GLUTETHIMIDEPREPARED BY

ABEER ALSANOOSI

INTRODUCTION*Glutethimide is a hypnotic sedative that was introduced in 1954 as a

safe alternative to barbiturates to treat insomnia .

*Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms .

*It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II more than a decade after recreational abusers discovered that combining the drug with codeine produced a euphoria which closely resembles that obtained from heroin .

*The street name for a combination of two doriden and four Codeine and a "load" or "doors and fours . "

*Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances[1]. Doriden is the brand-name version of the drug, which is rarely prescribed today

MEDICAL USE

*Used as an hypnotic in insomnia but rarely as a sedative

*glutethimide was initially believed to be almost free from side effects. However, further experience of its toxicity and because its dependence liability glutethimide has been banned in many countries and many companies have stopped production.

SIDE EFFECT

*Less commonSkin rash, Blurred vision; clumsiness or unsteadiness; confusion; dizziness; hangover effect; headache; nausea; vomiting

*Rare•Sore throat and fever; unusual bleeding or

bruising; unusual excitement; unusual tiredness or weakness

*More commonDrowsiness (daytime)

SIDE EFFECT

*Symptoms of overdoseBluish coloration of skin; confusion (continuing); convulsions (seizures); fever; low body temperature, memory problems;; muscle spasms or twitching; shortness of breath or slow or troubled breathing; slow heartbeat; slowness or loss of reflexes; slurred speech; staggering; trembling; trouble in concentrating.

ANALYSIS1)UV spectrophotometry:

*gives rather more specificity.

*Dissolve a portion of material in ethanol to achieve an appropriate instrument response. If necessary, centrifuge or filter the mixture and analyse the clear supernatant. The spectrum in ethanol gives deltamax at 252 nm, 258 nm (A| = 18) and 264 nm .

*Glutethimide is unstable at alkaline pH, due to hydrolysis of the glutarimide ring. Adjustment of the pH to >11 (e.g. by addition of 4M NaOH or ammonium hydroxide) to the ethanolic solution of glutethimide results in a characteristic decline in absorbance at 230 - 235 nm over a time period of some 20 minutes

ANALYSIS2)Thin layer chromatography:

*is highly appropriate for identification of glutethimide, and may be either an in-house system or a commercially-available system such as Toxi-Lab.

*The material can be dissolved in an organic solvent such as methanol or dichloromethane and applied directly to the plate. Using silica plates without modifiers and standard systems, the Rf of glutethimide is 0.75 on methanol / concentrated ammonia (100: 1.2), and 0.62 on ethyl acetate / methanol / ammonia (85:15:6) .

*Several locating reagents can be used. Mercurous nitrate reagent is the most specific, and gives a dark grey response with a sensitivity of approximately 10 ng. However, the purple response produced by mercuric chloride-diphenylcarbazone reagent, and the positive reaction to Dragendorff or acidified

iodoplatinate are also useful but are less characteristic.) .)

ANALYSIS3)Gas chromatography:

*can be used after dissolving the material in a small amount of organic solvent (e.g. 10 mg in 10 mL methanol) .

*The Retention index for glutethimide is 1836 on OV1, SE30, DB5 or similar phases. Isothermal analysis may be performed at about 220°C, without the need for derivatization. Flame ionization detection gives adequate sensitivity (2 to 5 ng on column), and nitrogen-phosphorus detection gives additional selectivity .

*Mass spectrometry can be applied to the gas chromatographic identification of glutethimide in suspect materials .

ANALYSIS

4)HPLC:*may be used to identify glutethimide, and most published methods

involve reverse phase chromatography with UV detection .

*Kabra et al. (1978) used a C18 column with a mobile phase of acetonitrile / phosphate buffer (300 µL 1M KH2PO4 and 50 µL 0.9 M phosphoric acid in 1800 mL water) [215:785].

*Using isocratic elution at 50°C glutethimide was detected at 195 nm with a relative retention of 0.55 to the internal standard methylphenytoin.

* Glutethimide was detected at 208 nm with a relative retention of 1.57 to the internal standard tolylphenobarbital. Additional confirmation of identity may be obtained by performing a full scan analysis on the appropriate portion of the HPLC effluent .

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