Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n
Action and use<\/strong><\/p>\n Purine nucleoside analogue; antiviral (herpesviruses).<\/p>\n Preparation <\/strong><\/p>\n Valaciclovir Tablets<\/p>\n 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate hydrochloride.<\/p>\n Content<\/strong><\/p>\n 95.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n White or almost white powder.<\/p>\n Freely soluble in water, slightly soluble in anhydrous ethanol. It shows polymorphism (5.9).<\/p>\n Carry out either tests A, B, C, E or tests A, B, D, E.<\/p>\n A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Comparison\u00a0 anhydrous valaciclovir hydrochloride CRS.<\/p>\n If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in the minimum volume of anhydrous ethanol R and evaporate to dryness in a desiccator, under high vacuum, over diphosphorus pentoxide R. Record new spectra using the residues.<\/p>\n B. It gives reaction (a) of chlorides (2.3.1).<\/p>\n C. It complies with the limit for impurity R given in test A for related substances.<\/p>\n D. Optical rotation (2.2.7): laevorotatory.<\/p>\n Dissolve 2.50 g in water R and dilute to 50.0 mL with the same solvent.<\/p>\n E. Water (see Tests).<\/p>\n Thin-layer chromatography (2.2.27).<\/p>\n Test solution\u00a0 Dissolve 0.250 g of the substance to be examined in 2 mL of water R and dilute to 5.0 mL with ethanol\u00a0(96 per cent) R.<\/p>\n Reference solution (a) Dissolve 5 mg of valaciclovir impurity D CRS, 5.0 mg of valaciclovir impurity E CRS, 5.0 mg of valaciclovir impurity G CRS and 8.4 mg of valaciclovir impurity F para-toluenesulfonate CRS in a mixture of 2 mL of water R and 6 mL of ethanol (96 per cent) R, and dilute to 10.0 mL with ethanol (96 per cent) R.<\/p>\n Reference solution (b) Dilute 3.0 mL of reference solution (a) to 10.0 mL with ethanol (96 per cent) R. Reference solution (c) Dilute 2.0 mL of reference solution (a) to 10.0 mL with ethanol (96 per cent) R. Reference solution (d) Dilute 0.5 mL of reference solution (a) to 10.0 mL with ethanol (96 per cent) R. Plate TLC silica gel F254 plate R (2-10 \u00b5m).<\/p>\n Pretreatment Wash the plate with methanol R until the solvent front has migrated over at least 4\/5 of the plate; allow the plate to dry.<\/p>\n Mobile phase concentrated ammonia R, tetrahydrofuran R, methanol R, methylene chloride R (3:12:34:54 V\/V\/V\/V); use freshly prepared mobile phase.<\/p>\n Application\u00a0 4 \u00b5L of the test solution and reference solutions (b), (c) and (d).<\/p>\n Development\u00a0 Over 4\/5 of the plate.<\/p>\n Drying\u00a0 In a current of air.<\/p>\n Detection\u00a0 Examine in ultraviolet light at 254 nm for impurities E and G; spray with a 0.1 g\/L solution of fluorescamine R in ethylene chloride R and examine in ultraviolet light at 365 nm for impurity F.<\/p>\n Retardation factors\u00a0 Impurity A = about 0; impurity B = about 0.2; valaciclovir = about 0.3; impurity C = about 0.5; impurity D = about 0.6; impurity E = about 0.7; impurity F = about 0.75; impurity G = about 0.79; impurity C is masked by the leading edge of the spot due to valaciclovir; impurities F and G may co-elute, but this does not adversely affect their quantification because they are visualised differently.<\/p>\n System suitability The chromatograms obtained with reference solutions (b), (c) and (d) each show 3 clearly separated spots when examined under ultraviolet light at 254 nm, due to impurities D, E and G.<\/p>\n Limits:<\/p>\n \u2014 impurity E: any spot due to impurity E is not more intense than the corresponding spot in the chromatogram obtained with reference solution (c) (0.2 per cent);<\/p>\n \u2014 impurity F: any spot due to impurity F is not more intense than the corresponding spot in the chromatogram obtained with reference solution (b) (0.3 per cent calculated as hydrochloride salt);<\/p>\n \u2014 impurity G: any spot due to impurity G is not more intense than the corresponding spot in the chromatogram obtained with reference solution (d) (0.05 per cent).<\/p>\n A. Impurities A, B, I and R.<\/p>\n Liquid chromatography (2.2.29): use the normalisation procedure.<\/p>\n Test solution Dissolve 50.0 mg of the substance to be examined in a 0.5 per cent V\/V solution of hydrochloric acid R and dilute to 100.0 mL with the same solution.<\/p>\n Reference solution (a) Dissolve 2.5 mg of valaciclovir for system suitability CRS (containing impurities A, B, C, D, H, I, J, M and R) in a 0.5 per cent V\/V solution of hydrochloric acid R and dilute to 5.0 mL with the same solution.<\/p>\n Reference solution (b)\u00a0 Dissolve 50.0 mg of anhydrous valaciclovir hydrochloride CRS in a 0.5 per cent V\/V solution of hydrochloric acid R and dilute to 100.0 mL with the same solution.<\/p>\n Reference solution (c) Dilute 3.0 mL of the test solution to 100.0 mL with a 0.5 per cent V\/V solution of hydrochloric acid R. Dilute 1.0 mL of this solution to 100.0 mL with a 0.5 per cent V\/V solution of hydrochloric acid R.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.15 m, \u00d8 = 4.0 mm;<\/p>\n \u2014 stationary phase: crown-ether silica gel for chiral separation R (5 \u00b5m);<\/p>\n \u2014 temperature: 10 \u00b0C.<\/p>\n Mobile phase perchloric acid R, methanol R, water for chromatography R (0.5:5:95 V\/V\/V). Flow rate 0.75 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 254 nm.<\/p>\n Injection\u00a0 10 \u00b5L of the test solution and reference solutions (a) and (c).<\/p>\n Run time\u00a0 1.5 times the retention time of valaciclovir.<\/p>\n Identification of impurities Use the chromatogram supplied with valaciclovir for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A + B, C + R, D, I and M.<\/p>\n Relative retention With reference to valaciclovir (retention time = about 21 min): impurities A and B = about 0.2; impurity I = about 0.4; impurities C and R = about 0.6; impurity D = about 0.7; impurity M = about 1.3.<\/p>\n System suitability\u00a0 Reference solution (a):<\/p>\n \u2014 peak-to-valley ratio: minimum 1.5, where Hp = height above the baseline of the peak due to impurity D and<\/p>\n Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to impurities C and R.<\/p>\n Limits:<\/p>\n \u2014 correction factor: for the calculation of content, multiply the peak area of impurities A and B by 0.7;<\/p>\n \u2014 impurity R: maximum 3.0 per cent; for the calculation, subtract the content of impurity C as determined in test B for related substances from the content of the coeluting impurities C and R as determined in this test;<\/p>\n \u2014 sum of impurities A and B: maximum 2.0 per cent;<\/p>\n \u2014 impurity I: maximum 0.2 per cent;<\/p>\n \u2014 disregard limit: the area of the principal peak in the chromatogram obtained with reference solution (c) (0.03 per cent); disregard any peaks due to impurities other than A + B, C + R or I.<\/p>\n B. Liquid chromatography (2.2.29): use the normalisation procedure. Use the solutions within 24 h of preparation.<\/p>\n Solvent mixture\u00a0 ethanol (96 per cent) R, water R (20:80 V\/V).<\/p>\n Test solution Dissolve 40 mg of the substance to be examined in the solvent mixture and dilute to 100.0 mL with the solvent mixture.<\/p>\n Reference solution (a) Dissolve 2.5 mg of valaciclovir for system suitability CRS (containing impurities A, B, C, D, H, I, J, M and R) in the solvent mixture and dilute to 5.0 mL with the solvent mixture.<\/p>\n Reference solution (b) Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 20.0 mL with the solvent mixture.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: end-capped phenylhexylsilyl silica gel for chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 15 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: trifluoroacetic acid R, water for chromatography R (0.2:100 V\/V);<\/p>\n \u2014 mobile phase B: trifluoroacetic acid R, methanol R2 (0.2:100 V\/V);<\/p>\n Flow rate\u00a0 0.8 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 254 nm.<\/p>\n Injection\u00a0 10 \u00b5L.<\/p>\n Identification of impurities Use the chromatogram supplied with valaciclovir for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B, C, D, H, I, J and M.<\/p>\n Relative retention\u00a0 With reference to valaciclovir (retention time = about 19 min): impurity A = about 0.3; impurity B = about 0.4; impurity H = about 0.5; impurity C = about 1.06; impurity I = about 1.09; impurity D = about 1.2; impurity J = about 1.3; impurity M = about 1.6.<\/p>\n System suitability\u00a0 Reference solution (a):<\/p>\n \u2014 peak-to-valley ratio: minimum 2.5, where Hp = height above the baseline of the peak due to impurity C and<\/p>\n Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to valaciclovir;<\/p>\n \u2014 the chromatogram obtained is similar to the chromatogram supplied with valaciclovir for system suitability CRS. Limits:<\/p>\n \u2014 impurity M: maximum 1.5 per cent;<\/p>\n \u2014 impurity D: maximum 0.5 per cent;<\/p>\n \u2014 impurity C: maximum 0.3 per cent;<\/p>\n \u2014 impurities H, J: for each impurity, maximum 0.10 per cent;<\/p>\n \u2014 unspecified impurities: for each impurity, maximum 0.05 per cent;<\/p>\n \u2014 disregard limit: 0.6 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.03 per cent); disregard the peaks due to impurities A, B and I.<\/p>\n Limit:<\/p>\n \u2014 total for tests A and B: maximum 5.0 per cent.<\/p>\n 9.4 to 9.9 per cent (anhydrous and solvent-free substance).<\/p>\n Dissolve 0.350 g in 100 mL of water R and add 0.2 mL of nitric acid R. Carry out a potentiometric titration (2.2.20), using 0.1 M silver nitrate. Use a silver indicator electrode and a silver-silver chloride reference electrode or a combined silver electrode. Discard the result from the first titration, which is used to condition the electrodes. Carry out a blank titration.<\/p>\n 1 mL of 0.1 M silver nitrate is equivalent to 3.543 mg of Cl.<\/p>\n Water (2.5.12)<\/strong><\/p>\n Maximum 2.0 per cent, determined on 0.250 g.<\/p>\n Sulfated ash (2.4.14)<\/strong><\/p>\n Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n Liquid chromatography (2.2.29) as described in test A for related substances with the following modification.<\/p>\n Injection\u00a0 Test solution and reference solution (b).<\/p>\n Calculate the percentage content of C13<\/sub>H21<\/sub>ClN6<\/sub>O4<\/sub> taking into account the assigned content of anhydrous valaciclovir hydrochloride CRS.<\/p>\n Specified impurities\u00a0 A, B, C, D, E, F, G, H, I, J, M, R.<\/em><\/p>\n 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) K, L, N, O, P, Q.<\/em><\/p>\n A. 2-amino-1,9-dihydro-6H-purin-6-one (guanine),<\/p>\n B. 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one (aciclovir),<\/p>\n C. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-methyl-L-valinate,<\/p>\n D. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-ethyl-L-valinate,<\/p>\n E. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate,<\/p>\n F. 2-hydroxyethyl L-valinate,<\/p>\n G. N,N-dimethylpyridin-4-amine,<\/p>\n H. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-alaninate,<\/p>\n I. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl acetate,<\/p>\n J. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-isoleucinate,<\/p>\n K. 9-[(2-hydroxyethoxy)methyl]-2-[[[(6-oxo-6,9-dihydro-1H-purin-2-yl)amino]methyl]amino]-1,9-dihydro-6H-purin-6-one,<\/p>\n L. 2,2\u2032-(methylenediazanediyl)bis[9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one],<\/p>\n M. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-formyl-L-valinate,<\/p>\n N. 2-[[6-oxo-2-[[[(6-oxo-6,9-dihydro-1H-purin-2-yl)amino]methyl]amino]-1,6-dihydro-9H-purin-9-yl]methoxy]ethyl L- valinate,<\/p>\n O. 2-[[2-[[[[9-[(2-hydroxyethoxy)methyl]-6-oxo-6,9-dihydro-1H-purin-2-yl]amino]methyl]amino]-6-oxo-1,6-dihydro-9H- purin-9-yl]methoxy]ethyl L-valinate,<\/p>\n P. [methylenebis[azanediyl(6-oxo-1,6-dihydro-9H-purine-2,9-diyl)methyleneoxyethan-2,1-diyl]] di-L-valinate,<\/p>\n Q. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl N-[[(6-oxo-6,9-dihydro-1H-purin-2-yl)amino]methyl]-L- valinate,<\/p>\n R. 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl D-valinate.<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Purine nucleoside analogue; antiviral (herpesviruses). Preparation Valaciclovir Tablets DEFINITION 2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate hydrochloride. Content 95.0 per cent to 102.0 per cent (anhydrous substance). CHARACTERS Appearance White or almost white powder. Solubility Freely soluble in water, slightly soluble in anhydrous ethanol. It shows polymorphism (5.9). IDENTIFICATION Carry…<\/p>\n","protected":false},"author":5,"featured_media":30874,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-30873","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicinal-substances"],"acf":[],"_links":{"self":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/30873","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=30873"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/30873\/revisions"}],"predecessor-version":[{"id":30882,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/30873\/revisions\/30882"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/30874"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=30873"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=30873"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=30873"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}DEFINITION<\/h2>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
Solubility<\/h3>\n
IDENTIFICATION<\/h2>\n
TESTS<\/h2>\n
Impurities E, F and G<\/h3>\n
Related substances<\/h3>\n
\n\n
\n Time (min)<\/td>\n Mobile phase A (per cent V\/V)<\/td>\n Mobile phase B (per cent V\/V)<\/td>\n<\/tr>\n \n 0 – 5<\/td>\n 90<\/td>\n 10<\/td>\n<\/tr>\n \n 5 – 35<\/td>\n 90 \u2192 60<\/td>\n 10 \u2192 40<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Chloride<\/h3>\n
ASSAY<\/h2>\n
IMPURITIES<\/h2>\n