CN108152418A - The HPLC detection methods of ketorolac tromethamine or/and impurity in ketorolac tromethamine or its preparation - Google Patents
The HPLC detection methods of ketorolac tromethamine or/and impurity in ketorolac tromethamine or its preparation Download PDFInfo
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- CN108152418A CN108152418A CN201810021084.5A CN201810021084A CN108152418A CN 108152418 A CN108152418 A CN 108152418A CN 201810021084 A CN201810021084 A CN 201810021084A CN 108152418 A CN108152418 A CN 108152418A
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses the HPLC detection methods of ketorolac tromethamine or/and impurity in a kind of ketorolac tromethamine or its preparation, and solution to be checked is detected using HPLC, qualitative or quantitative according to chromatographic results.The present invention is for the HPLC method for detecting impurities of related impurities in ketorolac tromethamine bulk pharmaceutical chemicals and parenteral solution, it angularly optimizes and improves from determining and test solution concentration the screening of Detection wavelength, flow visualizing, and angularly detection method of the present invention is verified from system suitability, degradation specificity, detection limit and quantitative limit, linear and range, precision, accuracy, stability of solution and method durability, the results show that the method for the invention has good impurity Detection capability.
Description
Technical field
The invention belongs to substance detection technique field, more particularly to Ketoralac ammonia in ketorolac tromethamine or its preparation
The HPLC detection methods of butantriol or/and impurity.
Background technology
Ketorolac tromethamine, English name Ketorolac Tromethamine, abbreviation KTT, CAS 74103-07-
4.Ketorolac tromethamine is a kind of non-steroid anti-inflammatory drug, can inhibit prostaglandin biosynthesis, bioactivity and its S- type
It is related.Zooscopy shows that ketorolac tromethamine has analgesic activity, no calm or angst resistance effect.
According to KTT synthetic routes, it is known that its impurity being likely to occur is mainly degradation impurity, for example, ketorolac and ammonia fourth
Triol reaction generation impurity A (CAS 167105-80-8), ketorolac generate impurity B (No. CAS in building-up process by oxidation
154476-25-2,1- hydroxyl ketorolac), impurity C (CAS 113502-52-6,1- ketone groups ketorolac), impurity D and impurity E
(CAS 80965-09-9) needs to control this 5 degradation impurities in bulk pharmaceutical chemicals.In addition, in KTT injection formulas due to
There is ethyl alcohol that may react as auxiliary material, acid and alcohol and generate ester, therefore in addition to 5 degradations in control bulk pharmaceutical chemicals are miscellaneous in preparation
Matter also needs impurity F (CAS 108061-03-6).
For in the liquid chromatographic detection of KTT bulk pharmaceutical chemicals impurity in USP and EP pharmacopeia, have the following disadvantages：Mobile phase salt
It is mutually the ammonium dihydrogen phosphate (with phosphorus acid for adjusting pH to 3.0) of 50mmol/L, organic phase is tetrahydrofuran, and tetrahydrofuran can be right
Detecting instrument causes certain injury.
Invention content
In view of this, the present invention intends optimizing the HPLC detection methods of impurity in KTT bulk pharmaceutical chemicals and its preparation,
Meanwhile the method for the invention also can qualitatively or quantitatively detect KTT in KTT bulk pharmaceutical chemicals and its preparation.
Above-mentioned purpose that the invention is realized by the following technical scheme：
The present invention provides the detection method of impurity in ketorolac tromethamine or its preparation, using HPLC to solution to be checked
It is detected, qualitative or quantitative according to chromatographic results, chromatographic condition includes：
Chromatographic column：C8 silica gel chromatographic columns；
Detection wavelength：200~400nm of Detection wavelength；
Mobile phase and elution program：Mobile phase A is the water phase containing phosphate buffer, and pH is 4.1~4.3；Mobile phase B is
The mixing organic phase of acetonitrile and tetrahydrofuran, the volume fraction of tetrahydrofuran is 10~15% in organic phase；By such as Gradient 1~
3 any programs carry out gradient elution：
Gradient 1：
Gradient 2：
Gradient 3：
Further, the impurity includes one or both of impurity A, impurity B, impurity C, impurity D, impurity E, impurity F
Above mixing：
Using detection method, the more a impurity of above-mentioned A-F can be effectively separated with main composition simultaneously, it can be with
Effective detection to one or more of which ingredient is realized simultaneously.
Further, containing dihydrogen phosphate ions and phosphate anion in the phosphate buffer, pH is 4.1~4.3；Into
One step, the phosphate buffer is ammonium dihydrogen phosphate-phosphate buffer；Further, pH 4.2；Further, phosphorus
Acid dihydride ammonium concentration is 5.75g/L.
Further, the chromatographic column specification be 4.6 × 250mm, 5 μm.
Further, flow rate of mobile phase is 0.6~1.2ml/min, is further selected from 0.9~1.1ml/min.
Further, column temperature is selected from 20~42 DEG C, is further selected from 38~42 DEG C.
In the present invention, the parameters such as column temperature, flow velocity, sample size can select in Typical ranges.
Further, the solvent of solution to be checked is selected from the acetonitrile solution of water or acetonitrile volume fraction below 25%；Further
Ground, the solution to be checked include at least test solution；Further, solution to be checked further includes reference substance solution.
In detection method, if using reference substance, reference substance is corresponding with target substance.Institute in the present invention
" reference substance is corresponding with target substance " is stated, refers to choose the corresponding reference substance of the compound, such as target according to target substance
Substance is impurity A, then corresponding is exactly impurity A reference substance；If target substance is impurity A and D, corresponding is exactly impurity A and D
Reference substance.
The present invention also provides the detection methods to ketorolac tromethamine in ketorolac tromethamine or its preparation, use
HPLC is detected solution to be checked, qualitative or quantitative according to chromatographic results, and chromatographic condition includes：
Chromatographic column：C8 silica gel chromatographic columns；
Detection wavelength：200~400nm of Detection wavelength；
Mobile phase and elution program：Mobile phase A is the water phase containing phosphate buffer, and pH is 4.1~4.3；Mobile phase B is
The mixing organic phase of acetonitrile and tetrahydrofuran, the volume fraction of tetrahydrofuran is 10~15% in organic phase；By such as Gradient 1~
3 any programs carry out gradient elution：
Gradient 1：
Gradient 2：
Gradient 3：
Selection can be adjusted by conventional means in aforementioned scope of disclosure in Detection wavelength of the present invention.It is finding
During best detection wavelength, the modes such as the matching used all band scanning of ultraviolet spectrophotometry, HPLC can be used to carry out, then match
The detection result (solvent is such as avoided to interfere) of HPLC detectors is closed, suitable Detection wavelength is found using routine techniques.This hair
In a bright specific embodiment, Detection wavelength is selected from 311~315nm, such as in 313nm.
The present invention research shows that, the volume fraction of tetrahydrofuran can just reach detection result of the present invention at 10%, real
Preferentially using the low mobile phase of content of tetrahydrofuran in the operation of border.
Qualitative detection in the present invention can be carried out using conventional method, such as reference substance is selected to be carried out pair by external standard method
After should analyzing or each ingredient being separated by HPLC, carry out qualitative analysis, such as mass spectrum, thin by general survey means
Layer, ultraviolet etc..
It is quantitatively detected in the present invention, the conventional methods such as external standard method, area normalization method can be used to carry out content calculation.
In addition, it is necessary to illustrate, the control of separating degree, the limit of impurities in the present invention passes through the conventional skill of this field
Art means are adjusted, and the limit of impurities can refer to USP or EP pharmacopeia.
In quantitative analysis, if using external standard method, make standard curve using conventional means and calculated；But fixed
Property analysis when, then need not make standard curve, can be judged by retention time.
The beneficial effects of the invention are as follows：The present invention is directed to ketorolac tromethamine bulk pharmaceutical chemicals and its preparation especially parenteral solution
The HPLC detection methods of middle related impurities optimize, from Detection wavelength, the determining and test solution of flow visualizing
The screening of concentration is angularly optimized and is improved, and from system suitability, degradation specificity, detection limit and quantitative limit, linear
And range, precision, accuracy, stability of solution and method durability angularly test detection method of the present invention
Card the results show that the method for the invention has good impurity Detection capability, by improving mobile phase, reduces tetrahydrofuran
Ratio, not only ensured the detection and separation of impurity, but also reduce damage of the tetrahydrofuran to pillar, in addition gradient elution of the invention
For isocratic elution, detection time used is shorter, and this method is more fast and simple, efficiently.
Description of the drawings
The ultraviolet absorpting spectrum of Fig. 1 KTT and each impurity, wherein, a-g figures are followed successively by KTT, impurity A, impurity B, impurity C, miscellaneous
Matter D, impurity E, impurity F ultraviolet absorpting spectrum；* DAD 1,22.252 (60.6mAU, -) reference value=21.885＆22.719 are
Mixed solution 1.D；
The typical liquid chromatographic spectrogram of Fig. 2 gradients 1；
The typical liquid chromatographic spectrogram of Fig. 3 gradients 2；
The typical liquid chromatographic spectrogram of Fig. 4 gradients 3；
The typical liquid chromatographic spectrogram of Fig. 5 gradients 4；
The typical liquid chromatographic spectrogram of Fig. 6 gradients 5；
The typical liquid chromatographic spectrogram of Fig. 7 gradients 6.
Specific embodiment
Chromatographic apparatus used in the present invention is 1260 high performance liquid chromatographs of Agilent.
The control limit of the prior art detection case of impurity and each impurity in ketorolac tromethamine (KTT) and its parenteral solution
Degree is shown in Table 1.
Table 1
Wherein, impurity A, B, C, D are obtained by buying, impurity E (with reference to patent U.S., 5621115) and impurity F (reference
“Kaneria,Ankur et al,Fe-EROS Encyclopedia of Reagents for Organic Synthesis,
Triethyl Methanetricarboxylate, 2001 ") it is synthesized respectively by laboratory.
Impurity or/and ketorolac tromethamine in ketorolac tromethamine and its preparation of the present invention especially parenteral solution
HPLC detection methods, it is specific as follows：
(1) chromatographic condition
Chromatographic column：ZORBAX Eclipse plus C8 chromatographic columns, specification 4.6 × 250mm, 5 μm, 40 DEG C of column temperature；
Detector：UV detector, Detection wavelength 313nm；
Mobile phase and elution program：5.75g/L ammonium dihydrogen phosphates buffer salt solution by the use of phosphoric acid tune pH value to 4.2 as flowing
Phase A；Acetonitrile：Tetrahydrofuran=90:10 (v/v) carry out gradient elution as Mobile phase B, by 2 program of table,
Table 2
Flow velocity：1.0ml/min；
Sample size：10μl.
(2) preparation of reagents
Test solution：Precision measures test sample 1ml (specification 30mg) or 2ml (specification 15mg), puts in 50ml measuring bottles, uses
Water is diluted to scale, shakes up, as test solution；Ketorolac tromethamine in per 1ml containing about 0.6mg；
Reference substance solution：Precision measures 1ml reference substance solutions, is placed in 100ml measuring bottles, is diluted with water to scale, shakes up,
To obtain the final product.
System suitability solution：Precision weighs impurity A, impurity B, impurity C, impurity D impurity Es and impurity F 10mg, puts
It in 10ml measuring bottles, is dissolved with methanol and is diluted to scale, shaken up, mother liquor is compareed as poly-doped impurity；Precision measures 0.6ml mixing
Impurity compares mother liquor, puts in 10ml measuring bottles, methanol dilution to scale, shakes up as impurity reference substance storing solution；Another precision weighs
Ketorolac tromethamine reference substance 60mg, puts in 10ml measuring bottles, is dissolved with methanol and is diluted to scale, shaken up, as reference substance
Storing solution；Precision measures impurity reference substance storing solution, each 1ml of reference substance storing solution, puts in 10ml measuring bottles, is diluted with water to quarter
Degree, shakes up, impure A in every 1ml, impurity B, impurity C, impurity D, impurity E, impurity F respectively about 1.2 μ g is made, containing Ketoralac ammonia
The mixed solution of butantriol about 0.6mg, as system suitability solution.
(3) sampling step
The first step, water intaking, sample introduction 1 time；
Second step takes system suitability solution, sample introduction 1 time；
Third walks, and takes reference substance solution, sample introduction 1 time；
4th step takes test solution, sample introduction 1 time.
(4) impurity content calculates
It is calculated by the following formula：
Wherein：
rfi：Correction factor for each impurity peak area of ketorolac tromethamine；
ri：Peak area for single impurity；
rs：Peak area for contrast solution.
The sum of total impurities content (%)=all impurity contents.
The specific optimization process of each condition is as described below.
First, Detection wavelength is determining
It is extracted from the respective positioning collection of illustrative plates of KTT and impurity A, impurity B, impurity C, impurity D, impurity E, impurity F corresponding
Ultraviolet absorpting spectrum, as shown in Figure 1, result shows that KTT has an absorption maximum at 313nm, Impurity Impurity A, impurity B, impurity C,
Impurity D, impurity E, impurity F have a larger absorption at 313nm, therefore select 313nm as KTT bulk pharmaceutical chemicals and parenteral solution, including
The Detection wavelength of impurity determination.
2nd, eluent gradient determines
Table 3
It tests below and correlated condition described in table 3 is used to carry out.
With reference to USP and EP pharmacopeia, mobile phase salt is mutually that the ammonium dihydrogen phosphate of 50mmol/L (uses phosphorus acid for adjusting pH extremely
3.0), organic phase is tetrahydrofuran.Consider that tetrahydrofuran is larger to the injury of instrument, the present invention attempts to add second in organic phase
Nitrile reduces the ratio for replacing tetrahydrofuran.KTT mixed solutions are selected (including KTT, impurity A, impurity B, impurity C, impurity D, impurity
E and impurity F) carry out mobile phase screening.Table 4 is the chromatographic condition 1 of screening.
4 chromatographic condition of table screening 1
As a result see Fig. 2, the results show that system suitability solution impurity detection number is insufficient, there may be impurity peaks phase mutual respect
It is folded, and impurity may be enclosed with from the point of view of the peak shape of main peak, initial guess mobile phase pH has the appearance time of impurity larger
It influences.Old terms mobile phase is prepared (with the ammonium dihydrogen phosphate buffer solution of 0.05mol/L (with phosphorus acid for adjusting pH to 3.0)：Tetrahydrochysene furan
Mutter (70:30) it is 5.5), to measure pH value, therefore investigates the pH value of mobile phase A in next step and plan, using gradient elution, to adjust flowing
The pH of phase A is extremely blended in initial proportion (A with organic phase:B=80:20) pH under is 5.5 or so, and the pH of mobile phase A is about at this time
It is 4.2.Table 5 is the chromatographic condition for screening mobile phase pH and gradient elution program, respectively sample introduction mixed solution.
5 chromatographic condition of table screening 2
Fig. 3 the results show that mixed solution 2 chromatographic condition impurity of gradient all detect, but impurity C be enclosed with it is unknown miscellaneous
Matter, impurity E and adjacent unknown impuritie separating effect are bad；Fig. 4 the results show that mixed solution in 3 chromatographic condition impurity of gradient
All detections, but main peak is enclosed with unknown impuritie.Therefore consider to change main peak and the mobile phase ratio near impurity C, Shao Liangzeng
Add the ratio of tetrahydrofuran in organic phase, whether investigate the separating effect of main peak and impurity B, impurity C and unknown impuritie can change
It is kind.Table 6 is the chromatographic condition for screening eluent gradient.Sample introduction is analyzed under following 2 chromatographic conditions respectively sample solution.
6 chromatographic condition of table screening 3
As a result see Fig. 5, the tailing factor of sample solution main peak under the chromatographic condition of gradient 4 is 0.9, selects gradient 4
Chromatographic condition positions solution to mixed solution and each impurity, and sample introduction is analyzed, and the tailing factor from mixed solution interpretation of result main peak is
0.9, each known impurities are kept completely separate, and the separating degree between each known impurities is all higher than 3.0, impurity C and adjacent unknown impuritie it
Between separating degree be more than 1.5, all impurity consider the optimization gradient second half section in 23min whole appearances, shorten gradient timetable.
Table 7 is the chromatographic condition optimized to gradient 4, and to mixed solution, sample introduction is analyzed.
7 chromatographic condition of table screening 4
As a result see Fig. 6, the tailing factor of mixed solution main peak under the chromatographic condition of gradient 5 is 0.9, in 0.8~1.5 model
In enclosing, main peak can reach baseline separation requirement with each known impurities, and separating degree is all higher than 3.0；Each known impurities are adjacent thereto
The separating degree of unknown impuritie is all higher than 2.0, so condition is optimal conditions.
In view of 15min to 20min, 20min to 25min is that mobile phase A gradually decreases in Gradient program, therefore by gradient 5
Gradient program optimization.The chromatographic condition that table 8 optimizes gradient 5, to mixed solution, sample introduction is analyzed.
8 chromatographic condition of table screening 5
The results are shown in Figure 7, sample introduction is analyzed under chromatographic condition after optimization mixed solution, and the tailing factor of main peak exists
In the range of 0.8~1.5, main peak and each known impurities can reach baseline separation requirement, and separating degree is all higher than 3.0, therefore by this condition
It is set to final analysis condition.
4th, the screening of test solution concentration
With reference to the quality standard of ketorolac tromethamine USP40 bulk pharmaceutical chemicals, the inspection to impurity in related substance detection is considered
Sensitivity is surveyed, the concentration of test solution is tentatively established as 0.6mg/ml by the present invention, and sampling volume is 10 μ l.Result of the test table
It is bright：Sample is analyzed under optimal conditions, main peak does not overload, and tailing factor is in the range of 0.8~1.5, theoretical version
Number is more than 5500, therefore, the concentration of test solution is tentatively established as 0.6mg/ml, sampling volume is 10 μ l.
5th, sample size is determining
The absolute sample size of test sample (6 μ g) is higher than less than absolute sample size (20 μ g) of the USP parenteral solutions in relation to substance
The absolute sample size (4 μ g) of USP38/40, BP2013, EP8.0.Meanwhile under the selected flowing phase pH value of the present invention, this product and
The ultraviolet absorption maximum of each known impurities is near 313nm, and main peak and known impurities are in the response of 313nm Detection wavelengths
Far above the response at 254nm Detection wavelengths of States Pharmacopoeia specifications.Therefore, the Detection capability to impurity can't be influenced.
The related of 6 batches of finished products of pilot scale is had detected using detection method of the present invention respectively with the detection method of USP pharmacopeia
Substance by the Comparative result of two methods, the results are shown in Table 9 and 10, the results show that inspection of the detection method of the present invention to impurity
Output capacity is not inferior to detection method of the USP parenteral solutions in relation to substance.
9 parenteral solution of table (15mg specifications) two methods contrasting detection result
Remarks：Detect the sample that sample is long-time stability September.
10 parenteral solution of table (30mg specifications) two methods contrasting detection result
Remarks：Detect the sample that sample is long-time stability September.
Further, it is of the invention from system suitability, degradation specificity, detection limit and quantitative limit, linear and range, precision
Degree, accuracy, stability of solution and method durability angularly verify that verification result is shown in Table 11 to the detection method.
Table 11
More than verification result shows that detection method of the present invention has good impurity Detection capability.
The foregoing is merely the embodiment of the present invention, are not intended to limit the scope of the invention, every to utilize this hair
The equivalent structure or equivalent flow shift that bright description is made directly or indirectly is used in other relevant technology necks
Domain is included within the scope of the present invention.
Claims (9)
1. the detection method of impurity in ketorolac tromethamine or its preparation, which is characterized in that using HPLC to solution to be checked into
Row detection, qualitative or quantitative according to chromatographic results, chromatographic condition includes：
Chromatographic column：C8 silica gel chromatographic columns；
Detection wavelength：200~400nm of Detection wavelength；
Mobile phase and elution program：Mobile phase A is the water phase containing phosphate buffer, and pH is 4.1~4.3；Mobile phase B is acetonitrile
With the mixing organic phase of tetrahydrofuran, the volume fraction of tetrahydrofuran is 10~15% in organic phase；By such as Gradient 1~3
One program carries out gradient elution：
Gradient 1：
Gradient 2：
Gradient 3：
2. detection method as described in claim 1, which is characterized in that the impurity includes impurity A, impurity B, impurity C, impurity
D, the mixing of one or more of impurity E, impurity F：
3. detection method as described in claim 1, which is characterized in that contain dihydrogen phosphate ions in the phosphate buffer
And phosphate anion, pH are 4.1~4.3；Further, the phosphate buffer is ammonium dihydrogen phosphate-phosphate buffer；More into
One step, pH 4.2；Further, a concentration of 5.75g/L of ammonium dihydrogen phosphate.
4. detection method as described in claim 1, which is characterized in that the chromatographic column specification be 4.6 × 250mm, 5 μm.
5. detection method as described in claim 1, which is characterized in that flow rate of mobile phase is 0.6~1.2ml/min, further
Selected from 0.9~1.1ml/min.
6. detection method as described in claim 1, which is characterized in that column temperature is selected from 20~42 DEG C, is further selected from 38~42
℃。
7. HPLC detection methods as described in claim 1, which is characterized in that the solvent of solution to be checked is selected from water or acetonitrile volume
Acetonitrile solution of the score below 25%；Further, the solution to be checked includes at least test solution；Further,
Solution to be checked further includes reference substance solution.
8. the detection method of ketorolac tromethamine in ketorolac tromethamine or its preparation, which is characterized in that using HPLC pairs
Solution to be checked is detected, qualitative or quantitative according to chromatographic results, and chromatographic condition includes：
Chromatographic column：C8 silica gel chromatographic columns；
Detection wavelength：200~400nm of Detection wavelength；
Mobile phase and elution program：Mobile phase A is the water phase containing phosphate buffer, and pH is 4.1~4.3；Mobile phase B is acetonitrile
With the mixing organic phase of tetrahydrofuran, the volume fraction of tetrahydrofuran is 10~15% in organic phase；By such as Gradient 1~3
One program carries out gradient elution：
Gradient 1：
Gradient 2：
Gradient 3：
9. the detection method as described in 1 or 8 any one of claim, it is characterised in that：The Detection wavelength for 311~
315nm；It is further selected from 313nm.
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| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
| CN113984928A (en) * | 2021-10-25 | 2022-01-28 | 南京锐志生物医药有限公司 | High performance liquid chromatography analysis method for 2-benzoylpyrrole related substances |
| CN115950992A (en) * | 2023-03-15 | 2023-04-11 | 苏州朗易生物医药研究有限公司 | Method for detecting related substances in phenylephrine ketorolac solution and application thereof |
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| CN108693293A (en) * | 2018-07-25 | 2018-10-23 | 广州白云山医药集团股份有限公司白云山制药总厂 | The method for detecting impurity in amoxicillin granules |
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| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
| CN113984928A (en) * | 2021-10-25 | 2022-01-28 | 南京锐志生物医药有限公司 | High performance liquid chromatography analysis method for 2-benzoylpyrrole related substances |
| CN113984928B (en) * | 2021-10-25 | 2024-01-26 | 南京锐志生物医药有限公司 | High performance liquid chromatography analysis method for 2-benzoyl pyrrole related substances |
| CN115950992A (en) * | 2023-03-15 | 2023-04-11 | 苏州朗易生物医药研究有限公司 | Method for detecting related substances in phenylephrine ketorolac solution and application thereof |
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