution injection liquid chromatograph described in 10 μ l, records chromatogram, edits detecting system to Nabumetone and replaces Buddhist nun
Main peak is more than 1.5 with the separating degree at the peak of other impurities B, and Nabumetone is not less than 10000, tailing factor for the number of theoretical plate of Buddhist nun's main peak
No more than 1.5；
(2) need testing solution and reference substance solution are prepared；
Take Nabumetone and be made the solution that concentration is 0.5mg/ml for Buddhist nun's testing sample, plus mobile phase A, as need testing solution；Take naphthalene
It is general to be made the solution that concentration is 0.005mg/ml for Buddhist nun's reference substance, plus mobile phase A, as reference substance solution；
(3) by impurity B and the related content about material in high performance liquid chromatography measure testing sample；
Liquid chromatograph after being edited through above-mentioned steps (1) with reference substance solution injection, adjusts detection sensitivity, then by test sample
Solution injects liquid chromatograph, and high performance liquid chromatography measure is carried out under the chromatographic condition described in step (1), and record chromatogram is extremely
Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time；
(4) content of each impurity in testing sample is calculated；
By external standard method with calculated by peak area, each impurity peak area sum must not exceed 1.0%.
2. the method described in claim 1, wherein in described gradient elution, the excursion of mobile phase A ratio is：In 0~
10 minutes, linear gradient elution, the ratio of mobile phase A turned to 55% from 75% change, and the ratio of Mobile phase B is turned to from 25% change
45%；In 10~20 minutes, isocratic elution, the ratio holding 55% of mobile phase A was constant, and the ratio of Mobile phase B keeps 45% not
Become；In 20~30 minutes, linear gradient elution, the ratio of mobile phase A became from 55% and turns to 0%, and the ratio of Mobile phase B is from 45%
Change turns to 100%；In 30~40 minutes, isocratic elution, the ratio of mobile phase A kept 0% constant, the ratio holding of Mobile phase B
100% is constant, and in 40~45 minutes, mobile phase A and B returned to initial proportion, and chromatographic column is rebalanced.
3. the method for claim 1, wherein the salt is selected from sodium dihydrogen phosphate.
4. method as claimed in claim 3, wherein the concentration of described sodium dihydrogen phosphate is 0.05mol/L, pH value is 7.5.
5. the method for claim 1, its chromatographic condition is：Chromatographic column be octadecylsilane bonding post (100 ×
4.6mm, 3.5 μm), the phosphate buffer-methyl alcohol with volume ratio as 82: 18, as mobile phase A, is 40 with volume ratio：60 phosphorus
Phthalate buffer-methyl alcohol is Mobile phase B, and gradient elution, column temperature is 30 DEG C, and flow velocity is 1.0ml/min, and Detection wavelength is 247nm.
6. method as claimed in claim 5, described chromatographic column is Waters XBridge C18Chromatographic column.
7. the method as described in claim any one of 1-6, it is characterised in that the Nabumetone is replaced for Buddhist nun's testing sample including Nabumetone
Buddhist nun's raw material, Nabumetone replace Buddhist nun's capsule for Buddhist nun's crude product, Nabumetone for Buddhist nun's tablet and Nabumetone.
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