CN105738493B - The analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity - Google Patents
The analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity Download PDFInfo
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Abstract
The invention provides a kind of analysis method of Lapatinib isomer impurity, methods described is carried out using the high performance liquid chromatography for combining UV-detector, wherein, using phenyl-pentafluoride pilum；Mobile phase is made up of mobile phase A and Mobile phase B；The mobile phase A is used as using ammonium acetate buffer；The Mobile phase B is used as using methanol；Type of elution is isocratic elution.Using this method, the isomer impurity of two p-methyl benzenesulfonic acid Lapatinibs can be separated well, and sensitivity is high, and specificity is strong, and separating degree reaches requirement.
Description
Technical field
The present invention relates to Pharmaceutical Analysis technical field, in particular it relates to two p-methyl benzenesulfonic acid Lapatinib isomers
The analysis method of impurity.
Background technology
Two p-methyl benzenesulfonic acid Lapatinibs have the structure shown in formula 1：
Lapatinib is that one kind can be while target human epidermal growth factor acceptor (EGFR) and human epidermal growth factor receptor
The small molecule kinase inhibitors of body -2 (HER2), medicinal is two p-methyl benzenesulfonic acid Lapatinibs, by Britain's GlaxoSmithKline PLC company
Exploitation, U.S. FDA approval is obtained in March, 2007, for drug combination：Share capecitabine treatment overexpression HER2 evening
Phase or metastatic breast cancer, share Letrozole treatment overexpression HER2, the metastatic breast cancer climacteric of hormone receptor positive
Women.
However, the analyzing detecting method of current two p-methyl benzenesulfonic acid Lapatinib isomer impurity still has much room for improvement.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.Therefore, the present invention
One purpose is to propose that a kind of used time is short, and the two p-methyl benzenesulfonic acid Lapatinibs that separating degree is good, separative efficiency is high are different with dividing
The analysis method of structure body impurity.
The present invention is that the following discovery based on inventor is completed：
Two isomers respectively with structure shown in formula 2, formula 3 are usually contained in two p-methyl benzenesulfonic acid Lapatinibs
Impurity, and the quality and stability of two p-methyl benzenesulfonic acid Lapatinibs can be influenceed containing isomer impurity.
In order to effectively test and analyze two p-methyl benzenesulfonic acid Lapatinib isomer impurity, improve separating degree,
The present inventor is carried out to the analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity of the present invention
Grope research.Inventor attempts to use C18Chromatographic column, using ammonium acetate buffer solution as mobile phase A, using acetonitrile as Mobile phase B,
Linear gradient elution condition shown according to the form below, two pairs of toluene are tested and analyzed using the high performance liquid chromatography for combining UV-detector
Sulfonic acid Lapatinib isomer impurity.
Specifically, comprise the following steps：
1. take two p-methyl benzenesulfonic acid Lapatinibs appropriate, with acetonitrile-water (volume ratio 4：1) dissolving and with acetonitrile-water (volume
Than 4：1) solution A that 1ml contains two p-methyl benzenesulfonic acid Lapatinib 0.8mg is made in quantitative dilution, takes the change of structure shown in appropriate formula 2
Compound impurity is added in solution A, produces mixed solution for need testing solution；
2. taking the need testing solution prepared in step 1 and blank solvent to shine above-mentioned chromatographic condition, it is injected separately into efficiently
Liquid chromatograph, records chromatogram.
As a result show：The main peak of the compound impurities of structure shown in formula 2 and two p-methyl benzenesulfonic acid Lapatinibs can not be realized
Good separation.
Therefore, inventor enters to the analysis method of above-mentioned two p-methyl benzenesulfonic acid Lapatinib isomer impurity
One step is adjusted.The present inventor gropes and studied by extremely hard and bitter experiment, it is proposed that a kind of used time is short, and point
From spending, the analysis method for the two p-methyl benzenesulfonic acid Lapatinib isomer impurity that separative efficiency is high.
Thus, the invention provides a kind of analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity.Root
According to embodiments of the invention, this method is carried out using the high performance liquid chromatography for combining UV-detector, wherein, chromatographic column is used
Phenyl-pentafluoride pilum；Mobile phase is made up of mobile phase A and Mobile phase B；The mobile phase A is used as using ammonium acetate buffer；Using
Methanol is used as the Mobile phase B；Type of elution is isocratic elution.Using the method for the present invention, two pairs of first can be separated well
The isomer impurity of benzene sulfonic acid Lapatinib, sensitivity is high, and specificity is strong, and separating degree reaches requirement.
The analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity according to embodiments of the present invention can be with
With following additional technical feature：
Embodiments in accordance with the present invention, the Detection wavelength of the UV-detector is 261 ± 2nm.Inventor is by two pairs of first
The need testing solution of benzene sulfonic acid Lapatinib, full scan, hair are carried out using ultraviolet-visible spectrophotometer in 190nm~400nm
The a length of 261nm of maximum absorption wave of existing two p-methyl benzenesulfonic acid Lapatinibs, therefore 261 ± 2nm of selection is used as Detection wavelength.
Embodiments in accordance with the present invention, methods described carries out analysis detection using high performance liquid chromatography.The mobile phase
It is made up of mobile phase A and Mobile phase B；The mobile phase A is used as using ammonium acetate buffer；The mobile phase is used as using methanol
B。
Embodiments in accordance with the present invention, in the mobile phase, the volume ratio of the ammonium acetate buffer and methanol is
(25~40)：(75~60), type of elution is isocratic elution.Thus, two p-methyl benzenesulfonic acid Lapatinibs and its same point are conducive to
Isomer impurities are separated, and the mobile phase of aforementioned proportion can realize the separating effect of the mobile phase better than other ratios.
According to the specific example of the present invention, the volume ratio of the ammonium acetate buffer and methanol is 30：70.By
This, separating effect is preferable.
Embodiments in accordance with the present invention, the column temperature of the high performance liquid chromatography is 35 degrees Celsius~40 degrees Celsius.Thus,
Two p-methyl benzenesulfonic acid Lapatinibs and its isomer impurity is conducive to be separated, if too high or too low for temperature, separation
Effect is undesirable.
Embodiments in accordance with the present invention, the flow velocity of the high performance liquid chromatography is 0.8~1.2ml/min.Thus, favorably
Separated in two p-methyl benzenesulfonic acid Lapatinibs and its isomer impurity, if flow velocity is too fast or excessively slow, separating effect
It is undesirable.
According to the specific example of the present invention, the flow velocity of the high performance liquid chromatography is 1.0ml/min.Thus, two
The separating effect of p-methyl benzenesulfonic acid Lapatinib and its isomer impurity is preferable.
Embodiments in accordance with the present invention, in the ammonium acetate buffer, the concentration of ammonium acetate is 40~60mmol/L.By
This, the effect that two p-methyl benzenesulfonic acid Lapatinibs and its isomer impurity are separated is preferable.
According to the specific example of the present invention, in the ammonium acetate buffer, the concentration of ammonium acetate is 50mmol/L.
Thus, separating effect is preferable.
Embodiments in accordance with the present invention, the ammonium acetate buffer adjusts pH to 4.0~5.0 with glacial acetic acid.Thus, favorably
Separated in two p-methyl benzenesulfonic acid Lapatinibs and its isomer impurity, if pH is too high or too low, separating effect is equal
It is undesirable.
According to the specific example of the present invention, the ammonium acetate buffer adjusts pH to 4.5 with glacial acetic acid.Thus, energy
Two p-methyl benzenesulfonic acid Lapatinibs and its isomer impurity are enough efficiently separated, and separating degree is preferable.
, can be quick using the analysis method of two p-methyl benzenesulfonic acid Lapatinib isomer impurity of the present invention
Effectively two p-methyl benzenesulfonic acid Lapatinibs are separated with its isomer impurity, and the used time is short, separating degree is good, separative efficiency
High, specificity is strong.
Embodiments in accordance with the present invention, the described method comprises the following steps：
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(2) chromatographic condition：Instrument is equipped with UV-detector using high performance liquid chromatograph；Chromatographic column uses pentafluorophenyl group
Post, using with glacial acetic acid adjust pH to 4.0~5.0 concentration as 40~60mmol/L ammonium acetate buffer be the mobile phase A,
Using methanol as the Mobile phase B, the volume ratio of the ammonium acetate buffer and methanol is (25~40)：(75~60), elution
Mode is isocratic elution, and Detection wavelength is 261 ± 2nm, and off-square formula is that flow velocity is 0.8~1.2ml/min, and column temperature is 35 Celsius
~40 degrees Celsius of degree, isocratic elution is carried out by above-mentioned shown condition；
(3) take the μ l of (1) sample 5, according to above-mentioned chromatographic condition, inject liquid chromatograph, record chromatogram.
Using this method of the present invention, the compound impurities of structure shown in chromatogram Chinese style 2 and formula 3 and two pairs of toluene
The main peak of sulfonic acid Lapatinib can realize good separation.
According to the specific example of the present invention, it the described method comprises the following steps：
(a-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound
Dissolving, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(a-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.5 concentration with glacial acetic acid as 50mmol/L's
Ammonium acetate buffer is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and stream
Dynamic phase B volume ratio is 30：70, Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius；
(a-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the efficient liquid of UV-detector
Chromatography, records chromatogram.
According to the specific example of the present invention, it the described method comprises the following steps：
(b-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound
Dissolving, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(b-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 5.0 concentration with glacial acetic acid as 40mmol/L's
Ammonium acetate buffer is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and stream
Dynamic phase B volume ratio is 25：75, Detection wavelength is 262nm, and flow velocity is 0.8ml/min, and column temperature is 38 degrees Celsius；
(b-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the efficient liquid of UV-detector
Chromatography, records chromatogram.
According to the specific example of the present invention, it the described method comprises the following steps：
(c-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound
Dissolving, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(c-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.0 concentration with glacial acetic acid as 60mmol/L's
Ammonium acetate buffer is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and stream
Dynamic phase B volume ratio is 40：60, Detection wavelength is 259nm, and flow velocity is 1.0ml/min, and column temperature is 36 degrees Celsius；
(c-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the efficient liquid of UV-detector
Chromatography, records chromatogram.
According to the specific example of the present invention, it the described method comprises the following steps：
(d-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound
Dissolving, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(d-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.4 concentration with glacial acetic acid as 45mmol/L's
Ammonium acetate buffer is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and stream
Dynamic phase B volume ratio is 35：65, Detection wavelength is 263nm, and flow velocity is 1.2ml/min, and column temperature is 35 degrees Celsius；
(d-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the efficient liquid of UV-detector
Chromatography, records chromatogram.
According to the specific example of the present invention, it the described method comprises the following steps：
(e-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound
Dissolving, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(e-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.8 concentration with glacial acetic acid as 55mmol/L's
Ammonium acetate buffer is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and stream
Dynamic phase B volume ratio is 30：70, Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius；
(e-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the efficient liquid of UV-detector
Chromatography, records chromatogram.
Thus, using method of the present invention, preferable separating effect is resulted in.
Embodiments in accordance with the present invention, the phenyl-pentafluoride pilum is preferably 2.6 μm of PFP of Phenmonex Kinetex
100 × 4.6mm chromatographic columns.Thus, separating effect is preferable.
Brief description of the drawings
Fig. 1 shows according to one embodiment of present invention, the UV scanning figure of two p-methyl benzenesulfonic acid Lapatinibs；
Fig. 2 is shown according to one embodiment of present invention, is analyzed two p-methyl benzenesulfonic acid using the method for gradient elution and is drawn
Handkerchief replaces the chromatogram of Buddhist nun's bulk drug；
Fig. 3 is shown according to one embodiment of present invention, is analyzed two p-methyl benzenesulfonic acid using the method for isocratic elution and is drawn
Handkerchief replace Buddhist nun's bulk drug chromatogram, wherein in chromatogram 1 be structure shown in formula 2 compound, 2 be structure shown in formula 3 chemical combination
Thing, 3 be two p-methyl benzenesulfonic acid Lapatinib main peaks.
Embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this hair
It is bright, and be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to text in the art
Offer described technology or condition or carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument,
For can be by the conventional products of acquisition purchased in market.
Embodiment 1：The determination of Detection wavelength
Take plus acetonitrile-water (volume ratio 4:1) mixed solvent dissolves and diluted and is made in every 1ml containing about 20 μ g bulk drugs
Solution, ultraviolet-visible spectrophotometer 190nm~400nm carry out full scan, two p-methyl benzenesulfonic acid Lapatinibs it is ultraviolet
Scanning result is shown in Fig. 1.As shown in Figure 1, a length of 261nm of maximum absorption wave of two p-methyl benzenesulfonic acid Lapatinibs, therefore selection 261 ±
2nm is used as Detection wavelength.
Embodiment 2：
Using Phenmonex luna C183 μm, 100 × 4.6mm chromatographic columns, with 50mmol/L ammonium acetate buffer solutions
(take 3.85g ammonium acetates, be dissolved in 990ml water, adjust PH to 4.5 with glacial acetic acid, be diluted with water to 1000ml) is mobile phase A,
Using acetonitrile as Mobile phase B, Detection wavelength 261nm, 40 DEG C of column temperature, the μ l of sample introduction 5, according to the form below carries out linear gradient elution gradient：
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 65 | 35 |
| 13 | 65 | 35 |
| 33 | 42 | 58 |
| 43 | 10 | 90 |
| 48 | 10 | 90 |
| 50 | 65 | 35 |
| 60 | 65 | 35 |
Experimental procedure：
1. take two p-methyl benzenesulfonic acid Lapatinibs appropriate, with acetonitrile-water (volume ratio 4：1) dissolving and with acetonitrile-water (volume
Than 4：1) solution A that 1ml contains two p-methyl benzenesulfonic acid Lapatinib 0.8mg is made in quantitative dilution, takes the change of structure shown in appropriate formula 2
Compound impurity is added in solution A, produces mixed solution for need testing solution.
2. taking need testing solution and blank solvent to shine above-mentioned chromatographic condition, high performance liquid chromatograph is injected separately into, color is recorded
Spectrogram.
As a result：The main peak of the compound impurities of structure and two p-methyl benzenesulfonic acid Lapatinibs shown in the chromatogram Chinese style 2 is not
Good separation, typical collection of illustrative plates such as Fig. 2 can be realized.
Embodiment 3
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
Chromatographic condition：
Instrument is equipped with UV-detector using high performance liquid chromatograph；Using phenyl-pentafluoride pilum Phenmonex Kinetex
2.6 μm of PFP 100 × 4.6mm chromatographic columns, are buffered using the concentration that pH to 4.5 is adjusted with glacial acetic acid as 50mmol/L ammonium acetate
Liquid is the mobile phase A, using methanol as the Mobile phase B, and the volume ratio of the ammonium acetate buffer and methanol is 30：70,
Type of elution is isocratic elution, and Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius, by above-mentioned shown
Condition carries out isocratic elution；
(2) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, liquid chromatograph is injected, records chromatogram.
As a result：The compound impurities of structure shown in the chromatogram Chinese style 2 and formula 3 and two p-methyl benzenesulfonic acid Lapatinibs
Main peak can realize good separation, typical collection of illustrative plates such as Fig. 3.
Embodiment 4
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
Chromatographic condition：
Instrument is equipped with UV-detector using high performance liquid chromatograph；Using phenyl-pentafluoride pilum Phenmonex Kinetex
2.6 μm of PFP 100 × 4.6mm chromatographic columns, are buffered using the concentration that pH to 5.0 is adjusted with glacial acetic acid as 40mmol/L ammonium acetate
Liquid is the mobile phase A, using methanol as the Mobile phase B, and the volume ratio of the ammonium acetate buffer and methanol is 25：75,
Type of elution is isocratic elution, and Detection wavelength is 262nm, and flow velocity is 0.8ml/min, and column temperature is 38 degrees Celsius, by above-mentioned shown
Condition carries out isocratic elution；
(2) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, liquid chromatograph is injected, records chromatogram.
As a result：The compound impurities of structure shown in the chromatogram Chinese style 2 and formula 3 and two p-methyl benzenesulfonic acid Lapatinibs
Main peak can realize good separation.
Embodiment 5
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
Chromatographic condition：
Instrument is equipped with UV-detector using high performance liquid chromatograph；Using phenyl-pentafluoride pilum Phenmonex Kinetex
2.6 μm of PFP 100 × 4.6mm chromatographic columns, are buffered using the concentration that pH to 4.0 is adjusted with glacial acetic acid as 60mmol/L ammonium acetate
Liquid is the mobile phase A, using methanol as the Mobile phase B, and the volume ratio of the ammonium acetate buffer and methanol is 40：60,
Type of elution is isocratic elution, and Detection wavelength is 259nm, and flow velocity is 1.0ml/min, and column temperature is 36 degrees Celsius, by above-mentioned shown
Condition carries out isocratic elution；
(2) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, liquid chromatograph is injected, records chromatogram.
As a result：The compound impurities of structure shown in the chromatogram Chinese style 2 and formula 3 and two p-methyl benzenesulfonic acid Lapatinibs
Main peak can realize good separation.
Embodiment 6
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
Chromatographic condition：
Instrument is equipped with UV-detector using high performance liquid chromatograph；Using phenyl-pentafluoride pilum Phenmonex Kinetex
2.6 μm of PFP 100 × 4.6mm chromatographic columns, are buffered using the concentration that pH to 4.4 is adjusted with glacial acetic acid as 45mmol/L ammonium acetate
Liquid is the mobile phase A, using methanol as the Mobile phase B, and the volume ratio of the ammonium acetate buffer and methanol is 35：65,
Type of elution is isocratic elution, and Detection wavelength is 263nm, and flow velocity is 1.2ml/min, and column temperature is 35 degrees Celsius, by above-mentioned shown
Condition carries out isocratic elution；
(2) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, liquid chromatograph is injected, records chromatogram.
As a result：The compound impurities of structure shown in the chromatogram Chinese style 2 and formula 3 and two p-methyl benzenesulfonic acid Lapatinibs
Main peak can realize good separation.
Embodiment 7
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasound is molten
Solution, is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
Chromatographic condition：
Instrument is equipped with UV-detector using high performance liquid chromatograph；Using phenyl-pentafluoride pilum Phenmonex Kinetex
2.6 μm of PFP 100 × 4.6mm chromatographic columns, are buffered using the concentration that pH to 4.8 is adjusted with glacial acetic acid as 55mmol/L ammonium acetate
Liquid is the mobile phase A, using methanol as the Mobile phase B, and the volume ratio of the ammonium acetate buffer and methanol is 30：70,
Type of elution is isocratic elution, and Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius, by above-mentioned shown
Condition carries out isocratic elution；
(2) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, liquid chromatograph is injected, records chromatogram.
As a result：The compound impurities of structure shown in the chromatogram Chinese style 2 and formula 3 and two p-methyl benzenesulfonic acid Lapatinibs
Main peak can realize good separation.
In the description of the invention, it is to be understood that term " first ", " second " are only used for describing purpose, and can not
It is interpreted as indicating or implies relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, define " the
One ", one or more this feature can be expressed or be implicitly included to the feature of " second ".In the description of the invention,
" multiple " are meant that two or more, unless otherwise specifically defined.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine specific features, structure, material or the spy that the embodiment or example are described
Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not
Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office
Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area
Art personnel can be tied the not be the same as Example or the feature of example and non-be the same as Example or example described in this specification
Close and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (13)
1. a kind of analysis method of Lapatinib isomer impurity, it is characterised in that methods described, which is utilized, combines ultraviolet inspection
The high performance liquid chromatography for surveying device is carried out, wherein,
Chromatographic column uses phenyl-pentafluoride pilum；
Mobile phase is made up of mobile phase A and Mobile phase B；
The mobile phase A is used as using ammonium acetate buffer；
The Mobile phase B is used as using methanol；
Type of elution is isocratic elution,
Wherein, the volume ratio (25~40) of the mobile phase A and Mobile phase B：(75~60).
2. according to the method described in claim 1, it is characterised in that the Detection wavelength of the UV-detector is 261 ± 2nm.
3. according to the method described in claim 1, it is characterised in that the column temperature of the high performance liquid chromatography is 35~40 Celsius
Degree.
4. according to the method described in claim 1, it is characterised in that the flow velocity of the high performance liquid chromatography is 0.8~
1.2ml/min。
5. according to the method described in claim 1, it is characterised in that in the ammonium acetate buffer, the concentration of ammonium acetate is
40~60mmol/L.
6. according to the method described in claim 1, it is characterised in that the ammonium acetate buffer adjusts pH to 4.0 with glacial acetic acid
~5.0.
7. according to the method described in claim 1, it is characterised in that comprise the following steps：
(1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution, matches somebody with somebody
The need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml is made；
(2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.0~5.0 concentration with glacial acetic acid as 40~60mmol/L
Ammonium acetate buffer be the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A with
The volume ratio of Mobile phase B is (25~40)：(75~60), Detection wavelength is 261 ± 2nm, and flow velocity is 0.8~1.2ml/min, post
Temperature is 35~40 degrees Celsius；
(3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high performance liquid chromatography of UV-detector
Instrument, records chromatogram.
8. method according to claim 7, it is characterised in that including：
(a-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution,
It is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(a-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.5 concentration with glacial acetic acid as 50mmol/L acetic acid
Ammonium buffer solution is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and Mobile phase B
Volume ratio be 30：70, Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius；
(a-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high-efficient liquid phase color of UV-detector
Spectrometer, records chromatogram.
9. method according to claim 7, it is characterised in that including：
(b-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution,
It is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(b-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 5.0 concentration with glacial acetic acid as 40mmol/L acetic acid
Ammonium buffer solution is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and Mobile phase B
Volume ratio be 25：75, Detection wavelength is 262nm, and flow velocity is 0.8ml/min, and column temperature is 38 degrees Celsius；
(b-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high-efficient liquid phase color of UV-detector
Spectrometer, records chromatogram.
10. method according to claim 7, it is characterised in that including：
(c-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution,
It is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(c-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.0 concentration with glacial acetic acid as 60mmol/L acetic acid
Ammonium buffer solution is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and Mobile phase B
Volume ratio be 40：60, Detection wavelength is 259nm, and flow velocity is 1.0ml/min, and column temperature is 36 degrees Celsius；
(c-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high-efficient liquid phase color of UV-detector
Spectrometer, records chromatogram.
11. method according to claim 7, it is characterised in that including：
(d-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution,
It is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(d-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.4 concentration with glacial acetic acid as 45mmol/L acetic acid
Ammonium buffer solution is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and Mobile phase B
Volume ratio be 35：65, Detection wavelength is 263nm, and flow velocity is 1.2ml/min, and column temperature is 35 degrees Celsius；
(d-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high-efficient liquid phase color of UV-detector
Spectrometer, records chromatogram.
12. method according to claim 7, it is characterised in that including：
(e-1) two p-methyl benzenesulfonic acid Lapatinib bulk drugs are taken, are 4 with volume ratio：1 acetonitrile-water mixed solvent ultrasonic dissolution,
It is configured to the need testing solution that two p-methyl benzenesulfonic acid Lapatinib concentration are 0.1mg/ml；
(e-2) chromatographic condition：Using phenyl-pentafluoride pilum, to adjust pH to 4.8 concentration with glacial acetic acid as 55mmol/L acetic acid
Ammonium buffer solution is the mobile phase A, using methanol as the Mobile phase B, in the mobile phase, the mobile phase A and Mobile phase B
Volume ratio be 30：70, Detection wavelength is 261nm, and flow velocity is 1.0ml/min, and column temperature is 40 degrees Celsius；
(e-3) the μ l of need testing solution 5 are taken, according to above-mentioned chromatographic condition, injection is equipped with the high-efficient liquid phase color of UV-detector
Spectrometer, records chromatogram.
13. the method according to any one of claim 7-12, it is characterised in that the phenyl-pentafluoride pilum is
2.6 μm of PFP 100 × 4.6mm chromatographic columns of Phenmonex Kinetex.
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