CN103776922A - Method for measuring trifluoroacetic acid residual quantity in darunavir - Google Patents
Method for measuring trifluoroacetic acid residual quantity in darunavir Download PDFInfo
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- CN103776922A CN103776922A CN201310569841.XA CN201310569841A CN103776922A CN 103776922 A CN103776922 A CN 103776922A CN 201310569841 A CN201310569841 A CN 201310569841A CN 103776922 A CN103776922 A CN 103776922A
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Abstract
The invention discloses a method for measuring trifluoroacetic acid residual quantity in darunavir. The method comprises the following steps: adopting a gas chromatographic method, selecting a capillary column, using an ECD as a detector, using sulphuric acid- methanol, dimethyl sulfate and methyl iodide as methyl esterification agents, and generating methyl trifluoroacetate suitable for headspace sampling from trifluoroacetic acid subjected to methyl esterification. Compared with the prior art, the method provided by the invention can be used for measuring the content of the trifluoroacetic acid in the darunavir.
Description
Technical field
The present invention relates to Pharmaceutical Analysis technology, more specifically, relate to the method for trifluoroacetic acid content in a kind of gas chromatography determination darunavir.
Background technology
Trifluoroacetic acid is a kind of extremely strong acid organic acid, has a lot of inorganicss and organic ability simultaneously, makes it to have excellent reactivity worth, thus at medicine, agricultural chemicals, fuel, amino acid protection, organic synthesis, the fields such as material processed are widely used.Intermediate as fluorine-containing medicines, agricultural chemicals and dyestuff is excellent active because trifluoromethyl group shows in fluorine-containing medicines, agricultural chemicals, dyestuff, and trifluoroacetic acid is as the primary raw material of introducing trifluoromethyl group.
Darunavir is a kind of anti-HIV agent, is also a kind of protease inhibitors, and its mechanism of action is to select the proteinase activity that suppresses HIV virus to play a role.
Owing to can have the residual of trifluoroacetic acid in darunavir preparation process.
Stipulate according to " Chinese Pharmacopoeia ", trifluoroacetic acid divides into, there is no the 4th kind solvent of enough toxicological informations, should be according to the feature of production technology, formulate corresponding limit, make it meet product specification, GMP (GMP) or other basic quality requirementss.
The method of existing detection trifluoroacetic acid:
1), after medicine being carried out to oxygen bottle burning and destroying, measure fluorine with Colorimetry, then be converted into the method for trifluoroacetic acid content.
2) chromatography of ions, principle is to utilize trifluoroacetic acid to be different from the conductivity of other negative ion, uses conductance cell detecting device to carry out quantitative and qualitative analysis to trifluoroacetic acid.
Compared with the conventional method, this method can be avoided using method 1, causes the interference of fluorine element to testing result in molecular structure, can also reach the detection sensitivity higher compared with method 2.
Summary of the invention
The object of invention is to provide a kind of method of measuring trifluoroacetic acid content in darunavir with gc analysis, can be used for the quality control of product in darunavir.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, adopt capillary column, take ECD as detecting device, sulfuric acid-methyl alcohol or dimethyl suflfate-methyl alcohol, iodomethane-methyl alcohol are solvent.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, the concentration that wherein volume ratio of solvent sulfuric acid-methyl alcohol is is 1 ~ 12:99 ~ 88, the concentration that the volume ratio of dimethyl suflfate-methyl alcohol is is 0.5 ~ 6:99.5 ~ 94, and the concentration that the volume ratio of iodomethane-methyl alcohol is is 0.5 ~ 6:99.5 ~ 94.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, the concentration that wherein volume ratio of solvent sulfuric acid-methyl alcohol is is 10:90, the concentration that the volume ratio of dimethyl suflfate-methyl alcohol is is 5:95, and the concentration that the volume ratio of iodomethane-methyl alcohol is is 5:95.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, the temperature of wherein said esterification is 60 ~ 85 ℃.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, wherein the temperature of headspace sampling sample introduction head space bottle is 45 ~ 55 ℃.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, comprise the steps:
1) get test sample in right amount to headspace sampling bottle, add sulfuric acid-methyl alcohol or dimethyl suflfate-methyl alcohol, iodomethane-dissolve with methanol solution is made the sample solution of every 1ml containing test sample 10mg.
2) the head space bottle after gland is put to 60 ~ 85 ℃ of heating water baths and derived for 60 minutes, preferably 80 ℃ of water-baths.
3) column temperature is set and is initially 60 ℃, keep 10 minutes, then rise to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keep 5 minutes; Injector temperature is 140 ℃; Detecting device is ECD; Detector temperature is 250 ~ 350 ℃, and optimum temperature is 350 ℃; Chromatographic column is DB-624 capillary column.
4) when headspace sampling, the temperature of head space bottle is 45 ~ 55 ℃, and optimum temperature is 55 ℃.
5) extract head space bottle upper gas 0.1 ~ 1.0ml, be preferably 0.1ml, inject gas chromatograph completes the mensuration of sample trifluoroacetic acid content.
Here the volume ratio of sulfuric acid-methyl alcohol is 1 ~ 12:99 ~ 88, preferably 10:90, and the volume ratio of dimethyl suflfate-methyl alcohol is 0.5 ~ 6:99.5 ~ 96, preferably 5:95, the volume ratio of iodomethane-methyl alcohol is 0.5 ~ 6:99.5 ~ 96, preferably 5:95.
The invention provides a kind of method with trifluoroacetic acid content in gas chromatography determination darunavir, comprise the steps:
1) get test sample in right amount to headspace sampling bottle, add sulfuric acid-dissolve with methanol solution and make the sample solution of every 1ml containing test sample 10mg.
2) the head space bottle after gland is put to 80 ℃ of heating water baths derives for 60 minutes.
3) column temperature is set and is initially 60 ℃, keep 10 minutes, then rise to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keep 5 minutes; Injector temperature is 140 ℃; Detecting device is ECD; Detector temperature is 350 ℃, and chromatographic column is DB-624 capillary column.
4), when headspace sampling, the temperature of head space bottle is 55 ℃.
5) extract head space bottle upper gas 0.1ml, inject gas chromatograph completes the mensuration of sample trifluoroacetic acid content.
Here the volume ratio of sulfuric acid methyl alcohol is 10:90, and the volume ratio of dimethyl suflfate-methyl alcohol is 5:95, and the volume ratio of iodomethane-methyl alcohol is 5:95.
After jasmine discloses medicine is carried out to the burning of oxygen bottle and destroys, measure fluorine with Colorimetry, then be converted into the method for trifluoroacetic acid content.(West China Journal of Pharmaceutical Sciences 2001,16(6): 427 ~ 428) the method is destroyed sample with the burning of oxygen bottle, makes the fluorine in trifluoroacetic acid become inorganic fluorion, measure fluorine with Colorimetry, be converted into again the amount of trifluoroacetic acid, but the method use there is limitation.Should be the method will carry out oxygen bottle burning destruction to sample, is only applicable to not contain in drug molecular structure the organic compound of fluorine element, if contain fluorine element in test compound molecule, cannot detect it.Detection method provided by the invention, has improved the specificity of measuring, and has avoided the interference to test findings of the fluorine element that contains in molecular structure.
Accompanying drawing explanation:
The gas chromatogram of Fig. 1 sulfuric acid-methyl alcohol;
Fig. 2 trifluoroacetic acid is through derivative gas chromatogram;
The gas chromatogram of Fig. 3 trifluoro-acetate;
The gas chromatogram of Fig. 4 sample 1;
The gas chromatogram of Fig. 5 sample 2.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
Embodiment 1
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Precision adds in 10% sulfuric acid-methanol solution 2ml top set empty bottle, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, the results are shown in Figure 1(does not have chromatographic peak in going out of trifluoro-acetate on peak position).
Embodiment 2
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Precision adds in the 10% sulfuric acid-methanol solution 2ml top set empty bottle that contains trifluoroacetic acid 4.0ug/ml to be made it to dissolve, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, the results are shown in Figure the chromatographic peak that in 2(Fig. 2, retention time is 6.18min is that trifluoroacetic acid process is derivative, the chromatographic peak of the trifluoro-acetate of generation).
Embodiment 3
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Precision adds the methanol solution 2ml that contains trifluoro-acetate 1ug/ml, makes it to dissolve in top set empty bottle, and sealing, as need testing solution.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, the chromatographic peak that to the results are shown in Figure chromatographic peak that in 3(Fig. 3, retention time is 6.21min be trifluoro-acetate).
Embodiment 4
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Get 19.6mg in test sample darunavir, accurately weighed, precision adds in 10% sulfuric acid-methanol solution 2ml top set empty bottle to be made it to dissolve, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, the results are shown in Figure the go out trifluoro-acetate that peak position on do not detect trifluoroacetic acid derivative rear generation of 4(at trifluoro-acetate).
Embodiment 5
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Get 19.4mg in test sample darunavir, accurately weighed, precision adds in 10% sulfuric acid-methanol solution 2ml top set empty bottle to be made it to dissolve, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, the results are shown in Figure the go out trifluoro-acetate that peak position on do not detect trifluoroacetic acid derivative rear generation of 5(at trifluoro-acetate).
Embodiment 6
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Get 20.7mg in test sample darunavir, accurately weighed, precision adds in 5% dimethyl suflfate-methanol solution 2ml top set empty bottle to be made it to dissolve, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, result does not detect the derivative rear trifluoro-acetate generating of trifluoroacetic acid.
Embodiment 7
Instrument and condition:
Clarus500GC type gas chromatograph is joined ECD detecting device, Turbomatrix40 type head-space sampler, DB-624 quartz capillary column chromatographic column.
Chromatographic condition: column temperature is initially 60 ℃, keeps 10 minutes, then rises to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keeps 5 minutes; Sample introduction temperature: 140 ℃; Detecting device: ECD; Detector temperature: 350 ℃; Carrier gas: N
2.
Head space condition: furnace temp: 55 ℃, sample size 0.1ml.
Test procedure:
Get 20.3mg in test sample darunavir, accurately weighed, precision adds in 5% iodomethane-methanol solution 2ml top set empty bottle to be made it to dissolve, and sealing, as need testing solution.
Head space bottle after gland is put to 80 ℃ of heating water baths and within 60 minutes, derive, place room temperature.
Get test sample and carry out gas phase analysis according to above-mentioned condition, record chromatogram, result does not detect the derivative rear trifluoro-acetate generating of trifluoroacetic acid.
Claims (9)
1. a method for trifluoroacetic acid content in gas chromatography determination darunavir, is characterized in that the capillary column with DB-624, take ECD as detecting device, and sulfuric acid-methyl alcohol, dimethyl suflfate, iodomethane is methyl esterification reagent, sample is through insulation esterification, headspace sampling.
2. method according to claim 1, wherein, in solvent sulfuric acid-methanol solution, the concentration that the volume ratio of sulfuric acid and methyl alcohol is is 1 ~ 12:99 ~ 88, dimethyl suflfate-methyl alcohol 0.5 ~ 6:99.5 ~ 94, iodomethane-methyl alcohol 0.5 ~ 6:99.5 ~ 94.
3. method according to claim 2, wherein, the ratio of sulfuric acid and methyl alcohol is 10:90, dimethyl suflfate-methyl alcohol 5:95, iodomethane-methyl alcohol 5:95.
4. method according to claim 1, sample is through insulation esterification, and the temperature of esterification is 60 ~ 85 ℃.
5. method according to claim 4, wherein, the temperature of esterification is 80 ℃.
6. method according to claim 1, the sample headspace sample introduction after esterification, the temperature of sample introduction head space bottle is 45 ~ 55 ℃.
7. method according to claim 6, wherein, the temperature of the head space bottle of sample introduction is 50 ℃.
8. a method for trifluoroacetic acid content in gas chromatography determination darunavir, comprises the steps:
1) get test sample in right amount to headspace sampling bottle, add sulfuric acid-methyl alcohol or dimethyl suflfate-methyl alcohol, iodomethane-dissolve with methanol solution is made the sample solution of every 1ml containing test sample 10mg;
2) the head space bottle after gland is put to 60 ~ 85 ℃ of heating water baths and derived for 60 minutes, preferably 80 ℃ of water-baths;
3) column temperature is set and is initially 60 ℃, keep 10 minutes, then rise to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keep 5 minutes; Injector temperature is 140 ℃; Detecting device is ECD; Detector temperature is 250 ~ 350 ℃, and optimum temperature is 350 ℃; Chromatographic column is DB-624 capillary column;
4) when headspace sampling, the temperature of head space bottle is 45 ~ 55 ℃, and optimum temperature is 55 ℃;
5) extract head space bottle upper gas 0.1 ~ 1.0ml, be preferably 0.1ml, inject gas chromatograph completes the mensuration of sample trifluoroacetic acid content.
9. a method for trifluoroacetic acid content in gas chromatography determination darunavir, comprises the steps:
1) get test sample in right amount to headspace sampling bottle, add sulfuric acid-methyl alcohol or dimethyl suflfate-methyl alcohol, iodomethane-dissolve with methanol solution is made the sample solution of every 1ml containing test sample 10mg;
2) the head space bottle after gland is put to 80 ℃ of heating water baths derives for 60 minutes;
3) column temperature is set and is initially 60 ℃, keep 10 minutes, then rise to 235 ℃ with the speed of 40 ℃ of per minute intensifications, keep 5 minutes; Injector temperature is 140 ℃; Detecting device is ECD; Detector temperature is 350 ℃; Chromatographic column is DB-624 capillary column;
4), when headspace sampling, the temperature of head space bottle is 55 ℃;
5) extraction head space bottle upper gas 0.1ml inject gas chromatograph completes the mensuration of sample trifluoroacetic acid content.
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| CN201310569841.XA CN103776922A (en) | 2013-11-13 | 2013-11-13 | Method for measuring trifluoroacetic acid residual quantity in darunavir |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0611498A (en) * | 1992-06-26 | 1994-01-21 | Hitachi Ltd | Gas chromatographic method and gas chromatograph mass-spectrometric method |
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2013
- 2013-11-13 CN CN201310569841.XA patent/CN103776922A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0611498A (en) * | 1992-06-26 | 1994-01-21 | Hitachi Ltd | Gas chromatographic method and gas chromatograph mass-spectrometric method |
Non-Patent Citations (4)
| Title |
|---|
| CHAD E.WUJCIK ET AL.: "Extraction and analysis of trifluoroacetic acid in environmental waters", 《ANAL.CHEM.》, vol. 70, no. 19, 1 October 1998 (1998-10-01) * |
| WULF AMELUNG ET AL.: "DETERMINATION OF NEUTRAL AND ACIDIC SUGARS IN SOIL BY CAPILLARY GAS-LIQUID CHROMATOGRAPHY AFTER TRIFLUOROACETIC ACID HYDROLYSIS", 《SOIL BIOL. BIOCHEM.》, vol. 28, no. 12, 31 December 1996 (1996-12-31) * |
| 冯建林 等: "气相色谱和气相色谱-质谱联用法测定药物扶素康中的三氟醋酸", 《分析测试学报》, vol. 24, 30 November 2005 (2005-11-30), pages 31 * |
| 张莉 等: "有机药物中残留三氟醋酸测定方法的研究", 《华西药学杂志》, vol. 16, no. 6, 31 December 2001 (2001-12-31) * |
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Application publication date: 20140507 |