盐酸二甲双胍

盐酸二甲双胍

中国药典：

拼音名：Yansuan Erjiashuanggua

英文名：Metformin Hydrochloride

【性状】本品为白色结晶或结晶性粉末；无臭。本品在水中易溶，在甲醇中溶解，在乙醇中微溶，在三氯甲烷或乙醚中不溶。

熔点本品的熔点（附录Ⅵ C）为220-225℃。

吸收系数取本品，精密称定，加水溶解并定量稀释制成每1ml中约含5μg的溶液。照紫外-可见分光光度法（附录Ⅳ A），在233nm的波长处测定吸光度，吸收系数（E1%/1cm）为778-818。

【鉴别】（1）取本品约10mg，加水10ml溶解后，加10%亚硝基铁氰化钠溶液-铁氰化钾试液-10%氢氧化钠溶液（等体积混合，放置20分钟使用）10ml，3分钟内溶液呈红色。（2）本品的红外光吸收图谱应与对照的图谱（光谱集631图）一致。

（3）本品的水溶液显氯化物的鉴别反应（附录Ⅲ）。

【检查】有关物质取本品适量，精密称定，加流动相溶解并稀释制成每1lml中约含0.5mg 的溶液，作为供试品溶液；另取双氰胺对照品适量，精密称定，用水溶解并稀释制成每1ml 中约含0.1mg的溶液，作为双氰胺对照品溶液。分别精密量取上述两种溶液各0.5ml，置同一100ml量瓶中，用流动相稀释至刻度，摇匀，作为对照溶液。照高效液相色谱法（附录Ⅴ D）测定，用磺酸基阳离子交换键合硅胶为填充剂，以1.7%磷酸二氢铝溶液（用磷酸调节pH值至3.0）为流动相，检测波长为218nm，理论板数按双氰胺峰计算不低于5000，盐酸二甲双胍峰与双氰胺峰的分离度均应符合要求。取对照溶液10μl注入液相色谱仪，调节检测灵敏度，使双氰胺色谱峰的峰高约为满量程的10%，再精密量取供试品溶液与对照溶液各10μl，分别注入液相色谱仪，记录色谱图至盐酸二甲双胍保留时间的2倍。供试品溶液的色谱图中如有与双氰胺峰保留时间一致的峰，按外标法以峰面积计算，其含量不得过0.02%，其他单个杂质峰面积不得大于对照溶液中盐酸二甲双胍峰面积的1/5，其他各杂质峰面积的和不得大于对照溶液中盐酸二甲双胍峰面积。

干燥失重取本品，在105℃干燥至恒重，减失重量不得过0.5%（附录Ⅷ L）。

炽灼残渣不得过0.1%（附录Ⅷ N）。

重金属取本品1.0g，依法检查（附录Ⅷ H第一法），含重金属不得过百万分之二十。【含量测定】取本品约70mg，精密称定，加冰醋酸10ml，醋酸汞试液5ml使溶解，加萘酚苯甲醇指示液2滴，用高氯酸滴定液（0.1mol/L）滴定至溶液显黄绿色，并将滴定结果用空白试验校正。每1ml高氯酸滴定液（0.1mol/L）相当于8.282mg的C4H11N5·HCl。【贮藏】密封保存。

【制剂】盐酸二甲双胍片

【化学成分】本品为1,1-二甲基双胍盐酸盐。按干燥品计算，含C4H11N5·HCl不得少于98.5%。

【分子式与分子量】 C4H11N5·HCl 165.63

【药理作用】降血糖药

美国药典：

Metformin Hydrochloride

C4H11N5·HCl 165.62

Imidodicarbonimidic diamide,N,N-dimethyl-,monohydrochloride.

1,1-Dimethylbiguanide monohydrochloride [1115-70-4].

?Metformin Hydrochloride contains not less than 98.5percent and not more than 101.0percent of C4H11N5·HCl,calculated on the dried basis.

USP Reference standards á11?—USP Metformin Hydrochloride https://www.360docs.net/doc/ea8476993.html,P Metformin Related Compound A RS.

Identification—A:Infrared Absorption 197K .

B:It meets the requirements of the tests for Chloride á191?.

Loss on drying á731?—Dry it at 105for 5hours:it loses not more than 0.5%of its weight. Residue on ignition á281?:not more than 0.1%.

Heavy metals,Method Iá231?:0.001%.

Related compounds—Mobile phase—Prepare a solution in water,containing 17g of monobasic ammonium phosphate per L,adjust with phosphoric acid to a pHof 3.0,and mix.

Standard solution—

Prepare a solution of USP Metformin Related Compound A RSin water having a known concentration of about 0.2mg per mL.Transfer 1.0mLof this solution to a 200-mLvolumetric flask,dilute with Mobile phase to volume,and mix.[NOTE—Metformin related compound Ais 1-cyanoguanidine.]

Test solution—Transfer about 500mg of Metformin Hydrochloride,accurately weighed,to a 100-mLvolumetric flask,dissolve in and dilute with Mobile phase to volume,and mix.

Diluted test solution—Transfer 1.0mLof the Test solution to a 10-mLvolumetric flask,dilute with Mobile phase to volume,and mix.Transfer 1.0mLof this solution to a 100-mLvolumetric flask,dilute with Mobile phase to volume,and mix.

Resolution solution—Transfer about 10mg of melamine to a 100-mLvolumetric flask,and dissolve in about 90mLof water.Add 5.0mLof the Test solution,dilute with water to volume,and mix.Transfer 1.0mLof this solution to a 50-mLvolumetric flask,dilute with Mobile phase to

volume,and mix.

Chromatographic system (see Chromatography á621?)—The liquid chromatograph is equipped with a 218-nm detector and a 4.6-mm ×25-cm column containing packing L9.The flow rate is about 1.0to 1.7mLper minute.Chromatograph the Resolution solution,and record the peak responses as directed for Procedure:the resolution,R,between melamine and metformin is not less than 10.

Procedure—Separately inject equal volumes (about 20μL)of the Test solution,the Standard solution,and the Diluted test solution into the chromatograph,record the chromatograms for not less than twice the retention time of metformin,and measure the peak areas.The area of a peak corresponding to metformin related compound Ain the chromatogram of the Test solution is not greater than the area of the corresponding peak in the chromatogram of the Standard solution:not more than 0.02%of metformin related compound Ais found.

The area of any other secondary peak in the chromatogram of the Test solution is not greater than the area of the major peak in the chromatogram of the Diluted test solution;and the sum of the areas of all secondary peaks in the chromatogram of the Test solution is not greater than five times the area of the major peak in the chromatogram of the Diluted test solution:not more than 0.1%of any other impurity is found;and not more than 0.5%of total impurities is found. Assay—[NOTE—To avoid overheating of the reaction medium,mix thoroughly throughout the titration,and stop the titration immediately after the endpoint has been reached.]Dissolve about 60mg of Metformin Hydrochloride,accurately weighed,in 4mLof anhydrous formic acid. Add 50mLof acetic anhydride.Titrate with 0.1Nperchloric acid VS, determining the endpoint potentiometrically. Perform a blank determination,and make any necessary correction (see Titrimetry á541?).Each mL of 0.1N perchloric acid is equivalent to 8.28mg of C4H11N5·https://www.360docs.net/doc/ea8476993.html,P28 Auxiliary Information—Staff Liaison: Elena Gonikberg,Ph.D.,Scientist

Expert Committee:(PA4)Pharmaceutical Analysis 4

USP28–NF23Page 1231

Pharmacopeial Forum: V olume No.29(6)Page 1925

Phone Number:1-301-816-8251

欧洲药典：

Metformin Hydrochloride

(Ph Eur monograph 0931)

C4H11N5,HCl 165.61115-70-4

Ph Eur

DEFINITION

1,1-Dimethylbiguanide hydrochloride.

Content

98.5 per cent to 101.0 per cent (dried substance).

CHARACTERS

Appearance

White crystals.

Solubility

Freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride.

IDENTIFICATION

First identification

B, E.

Second identification

A, C, D, E.

A. Melting point (2.2.14): 222 C to 226 C.

B. Infrared absorption spectrophotometry (2.2.24).

Preparation. Discs of potassium chloride R.

Comparison: Metformin hydrochloride CRS.

C. Thin-layer chromatography (2.2.27).

Test solution. Dissolve 20 mg of the substance to be examined in water R and dilute to 5 ml with the same solvent.

Reference solution. Dissolve 20 mg of metformin hydrochloride CRS in water R and dilute to 5

ml with the same solvent.

Plate. TLC silica gel G plate R.

Mobile phase. Upper layer of a mixture of 10 volumes of glacial acetic acid R, 40 volumes of butanol R and 50 volumes of water R.

Application. 5 μl.

Development. Over a path of 15 cm.

Drying. At 100C105 C for 15 min.

Detection. Spray with a mixture of equal volumes of a 100 g/l solution of sodium nitroprusside R, a 100 g/l solution of potassium ferricyanide R and a 100 g/l solution of sodium hydroxide R, prepared 20 min before use.

Results. The principal spot in the chromatogram obtained with the test solution is similar in position, colour and size to the principal spot in the chromatogram obtained with the reference solution.

D. Dissolve about 5 mg in water R and dilute to 100 ml with the same solvent. To 2 ml of the solution add 0.25 ml of strong sodium hydroxide solution R and 0.10 ml of a-naphthol solution R. Mix and allow to stand in iced water for 15 min. Add 0.5 ml of sodium hypobromite solution R and mix. A pink colour develops.

E. It gives reaction (a) of chlorides (2.3.1).

TESTS

Solution S

Dissolve 2.0 g in water R and dilute to 20 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

Related substances

Liquid chromatography (2.2.29).

Test solution

Dissolve 0.50 g of the substance to be examined in the mobile phase and dilute to 100.0 ml with the mobile phase.

Reference solution (a)

Dissolve 20.0 mg of cyanoguanidine R in water R and dilute to 100.0 ml with the same solvent. Dilute 1.0 ml to 200.0 ml with the mobile phase.

Reference solution (b)

Dilute 1.0 ml of the test solution to 50.0 ml with the mobile phase. Dilute 1.0 ml of this solution to 20.0 ml with the mobile phase.

Reference solution (c)

Dissolve 10.0 mg of melamine R in about 90 ml of water R. Add 5.0 ml of the test solution and dilute to 100.0 ml with water R. Dilute 1.0 ml of this solution to 50.0 ml with the mobile phase. Column:

size: l = 0.25 m, ? = 4.6 mm,

stationary phase: irregular, porous silica gel to which benzenesulphonic acid groups have been chemically bonded (10 μm),

or

size: l = 0.11 m, ? = 4.7 mm,

stationary phase: regular, porous silica gel to which benzenesulphonic acid groups have been chemically bonded (5 μm).

Mobile phase

17 g/l solution of ammonium dihydrogen phosphate R adjusted to pH 3.0 with phosphoric acid R. Flow rate

1 ml/min.

Detection

Spectrophotometer at 218 nm.

Injection

20 μl.

Run time

Twice the retention time of metformin hydrochloride.

System suitability

Reference solution (c):

resolution: minimum of 10 between the peaks due to melamine and to metformin hydrochloride. Limits:

impurity A: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (a) (0.02 per cent),

any other impurity: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent).

Heavy metals (2.4.8)

Maximum 10 ppm.

12 ml of solution S complies with limit test A. Prepare the standard using lead standard solution (1 ppm Pb) R.

Loss on drying (2.2.32)

Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100C105 C for 5 h. Sulphated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

ASSAY

Dissolve 0.100 g in 4 ml of anhydrous formic acid R. Add 80 ml of acetonitrile R. Carry out the titration immediately. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 ml of 0.1 M perchloric acid is equivalent to 16.56 mg of C4H12ClN5.

IMPURITIES

Qualified impurities

A.

Other detectable impurities

B, C, D, E, F.

A. cyanoguanidine,

B. R = NH-C(=NH)-NH2: (4,6-diamino-1,3,5-triazin-2-yl)guanidine,

C. R = N(CH3)2: N,N-dimethyl-1,3,5-triazine-2,4,6-triamine,

D. R = NH2: 1,3,5-triazine-2,4,6-triamine (melamine),

E. 1-methylbiguanide,

F. CH3-NH-CH3: N-methylmethanamine.

Ph Eur

Action and use Hypoglycaemic. Preparation Metformin Tablets

已知结构的潜在杂质：

A. 氰基胍cyanoguanidine,

B. R = NH-C(=NH)-NH2: (4,6-diamino-1,3,5-triazin-2-yl)guanidine,

C. R = N(CH3)2: N,N-dimethyl-1,3,5-triazine-2,4,6-triamine,

D. R = NH2: 1,3,5-triazine-2,4,6-triamine (melamine),

E. 1-methylbiguanide,

F. CH3-NH-CH3: N-methylmethanamine.