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拉米夫定
发表时间:2009-5-27 9:26:40      访问次数:6447次

中 文 名:拉米夫定

执行标准:USP28  USP30

中文别名:拉米夫定; 拉米呋啶;(2R-顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊-5-)-1H-嘧啶-2-

 

分子结构:  

拉米夫定, 拉米呋啶, (2R-顺式)-4-氨基-1-(2-羟甲基-1,3-氧硫杂环戊-5-基)-1H-嘧啶-2-酮, CAS #: 134678-17-4
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分  子  式C8H11N3O3S

分  子  量229.25

CAS 登录号134678-17-4

性      状:白色至类白色结晶性粉末。

应      用:乙肝、乙型肝炎病毒复制的慢性乙型肝炎。

药 理 毒 理:拉米夫定是核苷类抗病毒药,对体外及实验性感染动物体内的乙型肝炎病毒(HBV)有较强的抑制作用。拉米夫定可在HBV感染细胞和正常细胞内代谢生成拉米夫定三磷酸盐,它是拉米夫定的活性形式,既是HBV聚合酶的抑制剂,亦是此聚合酶的底物。拉米夫定三磷酸盐掺入到病毒DNA链中,阻断病毒DNA的合成。拉米夫定三磷酸盐不干扰正常细胞脱氧核苷的代谢,它对哺乳动物DNA聚合酶α和β的抑制作用微弱,对哺乳动物细胞DNA含量几乎无影响。拉米夫定对线粒体的结构、DNA含量及功能无明显的毒性。对数乙型肝炎的血清HBV DNA检测结果表明,拉米夫定能迅速抑制HBV复制,其抑制作用持续于整治疗过程。同时使血清转氨酶降至正常,长期应用可显著改善肝脏坏死炎症性改变并减轻或阻止肝脏纤维化的进展。

 

拉米夫定

Lamivudine

(质量检测标准)

C8H11N3O3S 229.26
2(1H)-Pyrimidinone,4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-,(2R-cis)-. (–)-1-[(2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine [134678-17-4].
»Lamivudine contains not less than 98.0percent and not more than 102.0percent of C8H11N3O3S,calculated on the anhydrous and solvent-free basis.Packaging and storage— Preserveinwell-closed,light-resistant containers.Store at room temperature.

USP Reference standards á11ñ USP Lamivudine RS.USP Lamivudine Resolution Mixture A RS.USP Lamivudine Resolution Mixture B RS.

Identification—

A: Infrared Absorption á197Mñ.

B: The retention time of the major peak in the chromatogram of the Test solutioncorresponds to that in the chromatogram of the Resolution solution,as obtained in the test for Limit of lamivudine enantiomer.

Light absorption— Its absorptivity (see Spectrophotometry and Light-Scattering á851ñ)at 440nm,determined in 4-cm cells with a 50mg per mLsolution in water,is not more than 0.0015.

Water,Method Ic á921ñ: not more than 0.2%.

Limit of lamivudine enantiomer—

0.1M Ammonium acetate solution— Dissolve about 7.7g of ammonium acetate in water,and dilute with water to 1000mL.

Mobile phase— Prepare a suitable mixture of 0.1M Ammonium acetate solutionand methanol (95:5),mix,filter,and degas.

Resolution solution— Dissolve the contents of 1vial of USP Lamivudine Resolution Mixture A RSin 5mLof water,and quantitatively transfer the solution to a 10-mLvolumetric flask using successive 2-mLportions of water.Dilute with water to volume,and mix.

Test solution— Transfer about 25mg of Lamivudine,accurately weighed,to a 100-mLvolumetric flask,dissolve in and dilute with water to volume,and mix.

Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 270-nm detector and a 4.6-mm ×25-cm column that contains packing L45.The column temperature is maintained at a constant temperature of between 15 and 30 .The flow rate is about 1.0mLper minute.Chromatograph the Resolution solution,and record the peak responses as directed for Procedure:the resolution,R,between lamivudine and lamivudine enantiomer is not less than 1.5.[NOTE—The relative retention times are about 1.0for lamivudine and about 1.2for lamivudine enantiomer.]

Procedure— Inject a volume (about 10µL)of the Test solutioninto the chromatograph,record the chromatogram,and measure the responses for the major peaks.Calculate the percentage of lamivudine enantiomer in the portion of Lamivudine taken by the formula:

100[rU/(rU+rS)],

in which rUand rSare the peak responses of lamivudine enantiomer and lamivudine,respectively:not more than 0.3%is found.

Limit of residual solvents—

Internal standard solution— Transfer about 1mLof 2-pentanone,accurately measured,to a 100-mLvolumetric flask,dilute with a mixture of methyl sulfoxide and water (1:1)to volume,and mix.

Standard solution— Transfer 10mLof Internal standard solution to a 100-mLvolumetric flask.To the same flask add an accurately measured quantity of about 100µLof each of the following:dehydrated alcohol,isopropyl acetate,methanol,and triethylamine.Dilute with a mixture of methyl sulfoxide and water (1:1)to volume,and mix.

Test solution— Transfer about 5g of Lamivudine,accurately weighed,to a 100-mLvolumetric flask,add 10mLof Internal standard solution,dilute with a mixture of methyl sulfoxide and water (1:1)to volume,and mix.

Chromatographic system (see Chromatography á621ñ)— The gas chromatograph is equipped with a split injection port,a flame-ionization detector,and a 0.53-mm ×50-m column coated with a 5-µm film of phase G1.The carrier gas is hydrogen at a pressure of 5psig.The split flow rate is about 320mLper minute.The chromatograph is programmed as follows.Initially the temperature of the column is maintained at 70 for 3minutes,then increased at a rate of 30 per minute to 200 ,and maintained at that temperature for 6.5minutes.The injection port temperature is maintained at 150 and the detector temperature is maintained at 250 .

Procedure— Separately inject equal volumes (about 0.5µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the peak areas.Calculate the percentage of each residual solvent in the portion of Lamivudine taken by the formula:

10(C/W)(RU/RS),

in which Cis the concentration,in mg per mL,of the respective analyte in the Standard solution;Wis the weight,in g,of Lamivudine taken;andRUand RSare the peak response ratios of the respective analyte to the internal standard obtained from the Test solutionand the Standard solution,respectively:not more than 0.2%of alcohol is found;not more than 0.2%of isopropyl acetate is found;not more than 0.1%of methanol is found;not more than 0.1%of triethylamine is found;and not more than 0.3%of total residual solvents is found.

Chromatographic purity—

0.025M Ammonium acetate solution,Mobile phase,System suitability solution,and Chromatographic system— Proceed as directed in the Assay.

Salicylic acid solution— Dissolve an accurately weighed quantity of salicylic acid in Mobile phase,and dilute quantitatively,and stepwise if necessary,with Mobile phase to obtain a solution having a concentration of about 0.625µg per mL.

Standard solution— Use the Standard preparation,prepared as directed in the Assay.

Test solution— Use the Assay preparation.

Procedure— Separately inject equal volumes (about 10µL)of Salicylic acid solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure all the peak responses.Calculate the percentage of salicylic acid in the portion of Lamivudine taken by the formula:

(10C/W)(rU/rS),

in which Cis the concentration,in µg per mL,of salicylic acid in the Salicylic acid solution;Wis the weight,in mg,of Lamivudine taken for the Test solution;and rUand rSare the salicylic acid peak responses obtained from the Test solutionand the Salicylic acid solution,respectively.Calculate the percentage of other individual impurities in the portion of Lamivudine taken by the formula:

100(ri/rs),

in which riis the peak response for each impurity other than salicylic acid obtained from the Test solution;and rsis the sum of the responses for all the peaks:not more than 0.3%for any peak at a relative retention time of about 0.4is found;not more than 0.2%for any peak at a relative retention time of about 0.9is found;not more than 0.1%of salicylic acid is found;not more than 0.1%of any other individual impurity is found;and not more than 0.6%of total impurities is found.

Assay—

0.025M Ammonium acetate solution— Transfer about 1.9g of ammonium acetate to a 1000-mLvolumetric flask,dissolve in about 900mLof water,adjust with acetic acid to a pHof 3.8±0.2,dilute with water to volume,and mix.

Mobile phase— Prepare a filtered and degassed mixture of 0.025M Ammonium acetate solutionand methanol (95:5).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).

System suitability solution— Dissolve the contents of 1vial of USP Lamivudine Resolution Mixture B RSin 2mLof Mobile phase.

Standard preparation— Dissolve an accurately weighed quantity of USP Lamivudine RSin Mobile phase,and dilute quantitatively,and stepwise if necessary,with Mobile phaseto obtain a solution having a known concentration of about 0.25mg per mL.

Assay preparation— Transfer about 25mg of Lamivudine,accurately weighed,to a 100-mLvolumetric flask,dissolve in and dilute with Mobile phaseto volume,and mix.

Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 277-nm detector and a 4.6-mm ×25-cm column that contains packing L1.The flow rate is about 1.0mLper minute.The column temperature is maintained at 35 .Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between lamivudine and lamivudine diastereomer is not less than 1.5.[NOTE—The relative retention times are about 1.0for lamivudine and 0.9for lamivudine diastereomer.]Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the lamivudine peaks.Calculate the quantity,in mg,of C8H11N3O3Sin the portion of Lamivudine taken by the formula:

100C(rU/rS),

in which Cis the concentration,in mg per mL,of USP Lamivudine RSin the Standard preparation;and rUand rSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.

Auxiliary Information— Staff Liaison:Behnam Davani,Ph.D.,MBA,Senior Scientist

Expert Committee:(PA7)Pharmaceutical Analysis 7

USP28–NF23Page 1106

Pharmacopeial Forum:Volume No.30(3)Page 881

Phone Number:1-301-816-8394

 


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