HSLF-FS 2017:33

1

Gemensamma författningssamlingen

avseende hälso- och sjukvård,

socialtjänst, läkemedel, folkhälsa m.m.

ISSN 2002-1054, Artikelnummer 88517033HSLF

Utgivare: Chefsjurist Pär Ödman, Socialstyrelsen

Läkemedelsverkets föreskrifter

om ikraftträdande av reviderad monografi för

erythromycin ethylsuccinate i Europafarmakopén;

beslutade den 10 april 2017.

Läkemedelsverket föreskriver följande på förslag av Svenska farmakopé-

kommittén och med stöd av 9 kap. 11 § läkemedelsförordningen (2015:458).

1 §

Monografin för erythromycin ethylsuccinate i nionde utgåvan av

Europafarmakopén (European Pharmacopoeia Ed. 9.0) ska ersättas med

monografin enligt bilagan till dessa föreskrifter och ska gälla som föreskrifter

i Sverige i frågor som rör läkemedelslagen (2015:315).

Dessa föreskrifter träder i kraft den 1 maj 2017.

Läkemedelsverket

CATARINA ANDERSSON FORSMAN

Joakim Brandberg

HSLF-FS

2017:33

Utkom från trycket

den 18 april 2017

HSLF-FS

2017:33

Bilaga

2

PA/PH/Exp. 7/T (17) 21 PUB

05/2017:0274

ERYTHROMYCIN ETHYLSUCCINATE

Erythromycini ethylsuccinas

DEFINITION

Mixture of the ethylsuccinate esters of erythromycin.

Main component : (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-C-methyl-

3-O-methyl-α-

L

-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-

hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-2-O-(4-ethoxy-4-oxobutanoyl)-β-

D

-xylo-hexopyranosyl]oxy]oxacyclotetradecane-2,10-dione (erythromycin A 2s-(ethyl

succinate)).

Semi-synthetic product derived from a fermentation product obtained using a strain of

Streptomyces erythreus.

Content :

– sum of erythromycins A, B and C expressed as ethylsuccinates : 93.0 per cent to

102.0 per cent (anhydrous substance) ;

– erythromycin B ethylsuccinate : maximum 5.0 per cent (anhydrous substance);

– erythromycin C ethylsuccinate : maximum 5.0 per cent (anhydrous substance).

CHARACTERS

Appearance: white or almost white, crystalline powder, hygroscopic.

Solubility : practically insoluble in water, freely soluble in acetone, in anhydrous ethanol

and in methanol.

IDENTIFICATION

Infrared absorption spectrophotometry (2.2.24).

Comparison: erythromycin ethylsuccinate CRS.

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PA/PH/Exp. 7/T (17) 21 PUB

TESTS

Related substances. Liquid chromatography (2.2.29).

Hydrolysis solution. A 20 g/L solution of dipotassium hydrogen phosphate R adjusted to

pH 8.0 with phosphoric acid R.

Test solution. Dissolve 0.115 g of the substance to be examined in 25 mL of methanol R.

Add 20 mL of the hydrolysis solution, mix and allow to stand at room temperature for at

least 12 h. Dilute to 50.0 mL with the hydrolysis solution.

Reference solution (a). Dissolve 40.0 mg of erythromycin A CRS in 10 mL of methanol R

and dilute to 20.0 mL with the hydrolysis solution.

Reference solution (b). Dissolve 10.0 mg of erythromycin B CRS and 10.0 mg of

erythromycin C CRS in 50 mL of methanol R. Add 5.0 mL of reference solution (a) and

dilute to 100.0 mL with the hydrolysis solution.

Reference solution (c). Dissolve 2 mg of N-demethylerythromycin A CRS in 20 mL

of reference solution (b).

Reference solution (d). Dilute 3.0 mL of reference solution (a) to 100.0 mL with a

mixture of equal volumes of methanol R and the hydrolysis solution.

Reference solution (e). Dissolve 40 mg of erythromycin A CRS, previously heated at

130 °C for 3 h, in 10 mL of methanol R and dilute to 20 mL with the hydrolysis solution.

Column :

– size : l = 0.25 m, Ø = 4.6 mm ;

– stationary phase : styrene-divinylbenzene copolymer R (8 μm)

(1)

with a pore size of

100 nm ;

– temperature : 70 °C using a water-bath for the column and at least one-third of the

tubing preceding the column.

Mobile phase : to 50 mL of a 35 g/L solution of dipotassium hydrogen phosphate R adjusted

to pH 8.0 with dilute phosphoric acid R, add 400 mL of water for chromatography R,

165 mL of 2-methyl-2-propanol R and 30 mL of acetonitrile R1, and dilute to 1000 mL

with water for chromatography R.

Flow rate : 2.0 mL/min.

Detection : spectrophotometer at 215 nm.

Injection: 200 μL of the test solution and reference solutions (a), (c), (d) and (e).

Run time : 5 times the retention time of erythromycin A ; begin integration after the

hydrolysis peak.

Relative retention with reference to erythromycin A (retention time = about 15 min) :

hydrolysis peak = less than 0.3; impurity B = about 0.45 ; erythromycin C = about 0.5;

impurity C = about 0.9 ; impurity G = about 1.3 ; impurity D = about 1.4 ;

impurity F = about 1.5 ; erythromycin B = about 1.8; impurity E = about 4.3.

System suitability : reference solution (c):

– resolution : minimum 0.8 between the peaks due to impurity B and erythromycin C

and minimum 5.5 between the peaks due to impurity B and erythromycin A.

Limits :

(1) PLRP-S 1000 Å is suitable.

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PA/PH/Exp. 7/T (17) 21 PUB

– correction factors: for the calculation of contents, multiply the peak areas of the

following impurities by the corresponding correction factor : impurity E = 0.09 ;

impurity F = 0.15 ; impurity G = 0.14 ; use the chromatogram obtained with reference

solution (e) to identify the peaks due to impurities E and F;

– any impurity : not more than the area of the principal peak in the chromatogram

obtained with reference solution (d) (3.0 per cent);

– total : not more than 1.67 times the area of the principal peak in the chromatogram

obtained with reference solution (d) (5.0 per cent);

– disregard limit : 0.02 times the area of the principal peak in the chromatogram

obtained with reference solution (d) (0.06 per cent).

Free erythromycin. Liquid chromatography (2.2.29).

Test solution. Dissolve 0.250 g of the substance to be examined in acetonitrile R1 and

dilute to 50.0 mL with the same solvent.

Reference solution. Dissolve 75.0 mg of erythromycin A CRS in acetonitrile R1 and

dilute to 50.0 mL with the same solvent. Dilute 5.0 mL of the solution to 25.0 mL with

acetonitrile R1.

Column :

– size : l = 0.25 m, Ø = 4.6 mm ;

– stationary phase : octylsilyl silica gel for chromatography R

(2)

(5 μm);

– temperature : 30 °C.

Mobile phase: mix 35 volumes of acetonitrile R1 and 65 volumes of a solution containing

3.4 g/L of potassium dihydrogen phosphate R and 2.0 g/L of triethylamine R, previously

adjusted to pH 3.0 with dilute phosphoric acid R.

Flow rate: 1 mL/min.

Detection : spectrophotometer at 195 nm.

Injection: 20 μL.

Run time : twice the retention time of erythromycin A (retention time = about 8 min)

for the reference solution ; twice the retention time of erythromycin ethylsuccinate

(retention time = about 24 min) for the test solution.

Limit :

– free erythromycin : not more than the area of the principal peak in the chromatogram

obtained with the reference solution (6.0 per cent).

Water (2.5.12): maximum 3.0 per cent, determined on 0.300 g.

Use a 100 g/L solution of imidazole R in anhydrous methanol R as the solvent.

Sulfated ash (2.4.14): maximum 0.3 per cent, determined on 1.0 g.

ASSAY

Liquid chromatography (2.2.29). Prepare the solutions immediately before use (apart

from the test solution).

(2) Nucleosil C8 is suitable.

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PA/PH/Exp. 7/T (17) 21 PUB

Solution A (hydrolysis solution). Dissolve 11.5 g of dipotassium hydrogen phosphate R

in 900 mL of water R, adjust to pH 8.0 with dilute phosphoric acid R and dilute to

1000 mL with water R.

Solvent mixture: methanol R, solution A (40:60 V/V).

Test solution. Dissolve 11.5 mg of the substance to be examined in 2.5 mL of methanol R.

Add 2 mL of solution A, mix and allow to stand at room temperature for at least 12 h.

Dilute to 5.0 mL with solution A.

Reference solution (a). Dissolve 40.0 mg of erythromycin A CRS in 10.0 mL of methanol R

and dilute to 20.0 mL with solution A.

Reference solution (b). Dissolve 10.0 mg of erythromycin B CRS and 10.0 mg of

erythromycin C CRS in 50.0 mL of methanol R and dilute to 100.0 mL with solution A.

Column :

– size : l = 0.25 m, Ø = 4.6 mm ;

– stationary phase : end-capped polar-embedded octadecylsilyl amorphous organosilica

polymer R (3.5 μm)

(3)

;

– temperature : 65 °C ; preheating the mobile phase may be required, for instance by

extending the inlet tubing in the oven to 30 cm.

Mobile phase:

– mobile phase A: phosphate buffer solution pH 7.0 R7, acetonitrile R1, water for

chromatography R (5:35:60 V/V/V);

– mobile phase B : phosphate buffer solution pH 7.0 R7, water for chromatography R,

acetonitrile R1 (5:45:50 V/V/V) ;

Time

(4)

(min)

Mobile phase A

(per cent V/V )

Mobile phase B

(per cent V/V )

0 - t

R

100

0

t

R

- (t

R

+ 2)

100 → 0

0 → 100

(t

R

+ 2) - (t

R

+ 15)

0

100

t

R

= retention time of erythromycin B, determined by injecting 20 μL of reference solution (b) and eluting with mobile phase A

Flow rate : 1.0 mL/min.

Detection : spectrophotometer at 210 nm.

Autosampler : set at 4 °C.

Injection: 200 μL.

System suitability : reference solution (a):

– symmetry factor: maximum 2.0 for the peak due to erythromycin A ;

– repeatability : maximum relative standard deviation of 1.0 per cent determined on

6 injections.

Calculate the percentage content of erythromycin A (C

37

H

67

NO

13

) using the

chromatogram obtained with reference solution (a). Calculate the percentage

contents of erythromycin B (C

37

H

67

NO

12

) and erythromycin C (C

36

H

65

NO

13

) using the

chromatogram obtained with reference solution (b).

(3) XTerra RP18 is suitable.

(4) D

0

(dwell volume used for development of the method) = 2.5 mL.

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PA/PH/Exp. 7/T (17) 21 PUB

Express the results as erythromycin A ethylsuccinate, erythromycin B ethylsuccinate and

erythromycin C ethylsuccinate by multiplying the percentage content of erythromycin A

by 1.1744, the percentage content of erythromycin B by 1.1783 and the percentage

content of erythromycin C by 1.1777.

For the calculation of content of erythromycin ethylsuccinate, use the sum of

erythromycins A, B and C expressed as ethylsuccinates as described above.

STORAGE

In an airtight container, protected from light.

IMPURITIES

A. (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-C-methyl-3-O-methyl-

α-

L

-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-3-(hydroxymethyl)-

5,7,9,11,13-pentamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-

D

-xylo-

hexopyranosyl]oxy]oxacyclotetradecane-2,10-dione (erythromycin F),

B. (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-

L

-

ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6-

[[3,4,6-trideoxy-3-(methylamino)-β-

D

-xylo-hexopyranosyl]oxy]oxacyclotetradecane-

2,10-dione (3s-N-demethylerythromycin A),

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PA/PH/Exp. 7/T (17) 21 PUB

C. (2S,4aR,4cR,5cS,6cS,7R,8S,9R,10R,12R,14R,15R,16S,16aS)-7-ethyl-5c,8,9,14-

tetrahydroxy-4c-methoxy-4c,6c,8,10,12,14,16-heptamethyl-15-[[3,4,6-trideoxy-3-

(dimethylamino)-β-

D

-xylo-hexopyranosyl]oxy]hexadecahydrospiro[5H,11H-1,3-

dioxino[5,4-c]oxacyclotetradecin-2,2c-pyrane]-5,11-dione (erythromycin E),

D. (1S,2R,3R,4S,5R,8R,9S,10S,11R,12R,14R)-9-[(2,6-dideoxy-3-C-methyl-3-O-methyl-

α-

L

-ribo-hexopyranosyl)oxy]-5-ethyl-3-hydroxy-2,4,8,10,12,14-hexamethyl-

11-[[3,4,6-trideoxy-3-(dimethylamino)-β-

D

-xylo-hexopyranosyl]oxy]-6,15,16-

trioxatricyclo[10.2.1.1

1,4

]hexadecan-7-one (anhydroerythromycin A),

E. (2R,3R,4S,5R,8R,9S,10S,11R,12R)-9-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-

L

-ribo-hexopyranosyl)oxy]-5-ethyl-3,4-dihydroxy-2,4,8,10,12,14-hexamethyl-

11-[[3,4,6-trideoxy-3-(dimethylamino)-β-

D

-xylo-hexopyranosyl]oxy]-6,15-

dioxabicyclo[10.2.1]pentadec-1(14)-en-7-one (erythromycin A enol ether),

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PA/PH/Exp. 7/T (17) 21 PUB

F. (2R,3R,6R,7S,8S,9R,10R)-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-

L

-ribo-

hexopyranosyl)oxy]-3-[(1R,2R)-1,2-dihydroxy-1-methylbutyl]-2,6,8,10,12-

pentamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)-β-

D

-xylo-hexopyranosyl]oxy]-4,

13-dioxabicyclo[8.2.1]tridec-1(12)-en-5-one (pseudoerythromycin A enol ether),

G. (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-C-methyl-3-O-

methyl-α-

L

-ribo-hexopyranosyl)oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-

hexamethyl-6-[[3,4,6-trideoxy-3-[(4-ethoxy-4-oxobutanoyl)methylamino]-β-

D

-

xylo-hexopyranosyl]oxy]oxacyclotetradecane-2,10-dione (3s-N-demethyl-3s-N-

(ethoxysuccinyl)erythromycin A).

E7

Elanders Sverige AB, 2017

HSLF-FS kan laddas ner via Läkemedelsverket.

Webb: www.lakemedelsverket.se

Författningen kan beställas via:

Wolters Kluwer

106 47 Stockholm

Telefon: 08-598 191 90 Fax: 08-598 191 91

E-post: kundservice@wolterskluwer.se

Webb: wolterskluwer.se/offentligapublikationer