Laboratory Synthesis Of Diclofenac

Chemical Synthesis Of Diclofenac

LINK TO THE PATENT DESCRIBING SYNTHESIS OF DICLOFENAC CLICK HERE
RN: 15307-86-5 EINECS: 239-348-5

Diclofenac MW: 296.15

Diclofenac MF: C14H11Cl2NO2

Diclofenac LD50: 170 mg/kg (M, p.o.);62.5 mg/kg (R, p.o.)

CN: 2- [(2 ,6- di chloro phenyl )amino ]benzene acetic acid

monosodium salt

RN: 15307-79-6 EINECS: 239-346-4

Diclofenac MW: 318.14

Diclofenac MF: C14H10Cl2NNaO2

Diclofenac LD50: 116 mg/kg (M, i.v.); 390 mg/kg (M, p.o.);117 mg/kg (R, i.v.); 150 mg/kg (R, p.o.);

Reference(s):

US 3 558 690 (Geigy; 26.1.1971; CH-prior. 8.4.1965, 25.2.1966, 30.3.1966, 20.12.1967).
DAS 1 543 639 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
DAS 1 793 592 (Ciba-Geigy; appl. 7.4.1966; CH-prior. 8.4.1965).
US 3 652 762 (Ciba-Geigy; 28.3.1972; prior. 9.12.1968, 29.9.1969, 14.4.1970).
US 3 778 470 (Geigy; 11.12.1973; appl. 2.10.1970; prior. 4.4.1966).
CH 492 679 (Geigy; appl. 30.3.1966).
alternative synthesis:
DOS 2 613 838 (Ikeda Mohando; appl. 31.3.1976; J-prior. 31.3.1975).

melting point diclofenac  156° to 158°.

Diclofenac Sodium

Synonyms. Diclofenacum Natricum; GP-45840.

Proprietary names. Acoflam; Arthrotec; Cataflam; Dicloflex; Diclomax; Diclotard; Diclovol; Diclozip; Econac; Flamatak; Flamrase; Flexotard; Isclofen; Lofensaid; Motifene; Pennsaid; Rheumatac; Rhumalgan; Slofenac; Solaraze; Volraman; Volsaid; Voltaren(e); Voltarol.

C₁₄H₁₀Cl₂NNaO₂=318.1

CAS—15307–79–6

Crystals. MELTING POINT of diclofenac . 283° to 285°.
Solubility at 25° (mg/mL): deionised water (pH 5.2) >9; methanol >24; acetone 6; acetonitrile <1; cyclohexane <1.

Dissociation Constant.

pK_a4.2.

Partition Coefficient.

Log P(octanol/water), 4.5.

Colour Tests.

Liebermann's Test—red–brown; Mandelin's Test—red–brown; Marquis Test—brown (slow).

Thin–layer Chromatography.

System TA—Rf 90; system TD—Rf 25; system TE—Rf 12; system TF—Rf 27; system TG—Rf 29; system TAD—Rf 47; system TAE—Rf 90; system TAJ—Rf 40; system TAK—Rf 64; system TAL—Rf 84. (Chromic acid solution, red.)

Gas Chromatography.

System GA—diclofenac RI 2271, diclofenac-Me RI 2195, diclofenac-Me₂ RI 2220, M (OH-)-Me₂ RI 2460; system GB—RI 2231; system GD—diclofenac-Me RRT 1.42 (relative to n-C₁₆H₃₄); system GL—diclofenac-Me RI 2200, M (OH-)-Me₂ RI 2460.

High Performance Liquid Chromatography.

System HD—k 11.5; system HV—RRT 0.85 (relative to meclofenamic acid); system HX—RI 616; system HY—RI 592; system HZ—retention time 14.8 min; system HAA—retention time 22.1 min; system HAX—retention time 8.7 min; system HAY—retention time 10.0 min.

Ultraviolet Spectrum.

Aqueous acid—273 nm (A¹₁=309b); aqueous alkali—275 nm (A¹₁=351b). 

Quantification

Gas chromatography.

In plasma: limit of detection 100 μg/L, ECD—M. Ikeda et al.,J. Chromatogr.,1980, 183(9) B Biomed. Appl., 41–47. In urine: diclofenac and hydroxy metabolites, ECD—W. Schneider and P. H. Degen,J. Chromatogr.,1981, 217, 263–271.

Gas chromatography–mass spectrometry.

In plasma: limit of detection 2 μg/L, SIM—M. Del Puppo et al.,Biol. Mass Spectrom.,1991, 20, 426–430. In plasma or urine: limit of detection 100 ng/L—A. Sioufi et al.,J. Chromatogr.,1991, 571, 87–100. In plasma: limit of detection 0.2 μg/L—M. R. Borenstein et al.,J. Chromatogr.,1996, 685 B Biomed. Appl., 59–66. In urine: diclofenac and other NSAIDs—B. M. el Haj et al.,Forensic Sci. Int.,1999, 105, 141–153. In urine: diclofenac and other NSAIDs, limits of detection 10 to 50 μg/L—H. H. Maurer et al.,J. Anal. Toxicol.,2001, 25, 237–244.

High performance liquid chromatography.

In plasma: limit of detection 5 μg/L, UV detection—K. K. H. Chan et al.,Anal. Lett. (Part B),1982, 15, 1649–1663. In plasma: limit of detection 6 μg/L, fluorescence detection—B. Wiese and J. Hermansson,J. Chromatogr.,1991, 567, 175–183. In plasma: limit of quantification 5 μg/L, UV detection—L. A. Brunner and R. C. Luders,J. Chromatogr. Sci.,1991, 29, 287–291. In plasma or cerebrospinal fluid: limit of detection <1 μg/L, electrochemical detection—L. Zecca et al.,J. Chromatogr.,1991, 567, 425–432. In plasma: limit of detection 1 μg/L, UV detection—S. R. Santos et al.,Braz. J. Med. Biol. Res.,1992, 25, 125–128. In serum: limit of quantification 20 μg/L, fluorescence detection—J. Moncrieff,J. Chromatogr.,1992, 577, 185–189. In plasma or synovial fluid: diclofenac and other NSAIDs—I. S. Blagbrough et al.,J. Chromatogr.,1992, 578, 251–257. In plasma: limit of detection <2.5 μg/L, UV detection—R. B. Miller,J. Chromatogr.,1993, 616, 283–290. In plasma or urine: limit of detection 0.2 mg/L, UV detection—A. Avgerinos et al.,J. Chromatogr.,1993, 619, 324–329. In serum: limit of detection 10 μg/L—S. Y. Zhang et al.,Yao Xue Xue Bao,1994, 29, 228–231. In aqueous humour: diclofenac and flurbiprofen, limit of detection for diclofenac 0.3 ng, UV detection—M. Riegel and P. P. Ellis,J. Chromatogr.,1994, 654 B Biomed. Appl., 140–145. In plasma: limit of detection 3 μg/L, UV detection—A. Hanses et al.,Arch. Pharm. (Weinheim),1995, 328, 257–260. In urine: diclofenac and its metabolites, limit of quantification 0.4 mg/L—R. J. Sawchuk et al.,Pharm. Res.,1995, 12, 756–762. In urine: diclofenac and other NSAIDs, limit of detection for diclofenac 0.05 mg/L, UV detection—T. Hirai et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 692, 375–388. In serum or aqueous humour: limit of detection 1 μg/L, UV detection—O. Kuhlmann and G. J. Krauss,J. Pharm. Biomed. Anal.,1997, 16, 553–559. In plasma: diclofenac and flurbiprofen—G. Giagoudakis and S. L. Markantonis,J. Pharm. Biomed. Anal.,1998, 17, 897–901. In aqueous humour: diclofenac and oxybuprocaine, limit of detection for diclofenac 500 ng/L, electrochemical detection—O. Kuhlmann et al.,J. Pharm. Biomed. Anal.,1998, 17, 1351–1356. In urine: diclofenac and other NSAIDs, limit of quantification for diclofenac 0.02 mg/L, UV detection—A. Bakkali et al.,J. Chromatogr. B Biomed. Sci. Appl.,1999, 729, 139–145. In plasma: diclofenac and aceclofenac, limit of detection 10 μg/L—H. S. Lee et al.,J. Pharm. Biomed. Anal.,2000, 23, 775–781. In plasma: limit of detection 5 μg/L—C. Arcelloni et al.,J. Chromatogr. B Biomed. Sci. Appl.,2001, 763, 195–200.

Disposition in the Body.

Well absorbed after oral administration but undergoes significant first–pass metabolism. Up to about 70% of a dose is excreted in the urine in 3 days, including 20 to 40% as glucuronide and sulfate conjugates of the major metabolite 4′-hydroxydiclofenac (active) and up to about 15% as conjugates of unchanged diclofenac. Other metabolites identified in the urine include 5–hydroxydiclofenac (about 12% of the dose), 3′-hydroxydiclofenac, and 4′,5–dihydroxydiclofenac. About 10 to 20% of a dose is excreted in the bile as 4′-hydroxydiclofenac and less than 5% as unchanged drug. Diclofenac enters the synovial fluid and maximum concentrations are measured 2 to 4 h after the peak plasma levels have been reached. Diclofenac is excreted in breast milk but in quantities so small that no adverse effects on breast–fed infants would be expected.

Therapeutic concentration

Following oral administration of 50 mg of diclofenac sodium three times a day to 4 subjects, peak plasma concentrations of 0.1 to 2.2 mg/L (mean 0.8) of diclofenac and 0.3 to 2.0 mg/L (mean 1.2) of 4′-hydroxydiclofenac were reported 3 h after a dose; peak concentrations in synovial fluid of 0.1 to 0.6 mg/L (mean 0.3) of diclofenac and 0.2 to 1.0 mg/L (mean 0.6) of 4′-hydroxydiclofenac were attained in 3 h; concentrations in synovial fluid exceeded those in plasma after 4 h. [P. D. Fowler et al.,Eur. J. Clin. Pharmacol.,1983, 25, 389–394.]
Diclofenac was administered as a single oral 150 mg dose to healthy subjects (n = 6) and to patients with either chronic active hepatitis (n = 6) or alcoholic cirrhosis (n=6). Peak plasma concentrations of diclofenac, 3′-hydroxydiclofenac, 4′-hydroxydiclofenac, and 3′-hydroxy–4′,5–methoxydiclofenac of 5.699, 0.412, 2.613, and 0.385 mg/L were attained at 0.63, 0.79, 0.88, and 5.8 h, respectively, in healthy subjects. The equivalent respective values in patients with hepatitis were: 6.574, 0.392, 2.786, and 0.306 mg/L at 0.42, 0.58, 0.50, and 4.0 h and in patients with cirrhosis were: 11.59, 0.264, 2.481, and 0.191 mg/L at 0.33, 1.04, 0.75, and 7.0 h. [J. S. Lill et al.,J. Clin. Pharmacol.,2000, 40, 250–257.]
In 20 healthy subjects given a single oral dose of diclofenac 100 mg as 2 different sustained–release tablets, respective peak plasma concentrations of 1.161 and 0.799 mg/L were attained in 4.2 and 4.5 h. [S. Zmeili et al.,Int. J. Clin. Pharmacol. Ther.,1996, 34, 564–570.]

Toxicity

A 19–year–old man was admitted to hospital following the ingestion of 1.5 g of diclofenac sodium and 4 g of chlormezanone. Plasma diclofenac concentrations of 60.1 mg/L and 0.19 mg/L were reported at 7 and 15 h, respectively; chlormezanone could not be determined. The subject recovered after about 2 days. [P. Netter et al.,Eur. J. Clin. Pharmacol.,1984, 26, 535–536.]

Bioavailability.

About 50 to 60%

Half–life.

Plasma half–life, about 1 to 2 h; synovial fluid half–life 3 to 6 h.

Volume of distribution.

0.17 L/kg.

Clearance.

Plasma clearance, about 4 mL/min/kg.

Protein binding.

In plasma, more than 99%.

Note.

For reviews of diclofenac see R. W. Brogden et al.,Drugs,1980, 20, 24–48 and N. M. Davies and K. E. Anderson,Clin. Pharmacokinet.,1997, 33, 184–213.

Dose.

75 to 150 mg of diclofenac sodium daily in divided doses.

Reference

Clarke's Analysis of Drugs and Poisons

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