CN101025409A - Method for determining impurities for paracetamol and tramadol hydrochloride preparation - Google Patents
Method for determining impurities for paracetamol and tramadol hydrochloride preparation Download PDFInfo
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- CN101025409A CN101025409A CN 200610024109 CN200610024109A CN101025409A CN 101025409 A CN101025409 A CN 101025409A CN 200610024109 CN200610024109 CN 200610024109 CN 200610024109 A CN200610024109 A CN 200610024109A CN 101025409 A CN101025409 A CN 101025409A
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- solution
- paracetamol
- aminophenol
- peak
- tramadol hydrochloride
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960003107 tramadol hydrochloride Drugs 0.000 title claims abstract description 45
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000012535 impurity Substances 0.000 title claims abstract description 15
- 229960005489 paracetamol Drugs 0.000 title claims description 50
- 238000001514 detection method Methods 0.000 claims abstract description 12
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 75
- 239000000243 solution Substances 0.000 claims description 62
- 238000012360 testing method Methods 0.000 claims description 28
- 239000007974 sodium acetate buffer Substances 0.000 claims description 20
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000013558 reference substance Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 230000014759 maintenance of location Effects 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000003556 assay Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 238000010812 external standard method Methods 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 2
- 239000000356 contaminant Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- -1 Compound Tramadol Hydrochloride Chemical class 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 229940091904 tramadol hydrochloride 37.5 mg Drugs 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229940093503 ethyl maltol Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940081924 tramadol hydrochloride 75 mg Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method to measure contaminant of acet amidogen phenol and tramadol hydrochloride preparation. Using this invention, it can be simple, rapid and accurate detect pair amidogen phenol content in the preparation, the detection error of only 0.4%, while it can detect others unknown impurity gross, the invention will be able to meet the needs of the parties concerned.
Description
Technical field
The present invention relates to the detection method of the impurity in the compound preparation of a kind of paracetamol and tramadol hydrochloride, be specifically related to the detection method of HPLC method to related substance in the compound preparation that contains paracetamol and tramadol hydrochloride.
Background technology
The compound preparation of tramadol hydrochloride (tramadol hydrochloride) and paracetamol (paracetamol) went on the market through the FDA approval in the U.S. August calendar year 2001, was used for the short (5d) of Acute Pain.Clinical research shows, compares with single component, and this compound preparation treatment pain is more effective, and rapid-action, long action time.
The existing more report of the HPLC method that related substance is checked in these two kinds of single preparationss of ephedrine, assay to compound preparation also has some researchs, and one piece of report is only arranged about method for determination related substances, " HPLC of Compound Tramadol Hydrochloride Tablets and related substance measures ", this report content mainly lays particular emphasis on assay, does not but relate to the mensuration of p-aminophenol.And p-aminophenol is the synthetic intermediate and the main degradation products of paracetamol, and toxicity is bigger, strict control its to limit the quantity of be important step in the chemical analysis work.Therefore, provide the detection method of p-aminophenol in the compound preparation of a kind of paracetamol and tramadol hydrochloride, be the parties concerned very need.
Summary of the invention
The object of the present invention is to provide a kind of assay method of measuring known impurities and unknown impuritie in paracetamol and the tramadol hydrochloride compound preparation simultaneously, to overcome above-mentioned defective of the prior art.
Method of the present invention comprises the steps:
It is an amount of to get the test sample fine powder, and accurate the title decides, and the solution of making the many 0.15～0.75mg of saliferous love song horse among every 1ml is also diluted in the solubilizer dissolving, shakes up, and filters, and gets subsequent filtrate as need testing solution; Accurate with 20～500 times of need testing solution solubilizer dilutions, as own control solution;
It is an amount of that other gets the p-aminophenol reference substance, and accurate the title decides, and solubilizer is made the solution that concentration is 1.3～6.5 μ g/ml, as the p-aminophenol contrast solution;
P-aminophenol contrast solution and own control solution can be prepared respectively, also can fit in the same measuring bottle.
Said solvent is selected from water, methanol aqueous solution or mobile phase A;
In the methanol aqueous solution, the volume ratio of water and methyl alcohol is 78: 22～86: 14;
Said mobile phase A is the acetic acid-sodium-acetate buffer and the methanol mixture of pH4～5, and the volume ratio of acetic acid-sodium-acetate buffer and methyl alcohol is 78: 22～86: 14.
According to high performance liquid chromatography, be filling agent with octadecyl silane; With pH is that 4～5 acetic acid-sodium-acetate buffer and methanol mixture are mobile phase A, and methyl alcohol is Mobile phase B, and according to the form below carries out gradient elution, and the detection wavelength is 260～280nm.Number of theoretical plate calculates by paracetamol peak and tramadol hydrochloride peak all should be not less than 2000, and the degree of separation of p-aminophenol, paracetamol and tramadol hydrochloride peak and adjacent peak all should meet the requirements.The volume ratio of acetic acid-sodium-acetate buffer and methyl alcohol is: acetic acid-sodium-acetate buffer: methyl alcohol=78: 22～86: 14.
The gradient elution table
| Time (minute) | A(％) | B(％) |
| 0 | 100 | 0 |
| 0～4 | 100 | 0 |
| 4～25 | 1060 | 0 40 |
| 25～45 | 60 | 40 |
Time and A, B ratio all can suitably be regulated in the table, make p-aminophenol, paracetamol and tramadol hydrochloride that suitable retention time and degree of separation all be arranged.
Precision is measured the need testing solution and the contrast solution of equal volume, inject liquid chromatograph respectively, the record chromatogram, in the chromatogram of need testing solution if any the chromatographic peak consistent with the p-aminophenol retention time, calculate the content of p-aminophenol by external standard method, other impurity peak area with the contrast solution chromatogram in the paracetamol peak compare with tramadol hydrochloride peak area sum, calculate by Self-control method.
Adopt method of the present invention, can the easy content that detects the p-aminophenol in the preparation fast and accurately, it detects error only is 0.4%, can detect the total amount of other unknown impuritie simultaneously, can satisfy the needs of the parties concerned.
Description of drawings
Fig. 1 is a tramado hydrochloride oral disnitegration tablet related substance contrast collection of illustrative plates.
Fig. 2 is a tramado hydrochloride oral disnitegration tablet related substance collection of illustrative plates.
Fig. 3 is that tramado hydrochloride oral disnitegration tablet related substance p-aminophenol application of sample reclaims collection of illustrative plates.
Fig. 4 is that acid destroys collection of illustrative plates.
Fig. 5 destroys collection of illustrative plates for alkali.
Fig. 6 destroys collection of illustrative plates for oxidation.
Fig. 7 destroys collection of illustrative plates for ultraviolet.
Fig. 8 is the heat damage collection of illustrative plates.
Embodiment
The application of the present invention in the tramado hydrochloride oral disnitegration tablet
325mg/37.5mg tramado hydrochloride oral disnitegration tablet
| Component | Addition |
| Paracetamol | 325mg |
| Tramadol hydrochloride | 37.5mg |
| Acryl resin | 8mg |
| Beta-schardinger dextrin- | 110mg |
| Ethyl cellulose | 15mg |
| Aspartame | 5mg |
| Ethyl maltol | 4mg |
| Lemon extract | 13mg |
| Polyvinylpolypyrrolidone | 46mg |
| Lauryl sodium sulfate | 10mg |
| Sweet mellow wine | 60mg |
| Silicon dioxide | 6.1mg |
| Polyvinylpyrrolidone | 0.4mg |
The determination of related substances method:
Get 10 of tramado hydrochloride oral disnitegration tablets, the accurate title, decide, porphyrize, precision takes by weighing in right amount (being equivalent to tramadol hydrochloride 37.5mg approximately), put in the 100ml measuring bottle, add mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)) ultrasonic make the dissolving and be diluted to scale, shake up, filter, get subsequent filtrate as tramado hydrochloride oral disnitegration tablet need testing solution;
It is an amount of that other gets the p-aminophenol reference substance, and accurate the title decides, and adds mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)) and makes the solution that contains 325 μ g among every 1ml, as the p-aminophenol reference substance solution;
Precision is measured tramado hydrochloride oral disnitegration tablet need testing solution 1ml, and p-aminophenol reference substance solution 1ml puts in the same 100ml measuring bottle, adds mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)) and is diluted to scale, solution in contrast.According to high performance liquid chromatography, with BDS HYPERSIL C18 chromatographic column; With acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18) is mobile phase A, and methyl alcohol is Mobile phase B, and according to the form below carries out gradient elution, and the detection wavelength is 271nm; Flow velocity 1.0ml/min.
The gradient elution table
| Time (minute) | A(％) | B(％) |
| 0 | 100 | 0 |
| 0～4 | 100 | 0 |
| 4～25 | 100→60 | 0→40 |
| 25～45 | 60 | 40 |
Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes paracetamol is 20%～25% of a full scale; Precision is measured tramado hydrochloride oral disnitegration tablet need testing solution and each 20 μ l of contrast solution again, inject liquid chromatograph respectively, the record chromatogram, in the chromatogram of tramado hydrochloride oral disnitegration tablet need testing solution if any the chromatographic peak consistent with the p-aminophenol retention time, its area must not be greater than the peak area (0.1%) of respective peaks in the contrast solution, other impurity peak area and, must not be greater than paracetamol in the contrast solution chromatogram and tramadol hydrochloride peak area sum (1.0%).
Measurement result:
Greater than 4000, greater than 70000, the degree of separation of p-aminophenol, paracetamol and tramadol hydrochloride peak and adjacent peak is all up to specification by the tramadol hydrochloride peak by the paracetamol peak for number of theoretical plate.Testing result is seen Fig. 1 and Fig. 2, and Fig. 1 is the contrast solution chromatogram, and 1 is paracetamol among the figure, and 2 is tramadol hydrochloride, and 3 is p-aminophenol; Fig. 2 is the need testing solution chromatogram, and 4 is paracetamol among the figure, and 5 is tramadol hydrochloride.
Three batch sample related substances
| Lot number | 031001 | 031002 | 031003 |
| P-aminophenol | 0％ | 0％ | 0％ |
| Other impurity | 0.31％ | 0.24％ | 0.25％ |
Three batch sample related substances are all up to specification.
325mg/37.5mg paracetamol and tramadol hydrochloride tablet
| Component | Addition |
| Paracetamol | 325mg |
| Tramadol hydrochloride | 37.5mg |
| Acryl resin | 15mg |
| Beta-schardinger dextrin- | 60mg |
| Ethyl cellulose | 8mg |
| Aspartame | 10mg |
| Lemon extract | 8mg |
| Polyvinylpolypyrrolidone | 50mg |
| Sodium carboxymethyl starch | 20mg |
| Sweet mellow wine | 70mg |
| Pregelatinized starch | 30mg |
| Silicon dioxide | 6.0mg |
| Polyvinylpyrrolidone | 0.5mg |
The determination of related substances method:
Get 10 of paracetamol and tramadol hydrochloride tablets, the accurate title, decided porphyrize, precision takes by weighing in right amount (being equivalent to tramadol hydrochloride 15mg approximately), puts in the 100ml measuring bottle, and solubilizer (water-methanol (78: 22)) is ultrasonic to be made dissolving and be diluted to scale, shake up, filter, get subsequent filtrate as the paracetamol and tramadol hydrochloride tablet need testing solution; Precision is measured paracetamol and tramadol hydrochloride tablet need testing solution 1ml, puts in the 100ml measuring bottle, and solubilizer (water-methanol (78: 22)) is diluted to scale, solution (1) in contrast; It is an amount of that other gets the p-aminophenol reference substance, and accurate the title decides, and solubilizer (water-methanol (78: 22)) is made the solution that contains 1.3 μ g among every 1ml, solution (2) in contrast.According to high performance liquid chromatography, with BDS HYPERSIL C18 chromatographic column; With acetic acid-sodium-acetate buffer (pH4.0)-methyl alcohol (78: 22) is mobile phase A, and methyl alcohol is Mobile phase B, and according to the form below carries out gradient elution, and the detection wavelength is 271nm; Flow velocity 1.0ml/min.
The gradient elution table
| Time (minute) | A(％) | B(％) |
| 0 | 100 | 0 |
| 0～4 | 100 | 0 |
| 4～25 | 100→65 | 0→35 |
| 25～40 | 65 | 35 |
Get contrast solution (1) 100 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes paracetamol is 20%～25% of a full scale; Precision is measured paracetamol and tramadol hydrochloride tablet need testing solution and contrast solution (1), (2) each 100 μ l again, inject liquid chromatograph respectively, the record chromatogram, in the chromatogram of paracetamol and tramadol hydrochloride tablet need testing solution if any the chromatographic peak consistent with the p-aminophenol retention time, its area must not be greater than the peak area (0.1%) of respective peaks in the contrast solution (2), other impurity peak area and, must not be greater than contrast solution (1) main peak area sum (1.0%).
Measurement result:
Greater than 4000, greater than 50000, the degree of separation of p-aminophenol, paracetamol and tramadol hydrochloride peak and adjacent peak is all up to specification by the tramadol hydrochloride peak by the paracetamol peak for number of theoretical plate.
Three batch sample related substances
| Lot number | 051201 | 051202 | 051203 |
| P-aminophenol | 0％ | 0％ | 0％ |
| Other impurity | 0.29％ | 0.26％ | 0.22％ |
Three batch sample related substances are all up to specification.
Preparation is with embodiment 2
The determination of related substances method:
Get 10 of paracetamol and tramadol hydrochloride tablets, the accurate title, decided porphyrize, precision takes by weighing in right amount (being equivalent to tramadol hydrochloride 75mg approximately), puts in the 100ml measuring bottle, and solubilizer (water) is ultrasonic to be made dissolving and be diluted to scale, shake up, filter, get subsequent filtrate as the paracetamol and tramadol hydrochloride tablet need testing solution; Precision is measured paracetamol and tramadol hydrochloride tablet need testing solution 1ml, puts in the 100ml measuring bottle, and solubilizer (water) is diluted to scale, in contrast solution (1); It is an amount of that other gets the p-aminophenol reference substance, and accurate the title decides, and solubilizer (water) is made the solution that contains 6.5 μ g among every 1ml, in contrast solution (2).According to high performance liquid chromatography, with BDSHYPERSIL C18 chromatographic column; With acetic acid-sodium-acetate buffer (pH5.0)-methyl alcohol (86: 14) is mobile phase A, and methyl alcohol is Mobile phase B, and according to the form below carries out gradient elution, and the detection wavelength is 271nm; Flow velocity 1.0ml/min.
The gradient elution table
| Time (minute) | A(％) | B(％) |
| 0 | 100 | 0 |
| 0～7 | 100 | 0 |
| 7～22 | 100→58 | 0→42 |
| 22～45 | 58 | 42 |
Get contrast solution (1) 10 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes paracetamol is 20%～25% of a full scale; Precision is measured paracetamol and tramadol hydrochloride tablet need testing solution and contrast solution (1), (2) each 10 μ l again, inject liquid chromatograph respectively, the record chromatogram, in the chromatogram of paracetamol and tramadol hydrochloride tablet need testing solution if any the chromatographic peak consistent with the p-aminophenol retention time, its area must not be greater than the peak area (0.1%) of respective peaks in the contrast solution (2), other impurity peak area and, must not be greater than contrast solution (1) main peak area sum (1.0%).
Measurement result:
Greater than 4000, greater than 50000, the degree of separation of p-aminophenol, paracetamol and tramadol hydrochloride peak and adjacent peak is all up to specification by the tramadol hydrochloride peak by the paracetamol peak for number of theoretical plate.
Three batch sample related substances
| Lot number | 051201 | 051202 | 051203 |
| P-aminophenol | 0％ | 0％ | 0％ |
| Other impurity | 0.22％ | 0.26％ | 0.24％ |
Three batch sample related substances are all up to specification.
P-aminophenol application of sample recovery test
Preparation is with embodiment 1
It is an amount of that precision takes by weighing p-aminophenol, dissolve with mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)), make the solution that contains p-aminophenol 32.5 μ g among every 1ml approximately, as p-aminophenol mother liquor (need face) with now joining, precision is measured 1ml, puts in the 10ml measuring bottle, adds mobile phase A and is diluted to scale, shake up, in contrast solution; Other precision takes by weighing tramado hydrochloride oral disnitegration tablet porphyrize powder an amount of (being equivalent to paracetamol 325mg approximately) and puts in the 50ml measuring bottle, add that mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)) is ultrasonic to be made dissolving and be diluted to scale, shake up, filter.Parallel two parts.Precision is measured subsequent filtrate 5ml and is put the 10ml measuring bottle, every part of test sample is all measured four parts, wherein three parts of difference precisions move into new p-aminophenol mother liquor 0.5ml, 1.0ml, the 1.5ml that prepare, another part is blank, add mobile phase A (acetic acid-sodium-acetate buffer (pH4.5)-methyl alcohol (82: 18)) and be diluted to scale, shake up.Measure each 20 μ l injecting chromatograph (chromatographic condition is with embodiment 1) of above-mentioned eight parts of solution and contrast solution respectively, the record chromatogram calculates the recovery that adds p-aminophenol.It the results are shown in Figure 3, and 6 is paracetamol among the figure, and 7 is tramadol hydrochloride, and 8 is p-aminophenol.
P-aminophenol application of sample recovery test
| Blank | 50％ | 100％ | 150％ | |||||
| No. | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 2 |
| Drop into (mg) | 0 | 0 | 8.04 | 8.19 | 16.25 | 16.53 | 24.07 | 24.12 |
| Record (mg) | 0 | 0 | 8.07 | 8.17 | 16.17 | 16.35 | 24.07 | 23.89 |
| The recovery (%) | 100.37 | 99.76 | 99.51 | 98.91 | 100.00 | 99.05 | ||
| The recovery | Average=99.60% RSD=0.56% | |||||||
The average average recovery of p-aminophenol is 99.60%, and RSD is 0.56%, proves this method mensuration p-aminophenol content accuracy height.
Destructive test
Preparation is with embodiment 1
Get 10 of this product, the accurate title, decide, porphyrize, precision take by weighing fine powder an amount of (being equivalent to paracetamol 162.5mg approximately) and put in the 50ml measuring bottle parallel 6 parts, a copy of it is as not destroying contrast, in addition five parts are carried out after heat, ultraviolet lighting, strong acid, highly basic, strong oxidation destroys according to following method respectively, add that moving phase (A) is ultrasonic to be made dissolving and be diluted to scale, shake up, filter, respectively get subsequent filtrate 20 μ l injecting chromatographs.Chromatographic condition is with embodiment 1.
(1) strong acid destroys: adding 1N hydrochloric acid makes wetting, places 6 hours down at 60 ℃.See Fig. 4,9 is paracetamol, and 10 is tramadol hydrochloride.
(2) highly basic destroys: adding 1N NaOH makes wetting, places 4 hours down at 60 ℃.See Fig. 5,11 is paracetamol, and 12 is tramadol hydrochloride.
(3) strong oxidation destroys: add 10% superoxol and make wettingly, placed 2 hours down at 60 ℃.See Fig. 6,13 is paracetamol, and 14 is tramadol hydrochloride.
(4) ultraviolet lighting destroys: put under the uviol lamp and shone 96 hours.See Fig. 7,15 is paracetamol, and 16 is tramadol hydrochloride.
(5) heat damage: 100 ℃ were heated 4 hours down.See Fig. 8,17 is paracetamol, and 18 is tramadol hydrochloride.
Chromatogram before and after relatively destroying, the result shows: this product is destroyed under strong acid, highly basic, strong oxidation, ultraviolet lighting and heat condition, all can produce catabolite, main peak all separates well with each catabolite peak, illustrate that this method specificity is strong, can separate and detect the impurity of tramadol hydrochloride/paracetamol compound preparation preferably.
Claims (2)
1. the assay method of impurity in paracetamol and the tramadol hydrochloride preparation is characterized in that, comprises the steps:
It is an amount of to get the test sample fine powder, and accurate the title decides, and the solution of making the many 0.15～0.75mg of saliferous love song horse among every 1ml is also diluted in the solubilizer dissolving, shakes up, and filters, and gets subsequent filtrate as need testing solution;
Accurate with 20～500 times of need testing solution solubilizer dilutions, as own control solution;
It is an amount of that other gets the p-aminophenol reference substance, and accurate the title decides, and solubilizer is made the solution that concentration is 1.3～6.5 μ g/ml, as the p-aminophenol contrast solution;
Said solvent is selected from water, methanol aqueous solution or mobile phase A;
In the methanol aqueous solution, the volume ratio of water and methyl alcohol is 78: 22～86: 14;
Said mobile phase A is the acetic acid-sodium-acetate buffer and the methanol mixture of pH4～5, and the volume ratio of acetic acid-sodium-acetate buffer and methyl alcohol is 78: 22～86: 14;
According to high performance liquid chromatography, be filling agent with octadecyl silane; With pH is that 4～5 acetic acid-sodium-acetate buffer and methanol mixture are mobile phase A, and methyl alcohol is Mobile phase B, carries out gradient elution, and the detection wavelength is 260～280nm; Number of theoretical plate calculates by paracetamol peak and tramadol hydrochloride peak all should be not less than 2000, and the degree of separation of p-aminophenol, paracetamol and tramadol hydrochloride peak and adjacent peak all should meet the requirements; In acetic acid-sodium-acetate buffer and the methanol mixture, the volume ratio of acetic acid-sodium-acetate buffer and methyl alcohol is:
Acetic acid-sodium-acetate buffer: methyl alcohol=78: 22～86: 14;
Precision is measured the need testing solution and the contrast solution of equal volume, inject liquid chromatograph respectively, the record chromatogram, in the chromatogram of need testing solution if any the chromatographic peak consistent with the p-aminophenol retention time, calculate the content of p-aminophenol by external standard method, other impurity peak area with compare with own control solution main peak area sum, calculate by Self-control method.
2. method according to claim 1 is characterized in that, according to the form below carries out gradient elution:
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101825613A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Method for determining related substance of compound paracetamol and tramadol hydrochloride tablet through high-performance liquid chromatography |
| CN106353428A (en) * | 2016-09-19 | 2017-01-25 | 山西好医生药业有限公司 | Quality standard for paracetamol and tramadol hydrochloride capsules |
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| CN111426779A (en) * | 2020-03-31 | 2020-07-17 | 安士制药（中山）有限公司 | Method for determining related substances of pharmaceutical preparation containing acetaminophen, dextromethorphan hydrobromide and phenylephrine hydrochloride |
| CN111751470A (en) * | 2020-07-07 | 2020-10-09 | 多多药业有限公司 | Detection control method for new impurities in tramadol hydrochloride preparation and impurities obtained by detection control method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101825613A (en) * | 2009-03-04 | 2010-09-08 | 北京德众万全药物技术开发有限公司 | Method for determining related substance of compound paracetamol and tramadol hydrochloride tablet through high-performance liquid chromatography |
| CN106353428A (en) * | 2016-09-19 | 2017-01-25 | 山西好医生药业有限公司 | Quality standard for paracetamol and tramadol hydrochloride capsules |
| CN106525994A (en) * | 2016-09-19 | 2017-03-22 | 山西好医生药业有限公司 | Method for determination of related substances of paracetamol and tramadol hydrochloride capsules |
| CN106525994B (en) * | 2016-09-19 | 2020-05-22 | 山西好医生药业有限公司 | Method for determining related substances of paracetamol and tramadol capsule |
| CN106353428B (en) * | 2016-09-19 | 2020-08-25 | 山西好医生药业有限公司 | Quality standard of paracetamol and tramadol capsule |
| CN110501441A (en) * | 2019-09-27 | 2019-11-26 | 地奥集团成都药业股份有限公司 | Detection method in relation to substance in a kind of paracetamol tablets |
| CN110501441B (en) * | 2019-09-27 | 2021-11-26 | 地奥集团成都药业股份有限公司 | Method for detecting related substances in acetaminophen tablet |
| CN111426779A (en) * | 2020-03-31 | 2020-07-17 | 安士制药（中山）有限公司 | Method for determining related substances of pharmaceutical preparation containing acetaminophen, dextromethorphan hydrobromide and phenylephrine hydrochloride |
| CN111751470A (en) * | 2020-07-07 | 2020-10-09 | 多多药业有限公司 | Detection control method for new impurities in tramadol hydrochloride preparation and impurities obtained by detection control method |
| CN111751470B (en) * | 2020-07-07 | 2023-05-05 | 多多药业有限公司 | Detection control method for new impurities in tramadol hydrochloride preparation |
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| CN100498330C (en) | 2009-06-10 |
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