Läkemedelsverkets föreskrifter (HSLF-FS 2021:24) om ikraftträdande av reviderade monografier för Candesartan cilexetil, Irbesartan, Losartan potassium, Olmesartan medoxomil och Valsartan i Europafarmakopén och om supplement 10.4 till Europafarmakopén

PA/PH/Exp. 10B/T (20) 129 PUB

NOTE ON THE MONOGRAPH

Further to the CHMP* opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use (see assessment report published on 25 June 2020**) and the CHMP* decision to apply these recommendations to “sartans medicinal products” (see news published on 13 November 2020***), a revised version of this monograph is proposed for adoption as a minor revision and publication in Supplement 10.6 to align the Ph. Eur. requirements with the latest regulatory decisions. Production: section completely reworded; recommendation to perform a risk assessment of the manufacturing process and, if needed, implement a control strategy for the detection and control of N-nitrosamine impurities added. Tests: Nitrosamines test deleted. CHMP*: Committee for Human Medicinal Products of the European Medicines Agency ** https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-

assessment-report_en.pdf

*** https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-

sartans-those-other-medicines

04/2021:2573

CANDESARTAN CILEXETIL

Candesartanum cilexetili

C33H34N6O6 Mr 611 [145040-37-5]

DEFINITION (1RS)-1-[[(Cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. Content: 99.0 per cent to 101.0 per cent (anhydrous substance).

PRODUCTION As N-nitrosamines are classified as probable human carcinogens, their presence in candesartan cilexetil should be avoided or limited as much as possible. For this reason, manufacturers of candesartan cilexetil for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy

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implemented to detect and control N-nitrosamine impurities in candesartan cilexetil. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers. CHARACTERS Appearance: white or almost white powder. Solubility: practically insoluble in water, freely soluble in methylene chloride and slightly soluble in anhydrous ethanol. It shows polymorphism (5.9). IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Comparison:candesartan cilexetil CRS. If the spectra obtained show differences, dissolve the substance to be examined and the reference substance separately in anhydrous ethanol R, evaporate to dryness and record new spectra using the residues. TESTS Related substances. Liquid chromatography (2.2.29). Prepare the solutions immediately before use. Solvent mixture: water R, acetonitrile R (40:60 V/V). Test solution. Dissolve 20 mg of the substance to be examined in 50.0 mL of the solvent mixture. Reference solution (a). Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture. Reference solution (b). Dissolve 5 mg ofcandesartan cilexetil for system suitability CRS (containing impurities A, B and F) in the solvent mixture and dilute to 10 mL with the solvent mixture. Reference solution (c). Dissolve 2.5 mg ofcandesartan cilexetil for peak identification CRS (containing impurities G and H) in the solvent mixture and dilute to 5 mL with the solvent mixture. Column: – size: l = 0.15 m, Ø = 3.9 mm; – stationary phase: end-capped octadecylsilyl silica gel for chromatography R (4 μm)(1). Mobile phase: – mobile phase A: glacial acetic acid R,water for chromatography R, acetonitrile R (1:43:57 V/V/V); – mobile phase B:glacial acetic acid R, water for chromatography R, acetonitrile R (1:10:90 V/V/V); (1) Nova-Pak C18 is suitable.

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Time(2) Mobile phase A Mobile phase B

(min) (per cent V/V) (per cent V/V)

0 - 3 100 0 3 - 33 100 → 0 0 → 100 33 - 40 0 100 Flow rate: 0.8 mL/min. Detection: spectrophotometer at 254 nm. Injection: 10 μL. Identification of impurities: use the chromatogram supplied withcandesartan cilexetil for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities A, B and F; use the chromatogram supplied with candesartan cilexetil for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities G and H. Relative retention with reference to candesartan cilexetil (retention time = about 11 min): impurity G = about 0.2; impurity A = about 0.4; impurity B = about 0.5; impurity F = about 2.0; impurity H = about 3.5. System suitability: reference solution (b): – resolution: minimum 4.0 between the peaks due to impurities A and B. Limits: – correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurities A and G = 0.7; impurity H = 1.6; – impurity B: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent); – impurities F, G: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent); – impurities A, H: for each impurity, not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent); – unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent); – total: not more than 6 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.6 per cent); – disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). Water (2.5.32): maximum 0.3 per cent, determined on 60.0 mg(3) . Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.

(2) D0(dwell volume used for development of the method) = 1.0 mL. (3) Dried methanol and Hydranal composite 1 are suitable.

E3

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ASSAY Dissolve 0.500 g in 60 mL of glacial acetic acid R. Titrate immediately with 0.1 M st perchloric acid, determining the end-point potentiometrically (2.2.20) at the 1 inflexion point. 1 mL of 0.1 M perchloric acid is equivalent to 61.1 mg of C33H34N6O6.

IMPURITIES Specified impurities: A, B, F, G, H. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): C, D, E, I.

A. ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole- 7-carboxylate,

B. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-oxo-3-[[2′-(1H-tetrazol-5yl)biphenyl-4-yl]methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylate,

C. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 3-[[2′-(1-ethyl-1H-tetrazol-5yl)biphenyl-4-yl]methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate,

E4

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D. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 3-[[2′-(2-ethyl-2H-tetrazol-5yl)biphenyl-4-yl]methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate,

E. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2′-(1-ethyl-1H-tetrazol-5yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate,

F. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2′-(2-ethyl-2H-tetrazol-5yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate,

G. 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7carboxylic acid (candesartan), E5

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H. (1RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2′-[1-(triphenylmethyl)- 1H-tetrazol-5-yl]biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (N-tritylcandesartan),

I. methyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole- 7-carboxylate. The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity A 2. impurity B 3. candesartan cilexetil 4. impurity F Figure 2573.-1. – Chromatogram for the test for related substances of candesartan

cilexetil: reference solution (b)

E6

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity G 3. impurity B 5. candesartan 7. impurity E 9. impurity H cilexetil 2. impurity A 4. impurity C 6. impurity D 8. impurity F Figure 2573.-2. – Chromatogram for the test for related substances of candesartan

cilexetil: test solution spiked with impurities A to H

E7

HSLF-FS Bilaga 2

2021:24

PA/PH/Exp. 10B/T (20) 126 PUB

NOTE ON THE MONOGRAPH

Further to the CHMP* opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use (see assessment report published on 25 June 2020**) and the CHMP* decision to apply these recommendations to “sartans medicinal products” (see news published on 13 November 2020***), a revised version of this monograph is proposed for adoption as a minor revision and publication in Supplement 10.6 to align the Ph. Eur. requirements with the latest regulatory decisions. Production: section completely reworded; recommendation to perform a risk assessment of the manufacturing process and, if needed, implement a control strategy for the detection and control of N-nitrosamine impurities added. Tests: Nitrosamines test deleted. CHMP*: Committee for Human Medicinal Products of the European Medicines Agency ** https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-

assessment-report_en.pdf

*** https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-

sartans-those-other-medicines

04/2021:2465

IRBESARTAN

Irbesartanum

C25H28N6O Mr 428.5 [138402-11-6]

DEFINITION 2-Butyl-3-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1en-4-one. Content: 99.0 per cent to 101.0 per cent (anhydrous substance).

PRODUCTION As N-nitrosamines are classified as probable human carcinogens, their presence in irbesartan should be avoided or limited as much as possible. For this reason, manufacturers of irbesartan for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy implemented to detect and control N-nitrosamine impurities in irbesartan. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.

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PA/PH/Exp. 10B/T (20) 126 PUB

CHARACTERS Appearance: white or almost white, crystalline powder. Solubility: practically insoluble in water, sparingly soluble in methanol, slightly soluble in methylene chloride. It shows polymorphism (5.9). IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Comparison: irbesartan CRS. If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in methanol R, evaporate to dryness at 60 °C and record new spectra using the residues. TESTS Appearance of solution. The solution is clear (2.2.1) and not more intensely coloured than reference solution B7 (2.2.2, Method II). Dissolve 0.50 g in a mixture of 1 volume of 2 M sodium hydroxide R and 9 volumes of methanol R2 and dilute to 10 mL with the same mixture of solvents. Impurity B. Liquid chromatography (2.2.29). Prepare the solutions immediately before use. Test solution. Dissolve 0.100 g of the substance to be examined in the mobile phase and dilute to 5.0 mL with the mobile phase. Reference solution. Dissolve 25.0 mg of sodium azide R (sodium salt of impurity B) in the mobile phase and dilute to 100.0 mL with the mobile phase. Dilute 0.25 mL of the solution to 200.0 mL with the mobile phase. Precolumn (used to prevent saturation of the column with irbesartan): – size: l = 0.05 m, Ø = 4 mm; – stationary phase:strongly basic anion-exchange resin for chromatography R(8.5 μm) . Column: – size: l = 0.25 m, Ø = 4 mm; – stationary phase:strongly basic anion-exchange resin for chromatography R(8.5 μm) . Mobile phase: 4.2 g/L solution of sodium hydroxide R incarbon dioxide-free water R. Flow rate: 1.0 mL/min. Detection: conductivity detector with a sensitivity of 3 μS; use a self-regenerating anion suppressor . Neutralisation of the eluent: either chemical or electrochemical: (1) IonPac AG10 is suitable. (2) IonPac AS10 is suitable. (3) Dionex AERS Ultra II is suitable.

E2

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– chemical: by continuous countercurrent circulation in a neutralising micromembrane, performed before detection: – neutralising solvent: 0.025 M sulfuric acid; – flow rate: 10 mL/min; – pressure: about 100 kPa. – electrochemical: 300 mA (for example). Injection: 200 μL; after each injection of the test solution, rinse the precolumn with a mixture of mobile phase and methanol R (40:60 V/V) for 10 min; equilibrate to initial conditions as necessary; a switch valve can be used to avoid disconnecting the precolumn from the column. Run time: 25 min. Retention time: impurity B = about 14 min. System suitability: reference solution: – signal-to-noise ratio: minimum 10 for the peak due to impurity B. Limit: – impurity B: not more than the area of the corresponding peak in the chromatogram obtained with the reference solution (10 ppm). Related substances. Liquid chromatography (2.2.29). Buffer solution pH 3.2. Mix 5.5 mL of phosphoric acid R and 950 mL of water for chromatography R and adjust to pH 3.2 with triethylamine R. Test solution. Dissolve 50 mg of the substance to be examined in methanol R2 and dilute to 50.0 mL with the same solvent. Reference solution (a). Dilute 1.0 mL of the test solution to 100.0 mL withmethanol R2. Dilute 1.0 mL of this solution to 10.0 mL with methanol R2. Reference solution (b). Dissolve 5 mg of the substance to be examined and 5 mg of irbesartan impurity A CRS in methanol R2 and dilute to 10 mL with the same solvent. Dilute 1 mL of the solution to 10 mL with methanol R2. Column: – size: l = 0.25 m, Ø = 4 mm; – stationary phase: end-capped octadecylsilyl silica gel for chromatography R(5 μm) . Mobile phase:acetonitrile R1, buffer solution pH 3.2 (33:67 V/V). Flow rate: 1.0 mL/min. Detection: spectrophotometer at 220 nm. Injection: 10 μL. Run time: 1.4 times the retention time of irbesartan. Identification of impurities: use the chromatogram obtained with reference solution (b) to identify the peak due to impurity A. Relative retention with reference to irbesartan (retention time = about 23 min): impurity A = about 0.7. System suitability: reference solution (b): (4) Nucleosil C18 is suitable.

E3

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– resolution: minimum 3.0 between the peaks due to impurity A and irbesartan. Limits: – impurity A: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent); – unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 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: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). Water (5) (2.5.12): maximum 0.5 per cent, determined on 1.00 g . Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.

ASSAY Dissolve 0.300 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 acidis equivalent to 42.85 mg of C25H28N6O. IMPURITIES Specified impurities: A, B.

A. 1-(pentanoylamino)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]cyclopentane-1-carboxamide, - B. N3 : trinitride (azide). (5) Methanol or Hydranal Auxiliary 5K as solvent and Hydranal medium K 34698 or Hydranal composite 5K as titration reagent are suitable. E4

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity B Figure 2465.-1. – Chromatogram for the test for impurity B of irbesartan: reference

solution

The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

Figure 2465.-2. – Chromatogram for the test for impurity B of irbesartan: test solution

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity A 2. irbesartan Figure 2465.-3. – Chromatogram for the test for related substances of irbesartan:

reference solution (b)

E6

HSLF-FS Bilaga 3

2021:24

PA/PH/Exp. 10B/T (20) 128 PUB

NOTE ON THE MONOGRAPH

Further to the CHMP* opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use (see assessment report published on 25 June 2020**) and the CHMP* decision to apply these recommendations to “sartans medicinal products” (see news published on 13 November 2020***), a revised version of this monograph is proposed for adoption as a minor revision and publication in Supplement 10.6 to align the Ph. Eur. requirements with the latest regulatory decisions. Production: section completely reworded; recommendation to perform a risk assessment of the manufacturing process and, if needed, implement a control strategy for the detection and control of N-nitrosamine impurities added. Tests: Nitrosamines test deleted. CHMP*: Committee for Human Medicinal Products of the European Medicines Agency ** https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-

assessment-report_en.pdf

*** https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-

sartans-those-other-medicines

04/2021:2232

LOSARTAN POTASSIUM

Losartanum kalicum

C22H22ClKN6O Mr 461.0 [124750-99-8]

DEFINITION Potassium 5-[4′-[[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1yl]methyl]biphenyl-2-yl]tetrazol-1-ide. Content: 98.5 per cent to 101.5 per cent (dried substance).

PRODUCTION As N-nitrosamines are classified as probable human carcinogens, their presence in losartan potassium should be avoided or limited as much as possible. For this reason, manufacturers of losartan potassium for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy implemented to detect and control N-nitrosamine impurities in losartan potassium. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.

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CHARACTERS Appearance: white or almost white, crystalline powder, hygroscopic. Solubility: freely soluble in water and in methanol, slightly soluble in acetonitrile. It shows polymorphism (5.9). IDENTIFICATION A. Infrared absorption spectrophotometry (2.2.24). Comparison: losartan potassium CRS. If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in methanol R, evaporate to dryness and record new spectra using the residues. B. Dissolve 25 mg in 3 mL of water R. The solution gives reaction (a) of potassium (2.3.1). TESTS Related substances. Liquid chromatography (2.2.29). Prepare the solutions immediately before use. Test solution. Dissolve 30.0 mg of the substance to be examined in methanol R and dilute to 100.0 mL with the same solvent. Reference solution (a). Dilute 1.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R. Reference solution (b). Dissolve 6 mg of triphenylmethanol R (impurity G) in 100 mL of methanol R. Dilute 1 mL of the solution to 100 mL withmethanol R. Use 1 mL of this solution to dissolve the contents of a vial of losartan for system suitability CRS (containing impurities J, K, L and M) and sonicate for 5 min. Reference solution (c). Dissolve 3.0 mg of losartan impurity D CRS inmethanol R and dilute to 100.0 mL with the same solvent. Dilute 1.5 mL of this solution to 100.0 mL with methanol R. Column: – size: l = 0.25 m, Ø = 4.6 mm; stationary phase end-capped octadecylsilyl silica gel for chromatography R (1) – : (5 μm) ; – temperature: 35 °C. Mobile phase: – mobile phase A: dilute 1.0 mL of phosphoric acid R to 1000 mL withwater for chromatography R; – mobile phase B: acetonitrile R1;

Time Mobile phase A Mobile phase B

(min) (per cent V/V) (per cent V/V)

0 - 5 75 25 5 - 30 75 → 10 25 → 90 30 - 40 10 90 Flow rate: 1.3 mL/min. (1) Kromasil C18 with a specific surface area of 340 m2/g and pore size of 10 nm is suitable.

E2

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Detection: spectrophotometer at 220 nm. Injection: 10 μL. Identification of impurities: use the chromatogram supplied with losartan for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities G, J, K, L and M; use the chromatogram obtained with reference solution (c) to identify the peak due to impurity D. Relative retention with reference to losartan (retention time = about 14 min): impurity D = about 0.9; impurity J = about 1.4; impurity K = about 1.5; impurity L = about 1.6; impurity M = about 1.75; impurity G = about 1.8. System suitability: reference solution (b): – peak-to-valley ratio: minimum 2.0, where Hp = height above the baseline of the peak due to impurity M and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to impurity G. Limits: – impurity D: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (c) (0.15 per cent); – impurities J, K, L, M: for each impurity, not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent); – unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent); – total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent); – disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). Loss on drying (2.2.32): maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C.

ASSAY Dissolve 0.200 g in 75 mL of anhydrous acetic acid R and sonicate for 10 min. Carry out a potentiometric titration (2.2.20) using 0.1 M perchloric acid. 1 mL of 0.1 M perchloric acidis equivalent to 23.05 mg of C22H22ClKN6O. STORAGE In an airtight container. IMPURITIES Specified impurities: D, J, K, L, M. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): B, C, E, F, G, H, I.

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B. [2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methanol, C. [2-butyl-5-chloro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazol-4yl]methanol, D. 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde, E. 5-(4′-methylbiphenyl-2-yl)-1H-tetrazole, F. 5-[4′-[[2-butyl-4-chloro-5-[[(1-methylethyl)oxy]methyl]-1H-imidazol-1yl]methyl]biphenyl-2-yl]-1H-tetrazole, G. triphenylmethanol, E4

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H. [2-butyl-4-chloro-1-[[2′-[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4yl]methyl]-1H-imidazol-5-yl]methanol,

I. 5-[4′-[[2-butyl-4-chloro-5-[[(triphenylmethyl]oxy]methyl]-1H-imidazol-1yl]methyl]biphenyl-2-yl]-1H-tetrazole,

J. [2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazol-5yl]methyl acetate,

K. 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazol-5carbaldehyde, E5

PA/PH/Exp. 10B/T (20) 128 PUB

L. [2-butyl-1-[[2′-[1-[[2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-imidazol-5-yl]methyl]-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]-4-chloro-1Himidazol-5-yl]methanol,

M. [2-butyl-1-[[2′-[2-[[2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4yl]methyl]-1H-imidazol-5-yl]methyl]-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-4chloro-1H-imidazol-5-yl]methanol.

E6

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity C 3. losartan 5. impurity K 7. impurity M 2. impurity D 4. impurity J 6. impurity L 8. impurity G Figure 2232.-1. – Chromatogram for the test for related substances of losartan potassium

E7

Bilaga 4

PA/PH/Exp. 10B/T (20) 127 PUB

NOTE ON THE MONOGRAPH

Further to the CHMP* opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use (see assessment report published on 25 June 2020**) and the CHMP* decision to apply these recommendations to “sartans medicinal products” (see news published on 13 November 2020***), a revised version of this monograph is proposed for adoption as a minor revision and publication in Supplement 10.6 to align the Ph. Eur. requirements with the latest regulatory decisions. Production: section completely reworded; recommendation to perform a risk assessment of the manufacturing process and, if needed, implement a control strategy for the detection and control of N-nitrosamine impurities added. Tests: Nitrosamines test deleted. CHMP*: Committee for Human Medicinal Products of the European Medicines Agency ** https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-

assessment-report_en.pdf

*** https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-

sartans-those-other-medicines

04/2021:2600

OLMESARTAN MEDOXOMIL

Olmesartanum medoxomilum

C29H30N6O6 Mr 558.6 [144689-63-4]

DEFINITION (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate. Content: 97.5 per cent to 102.0 per cent (anhydrous substance).

PRODUCTION As N-nitrosamines are classified as probable human carcinogens, their presence in olmesartan medoxomil should be avoided or limited as much as possible. For this reason, manufacturers of olmesartan medoxomil for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control

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strategy implemented to detect and control N-nitrosamine impurities in olmesartan medoxomil. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers. CHARACTERS Appearance: white or almost white, crystalline powder. Solubility: practically insoluble in water, slightly soluble in ethanol (96 per cent), practically insoluble in heptane. IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Comparison: olmesartan medoxomil CRS. TESTS Related substances. Liquid chromatography (2.2.29). Test solution (a). Dissolve 25 mg of the substance to be examined inacetonitrile R and dilute to 25.0 mL with the same solvent. Test solution (b). Dissolve 25.0 mg of the substance to be examined in acetonitrile R and dilute to 50.0 mL with the same solvent. Reference solution (a). Dissolve 5 mg ofolmesartan medoxomil for system suitability CRS (containing impurities A, B and C) in acetonitrile R and dilute to 5 mL with the same solvent. Reference solution (b). Dilute 1.0 mL of test solution (a) to 50.0 mL with acetonitrile R. Dilute 1.0 mL of this solution to 10.0 mL with acetonitrile R. Reference solution (c). Dissolve 25.0 mg of olmesartan medoxomil CRS in acetonitrile R and dilute to 50.0 mL with the same solvent. Column: – size: l = 0.10 m, Ø = 4.6 mm; – stationary phase: end-capped octylsilyl silica gel for chromatography R (3.5 μm) ; – temperature: 40 °C. Mobile phase: – mobile phase A: mix 20 volumes of acetonitrile R and 80 volumes of a 2.04 g/L solution of potassium dihydrogen phosphate R previously adjusted to pH 3.4 with a 1.73 g/L solution of phosphoric acid R; – mobile phase B: mix 20 volumes of a 2.04 g/L solution of potassium dihydrogen phosphate R, previously adjusted to pH 3.4 with a 1.73 g/L solution ofphosphoric acid R, and 80 volumes of acetonitrile R; Time(2) Mobile phase A Mobile phase B

(min) (per cent V/V) (per cent V/V)

0 - 10 75 25 10 - 35 75 → 0 25 → 100 35 - 45 0 100

(1) Symmetry C8 is suitable. (2) D0(dwell volume used for development of the method) = 0.79 mL.

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Flow rate: 1.0 mL/min. Detection: spectrophotometer at 250 nm. Injection: 10 μL of test solution (a) and reference solutions (a) and (b). Identification of impurities: use the chromatogram supplied with olmesartan medoxomil for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B and C. Relative retention with reference to olmesartan medoxomil (retention time = about 10 min): impurity A = about 0.2; impurity B = about 0.7; impurity C = about 1.5. System suitability: reference solution (a): – resolution: minimum 3.5 between the peaks due to impurity B and olmesartan medoxomil. Limits: – impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.4 per cent); – impurity C: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 per cent); – unspecified impurities: for each impurity, not more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent); – total: not more than 3.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.7 per cent); – disregard limit: 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent). Acetone. Head-space gas chromatography (2.2.28): use the direct calibration method. Internal standard solution. Dilute 1.0 mL of butanol R to 100.0 mL with dimethyl sulfoxide R. Test solution. Dissolve 0.250 g of the substance to be examined in dimethyl sulfoxide R, add 2.0 mL of the internal standard solution and dilute to 10.0 mL with dimethyl sulfoxide R. Reference solution. Dilute 0.50 mL of acetone R to 200.0 mL with dimethyl sulfoxide R. Dilute 15.0 mL of the solution to 100.0 mL with dimethyl sulfoxide R. To 25.0 mL of this solution add 10.0 mL of the internal standard solution and dilute to 50.0 mL with dimethyl sulfoxide R. Column: – material: fused silica; – size: l = 30 m, Ø = 0.53 mm; – stationary phase: macrogol 20 000 R (film thickness 1 μm). Carrier gas: nitrogen for chromatography Ror helium for chromatography R. Flow rate: 4.0 mL/min. Split ratio: 1:5. Static head-space conditions that may be used: – equilibration temperature: 80 °C;

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– equilibration time: 30 min. Temperature:

Time Temperature

(min) (°C)

Column 5 50 5 - 18 50 → 180 18 - 23 180 Injection port 200 Detection 200 Detection: flame ionisation. Injection: 1 mL. Calculate the content of acetone, taking its relative density to be 0.79 at 20 °C. Limit: – acetone: maximum 0.6 per cent. Water (2.5.32): maximum 0.5 per cent, determined on 0.500 g . Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.

ASSAY Liquid chromatography (2.2.29) as described in the test for related substances with the following modifications. Mobile phase: mobile phase B, mobile phase A (25:75 V/V). Injection: test solution (b) and reference solution (c). Retention time: olmesartan medoxomil = about 10 min. Run time: 1.5 times the retention time of olmesartan medoxomil. Calculate the percentage content of C29H30N6O6 taking into account the assigned content of olmesartan medoxomil CRS. IMPURITIES Specified impurities: A, C. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): B, D.

A. 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (olmesartan), (3) Aquastar Coulomat AK is suitable.

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B. 6,6-dimethyl-2-propyl-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3,6-dihydro- 4H-furo[3,4-d]imidazol-4-one,

C. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-methylethenyl)-2-propyl-1-[[2′-(1Htetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylate,

D. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [[2′-[(2-triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-1H-imidazole- 5-carboxylate. The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

1. impurity A 2. impurity B 3. olmesartan 4. impurity C 5. impurity D medoxomil

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Figure 2600.-1. – Chromatogram for the test for related substances: solution of olmesartan

medoxomil spiked with impurities A, B, C and D

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NOTE ON THE MONOGRAPH

Further to the CHMP* opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use (see assessment report published on 25 June 2020**) and the CHMP* decision to apply these recommendations to “sartans medicinal products” (see news published on 13 November 2020***), a revised version of this monograph is proposed for adoption as a minor revision and publication in Supplement 10.6 to align the Ph. Eur. requirements with the latest regulatory decisions. Production: section completely reworded; recommendation to perform a risk assessment of the manufacturing process and, if needed, implement a control strategy for the detection and control of N-nitrosamine impurities added. Tests: Nitrosamines test deleted. CHMP*: Committee for Human Medicinal Products of the European Medicines Agency ** https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-

assessment-report_en.pdf

*** https://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-

sartans-those-other-medicines

04/2021:2423

VALSARTAN

Valsartanum

C24H29N5O3 Mr 435.5 [137862-53-4]

DEFINITION (2S)-3-Methyl-2-[pentanoyl[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]butanoic acid. Content: 99.0 per cent to 101.0 per cent (anhydrous substance).

PRODUCTION As N-nitrosamines are classified as probable human carcinogens, their presence in valsartan should be avoided or limited as much as possible. For this reason, manufacturers of valsartan for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy implemented to detect and control N-nitrosamine impurities in valsartan. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.

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CHARACTERS Appearance: white or almost white, hygroscopic powder. Solubility: practically insoluble in water, freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride. IDENTIFICATION Carry out either tests A, B or tests A, C. A. Infrared absorption spectrophotometry (2.2.24). Comparison: valsartan CRS. B. Enantiomeric purity (see Tests). C. Specific optical rotation (2.2.7): − 69.0 to − 64.0 (anhydrous substance). Dissolve 0.200 g in methanol R and dilute to 20.0 mL with the same solvent. TESTS Enantiomeric purity. Liquid chromatography (2.2.29). Test solution. Dissolve 50 mg of the substance to be examined in the mobile phase and dilute to 50.0 mL with the mobile phase. Reference solution (a). Dissolve 5 mg of valsartan for peak identification CRS (containing impurity A) in the mobile phase and dilute to 5 mL with the mobile phase. Reference solution (b). Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Column: – size: l = 0.25 m, Ø = 4.6 mm; – stationary phase: cellulose derivative of silica gel for chiral separation R (5 μm) . Mobile phase:trifluoroacetic acid R, 2-propanol R, hexane R (0.1:15:85 V/V/V). Flow rate: 0.8 mL/min. Detection: spectrophotometer at 230 nm. Injection: 10 μL. Run time: 1.5 times the retention time of valsartan. Identification of impurities: use the chromatogram supplied with valsartan for peak identification CRS and the chromatogram obtained with reference solution (a) to identify the peak due to impurity A. Relative retention with reference to valsartan (retention time = about 13 min): impurity A = about 0.6. System suitability: reference solution (a): – resolution: minimum 2.0 between the peaks due to impurity A and valsartan. Limit: – impurity A: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent). (1) Chiralcel OD is suitable.

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Related substances. Liquid chromatography (2.2.29). Test solution. Dissolve 50 mg 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. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase. Reference solution (b). Dissolve the contents of a vial of valsartan for system suitability CRS (containing impurity C) in 1 mL of the mobile phase. Column: – size: l = 0.125 m, Ø = 3.0 mm; – stationary phase: end-capped octadecylsilyl silica gel for chromatography R(5 μm) . Mobile phase: glacial acetic acid R, acetonitrile R1, water for chromatography R (1:500:500 V/V/V). Flow rate: 0.4 mL/min. Detection: spectrophotometer at 225 nm. Injection: 10 μL. Run time: 6 times the retention time of valsartan. Identification of impurities: use the chromatogram supplied withvalsartan for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peak due to impurity C. Relative retention with reference to valsartan (retention time = about 5 min): impurity C = about 0.8. System suitability: reference solution (b): – resolution: minimum 3.0 between the peaks due to impurity C and valsartan. Limits: – impurity C: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent); – unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent); – total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent); – disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). Water (3) (2.5.12): maximum 2.0 per cent, determined on 0.500 g . Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.

ASSAY Dissolve 0.170 g in 70 mL of 2-propanol R. Titrate with 0.1 M tetrabutylammonium hydroxide in 2-propanol , determining the endpoint potentiometrically (2.2.20). Perform all operations under nitrogen. (2) Nucleosil 100 C18 is suitable. (3) Hydranal composite 5 is suitable as titrant. (4) Merck No 109162, 0.1M TBAH in 2-propanol/methanol is suitable.

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1 mL of 0.1 M tetrabutylammonium hydroxide in 2-propanol is equivalent to 21.78 mg of C24H29N5O3. STORAGE In an airtight container.

IMPURITIES Specified impurities: A, C. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): B.

A. (2R)-3-methyl-2-[pentanoyl[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]butanoic acid,

B. benzyl (2S)-3-methyl-2-[pentanoyl[[2′-(1H-tetrazol-5-yl)biphenyl-4yl]methyl]amino]butanoate,

C. (2S)-2-[butanoyl[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]-3methylbutanoic acid.

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The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

Figure 2423.-1. –Chromatogram for the test for enantiomeric purity of valsartan The following chromatogram is shown for information but will not be published in the European Pharmacopoeia.

Figure 2423.-2. – Chromatogram for the test for related substances of valsartan

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Namn på monografier i supplement 10.4 till Europafarmakopén

Nya monografier

Ändrade engelska och svenska namn

Engelskt namn Tidigare Svenskt namn Tidigare svenskt engelskt namn namn

Piperacillin Piperacillin Piperacillin- Piperacillin monohydrate monohydrat Cyproheptadine Cyproheptadine Cyproheptadin- Cyproheptadinhydrochloride hydrochloride hydroklorid-1,5- hydroklorid 1.5-hydrate hydrat

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