Drugs/Cocain term paper 20323

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A Critical Appraisal Of The Analytical Methods Available For Qualitative And Quantitative Analysis Of Cocaine.

Introduction:

Cocaine is an alkaloid extracted from the leaves of the cocoa plants Erythroxylum coca and Erythroxylum novogranatense. It is a potent stimulant that targets the Central Nervous System (CNS) and the Cardio-Vascular system (CVS). It is a vasoconstrictor and activates the CNS, hence increasing the heart rate and blood pressure and causing a sensation of euphoria, energy and mental alertness. Cocaine is highly addictive, since its effect wears off after 20 to 40 minutes and the person often feels depressed, and usually opts for another dose to try to regain the condition of well-being. (Gold, Mark S. (2006)).

Cocaine is available in two forms: the hydrochloride salt and the “freebase”. The hydrochloride salt, or powdered form of cocaine, can be taken intravenously or intra-nasally. Freebase is a compound that has not been neutralized by an acid to make the hydrochloride salt. The freebase form of cocaine is smokable.

Physical properties:

Cocaine hydrochloride crystals are colourless or white, hygroscopic, odourless and bitter-tasting. They are soluble in water and alcohol with solubility 200gm/100ml and 25gm/100ml respectively. These crystals are insoluble in ether. Their melting point is 197°C and a 1% solution is of neutral pH.

The freebase form (or crack-cocaine) has white crystals that are slightly volatile, anhydrous and bitter-tasting. They are soluble in water, alcohol and ether with solubility 0.17gm/100ml, 15.4gm/100ml and 28.6gm/100ml respectively. They melt at a lower temperature than the cocaine hydrochloride crystals - 98°C and boil at about 187-188°C.

Street cocaine used by addicts can be mixed with a number of diluents ("cut"), and these include amphetamines, anti-histamines, benzocaine, inositol, lactose, lidocaine, mannitol, opioids, phencyclidine, procaine, sugars, tetracaine, and sometimes arsenic, caffeine, quinidine, and even flour or talc (Claustre, A. (1993)).

Chemical properties and metabolism:

The chemical name of cocaine is 3-tropanylbenzoate-2-carboxylic acid methyl ester. Its molecular weight is 303.4 and molecular formula C17 H21 NO4. (Clarke, (1986))

Molecular structure of cocaine.

Cocaine is metabolized mainly to benzoylecgonine and ecgonine methylester. Cocaethylene is an indication of concurrent cocaine and alcohol consumption. Hydroxybenzoylecgonine is a metabolite mainly present in meconium. Serum half-life of cocaine is 1-5 hours. Benzoylecgonine appears in circulation 15-30 minutes after cocaine administration. Elimination half-life of benzoylecgonine is 5-6 hours. Benzoylecgonine will be detectable in urine after 2-3 hours and urine remains positive for 2-3 days (longer for chronic abusers) after cocaine use.

Cocaine in bodily fluids:

1 to 9% of cocaine is eliminated unchanged in the urine, with a higher proportion in acid urine. The metabolites ecgonine methyl ester, benzoylecgonine, and ecgonine are recovered in variable proportions which depend on the route of administration (Clarke, 1986). At the end of 4 hours, most of the drug is eliminated from plasma, but metabolites may be identified up to 144 hours after administration (Ellenhorn & Barceloux, 1988).

Unchanged cocaine is excreted in the stool and in saliva (Clarke, 1986; Cone & Weddington, 1989). Cocaine and benzoylecgonine can be detected in maternal milk up to 36 hours after administration, and in the urine of neonates for as much as 5 days. (Chasnoff et al., 1987, 1989).

Freebase cocaine crosses the placenta, and norcocaine persists for 4 to 5 days in amniotic fluid, even when it is no longer detectable in maternal blood (Stinus, 1992).

Detection limits:

The detection of Cocaine in serum/plasma is limited for approx. 4-6 h (HT: 42-90 min.). In stored blood samples it decomposes without stabilizing addition of NaF and cooling within 2 days completely. As metabolites benzoylecgonine (HT: 5-7 h) and methylecgonine (HT: 4-5 h), which are both pharmacologically inactive, are detected. In the urine is possible by means of immunological quick tests (as Benzoylecgonine) for 3 to 5 days after the last consumption.

By means of hair analysis with GC/MS-detection, Cocaine and its metabolites are to be found as well as Coca ethylene up to 6 months.

Analysis of cocaine:

Qualitative tests:

a. Solubility tests:

The sample is dissolved in water and ethanol separately. Dissolving in ethanol confirms presence of any ethanol insoluble carbohydrates in the sample. Solubility test is best when large quantity of sample is available.

b. Thin-layer chromatography:

TLC relies on a reproducible migration pattern by drug of a thin layer adsorbent (eg: silica gel coated glass plates). Characterization of a particular drug is achieved by color reaction produced by spraying the plate with coloring reagents. (Margoob, MA. et al. (2004)).

Quantitative tests:

1. Immunoassay tests

These tests are widely used in the medico-legal laboratories and are based on the competitive binding of drug (that may be in a specimen) and a labeled drug to an antibody. A known amount of an antibody is added to the urine specimen. In addition, a known amount of labeled drug or drug metabolite (antigen) is added to the specimen. Any drug or drug metabolite present in the specimen will compete with the labeled drug or metabolite to bind with the antibodies forming antigen-antibody complexes. The amount of labeled antigen that is able to bind with an antibody is a function of the amount of drug or drug metabolite in the urine. Spectrophotometric endpoints of these reactions are used to semi-quantitatively identify drugs and/or drug metabolites in each urine specimen.

A schematic diagram of the process is as follows:

(Source: )

2. High performance liquid chromatography:

High-performance liquid chromatography (HPLC) is a form of liquid chromatography to separate compounds that are dissolved in solution. HPLC instruments consist of a reservoir of mobile phase, a pump, an injector, a separation column, and a detector. Compounds are separated by injecting a plug of the sample mixture onto the column. The different components in the mixture pass through the column at different rates due to differences in their partitioning behavior between the mobile liquid phase and the stationary phase.

(Diagram taken from: )

HPLC can detect cocaine enantiomers. Recent development in HPLC coupled with electrospray (ESI) time-of-flight mass spectrometry provides a sensitive chromatographic confirmation method for cocaine and its metabolites. Use of a special PFP Propyl column in combination with a high-organic mobile phase has resulted in short analysis times and allows detection limits at low picogram levels. (Sellers, K. (2005a)).

3. An FT-IR (Fourier Transform- Infrared spectroscopy):

This system presumptively identifies unknown liquids and solids. It also distinguishes the cocaine salt from the free-base form since the presence of chloride ion in the salt form alters the absorption pattern of the cocaine molecule in FTIR.

4. Gas Chromatography-Mass Spectrometry (GC-MS)

GC/MS is a combination of two different analytical techniques. Gas chromatography relies on physically separating the drug or drug metabolites in the extract from one another as they pass through a long, small diameter column. The drug or drug metabolites migrate at different rates along the column and, therefore, exit the column at different times before passing through a mass spectrometer which can positively identify a particular drug or drug metabolite. A mass spectrometer converts a drug or drug metabolite into charged particles and the mass-to-charge (m/z) ratios of the particles generated create a pattern that provides a positive identification of the drug or drug metabolite at the measured retention time compared to a standard. (Analytical Testing Methods. (2005))

Gas Chromatography:

Gas Chromatography is the separation of a mixture of compounds (solutes) into separate components, which then can me analyzed by a Mass Spectrometer to give us detailed empirical molecular information regarding the chemistry of the samples. In gas chromatography (GC), the sample is vaporized and injected onto chromatographic columns and then separate into many components. The elution is brought about by the flow of an inert gaseous mobile phase. Carrier gases, which compose the mobile phase of GC, include helium, argon, and nitrogen. And the stationary phase of GC is a solid or liquid with a large surface where the absorption of the solutes takes place.

The schematic diagram of a Gas Chromatograph is as follows:

Below is a typical flow chart of Gas Chromatography

Mass Spectrometery:

In mass spectroscopy, the sample (liquid, solid, solution, or vapor) enters the vacuum chamber through an inlet and depending on the sample, it may be ionized if it already isn’t. The ions are sorted in the mass analyzer according to their mass-to-charge ratios and then collected by a detector where the ion flux is converted to a proportional electrical current that is used to produce a mass spectrum.

A typical flow chart of Mass Spectrometry is as follows:

(All diagrams are taken from: )

Sample preparation for GC-MS:

The drug or drug metabolite is selectively extracted from a urine specimen and it is then concentrated to a small volume (e.g., 0.5 mL or less) of an appropriate solution. The extraction procedure is necessary to remove the drug or drug metabolite of interest from other “interfering” substances present in urine. Once the drug or drug metabolite has been isolated and concentrated into an appropriate extract using a solid phase or solvent-solvent extraction procedure, the extract is injected into a GC/MS. (Analytical Testing Methods. (2005))

Advantages and disadvantages of the methods of analysis of cocaine:

The problem of false positive results makes the colour and odour tests unreliable. The presence of harmless white powders that could be controlled drugs like methaqualone or synthetic local anaesthetics which are usually substituted for cocaine in the illicit traffic usually hinder with the detection of cocaine in the colour test.

Thin layer chromatography (TLC) has been used as a broad spectrum screen for detection of cocaine. Although this method is rapid and cheap, the results of TLC can not be quantified. The major drawback of TLC is its low sensitivity and low specificity, thus negative results of TLC are not always negative by other methods. (Margoob, Mushtaq A. et al. (2004)).

Immunoassay tests, HPLC, GC-MS, LC/MS-MS all require sophisticated instruments and technical expertise and are hence expensive. Immunoassay tests are readily automated and easy to perform, but they have several disadvantages. These tests are slow and may have some cross-reactivity with the drug or drug-metabolite apart from the one it is primarily testing for.

HPLC methods are also suitable for detection of samples of “street cocaine” containing sugars since sugars are not volatilized easily and are difficult to analyse by GC. However, the methods are not yet well-developed and hence are not used widely. (Sellars, K. (2005b)).

GC-MS is time consuming due to multiple sample preparation steps, and poses the risk of exposure to hazardous solvents. However, the procedure is well established and it is still the method of choice. Confirmation of any positive cocaine result by this method is essential in any potential legal situation on both serum and urine samples. (Stimmel, B. (ed.), pp. 138).

Conclusion:

Of all the techniques available, GC-MS is the most feasible and reliable to date. Forensic testing laboratories around the world use GC-MS for the confirmation of cocaine in a sample. The procedures of analysis are well-established and have been shown to detect cocaine at picogram levels with accuracy. It provides undisputable identification of cocaine, its metabolites and adulterants and is hence generally preferred upon all the other methods available.

References:

Chasnoff IJ, Lewis DE & Squires L. 1987. Cocaine intoxication in a breast-fed infant. Pediatrics, 80 (6): 836-838.

Chasnoff IJ, Lewis DE, Griffith DR & Willey S. 1989. Cocaine and pregnancy: clinical and toxicological implications for the neonate. Clin Chem, 35 (7): 1276-1278.

Clarke, EGC. 1986. Clarke's isolation and identification of drugs in pharmaceuticals, body fluids, and post-mortem materials. 2nd ed., London, The Pharmaceutical Press.

Claustre, A., Bresch-Rieu, I & Fouilhé, N. 1993. Cocaine.

Cone EJ & Weddington WW. 1989. Prolonged occurrence of cocaine in human saliva and urine after chronic use. J Anal Toxicol, 13:65-68.

D.-T. Vu. GC-MS Detection and Quantification of Cocaine at Picogram Levels - Factors to consider when doing trace-level work. U.S. Customs Research Laboratory, Springfield, VA 22153.

Ellenhorn MJ ed. & Barceloux DG (ed). 1988. Medical Toxicology: diagnosis and treatement of human poisoning. New York, Elsevier Science Publishing Company, Inc., 644-661.

Gold, Mark S. Cocaine. World Book Online Reference Center. 2006.

Margoob, MA, Majid, AB, Dhuha, M, Murtaza, I, Abbas, Z, Tanveer, M, Wani, ZA, Husain, A, Ahmad, M,

Jehangeer, I, Huda, M, Ahmad, I. 2004. ‘Thin layer chromatography (TLC) in detection of current nature of drug abuse in Kashmir.’ JK – Practitioner no. 11(4) pp. 257-260.

Sellers, K. 2005a. 0.5pg Limit of Detection for Cocaine Using an Allure™ PFP Propyl Column and HPLC/TOF-MS.

Sellers, K. 2005b. Identify and Quantify Adulterants in Seized Cocaine Using GC/MS (Rtx®-440 Column) and HPLC/RI (Pinnacle II™ Amino Column).

Stimmel, B. (ed.) Cocaine: Pharmacology, Addiction and Therapy. Haworth Press.

Stinus L. 1992. La dépendance à la cocaïne. Rev Prat, 6 (179): 1203-1210.

Analytical Testing Methods. 2005

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