CN105181859A - Cysteine hydrochloride in acetaminophen injection and test method of degradation product cystine - Google Patents
Cysteine hydrochloride in acetaminophen injection and test method of degradation product cystine Download PDFInfo
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- CN105181859A CN105181859A CN201510654522.8A CN201510654522A CN105181859A CN 105181859 A CN105181859 A CN 105181859A CN 201510654522 A CN201510654522 A CN 201510654522A CN 105181859 A CN105181859 A CN 105181859A
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- cystine
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Abstract
The invention discloses cysteine hydrochloride in acetaminophen injection and a test method of degradation product cystine. The method adopts efficient liquid chromatography, a flowing phase adopts a phosphate buffer containing ion pairs and an organic solvent, and a gradient evaluation method is adopted. The method can be used for testing the content of cysteine hydrochloride in the acetaminophen injection, controlling the content of the content of cysteine degradation product cystine and testing the content of cysteine hydrochloride raw materials, the cysteine and the cystine have good resolution, the specificity and the sensitivity are high, and the operation is simple and convenient.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, relate to the analytical approach of paracetamol injection determined, be specifically related to the assay method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined.
Background technology
Paracetamol is used for heating, also can be used for alleviating light moderate pain, as headache, courbature, arthralgia and neuralgia, dysmenorrhoea, carcinomas pain and postoperative analgesia etc.This product can be used for aspirin-sensitive or not tolerant patient.
Cysteine hydrochloride is adopted to be antioxidant in the prescription of paracetamol injection determined, the toxicity of cysteine hydrochloride is little, itself is not easy to change, and have certain hydrotropy effect, color and the clarity of solution can be improved, but cysteine hydrochloride is very easily oxidized, generate oxidative degradation impurity cystine, above-mentioned two kinds of materials content in the formulation all needs to control.For such demand, study and develop the assay method of cysteine hydrochloride and catabolite cystine in a kind of paracetamol injection determined, this seems particularly important.
In Chinese Pharmacopoeia version, American Pharmacopeia (USP35-NF30) and EP8.0 in 2010, cysteine hydrochloride material content assay method all adopts titrimetry, but paracetamol injection determined is parenteral solution, composition is more complicated, and it is lower as the cysteine content of additives, indicator addition in titration process, between directing terminal and equivalent, operator is to color judgement etc., easily cause comparatively big error, therefore the method impact is inapplicable to the quality control of product.
In addition, conventional derivatization method sample preparation process is more complicated, and repeatability is poor.Moreover Chinese Pharmacopoeia versions in 2010 and American Pharmacopeia (USP35-NF30) related substance adopt thin-layered chromatography, but the method sensitivity is low, and accuracy is low, can not carry out quantitative measurement to halfcystine and catabolite thereof, only can as limit test.In EP8.0, halfcystine related substance method adopts amino-acid analyzer, and costly, specificity is strong, and most of producer does not have for this instrument price.
Summary of the invention
In order to solve the problem of the analytical approach of cysteine hydrochloride and catabolite cystine in paracetamol injection determined, the present inventor has groped the method for quality control of said preparation by lot of experiments, finally with containing the phosphate buffer of ion pair and methyl alcohol for mobile phase, the method of gradient elution is adopted successfully to be separated cysteine hydrochloride and impurity, and strictly carry out method validation, the scientific and precise of ensuring method, the demand meeting research and development and produce.
Therefore, the object of the present invention is to provide the detection method of cysteine hydrochloride and catabolite cystine in a kind of paracetamol injection determined, the method is applicable to the separation of cysteine hydrochloride and catabolite cystine thereof in Paracetamol parenteral solution and quantitatively detects.
Particularly, the concrete technical scheme overview realizing the object of the invention is as follows:
The detection method of cysteine hydrochloride and catabolite cystine in a kind of paracetamol injection determined, it adopts high performance liquid chromatography, gradient elution is carried out: mobile phase A is the phosphate solution containing ion pair, regulates pH=3.5-5.0 with phosphoric acid by following mobile phase condition; Mobile phase B is methyl alcohol; The gradient counting mobile phase by volume arranges as follows:
| Time (min) | Mobile phase A | Mobile phase B |
| 0～10 | 96～99 | 1～4 |
| 11～20 | 20～90 | 10～80 |
| 21～40 | 80～100 | 0～20 |
Described ion pair concentration is in the solution 0.2 ~ 20mmol/L, and described phosphate concentration is in the solution 0.2 ~ 20mmol/L.
Preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, the gradient counting mobile phase by volume arranges as follows:
| Time (min) | Mobile phase A | Mobile phase B |
| 0～10 | 98 | 2 |
| 11～20 | 50 | 50 |
| 21～40 | 98 | 2 |
Described ion pair concentration is in the solution 2 ~ 5mmol/L; Described phosphate concentration is in the solution 1 ~ 5mmol/L.
Preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, described ion pair is selected from following one or more: sodium hexanesulfonate, sodium heptanesulfonate, perfluorooctane sulfonate; Described phosphate is selected from potassium dihydrogen phosphate or/and sodium dihydrogen phosphate.
Further preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, described ion pair is sodium hexanesulfonate; Described phosphate is potassium dihydrogen phosphate.
Again further preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, the chromatographic column of described high performance liquid chromatography selects octadecylsilane chemically bonded silica post or octyl silane group silicagel column.
Again further preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, the determined wavelength of described high performance liquid chromatography is 200 ~ 230nm.
Again further preferably, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, the determined wavelength of described high performance liquid chromatography is 205nm.
In a most preferred embodiment of the present invention, the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined described above, wherein chromatographic column is octadecylsilane chemically bonded silica post; Column temperature is 25 DEG C, and sample size is 20 μ l, and flow velocity is 1.0ml/min, and determined wavelength is 220nm, and the gradient counting mobile phase by volume arranges as follows:
| Time (min) | Mobile phase A | Mobile phase B |
| 0～10 | 98 | 2 |
| 11～20 | 50 | 50 |
| 21～40 | 98 | 2 |
Compared with prior art, the inventive method has following beneficial effect:
(1) compare with thin-layered chromatography, method of the present invention can realize the quantitative measurement to cysteine hydrochloride, effectively can control the content of the cystine that cysteine hydrochloride oxidative degradation produces, be far superior to the thin-layered chromatography of pharmacopeia.
(2) compared with titrimetry, catabolite cystine not because of the error that operation and subjective judgement produce, and can quantitatively detect by method of the present invention, and other material is also less to the interference of halfcystine, and accuracy is high.
(3) with the Measures compare adopting amino-acid analyzer, method of the present invention is on common high performance liquid chromatograph and UV-detector basis, adopt common chromatographic column, be aided with gradient elution method, sensitivity is higher, degree of separation and accuracy are all better, and this law is low compared with the testing cost of amino-acid analyzer, are more applicable for conventional cysteine hydrochloride and the detection of catabolite cystine.
In a word, the content of content detection and halfcystine catabolite cystine that the present invention can be used for cysteine hydrochloride in paracetamol injection determined controls, and the assay of CYSTEAMINE HCL acid starting material, and halfcystine and cystine have good degree of separation, specificity is strong, highly sensitive, easy and simple to handle.
Accompanying drawing illustrates:
Fig. 1: halfcystine is located; Fig. 2: cystine is located;
Fig. 3: sample; Fig. 4: cystine and halfcystine degree of separation;
Fig. 5: halfcystine raw material acid is destroyed; Fig. 6: halfcystine raw material alkali destroys;
Fig. 7: halfcystine material oxidation destroys; Fig. 8: halfcystine raw material high temperature;
Fig. 9: the illumination of halfcystine raw material destroys; Figure 10: sample acid destroys;
Figure 11: sample alkali destroys; Figure 12: sample oxidation destroys;
Figure 13: high-temperature sample destroys; Figure 14: sample illumination destroys;
Figure 15: sample survey-1403161 batches; Figure 16: sample survey-1403171 batches;
Figure 17: sample survey-1403181 batches.
Embodiment
Form by the following examples, the detection method of cysteine hydrochloride and catabolite cystine in the paracetamol injection determined that the present invention relates to is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
The exploitation of the analytical approach of embodiment one, cysteine hydrochloride and catabolite cystine
For controlling the quality of product, antioxidant content is index important in parenteral solution, content detection for cysteine hydrochloride has the method for more standard and document, but it is inapplicable for the detection of the cysteine hydrochloride in paracetamol injection determined and catabolite cystine thereof, to this, we expand cysteine hydrochloride and catabolite cystine in parenteral solution the research of detection method and exploration.
The detection method of cysteine hydrochloride has titrimetry, UV method and HPLC method etc., and we adopt HPLC method to set up the detection method of cysteine hydrochloride and catabolite cystine in this product.
Chromatographic condition: Agilent1100 series HPLC instrument, test adopts chromatographic column to be CHROMASILC18 (250mm × 4.6mm, 5 μm), [sodium hexanesulfonate 0.5g is got with phosphate buffer, potassium dihydrogen phosphate 0.2g, the 1000ml that adds water dissolves, and is 4.0 with phosphorus acid for adjusting pH] be mobile phase A; Methyl alcohol is Mobile phase B, gradient elution, and flow velocity is 1.0ml per minute; Column temperature is 25 DEG C; Determined wavelength is 205nm; Sample size is 20 μ l.
Gradient elution: the volume ratio of methyl alcohol and phosphate buffered saline(PBS) is: during 0-10 minute, 2:98; During 11-20 minute, 50:50; During 21-40 minute, 2:98.
The screening of mobile phase: containing main ingredient paracetamol, auxiliary material cysteine hydrochloride and other auxiliary material in paracetamol injection determined, it is as follows that the selection of mobile phase mainly considers that the separating effect of paracetamol and other auxiliary materials and cystine and cysteine hydrochloride, the present inventor have employed the concrete test findings after various different mobile phase:
1, adopt mixture of acetonitrile-phosphate buffer to be mobile phase, cysteine hydrochloride almost without reserve, goes out peak comparatively early, reduces acetonitrile ratio to 0% step by step, retention time without obvious delay, and with other auxiliary material peak and catabolite degree of separation less, and inapplicable.
2, phosphate buffer (containing TBAH)-acetonitrile (92:8) is adopted, cysteine hydrochloride almost without reserve, reduce methanol ratio to 10%, 5%, 0% step by step, cysteine hydrochloride still goes out peak comparatively early, retention time is without obvious delay phenomenon, with other auxiliary material peak and catabolite degree of separation less, and inapplicable.
3, with ammonium acetate solution-methyl alcohol (85:15) for mobile phase, cysteine hydrochloride almost without reserve, reduce methanol ratio to 10%, 5%, 0% step by step, cysteine hydrochloride still goes out peak comparatively early, retention time is without obvious delay phenomenon, with other auxiliary material peak and catabolite degree of separation less, and inapplicable.
4, (sodium heptanesulfonate 5g and potassium dihydrogen phosphate 3g is got with phosphate buffer, be dissolved in water and be diluted to 500ml, by phosphoric acid adjust ph to 4.0)-methyl alcohol (98:2) for mobile phase time, halfcystine retention time is about 7min, blank auxiliary without impact, but have in sample impurity peaks and halfcystine inseparable, and in mobile phase, salinity is higher, easy damaged chromatographic column, intends reducing salinity test.
5, (sodium heptanesulfonate 1.02g and potassium dihydrogen phosphate 0.68g is got with phosphate buffer, be dissolved in water and be diluted to 500ml, by phosphoric acid adjust ph to 4.0)-methyl alcohol (98:2) is mobile phase, halfcystine and impurity peaks degree of separation still poor.Replacing ion-pairing agent is sodium hexanesulfonate.
6, when employing phosphate buffer (gets sodium hexanesulfonate 0.5g, potassium dihydrogen phosphate 0.2g, the 1000ml that adds water dissolves, and be 4.0 with phosphorus acid for adjusting pH)-methyl alcohol (80 ~ 95:5 ~ 20) for mobile phase time, cysteine hydrochloride and cystine degree of separation poor, and go out peak comparatively early; Mobile phase ratio is adjusted to phosphate buffer and (gets sodium hexanesulfonate 0.5g, potassium dihydrogen phosphate 0.2g, the 1000ml that adds water dissolves, and be 4.0 with phosphorus acid for adjusting pH)-methyl alcohol (98:2) time, cystine and cysteine hydrochloride retention time are after 3min, the degree of separation at two peaks and main peak and other peak is all greater than 1.5, and peak shape is better.Therefore select phosphate buffer (get sodium hexanesulfonate 0.5g, potassium dihydrogen phosphate 0.2g, the 1000ml that adds water dissolves, and is 4.0 with phosphorus acid for adjusting pH)-methyl alcohol (96 ~ 99:1 ~ 4 are preferably 98:2) to be initial flow phase.
The selection of determined wavelength: respectively the cysteine hydrochloride of 0.2mg/ml and cystine are carried out UV scanning in 200 ~ 400nm wavelength coverage, both results are end and absorb, therefore select 205nm as mensuration wavelength.
On the basis of above-mentioned research, we adopt selected chromatographic condition to carry out system suitability, and from chromatogram, blank solvent and auxiliary material peak retention time are before 2.5min, and paracetamol peak, at about 15min, does not disturb the mensuration of halfcystine.Inject halfcystine reference substance and cystine reference substance and sample test liquid respectively, record chromatogram.Halfcystine retention time is 4.6min, and cystine retention time is 3.8min, and both degree of separation are 2.6.In need testing solution chromatogram, the degree of separation of the degree of separation of cysteine hydrochloride and cystine, halfcystine and main ingredient is all greater than 2 (see Fig. 1 ~ 4).
The checking of the analytical approach of embodiment two, cysteine hydrochloride and catabolite cystine
Specificity investigation is carried out to the method that above-mentioned plan is selected, following test has been carried out respectively: (1) acid destroys: get cysteine hydrochloride 0.25mg/ml and sample 10ml respectively according to medicine quality standard analytical approach verification guide principle, add 1mol/L hydrochloric acid solution 2ml, room temperature places 2h.(2) alkali destroys: get cysteine hydrochloride 0.25mg/ml and sample 10ml respectively, add 1mol/L sodium hydroxide solution 2ml, and room temperature places 2h.(3) Oxidative demage: get cysteine hydrochloride 0.25mg/ml and sample 10ml respectively, adds 30% hydrogen peroxide 2ml.(4) high temperature: get cysteine hydrochloride 0.25mg/ml and sample 10ml respectively, places 4h under 80 DEG C of conditions.(5) illumination destroys: get cysteine hydrochloride 0.25mg/ml and sample 10ml respectively, and putting illumination is place 6 hours under 4500LX illumination.
Whether get above-mentioned 5 kinds and destroy solution, sample introduction under above-mentioned chromatographic condition, detecting halfcystine has obvious degradation, is greater than 1.5 bases for estimation (see Fig. 5 ~ 14) that are criterion of acceptability with catabolite peak and halfcystine peak degree of separation.
Adopt above-mentioned detection method to find, in the sample of failure test, halfcystine all has degraded in various degree, and is all degraded into cystine, as from the nearest impurity of halfcystine, the degree of separation of cysteine plus cystine is all greater than 1.5, and degree of separation is good, shows that this law specificity is better.
We have carried out following research to this method further, and result is as follows:
1, the range of linearity
Result shows: cysteine hydrochloride is in 1 ~ 500 μ g/ml concentration range, and peak area and concentration are good linear relationship.Cystine is in 1 ~ 500 μ g/ml concentration range, and peak area and concentration are good linear relationship.
2, precision test
Get the cysteine plus cystine mixed solution that concentration is about 0.25mg/ml, continuous sample introduction 6 times, the relative standard deviation of its peak area, halfcystine is 0.89%, and cystine is 0.62%.
3, sensitivity
Get the reference substance solution of halfcystine and cystine, stepwise dilution, concentration corresponding when being 3 with signal to noise ratio (S/N ratio) is detectability, is quantitative limit when signal to noise ratio (S/N ratio) is 10, and the detection sensitivity of halfcystine is 0.3 μ g/ml, and the detection sensitivity of cystine is 0.6 μ g/ml.
4, replica test
Get with 6 parts, a collection of paracetamol injection determined sample, measure its cysteine content according to said method, the relative standard deviation of 6 parts of sample sizes is 0.35% as a result, and precision is better.
5, the recovery
Adopt the method adding halfcystine and cystine reference substance in recipe quantity auxiliary material and main ingredient, investigate the accuracy of said method, result halfcystine average recovery rate is 98.84%, relative standard deviation is 1.2%, cystine average recovery rate is 99.35%, relative standard deviation is 0.96%, and accuracy is better.
6, stability of solution
Get need testing solution respectively under normal temperature and cryogenic conditions in 0,2,4,6,8 hour sample introduction, result halfcystine at normal temperatures oxidative degradation is very fast, very unstable, in 8 hours, peak area keeps stable under cryogenic, relative standard deviation is 1.8%, therefore need now with the current under this product normal temperature, or Cord blood, use in 8 hours.
Verified by said method, we determine that this chromatographic condition accuracy and precision etc. are all better, this product three batch sample are carried out to the mensuration of halfcystine and catabolite cystine, result following (see Figure 15 ~ 17):
Beneficial effect of the present invention is:
1, compare with thin-layered chromatography, method of the present invention can realize the quantitative measurement to cysteine hydrochloride, effectively can control the content of the cystine that cysteine hydrochloride oxidative degradation produces, be far superior to the thin-layered chromatography of pharmacopeia.
2, compared with titrimetry, catabolite cystine not because of the error that operation and subjective judgement produce, and can quantitatively detect by this law, and other material is also less to the interference of halfcystine, and accuracy is high.
3, with the Measures compare adopting amino-acid analyzer, this method is on common high performance liquid chromatograph and UV-detector basis, adopt common chromatographic column, be aided with gradient elution method, sensitivity is higher, degree of separation and accuracy are all better, and this law is low compared with the testing cost of amino-acid analyzer, are more applicable for conventional cysteine hydrochloride and the detection of catabolite cystine.
Claims (8)
1. the detection method of cysteine hydrochloride and catabolite cystine in a paracetamol injection determined, it is characterized in that, adopt high performance liquid chromatography, carry out gradient elution by following mobile phase condition: mobile phase A is the phosphate solution containing ion pair, regulates pH=3.5-5.0 with phosphoric acid; Mobile phase B is methyl alcohol; The gradient counting mobile phase by volume arranges as follows:
Described ion pair concentration is in the solution 0.2 ~ 20mmol/L, and described phosphate concentration is in the solution 0.2 ~ 20mmol/L.
2. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to claim 1, it is characterized in that, the gradient counting mobile phase by volume arranges as follows:
Described ion pair concentration is in the solution 2 ~ 5mmol/L; Described phosphate concentration is in the solution 1 ~ 5mmol/L.
3. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to claim 1, it is characterized in that, described ion pair is selected from following one or more: sodium hexanesulfonate, sodium heptanesulfonate, perfluorooctane sulfonate; Described phosphate is selected from potassium dihydrogen phosphate or/and sodium dihydrogen phosphate.
4. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to claim 3, it is characterized in that, described ion pair is sodium hexanesulfonate; Described phosphate is potassium dihydrogen phosphate.
5. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to any one of claim 1-4, it is characterized in that, the chromatographic column of described high performance liquid chromatography selects octadecylsilane chemically bonded silica post or octyl silane group silicagel column.
6. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to any one of claim 1-4, it is characterized in that, the determined wavelength of described high performance liquid chromatography is 200 ~ 230nm.
7. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to claim 6, it is characterized in that, the determined wavelength of described high performance liquid chromatography is 205nm.
8. the detection method of cysteine hydrochloride and catabolite cystine in paracetamol injection determined according to any one of claim 1-4, it is characterized in that, chromatographic column is octadecylsilane chemically bonded silica post; Column temperature is 25 DEG C, and determined wavelength is 220nm.
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| CN112782327A (en) * | 2019-11-11 | 2021-05-11 | 广东逸舒制药股份有限公司 | Method for separating and determining carbocisteine and impurities thereof by liquid chromatography |
| CN112782327B (en) * | 2019-11-11 | 2022-02-01 | 广东逸舒制药股份有限公司 | Method for separating and determining carbocisteine and impurities thereof by liquid chromatography |
| CN114651177A (en) * | 2019-11-11 | 2022-06-21 | 广东华南药业集团有限公司 | Carbocisteine raw material and quality control method and application of preparation thereof |
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Application publication date: 20151223 |