依诺肝素钠标准(USP 39)

•L IMIT OF F LUORIDE ADDITIONAL REQUIREMENTS [N OTE—Use plasticware throughout this test.]•P ACKAGING AND S TORAGE: Preserve in tight, light-resistant Buffer: Dissolve 110g of sodium chloride and 1g of containers, and avoid exposure to excessive heat.sodium citrate in 700mL of water in a 2000-mL volu-•USP R EFERENCE S TANDARDS〈11〉metric flask. Cautiously add 150g of sodium hydroxide,USP Enflurane RSand dissolve with shaking. Cool to room temperature,and, while stirring, cautiously add 450mL of glacialacetic acid to the cooled solution. Cool, add 600mL ofisopropyl alcohol, and dilute with water to volume; thepH of this solution is 5.0–5.5.Enoxaparin SodiumStandard stock solution: 1mg/mL of fluoride ion, pre-pared as follows. Transfer 221mg of sodium fluoride, previously dried at 150° for 4 h, to a 100-mL volumet-ric flask. Add 20mL of water, and mix to dissolve. Add 1.0mL of sodium hydroxide solution (1 in 2500), and dilute with water to volume. [N OTE—Store in a tightly closed plastic container.]Standard solution A: 100mL of a solution containing 1µg/mL of fluoride ion in Buffer, from Standard stock solutionStandard solution B: 100mL of a solution containing 3µg/mL of fluoride ion in Buffer, from Standard stock solutionStandard solution C: 100mL of a solution containing 5µg/mL of fluoride ion in Buffer, from Standard stock solutionStandard solution D: 100mL of a solution containing 10µg/mL of fluoride ion in Buffer, fromStandard stocksolution[9041-08-1].Sample stock solution: Enflurane and water (1:1).Shake the Sample stock solution for 5 min, allow theDEFINITIONliquids to separate completely, and use the water layer.Enoxaparin Sodium is the sodium salt of a depolymerized Sample solution: Sample stock solution and Bufferheparin. It is obtained by alkaline depolymerization of (1:1). Use volumetric glassware.heparin benzyl ester. The starting material, heparin, is ob-Electrode system: Use a pH meter capable of a mini-tained exclusively from porcine intestinal mucosa. Heparin mum reproducibility of ±0.2 mV, equipped with a glass-source material used in the manufacture of Enoxaparin sleeved, calomel-fluoride, specific-ion electrode systemSodium complies with the compendial requirements (see pH 〈791〉).stated in the Heparin Sodium monograph. Enoxaparin So-Analysisdium consists of a complex set of oligosaccharides that Samples: Standard solutions and Sample solutionhave not yet been completely characterized. The majority Transfer the solution to a 150-mL beaker, add aof the components have a 4-enopyranose uronate struc-polytef-coated stirring bar, and immerse the elec-ture at the nonreducing end of their chain. About 20% of trodes in the solution. Stir with a magnetic stirrerthe materials contain a 1,6-anhydro derivative on the re-having an insulated top until equilibrium is obtainedducing end of the chain, the range being between 15% (1–2 min), and record the potential, in mv. [N OTE—and 25%. The weight-average molecular weight of Enox-Rinse and dry the electrodes between measurements,aparin Sodium is 4500 Da, the range being between taking care to avoid damaging the crystal of the spe-3800 and 5000 Da; about 16% have a molecular weight cific-ion electrode.]of less than 2000 Da, the range being between 12.0% Plot the logarithm of the fluoride-ion concentrations,and 20.0%; about 74% have a molecular weight between in µg/mL, of the Standard solutions versus the poten-2000 and 8000 Da, the range being between 68.0% and tial, in mV. From the measured potential of the Sam-82.0%. NMT 18.0% have a molecular weight higher thanple solution and the standard curve, determine the8000 Da. When prepared as a solution, the solution is concentration, in µg/mL, of fluoride ions in the Sam-analyzed for clarity and degree of color using a validated ple solution.method. The degree of sulfation is NLT 1.8per disaccha-Acceptance criteria: NMT 10µg/mLride unit. It has a potency of NLT 90 and NMT 125 Anti-•L IMIT OF N ONVOLATILE R ESIDUEFactor Xa International Units (IU)/mg, and NLT 20.0 and Analysis: Allow 10.0mL to evaporate at room tempera-NMT 35.0 Anti-Factor IIa IU/mg, calculated on the dried ture in a tared evaporating dish, dry the residue at 50°basis. The ratio of Anti-Factor Xa activity to Anti-Factor IIa for 2 h, and weigh.activity is between 3.3 and 5.3.Acceptance criteria: NMT 2mg of residue remains.IDENTIFICATIONSPECIFIC TESTS•A. U LTRAVIOLET A BSORPTION〈197U〉•S PECIFIC G RAVITY〈841〉: 1.516–1.519Medium: 0.01 N hydrochloric acid•R EFRACTIVE I NDEX〈831〉: 1.3020–1.3038 at 20°Sample solution: 500µg/mL•W ATER D ETERMINATION, Method I〈921〉: NMT 0.14%Acceptance criteria: The spectra exhibit maxima at •A CIDITY OR A LKALINITY231±2 nm.Sample: Shake 20mL of Enflurane with 20mL of car-bon dioxide-free water for 3 min, and allow the layersto separate. Draw off the water layer, add bromocresol Change to read:purple TS as the indicator, and titrate with 0.010 Nsodium hydroxide or 0.010 N hydrochloric acid.•B.13C NMR S PECTRUMAcceptance criteria: NMT 0.10mL of 0.010 N sodium(See •Nuclear Magnetic Resonance Spectroscopy 〈761〉•(CN hydroxide or NMT 0.60mL of 0.010 N hydrochloric1-May-2016).)acid is required for neutralization.Standard solution: Dissolve 200mg of USP EnoxaparinSodium RS in a mixture of 0.2mL of deuterium oxideand 0.8mL of water. Add 0.05mL of deuterated meth-Acceptance criteria:M2000 is between 12.0% and anol to serve as an internal reference.20.0%, M2000–8000 is between 68.0% and 82.0%, and Sample solution: Dissolve 200mg of Enoxaparin So-M8000 is NMT 18.0%.dium in a mixture of 0.2mL of deuterium oxide and•E. I DENTIFICATION T ESTS—G ENERAL, Sodium〈191〉: Meets0.8mL of water. Add 0.05mL of deuterated methanol.the requirementsAnalysis: Transfer the Standard solution and the SampleASSAYsolution to NMR tubes of 5-mm diameter. Using apulsed (Fourier transform) NMR spectrometer operatingat NLT 75MHz for 13C, record the 13C NMR spectra of Change to read:the Standard solution and the Sample solution at 40°.Acceptance criteria: The spectra are similar.•ANTI-F ACTOR X a A CTIVITY•C. The ratio of the numerical value of the Anti-Factor Xa Acetic acid solution: Glacial acetic acid and water activity, in Anti-Factor Xa IU/mg, to the numerical value(42:58)of the Anti-Factor IIa activity, in Anti-Factor IIa IU/mg, as pH 7.4polyethylene glycol 6000 buffer: Dissolve determined by the Assay (Anti-Factor Xa Activity) and Im- 6.08g of tris(hydroxymethyl)aminomethane and 8.77g purities (Anti-Factor IIa Activity), respectively, is NLT 3.3of sodium chloride in 500mL of water. Add 1.0g of and NMT 5.3.polyethylene glycol 6000, adjust with hydrochloric acid •D. M OLECULAR W EIGHT D ISTRIBUTION AND W EIGHT-A VERAGE to a pH of 7.4, and dilute with water to 1000mL.M OLECULAR W EIGHT pH 7.4 buffer: Dissolve 6.08g of tris(hydroxymethyl)-Mobile phase: Prepare a 0.5 M lithium nitrate solution.aminomethane and 8.77g of sodium chloride in Pass through a membrane filter of 0.45-µm or smaller500mL of water. Adjust with hydrochloric acid to a pH pore size, and degas with helium.of 7.4, and dilute with water to 1000mL.Standard solution: 10mg/mL of USP Enoxaparin So-pH 8.4 buffer: Dissolve 3.03g of tris(hydroxymethyl)-dium RS in Mobile phase aminomethane, 5.12g of sodium chloride, and 1.40g Sample solution: 10mg/mL of Enoxaparin Sodium in of edetate sodium in 250mL of water. Adjust with hy-Mobile phase drochloric acid to a pH of 8.4, and dilute with water to Chromatographic system500mL.(See Chromatography 〈621〉, System Suitability.)Human antithrombin III solution: Reconstitute a vial Mode: Size exclusion LC of antithrombin III (see Reagents, Indicators, and Solu-Detector: Differential refractive index tions—Reagent Specifications) in water to obtain a solu-Column tion containing 5 Antithrombin III Units/mL. Dilute this Guard: 6-mm × 40-mm; packing L59solution with pH 7.4polyethylene glycol 6000 buffer to Analytical: Two 7.8-mm × 300-mm columns in series;obtain a solution having a concentration of 1.0 Anti-packing L59thrombin III Unit/mL.Temperature: Room temperature Factor Xa solution: Reconstitute a weighed quantity of Flow rate: 0.6mL/min maintained constant to ± 1.0%bovine factor Xa (see Reagents, Indicators, and Solu-Analysis: Reconstitute 1 vial each of USP Enoxaparin tions—Reagent Specifications) in pH 7.4polyethylene gly-Sodium Molecular Weight Calibrant A RS and USP col 6000 buffer to obtain a solution that gives an in-Enoxaparin Sodium Molecular Weight Calibrant B RS in crease in absorbance value at 405 nm of NMT 0.20 1mL of Mobile phase. Separately inject 20µL of USP absorbance units/min when assayed as described below Enoxaparin Sodium Molecular Weight Calibrant A RS but using as an appropriate volume, V, the volume in and USP Enoxaparin Sodium Molecular WeightµL of pH 7.4 buffer instead of VµL of the enoxaparin Calibrant B RS, record the chromatograms, and meas-solution.ure the retention times. Inject in duplicate 20µL each Chromogenic substrate solution: Prepare a solution of of the Standard solution and the Sample solution, and a suitable chromogenic substrate for amidolytic test record the chromatograms for a length of time to en-(see Reagents, Indicators, and Solutions—Reagent Specifi-sure complete elution, including salt and solvent peaks.cations) for factor Xa in water to obtain a concentration Calculate the total peak areas under each of the Stan-of about 3 mM. Dilute with pH 8.4 buffer to obtain a dard solution and Sample solution chromatograms, ex-solution having a concentration of 0.5 mM.cluding salt and solvent peaks at the end.Standard solutions: Reconstitute the entire contents of Calibration curve: Plot the retention times on the x-an ampul of USP Enoxaparin Sodium for Bioassays RS axis against the peak molecular weights on the y-axis with water, and dilute with pH 7.4 buffer to obtain four for the peaks from USP Enoxaparin Sodium Molecular dilutions in the concentration range between 0.025 and Weight Calibrant A RS and USP Enoxaparin Sodium Mo-0.2 Anti-Factor Xa IU/mL.lecular Weight Calibrant B RS, and fit the data to a Sample solutions: Proceed as directed for Standard so-third-order polynomial, using suitable gel permeation lutions to obtain concentrations of Enoxaparin Sodium chromatography (GPC) software.similar to those obtained for the Standard solutions.Calculations: Compute the data, using the same GPC Analysissoftware; determine the weight-average molecular Samples:Standard solutions, Sample solutions, Human weight, M w, for each of the duplicate chromatograms of antithrombin III solution, pH 7.4 buffer, Factor Xa solu-the Standard solution and the Sample solution; and take tion, Chromogenic substrate solution, and Acetic acid the average for each solution. Correct the mean value solutionof M w to the nearest 50. The Chromatographic system is Label 18 suitable tubes: B1 and B2 for blanks; T1, T2, suitable if M w for USP Enoxaparin Sodium RS is within T3, and T4 each in duplicate for the dilutions of the 150 Da of the labeled M w value. The M w for the Sample Sample solutions; and S1, S2, S3, and S4 each in dupli-solution is between 3800 and 5000 Da. Using the same cate for the dilutions of the Standard solutions. [NOTE—software, determine for each of the duplicate Sample Treat the tubes in the order B1, S1, S2, S3, S4, T1, T2,solution chromatograms the percentage of Enoxaparin T3, T4, T1, T2, T3, T4, S1, S2, S3, S4, B2.] To each Sodium chains with molecular weights lower than 2000tube add the same volume, V (20–50µL), of Human Da, M2000, the percentage of Enoxaparin Sodium chains antithrombin III solution and an equal volume, V, of with molecular weights in the range 2000–8000 Da,either the blank (pH 7.4 buffer) or an appropriate dilu-M2000–8000, and the percentage of Enoxaparin Sodium tion of the Sample solutions or the Standard solutions.chains with molecular weights greater than 8000 Da,Mix, but do not allow bubbles to form. Incubate at M8000. Average the duplicate values, and express to the37° for 1.0 min. Add to each tube 2V (40–100µL) of nearest 0.5%.Factor Xa solution, and incubate for 1.0 min. Add a 5V Analysis(100–250µL) volume of Chromogenic substrate solu-Samples:Standard solution A, Standard solution B, tion. Stop the reaction after 4.0 min with a 5V Standard solution C, Cesium chloride solution, and Sam-(100–250µL) volume of Acetic acid solution. Measure ple solutionthe absorbance of each solution at 405 nm, using a Concomitantly determine the absorbances of the Ce-suitable spectrophotometer (see •Ultraviolet-Visible sium chloride solution (blank), Sample solution, and Spectroscopy 〈857〉•(CN 1-May-2016)) against blank B1. The Standard solutions at 330.3 nm, using a sodiumreading of blank B2 relative to blank B1 is NMT ± 0.05hollow-cathode lamp and an air–acetylene flame. Us-absorbance unit.ing the absorbances of Standard solutions A–C, deter-Calculations: For each series, calculate the regression mine the sodium content in the Sample solution after of the absorbance against log concentrations of the an appropriate blank correction.Sample solutions and of the Standard solutions, and cal-Acceptance criteria: 11.3%–13.5% on the dried basis culate the potency of the Enoxaparin Sodium in IU ofIMPURITIESAnti-Factor Xa activity/mL, using statistical methods forparallel-line assays. The four independent log relativepotency estimates are then combined to obtain the Delete the following:final geometric mean. Its confidence limits are calcu-lated. Express the Anti-Factor Xa activity of Enoxaparin••H EAVY M ETALS, Method I〈231〉: NMT 30µg/g, using a Sodium/mg. 2.7% solution in water•(Official 1-Jan-2018) Acceptance criteria: The potency is NLT 90 and NMT125 Anti-Factor Xa IU/mg on the dried basis.SPECIFIC TESTS•P H 〈791〉: 6.2–7.7 for a 10.0% solution in water OTHER COMPONENTS•LOSS ON D RYING〈731〉: Dry 1g in a vacuum at 70° for 6•B ENZYL A LCOHOL C ONTENT h: it loses NMT 10.0% of its weight.Mobile phase: Acetonitrile, methanol, and water(3:1:16)Standard solution: 0.1mg/mL of USP Benzyl Alcohol Change to read:RS in waterSample solution: Weigh 0.5g of Enoxaparin Sodium•S PECIFIC A BSORBANCEinto a 10-mL volumetric flask, and dissolve in 5.0mL of(See •Ultraviolet-Visible Spectroscopy 〈857〉•(CN 1-May-2016).) 1N sodium hydroxide. Allow to stand at room temper-Sample solution: 0.5mg/mL of Enoxaparin Sodium in ature for about 1 h. Add 1.0mL of glacial acetic acid,0.01 N hydrochloric aciddilute with water to volume, and mix.Analysis: Obtain the UV spectra of the Standard solution Chromatographic system and the Sample solution between 200 nm and 300 nm (See Chromatography 〈621〉, System Suitability.)against a 0.01 N hydrochloric acid blank.Mode: LC Calculate the specific absorbance at the wavelength of Detector: UV 256 nm maximum absorbance at 231±2 nm, with reference Column: 4.6-mm × 15-cm stainless steel; packing L7to the dried substance:Flow rate: 1.0mL/min, maintained constant to ±10%Injection volume: 20µL Result = A× 100×1000/[M×l× (100 −E)] AnalysisA= absorbance at the wavelength of maximum Samples:Standard solution and Sample solutionabsorbanceCalculate the percentage of benzyl alcohol in the por-M= weight of Enoxaparin Sodium in the Sample tion of Enoxaparin Sodium taken:solution (mg)Result = (r U/r S) × (C S/C U) × 100l= path length (typically 1cm)E= loss on drying (%)r U= peak area of benzyl alcohol from the Sample Acceptance criteria: 14.0–20.0 on the dried basis solution•B ACTERIAL E NDOTOXINS T EST〈85〉: It contains NMT 0.01 r S= peak area of benzyl alcohol from the Standard USP Endotoxin Unit/IU of Anti-Factor Xa activity.solution•A NTI-F ACTOR II a A CTIVITYC S= concentration of benzyl alcohol in the Acetic acid solution, pH 7.4polyethylene glycol 6000Standard solution (mg/mL)buffer, pH 7.4 buffer, pH 8.4 buffer, and HumanC U= concentration of Enoxaparin Sodium in the antithrombin III solution: Proceed as directed in theSample solution (mg/mL)Assay for Anti-Factor Xa Activity, except that the concen-Acceptance criteria: NMT 0.1%tration of the Human antithrombin III solution is 0.5•N ITROGEN D ETERMINATION, Method II〈461〉: 1.8%–2.5%Antithrombin III Unit/mL.on the dried basis Thrombin human solution: Reconstitute thrombinhuman (see Reagents, Indicators and Solutions—ReagentSpecifications) in water, and dilute in pH 7.4polyethylene Change to read:glycol 6000 buffer to obtain a solution having a concen-tration of 5 Thrombin Units/mL.•S ODIUM C ONTENT Chromogenic substrate solution: Prepare a solution of (See •Atomic Absorption Spectroscopy 〈852〉•(CN 1-May-2016).) a suitable chromogenic substrate for an amidolytic test Cesium chloride solution: 1.27mg/mL of cesium chlo-(see Reagents, Indicators, and Solutions—Reagent Specifi-ride in 0.1 N hydrochloric acid cations) for thrombin in water to obtain a concentration Standard solution A: 0.0025% of sodium chloride in of about 3 mM. Immediately before use, dilute with pH Cesium chloride solution8.4 buffer to 0.5 mM.Standard solution B: 0.0050% of sodium chloride in Standard solutions: Reconstitute the entire contents of Cesium chloride solution an ampul of USP Enoxaparin Sodium for Bioassays RS Standard solution C: 0.0075% of sodium chloride in with water, and dilute with pH 7.4 buffer to obtain four Cesium chloride solution dilutions having concentrations in the range between Sample solution: Transfer 50.0mg of Enoxaparin So-0.015 and 0.075 IU of Anti-Factor IIa activity/mL.dium to a 100-mL volumetric flask, and dissolve in anddilute with Cesium chloride solution to volume.Sample solutions: Proceed as directed under Standard ADDITIONAL REQUIREMENTSsolutions to obtain concentrations of Enoxaparin Sodium•P ACKAGING AND S TORAGE: Preserve in tight containers, similar to those obtained for the Standard solutions.and store below 40°, preferably at room temperature.Analysis: Proceed as directed in the Assay for Anti-Factor•USP R EFERENCE S TANDARDS〈11〉Xa Activity, except to use Thrombin human solution in-USP Benzyl Alcohol RSstead of Factor Xa solution and to use Human antithrom-USP Endotoxin RSbin III solution as described P Enoxaparin Sodium RSCalculations: For each series, calculate the regression of USP Enoxaparin Sodium Molecular Weight Calibrant A RS the absorbance against log concentrations of the Sam-USP Enoxaparin Sodium Molecular Weight Calibrant B RS ple solutions and of the Standard solutions, and calculate USP Enoxaparin Sodium for Bioassays RSthe potency of the Enoxaparin Sodium in IU of Anti-Factor IIa activity/mg, using statistical methods for par-allel-line assays. The four independent dilution estimatesare then combined to obtain the final weighted mean.Then calculate the confidence limits. Express the Anti-Enoxaparin Sodium InjectionFactor IIa activity of Enoxaparin Sodium/mg.Acceptance criteria: It has a potency of NLT 20.0 and DEFINITIONNMT 35.0 Anti-Factor IIa IU/mg on the dried basis.Enoxaparin Sodium Injection is a sterile solution of Enox-•M OLAR R ATIO OF S ULFATE TO C ARBOXYLATE aparin Sodium in Water for Injection. Its appearance is Mobile phase: Carbon dioxide-free water analyzed for clarity and degree of color, using a validated Sample solution: 5mg/mL of Enoxaparin Sodium in method. Its potency value is NLT 90% and NMT 110% of carbon dioxide-free water the potency stated on the label in terms of International Chromatographic system Anti-Factor Xa Units (IU). It may contain, in multiple-dose (See Chromatography 〈621〉, System Suitability.)containers, a suitable antimicrobial preservative, such as Mode: LC benzyl alcohol.Detector: IonColumn: Two columns; one 1.5-cm × 2.5-cm column,IDENTIFICATIONpacked with an anion-exchange resin L64packing; and•A.one 1.5-cm × 7.5-cm column, packed with a cation-Analysis: Transfer the total contents of a single-dose exchange resin L65packing. The outlet of the anion-container or 0.4mL from a multiple-dose container to a exchange column is connected to the inlet of the cat-glass test tube, add 2mL of water and 1mL of 2% ion-exchange column.(w/v) protamine sulfate solution, and mix.Flow rate: 1mL/min Acceptance criteria: A creamy white precipitate is Analysis formed.Sample:Sample solution•B. U LTRAVIOLET A BSORPTION〈197U〉[N OTE—Regenerate the anion-exchange column and the Medium: 0.01 N hydrochloric acidcation-exchange column with 1N sodium hydroxide Standard solution: 500µg/mLand 1N hydrochloric acid, respectively, between two Sample solution: Transfer the total content of a single-injections.]dose container or 0.4mL from a multiple-dose con-Inject the Sample solution into the anion-exchange col-tainer to a 100-mL volumetric flask. Dilute with Medium umn, and collect the eluate from the cation-exchange to volume.column in a beaker at the outlet until the ion detector Acceptance criteria: The spectra exhibit maxima at reading returns to the baseline value. Quantitatively231±2 nm.transfer the eluate to a titration vessel containing a•C. I DENTIFICATION T ESTS—G ENERAL, Sodium〈191〉: Meets magnetic stirring bar, and dilute with carbon dioxide-the requirementsfree water to about 60mL. Position the titration vesselASSAYon a magnetic stirrer, and immerse the electrodes.Note the initial conductivity reading, and titrate withapproximately 0.1 N sodium hydroxide added in Change to read:100-µL portions. [N OTE—Prepare the sodium hydroxidesolution in carbon dioxide-free water.] Record the bu-•A NTI-F ACTOR X a A CTIVITYret reading and the conductivity meter reading after Acetic acid solution: Glacial acetic acid and water each addition of the sodium hydroxide solution.(42:58)Calculations: Plot the conductivity measurements on pH 7.4polyethylene glycol 6000 buffer: Dissolve the y-axis against the volumes of sodium hydroxide 6.08g of tris(hydroxymethyl)aminomethane and 8.77g added on the x-axis. The graph will have three linear of sodium chloride in 500mL of water. Add 1.0g of sections—an initial downward slope, a middle slight polyethylene glycol 6000, adjust with hydrochloric acid rise, and a final rise. For each of these sections draw the to a pH of 7.4, and dilute with water to 1000mL.best-fit straight lines, using linear regression analysis. At pH 7.4 buffer: Dissolve 6.08g of tris(hydroxymethyl)-the points where the first and second straight lines in-aminomethane and 8.77g of sodium chloride in tersect and where the second and third lines intersect,500mL of water. Adjust with hydrochloric acid to a pH draw perpendiculars to the x-axis to determine the of 7.4, and dilute with water to 1000mL.volumes of sodium hydroxide taken up by the sample pH 8.4 buffer: Dissolve 3.03g of tris(hydroxymethyl)-at those points. The point where the first and second aminomethane, 5.12g of sodium chloride, and 1.40g lines intersect corresponds to the volume of sodium hy-of edetate sodium in 250mL of water. Adjust with hy-droxide taken up by the sulfate groups (V S). The point drochloric acid to a pH of 8.4, and dilute with water to where the second and third lines intersect corresponds500mL.to the volume of sodium hydroxide consumed by the Human antithrombin III solution: Reconstitute a vial sulfate and the carboxylate groups together (V T).of antithrombin III (see Reagents, Indicators, and Solu-Calculate the molar ratio of sulfate to carboxylate:tions—Reagent Specifications) in water to obtain a solu-tion containing 5 Antithrombin III Units/mL. Dilute this Result = V S/(V T−V S)solution with pH 7.4polyethylene glycol 6000 buffer toobtain a solution having a concentration of 1.0 Anti-Acceptance criteria: The molar ratio of sulfate to car-thrombin III Unit/mL.boxylate is NLT 1.8.。