{"id":27791,"date":"2025-11-07T11:26:04","date_gmt":"2025-11-07T04:26:04","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=27791"},"modified":"2025-11-07T11:26:04","modified_gmt":"2025-11-07T04:26:04","slug":"melphalan","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/melphalan\/","title":{"rendered":"Melphalan"},"content":{"rendered":"

Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n

General Notices
\n(Ph. Eur. monograph 1698)<\/p>\n

\"C13H18Cl2N2O2
C13H18Cl2N2O2 305.2 148-82-3<\/figcaption><\/figure>\n

Action and use<\/p>\n

Cytotoxic alkylating agent.<\/p>\n

Preparations<\/p>\n

Melphalan Tablets<\/p>\n

Melphalan for Injection<\/p>\n

Ph Eur<\/p>\n

DEFINITION<\/h2>\n

4-[Bis(2-chloroethyl)amino]-L-phenylalanine.<\/p>\n

Content
\n94.0 per cent to 102.0 per cent (anhydrous and diethylamine-free substance).<\/p>\n

CHARACTERS<\/h2>\n

Appearance<\/h3>\n

White or almost white, hygroscopic powder.<\/p>\n

Solubility<\/h3>\n

Practically insoluble in water, slightly soluble in methanol. It dissolves in dilute mineral acids.<\/p>\n

IDENTIFICATION<\/h2>\n

Infrared absorption spectrophotometry (2.2.24).<\/p>\n

Comparison Ph. Eur. reference spectrum of melphalan.<\/p>\n

TESTS<\/h2>\n

Appearance of solution<\/h3>\n

If intended for use in the manufacture of parenteral preparations, the solution is clear (2.2.1) and colourless (2.2.2, Method II).
\nDissolve 0.25 g in dilute hydrochloric acid R and dilute to 25 mL with the same acid.<\/p>\n

Specific optical rotation (2.2.7)
\n-36.0 to -30.0 (anhydrous and diethylamine-free substance).
\nDissolve 0.175 g at 45 \u00b0C for 10 min in methanol R and dilute to 25.0 mL with the same solvent.<\/p>\n

Related substances<\/h3>\n

Liquid chromatography (2.2.29). Use freshly prepared solutions and protect from light.
\nTest solution (a) Dissolve 50.0 mg of the substance to be examined in methanol R1 and dilute to 50.0 mL with the same solvent.
\nTest solution (b) Dilute 1.0 mL of test solution (a) to 10.0 mL with methanol R1.
\nReference solution (a) Dissolve 50.0 mg of melphalan hydrochloride CRS in methanol R1 and dilute to 50.0 mL with the same solvent. Dilute 1.0 mL of the solution to 10.0 mL with methanol R1.
\nReference solution (b) Dilute 10.0 mL of test solution (a) to 100.0 mL with methanol R1.
\nReference solution (c) Dilute 1.0 mL of reference solution (b) to 100.0 mL with methanol R1.
\nReference solution (d) Dilute 5.0 mL of reference solution (b) to 100.0 mL with methanol R1.
\nReference solution (e) In order to prepare impurity I in situ, dissolve 5 mg of melphalan for system suitability CRS (containing impurities B, D, G, H and J) in methanol R1, dilute to 5.0 mL with the same solvent and heat at 60 \u00b0C for 15 min.<\/p>\n

Column:
\n\u2014 size: l = 0.15 m, \u00d8 = 4.6 mm;
\n\u2014 stationary phase: base-deactivated end-capped octadecylsilyl silica gel for chromatography R (5 \u03bcm).<\/p>\n

Mobile phase:
\n\u2014 mobile phase A: mixture of 5 volumes of acetonitrile for chromatography R and 95 volumes of water R containing 0.01 per cent V\/V of triethylamine R, 0.05 per cent m\/m of ammonium acetate R and 0.05 per cent V\/V of glacial acetic acid R;
\n\u2014 mobile phase B: mixture of 40 volumes of water R containing 0.01 per cent V\/V of triethylamine R, 0.05 per cent m\/m of ammonium acetate R and 0.05 per cent V\/V of glacial acetic acid R, and 60 volumes of acetonitrile for chromatography R;<\/p>\n\n\n\n\n\n
Time (min)<\/td>\nMobile phase A (per cent V\/V)<\/td>\nMobile phase B (per cent V\/V)<\/td>\n<\/tr>\n
0 – 20<\/td>\n100 \u2192 0<\/td>\n0 \u2192 100<\/td>\n<\/tr>\n
20 – 25<\/td>\n0<\/td>\n100<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Flow rate 1.5 mL\/min.
\nDetection Spectrophotometer at 260 nm.
\nInjection 20 \u03bcL of test solution (a) and reference solutions (c), (d) and (e).<\/p>\n

Identification of impurities Use the chromatogram supplied with melphalan for system suitability CRS and the chromatogram obtained with reference solution (e) to identify the peaks due to impurities B, D, G, H, I and J.
\nRelative retention
\nWith reference to melphalan (retention time = about 10 min): impurity B = about 0.3; impurity D = about 0.6; impurity I = about 0.8; impurity J = about 1.04; impurity G = about 1.4; impurity H = about 1.5.<\/p>\n

System suitability Reference solution (e):
\n\u2014 peak-to-valley ratio: minimum 2.5, where Hp = height above the baseline of the peak due to impurity J and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to melphalan.<\/p>\n

Limits:
\n\u2014 impurity D: not more than 6 times the area of the principal peak in the chromatogram obtained with reference solution (d) (3.0 per cent);
\n\u2014 impurity G: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (d) (1.0 per cent);
\n\u2014 impurities J, H: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (d) (0.5 per cent);
\n\u2014 impurity B: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.3 per cent);
\n\u2014 impurity I: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent);
\n\u2014 unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.10 per cent);
\n\u2014 total: not more than 11 times the area of the principal peak in the chromatogram obtained with reference solution (d) (5.5 per cent);
\n\u2014 disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent).<\/p>\n

Impurity K (diethylamine)
\nGas chromatography (2.2.28).
\nTest solution
\nDissolve 0.125 g of substance to be examined in 0.15 mL of hydrochloric acid R and dilute to 5.0 mL with dimethyl sulfoxide R.
\nReference solution
\nDilute 1 mL of methanol R and 0.125 g of diethylamine R1 (impurity K) to 10.0 mL with dimethyl sulfoxide R. Dilute 1.0 mL of the solution to 100.0 mL with dimethyl sulfoxide R.<\/p>\n

Column:
\n\u2014 material: glass;
\n\u2014 size: l = 1.6 m, \u00d8 = 4 mm;
\n\u2014 stationary phase: styrene-divinylbenzene copolymer R coated with potassium carbonate (149-177 \u03bcm).<\/p>\n

Carrier gas nitrogen for chromatography R.
\nFlow rate 42.5 mL\/min.
\nTemperature:
\n\u2014 column: 170 \u00b0C;
\n\u2014 injection port: 190 \u00b0C;
\n\u2014 detector: 250 \u00b0C.
\nDetection Flame ionisation.
\nInjection 1 \u03bcL.
\nElution order Methanol, impurity K.<\/p>\n

System suitability Reference solution:
\n\u2014 resolution: minimum 2.0 between the peaks due to methanol and impurity K.<\/p>\n

Limit:
\n\u2014 impurity K: not more than the area of the corresponding peak in the chromatogram obtained with the reference solution (0.5 per cent).<\/p>\n

Water (2.5.12)
\nMaximum 5.0 per cent, determined on 0.200 g.<\/p>\n

Sulfated ash (2.4.14)
\nMaximum 0.1 per cent, determined on 1.0 g.<\/p>\n

ASSAY<\/h2>\n

Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.<\/p>\n

Injection Test solution (b) and reference solution (a).
\nCalculate the percentage content of C13H18Cl2N2O2 taking into account the assigned content of melphalan hydrochloride CRS and a conversion factor of 0.8933.<\/p>\n

STORAGE<\/h2>\n

In an airtight container, protected from light.<\/p>\n

IMPURITIES<\/h2>\n

Specified impurities B, D, G, H, I, J, K.
\nOther 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.
\nControl of impurities in substances for pharmaceutical use) A, C, E, F.<\/p>\n

\"A.
A. 4-[bis(2-hydroxyethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>\n
\"B.
B. 4-morpholin-4-yl-L-phenylalanine,<\/figcaption><\/figure>\n
\"C.
C. 4-[(2-chloroethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>
\"D.
D. 4-[(2-chloroethyl)(2-hydroxyethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>
\"E.
E. 4-[(2-chloroethyl)(2-ethoxyethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>
\"F.
F. 4-[bis(2-chloroethyl)amino]-3-chloro-L-phenylalanine (3-chloromelphalan),<\/figcaption><\/figure>
\"G.
G. 4-[[2-[[4-[bis(2-chloroethyl)amino]-L-phenylalanyl]oxy]ethyl](2-chloroethyl)amino]-L-phenylalanine (melphalan dimer),<\/figcaption><\/figure>
\"H.
H. methyl 4-[bis(2-chloroethyl)amino]-L-phenylalaninate,<\/figcaption><\/figure>
\"I.
I. 4-[(2-chloroethyl)(2-methoxyethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>
\"J.
J. 4-[[2-(2-chloroethoxy)ethyl](2-chloroethyl)amino]-L-phenylalanine,<\/figcaption><\/figure>\n
\"K.
K. N-ethylethanamine (diethylamine).<\/figcaption><\/figure>\n","protected":false},"excerpt":{"rendered":"

Edition: BP 2025 (Ph. Eur. 11.6 update) General Notices (Ph. Eur. monograph 1698) Action and use Cytotoxic alkylating agent. Preparations Melphalan Tablets Melphalan for Injection Ph Eur DEFINITION 4-[Bis(2-chloroethyl)amino]-L-phenylalanine. Content 94.0 per cent to 102.0 per cent (anhydrous and diethylamine-free substance). CHARACTERS Appearance White or almost white, hygroscopic powder. Solubility Practically insoluble in water, slightly…<\/p>\n","protected":false},"author":5,"featured_media":27794,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-27791","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\/27791","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=27791"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/27791\/revisions"}],"predecessor-version":[{"id":27810,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/27791\/revisions\/27810"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/27794"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=27791"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=27791"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=27791"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}