CN109374782A - A method of with the related substance of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie - Google Patents
A method of with the related substance of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie Download PDFInfo
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Abstract
The present invention provides a kind of with method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance, include the following steps: using octadecylsilane chemically bonded silica as filler, it is that Mobile phase B carries out gradient elution using water as mobile phase A, acetonitrile, flow velocity is 0.8~1.2ml/min, column temperature is 25~40 DEG C, it is detected using related substance of the UV detector to the net bulk pharmaceutical chemicals of Yi Palie, the Detection wavelength of the UV detector is 205~230nm.Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, by comprehensively considering analytical column, mobile phase, gradient elution program and flow velocity, column temperature to the combined influence of separation detection, to effectively control the quality of bulk pharmaceutical chemicals, and the detection method high sensitivity, specificity is strong, precision is high, accuracy is strong, fast and convenient, easy to operate, the related substance suitable for the net bulk pharmaceutical chemicals of separation determination Yi Palie.
Description
Technical field
The present invention relates to technical field of analytical chemistry, and in particular to a kind of net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie have
The method for closing substance.
Background technique
Yi Palie is net (Empagliflozin, trade name Jardiance), is combined by Boehringer Ingelheim with Li Lai company
The novel antidiabetic medicine of one kind of exploitation, in 08 month 2014 01 Nikkei U.S. Food and Drug Administration (FDA) batch
Quasi- listing, for improving the glycemic control of diabetes B adult patient.Yi Palie is a kind of new sodium-glucose collaboration turn only
Albumen 2 (SGLT2) inhibitor medicaments are transported, by inhibiting reabsorption of the kidney to glucose, increase glucose excretion, and then reduce
The elevated blood glucose level of diabetic.Molecular formula is C23H27ClO7, molecular weight 450.91, structural formula such as following formula (1):
Yi Palie only during the preparation process, because many factors such as starting material, synthesis technology, degradation generate multiple impurity,
It is wherein relatively also easy to produce in synthesis technology with impurity A, impurity B, impurity C, impurity D and impurity E, as main in related substance project
Investigate impurity, bound requirements must not be 0.10wt%.
The net impurity A of Yi Palie is synthesis technology starting material, molecular formula: C17H16BrClO2, molecular weight: 367.66, chemistry
Structural formula such as following formula (2):
The net impurity B of Yi Palie is intermediate IV, molecular formula: C31H35ClO11, molecular weight: 619.06, chemical structural formula is as follows
Formula (3):
The net impurity C of Yi Palie is intermediate II, molecular formula: C24H29ClO8, molecular weight: 480.93, chemical structural formula is as follows
Formula (4):
The net impurity D of Yi Palie is the carbonyl on carbanion different location attack glucolactone in intermediate-II synthesis
Base forms different chiral intermediates, ultimately generates Yi Palie corresponding isomer impurities only, molecular formula: C23H27ClO7, molecule
Amount: 450.91, chemical structural formula such as following formula (5):
The net impurity E of Yi Palie is to synthesize the net middle possible open loop of sugared segment of Yi Palie to form impurity, molecular formula:
C23H29ClO8, molecular weight: 468.9, chemical structural formula such as following formula (6):
In order to control the quality of the net bulk pharmaceutical chemicals of Yi Palie, need to control main component and impurity, in existing skill
In art, quick, easy, Accurate Analysis detection analysis method of the net bulk pharmaceutical chemicals of Yi Palie in relation to substance it is not suitable for.Therefore, right
There is further improvement and optimization demand in relation to the measuring method of substance in the net bulk pharmaceutical chemicals of Yi Palie.
Summary of the invention
In order to overcome above-mentioned technical problem of the existing technology, the present inventor is carrying out a large amount of further investigation
Afterwards, to provide a kind of method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance, have fast and convenient, sensitive
Degree height, accurate and reliable advantage.
The technical solution adopted by the present invention is that:
A method of with the related substance of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie, include the following steps: with octadecane
Base silane bonded silica gel be filler, using water as mobile phase A, acetonitrile be Mobile phase B carry out gradient elution, flow velocity be 0.8~
1.2ml/min, column temperature are 25~40 DEG C, are detected using related substance of the UV detector to the net bulk pharmaceutical chemicals of Yi Palie, institute
The Detection wavelength for stating UV detector is 205~230nm.
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein column length
For 150mm~250mm, preferably 250mm.Thus, it is possible to improve the separating degree of main peak Yu the peak impurity D and impurity E peak.
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein the filling
The partial size of agent is 1.8~5 μm, preferably 5 μm.Thus, it is possible to further increase separating degree.
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein flow velocity is
1.0ml/min, column temperature are 30 DEG C of column temperatures.The separating degree between impurity can be improved as a result,.
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein the gradient
The condition of elution are as follows:
| Time, minute | Mobile phase A, volume % | Mobile phase B, volume % |
| 0 | 70~80 | 20~30 |
| 15 | 55 | 45 |
| 30~40 | 5~15 | 85~95 |
| 55 | 5~15 | 85~95 |
。
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein the gradient
The condition of elution are as follows:
| Time, minute | Mobile phase A, volume % | Mobile phase B, volume % |
| 0 | 75 | 25 |
| 15 | 55 | 45 |
| 30 | 10 | 90 |
| 55 | 10 | 90 |
Thus obtained separating effect is best, and peak shape is best.
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, wherein described ultraviolet
The Detection wavelength of detector is 224nm.Thus, it is possible to improve the detection sensitivity of impurity.
Compared with prior art, beneficial effects of the present invention are as follows:
Method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance of the present invention, by comprehensively considering point
Column, mobile phase, gradient elution program and flow velocity, column temperature are analysed to the combined influence of separation detection, so that testing result reaches
Optimize, can by the net bulk pharmaceutical chemicals of Yi Palie impurity A, impurity B, impurity C, impurity D and impurity E, in same chromatographic condition
Separation rapidly and efficiently is carried out, to effectively control the quality of bulk pharmaceutical chemicals, and the detection method high sensitivity, specificity
By force, precision is high, accuracy is strong, fast and convenient, easy to operate, and the quality of drug can be effectively controlled, be suitable for separation determination according to
Pa arranges the related substance of net bulk pharmaceutical chemicals.
Detailed description of the invention
Fig. 1 is the chromatogram of the blank solution in the present invention by the detection of 1 condition of embodiment；
Fig. 2 is the chromatogram of the system suitability solution in the present invention by the detection of 1 condition of embodiment；
Fig. 3 is the chromatogram of the quantitative limit solution in the present invention by the detection of 1 condition of embodiment；
Fig. 4 is the chromatogram of the test solution in the present invention by the detection of 1 condition of embodiment；
Fig. 5 is in the present invention by the chromatogram of the detection limit solution of 1 condition of embodiment detection；
Fig. 6 is the chromatogram of the blank solution in the present invention by the detection of 2 condition of embodiment；
Fig. 7 is the chromatogram of the test solution in the present invention by the detection of 2 condition of embodiment；
Fig. 8 is the chromatogram of the system suitability solution in the present invention by the detection of 2 condition of embodiment；
Fig. 9 is the chromatogram of the quantitative limit solution in the present invention by the detection of 2 condition of embodiment；
Figure 10 is in the present invention by the chromatogram of the detection limit solution of 2 condition of embodiment detection.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection scope.Production firm person is not specified in agents useful for same and instrument, can pass through commercially available acquisition conventional products.
The net bulk pharmaceutical chemicals of Yi Palie used in the embodiment of the present invention and impurity reference substance are inventor's self-control.
Embodiment 1
Chromatographic condition is as follows:
Chromatographic column: (2) 250 × 4.6mm of Agilent 5TC-C18
Mobile phase A: water
Mobile phase B: acetonitrile
Column temperature: 30 DEG C
Flow velocity: 1.0ml/min
Detection wavelength: 224nm
Sample volume: 10 μ L
Gradient elution program are as follows:
1 gradient elution program of table
| Time, minute | Mobile phase A, volume % | Mobile phase B, volume % |
| 0 | 75 | 25 |
| 15 | 55 | 45 |
| 30 | 10 | 90 |
| 55 | 10 | 90 |
Solution is prepared:
Impurity reference substance stock solution: impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance, miscellaneous is taken
Matter E reference substance each about 12.5mg, it is accurately weighed, it sets in same 25ml measuring bottle, adds diluent to dissolve and be diluted to scale, shake up,
To obtain the final product；The diluent are as follows: acetonitrile-water (50:50) (V/V).
System suitability solution: taking the net working reference substance of Yi Palie about 50mg, accurately weighed, sets in 100ml measuring bottle, accurate
Above-mentioned impurity reference substance stock solution 1ml is added to set in above-mentioned 100ml measuring bottle, then plus diluent be diluted to scale, shake up to get.
Test solution: taking the net bulk pharmaceutical chemicals of Yi Palie about 50mg, accurately weighed, sets in 100ml measuring bottle, diluent is added to dissolve
And it is diluted to scale, it shakes up.
The net reference substance stock solution of Yi Palie: taking the net working reference substance of Yi Palie about 50mg, accurately weighed, sets 100ml measuring bottle
In, add diluent to dissolve and be diluted to scale, shake up to get.
Quantitative limit solution: precision measures the impurity reference substance stock solution and the net reference substance stock solution of the Yi Palie is each
1ml adds diluent to be diluted to scale into 100ml measuring bottle, shakes up, and precision measures 1ml to 25ml, and diluent is added to be diluted to quarter
Degree, shake up to get.
Detection limit solution: precision measures the quantitative limit solution 5ml and sets in 10ml measuring bottle, and diluent is added to be diluted to scale,
Shake up to get.
Measurement: respectively by blank solution (i.e. diluent), system suitability solution, quantitative limit solution, test solution and
Detection limit solution injection high performance liquid chromatograph is detected, and is that (partial size is 5 μ to filler with octadecylsilane chemically bonded silica
M, column internal diameter 4.6mm, column length 250mm), it is detected by 1 gradient elution program of table, records chromatogram.
Blank solution (i.e. diluent), system suitability solution, quantitative limit solution, test solution and detection limit solution
Chromatogram is respectively as shown in Fig. 1,2,3,4 and 5, it is known that, Fig. 1 shows that blank does not interfere determination of foreign matter；Fig. 2 show each impurity and according to
Separating degree is good between pa column are net, and the specific net system suitability spectrum data of Yi Palie is shown in Table 2；Fig. 3 shows that Yi Palie is net and miscellaneous
Matter A, impurity B, impurity C, impurity D and impurity E quantitative limit be respectively 0.04wt%, 0.04wt%, 0.04wt%, 0.04wt%,
0.04wt% and 0.04wt%；Fig. 4 show to be not detected in the net sample of homemade Yi Palie impurity A, impurity B, impurity C, impurity D and
Impurity E, other single impurity of detection are in 0.1wt% or less；Fig. 5 shows Yi Palie net and impurity A, impurity B, impurity C, miscellaneous
Matter D and impurity E detection limit respectively 0.02wt%, 0.02wt%, 0.02wt%, 0.02wt%, 0.02wt% and 0.02wt%,
Lower than the limit 0.10wt% of each impurity；The detection sensitivity of this law is high.
The net system suitability spectrum data table of Yi Palie in 2 embodiment 1 of table
Embodiment 2
Chromatographic condition is as follows:
Chromatographic column: (2) 250 × 4.6mm of Agilent 5TC-C18
Mobile phase A: water
Mobile phase B: acetonitrile
Column temperature: 30 DEG C
Flow velocity: 1.0ml/min
Detection wavelength: 224nm
Sample volume: 10 μ l
Gradient elution program are as follows:
3 gradient elution program of table
| Time, minute | Mobile phase A, volume % | Mobile phase B, volume % |
| 0 | 80 | 20 |
| 15 | 55 | 45 |
| 30 | 15 | 85 |
| 55 | 15 | 85 |
Solution is prepared:
Impurity reference substance stock solution: impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance, miscellaneous is taken
Matter E reference substance each about 12.5mg, it is accurately weighed, it sets in same 25ml measuring bottle, adds diluent to dissolve and be diluted to scale, shake up,
To obtain the final product；The diluent are as follows: acetonitrile-water (50:50) (V/V).
System suitability solution: taking the net working reference substance of Yi Palie about 50mg, accurately weighed, sets in 100ml measuring bottle, accurate
Above-mentioned impurity reference substance stock solution 1ml is added to set in above-mentioned 100ml measuring bottle, then plus diluent be diluted to scale, shake up to get.
Test solution: taking the net bulk pharmaceutical chemicals of Yi Palie about 50mg, accurately weighed, sets in 100ml measuring bottle, diluent is added to dissolve
And it is diluted to scale, it shakes up.
The net reference substance stock solution of Yi Palie: taking the net working reference substance of Yi Palie about 50mg, accurately weighed, sets 100ml measuring bottle
In, add diluent to dissolve and be diluted to scale, shake up to get.
Quantitative limit solution: precision measures above-mentioned impurity reference substance stock solution and the net reference substance stock solution of the Yi Palie is each
1ml adds diluent to be diluted to scale into 100ml measuring bottle, shakes up, and precision measures 1ml to 25ml, and diluent is added to be diluted to quarter
Degree, shake up to get.
Detection limit solution: precision measures above-mentioned quantitative limit solution 5ml and sets in 10ml measuring bottle, and diluent is added to be diluted to scale,
Shake up to get.
Measurement: respectively by blank solution (i.e. diluent), system suitability solution, quantitative limit solution, test solution and
Detection limit solution injection high performance liquid chromatograph is detected, and is that (partial size is 5 μ to filler with octadecylsilane chemically bonded silica
M, column internal diameter 4.6mm, column length 250mm), it is detected by 3 gradient elution program of table, records chromatogram.
Blank solution (i.e. diluent), test solution, system suitability solution, quantitative limit solution and detection limit solution
Chromatogram is respectively as shown in Fig. 6,7,8,9 and 10, it is known that, Fig. 6 shows that blank does not interfere determination of foreign matter；Fig. 7 show it is homemade according to
Pa arranges in net sample and impurity A, impurity B, impurity C, impurity D and impurity E is not detected, and other single impurity of detection exist
0.1wt% or less；Fig. 8 show each impurity and Yi Palie it is net between separating degree it is good, the specific net system suitability map of Yi Palie
Data are shown in Table 4；Fig. 9 shows that Yi Palie is net and impurity A, impurity B, impurity C, impurity D and impurity E quantitative limit are respectively
0.04wt%, 0.04wt%, 0.04wt%, 0.04wt%, 0.04wt% and 0.04wt%；Figure 10 shows that Yi Palie is net and impurity
A, impurity B, impurity C, impurity D and impurity E detection limit be respectively 0.02wt%, 0.02wt%, 0.02wt%, 0.02wt%,
0.02wt% and 0.02wt%, lower than the limit 0.10wt% of each impurity；The detection sensitivity of this law is high.
The net system suitability spectrum data table of Yi Palie in 4 embodiment 2 of table
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring substantive content of the invention.
Claims (9)
1. a kind of method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance, characterized by the following steps:
It is that Mobile phase B carries out gradient elution using water as mobile phase A, acetonitrile, flow velocity is using octadecylsilane chemically bonded silica as filler
0.8~1.2ml/min, column temperature are 25~40 DEG C, are examined using related substance of the UV detector to the net bulk pharmaceutical chemicals of Yi Palie
It surveys, the Detection wavelength of the UV detector is 205~230nm.
2. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: column length is 150mm~250mm.
3. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: column length 250mm.
4. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: the partial size of the filler is 1.8~5 μm.
5. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: the partial size of the filler is 5 μm.
6. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: the flow velocity is 1.0ml/min, and column temperature is 30 DEG C of column temperatures.
7. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: the condition of the gradient elution are as follows:
。
8. method of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to claim 1, feature exist
In: the condition of the gradient elution are as follows:
。
9. side of the net bulk pharmaceutical chemicals of HPLC separation determination Yi Palie in relation to substance according to any one of claims 1 to 8
Method, it is characterised in that: the Detection wavelength of the UV detector is 224nm.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111983054A (en) * | 2020-07-28 | 2020-11-24 | 安徽联创生物医药股份有限公司 | Method for separating and measuring related substances of empagliflozin intermediate by using HPLC (high performance liquid chromatography) |
| CN114264747A (en) * | 2021-12-27 | 2022-04-01 | 浙江海翔药业股份有限公司 | High performance liquid chromatography detection method for empagliflozin intermediate and related substances thereof |
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| CN111983054A (en) * | 2020-07-28 | 2020-11-24 | 安徽联创生物医药股份有限公司 | Method for separating and measuring related substances of empagliflozin intermediate by using HPLC (high performance liquid chromatography) |
| CN114264747A (en) * | 2021-12-27 | 2022-04-01 | 浙江海翔药业股份有限公司 | High performance liquid chromatography detection method for empagliflozin intermediate and related substances thereof |
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