Материал: furany_posobie

2. Препарат дает характерную реакцию на хлориды.

R

Нефармакопейные реакции

3. Как алкалоид, пилокарпина гидрохлорид реагирует с общеалкалоидными осадительными реактивами, в том числе с реактивом Драгендорфа K[BiI4], образуя осадок, имеющий четкую температуру плавления.

Реакция идет по N1.

Количественное определение

1. Ацидиметрический метод неводного титрования в среде ледяной уксусной кислоты и ацетата ртути. Метод основан на сла-

54

бых основных свойствах пилокарпина-основания, которые усиливаются в протогенном растворителе. Ацетат ртути добавляют для связывания хлорид-ионов. Титрант – 0,1 М HClO4, индикатор – кристаллический фиолетовый.

fэкв = 1.

Нефармакопейные методы

2. Алкалиметрия по связанной хлороводородной кислоте методом нейтрализации в спиртовом растворе или в присутствии хлороформа (извлечение основания)

Пилокарпин HCl + NaOH  Пилокарпин + NaCl + H2O

fэкв = 1.

3. Аргентометрический метод (вариант Фаянса) в CH3COOH,

индикатор – бромфеноловый синий.

fэкв = 1.

Анализ качества метронидазола

Metronidazole Метронидазол (British Pharmacopoeia 2012)

C6H9N3O3 171.2 443-48-1

Action and use

Imidazole antibacterial.

Preparations

Metronidazole Gel

Metronidazole Intravenous Infusion

55

Metronidazole Suppositories Metronidazole Tablets

DEFINITION

2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethanol. Content

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

CHARACTERS Appearance

White or yellowish, crystalline powder.

Solubility

Slightly soluble in water, in acetone, in alcohol and in methylene chloride.

IDENTIFICATION

First identification C. Second identification A, B, D.

A.Melting point (2.2.14): 159 °C to 163 °C.

B.Dissolve 40.0 mg in 0.1 M hydrochloric acid and dilute to 100.0 mL with the same acid. Dilute 5.0 mL of the solution to 100.0 mL with 0.1 M hydrochloric acid. Examined between 230 nm and 350 nm (2.2.25), the solution shows an absorption maximum at 277 nm and a minimum at 240 nm. The specific absorbance at the maximum is 365 to 395.

C.Infrared absorption spectrophotometry (2.2.24).

Preparation Discs.

Comparison metronidazole CRS.

D. To about 10 mg add about 10 mg of zinc powder R, 1 mL of water R and 0.25 mL of dilute hydrochloric acid R. Heat on a water-bath for 5 min. Cool. The solution gives the reaction of primary aromatic amines (2.3.1).

TESTS

Appearance of solution

The solution is not more opalescent than reference suspension II (2.2.1) and not more intensely coloured than reference solution GY6 (2.2.2, Method II).

Dissolve 1.0 g in 1 M hydrochloric acid and dilute to 20 mL with the same acid.

Related substances

Liquid chromatography (2.2.29). Prepare the solutions protected from light.

56

Test solution Dissolve 0.05 g of the substance to be examined in the mobile phase and dilute to 100.0 mL with the mobile phase.

Reference solution (a) Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase and dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.

Reference solution (b) Dissolve 5.0 mg of metronidazole impurity A CRS in the mobile phase, add 10.0 mL of the test solution and dilute to 100.0 mL with the mobile phase. Dilute 1.0 mL to 100.0 mL with the mobile phase.

Column:

–size: l = 0.25 m, Ø = 4.6 mm,

–stationary phase: octadecylsilyl silica gel for chromatography R (5 µm).

Mobile phase Mix 30 volumes of methanol R and 70 volumes of a 1.36 g/L solution of potassium dihydrogen phosphate R,

Flow rate 1 mL/min.

Detection Spectrophotometer at 315 nm. Injection 10 µL.

Run time 3 times the retention time of metronidazole.

Relative retention With reference to metronidazole (retention time = about 7 min): impurity A = about 0.7.

System suitability Reference solution (b):

– resolution: minimum of 2.0 between the peaks due to metronidazole and to impurity A.

Limits:

–any impurity: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent),

–total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent),

–disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.01 per cent).

Heavy metals (2.4.8)

Maximum 20 ppm.

1.0 g complies with limit test C. Prepare the standard using 2 mL of lead standard solution (10 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 105 °C for 3 h.

57

Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

ASSAY

Dissolve 0.150 g in 50 mL of anhydrous acetic acid R. 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 17.12 mg of C6H9N3O3.

STORAGE

Protected from light.

IMPURITIES

A.R1 = R4 = H, R2 = CH3, R3 = NO2: 2-methyl-4-nitroimidazole,

B.R1 = R2 = R4 = H, R3 = NO2: 4-nitroimidazole,

C.R1 = CH2-CH2-OH, R2 = R4 = H, R3 = NO2: 2-(4-nitro-1H- imidazol-1-yl)ethanol,

D.R1 = CH2-CH2-OH, R2 = R3 = H, R4 = NO2: 2-(5-nitro-1H- imidazol-1-yl)ethanol,

E.R1 = CH2-CH2-OH, R2 = CH3, R3 = NO2, R4 = H: 2-(2-methyl- 4-nitro-1H-imidazol-1-yl)ethanol,

F.R1 = CH2-CH2-O-CH2-CH2-OH, R2 = CH3, R3 = H, R4 = NO2: 2-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy]ethanol,

G.R1 = CH2-CO2H, R2 = CH3, R3 = H, R4 = NO2: 2-(2-methyl-5- nitro-1H-imidazol-1-yl)acetic acid.

Фармакопейный анализ метронидазола

58