COCAINE Chemical Properties

Melting point:

98°

alpha 

D18 -35° (50% alcohol); D20 -16° (c = 4 in chloroform)

Boiling point:

bp0.1 187-188°

Density 

1.1014 (rough estimate)

refractive index 

1.5022 (estimate)

Flash point:

2℃

storage temp. 

2-8°C

solubility 

DMF: 1 mg/ml; DMSO: 2 mg/ml; Ethanol: 10 mg/ml; PBS (pH 7.2): 0.5 mg/ml

form 

A neat solid

pka

pKa (15°) 8.61; pKb (15°) 5.59

Water Solubility 

1.664g/L(25 ºC)

Dielectric constant

3.1（20.0℃）

CAS DataBase Reference

50-36-2(CAS DataBase Reference)

EPA Substance Registry System

8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))- (50-36-2)

Safety Information

Hazard Codes 

T,Xn,F

Risk Statements 

23/24/25-43-36-20/21/22-11

Safety Statements 

26-36/37-45-36/37/39-22-16

RIDADR 

UN 1648 3/PG 2

WGK Germany 

3

RTECS 

YM2800000

HazardClass 

6.1(a)

PackingGroup 

II

Hazardous Substances Data

50-36-2(Hazardous Substances Data)

Toxicity

LD50 i.v. in rats: 17.5 mg/kg (Rose)

MSDS

• Language:English Provider:SigmaAldrich

COCAINE Usage And Synthesis

Description

Cocaine is best known as an illegal drug that produces a euphoric “high” in individuals who use it. Cocaine is an alkaloid obtained from the leaves of the coca plant, Erythroxylum coca, which is native to northwestern South America and Central America.

Description

Cocaine (Item No. 16186) is an analytical reference material categorized as a tropane. Cocaine has a high potential for abuse and has been found in samples seized by law enforcement. Cocaine is regulated as a Schedule II compound in the United States. This product is intended for research and forensic applications.

Chemical Properties

Cocaine (also known as methylbenzoylepgonine), C17H21NO4, is a colorless-to-white crystalline substance, usually reduced to powder. Cocaine is soluble in alcohol, chloroform, and ether, slightly soluble in water, giving a solution slightly alkaline to litmus.

Chemical Properties

Colorless to white crystals or white powder.Soluble in alcohol, chloroform, and ether; slightly soluble in water (solution is alkaline to litmus). The hydrochloric acid solution is levorotatory.

Physical properties

Appearance: pure white crystal, odorless. Solubility: insoluble in water (1:600); soluble in chloroform (1:0.7), ethyl ether (1:3), ethanol (1:7), and other organic solvents; soluble in acetone, benzene, ethyl acetate, two carbonyl sulfide, and petroleum ether; show monoclinic flaky crystal in ethanol. Melting point: 98° (it can be slowly evaporated over 90°), the specific rotation of ?16°.

History

In 1855, cocaine was first extracted from the leaves of herbal ingredients and named Erythroxylon by the German chemist Friedrich (G. Friedrich) (1828–1890). In 1859, the German chemist Niemann (Albert Niemann) (1834–1861) defined a higher purity of material, named cocaine. In 1880, cocaine was used as a local anesthetic by the “father of modern surgery,” William Stewart Halsted. In 1884, cocaine was firstly recommended to be used as a local anesthetic, sexual stimulant, and antidepressant by Sigmund Freud, a famous psychologist in Austria (1856– 1939). He called it “a magical substance”

Uses

Cocaine is derived from the leaves of the erythroxylum coca plant and was first used as an anaesthetic by Karl Koller in 1884. It is a potent vasoconstrictor, blocking reuptake of noradrenaline, but has significant potential for systemic toxicity. Cocaine has been used in nasal surgery as a paste or 4% solution for its properties of topical anaesthesia and vasoconstriction.

Uses

Use of cocaine is known since early times.It occurs in the South American coca leaves.Chewing of leaves mixed with lime was acommon practice among natives, who traveledgreat distances without experiencingfatigue (Cordell 1978). Cocaine is obtainedby extraction of coca leaves. It is also preparedby methylation and benzoylation of thealkaloid, ecgonine. The dilute aqueous solutionsof its hydrochloride is used as a topicalanesthetic in ophthalmology. Cocaine and itsderivatives are controlled substances listedin the U.S. Code of Federal Regulations(Title 21, Parts 321.1 and 1308.12, 1987).

Uses

Anesthetic (topical).

Uses

It was widely used as a topical anesthetic in dentistry and in ophthalmology; it also found use as an appetite suppressant, a drug used to treat morphine addiction, a stimulant, and a general elixir. Its popularity to treat depression was originally advanced by Sigmund Freud (1856 1939).
Cocaine is used medicinally for local anesthesia and vasoconstriction, especially in surgery involving the ear, nose, and throat. It is the only naturally occurring anesthetic. Although it is still used in limited quantities for surgery, many surgeons and anesthesiologists have turned to safer alternatives such as lidocaine and benzocaine. Also, the use of alternatives eliminates the storage of a well-known addictive drug in clinics and hospital pharmacies.

Production Methods

Colombia is the world’s leading producer of cocaine, with about 75% of the world’s production.Coca is grown locally and is also imported from Peru and Bolivia.the processing of coca involves mashing the leaves with a base, kerosene, and sulfuric acid to produce a pastecontaining between 40% and 70% cocaine. It can then be exported where it is dried andpurified into cocaine hydrochloride. Estimates of global consumption of cocaine vary, but areasonable approximation is roughly 750 tons. Of this amount, approximately one-third isimported into the United States, which is the leading consumer of cocaine.

Production Methods

Cocaine is derived by extraction of the leaves of coca (Erythroxylon) with sodium carbonate solution, followed by treatment with dilute acid and extraction with ether. The solvent is evaporated after which the substance is re-dissolved and subsequently crystallized. Cocaine also is prepared synthetically from the alkaloid ecgonine. Cocaine is highly toxic and habit -forming.

Definition

ChEBI: A tropane alkaloid obtained from leaves of the South American shrub Erythroxylon coca.

Definition

cocaine: A powerful drug present inthe leaver of the coca plant (Erythroxyloncoca). It stimulates the centralnervous system and has effects similarto the amphetamines. It was originallyused as a local anaesthetic. Theillegal drug is usually the soluble hydrochloride.This can be convertedinto the free-base form (known ascrack cocaine) by dissolving in waterand heating with sodium bicarbonate.Cocaine is a class A drug in theUK. It can be detected by Scott’stest.

Indications

It is mainly used for local anesthesia in various operations. It is also suitable for nasal, pharyngeal, ear, urethra, vagina, and other operations (with 5–10% solution). 2% to 3% solution is used for eye surgery.

General Description

Cocaine as a euphoriant–stimulant, psychotomimetic, anddrug of abuse could as well be discussed with amphetamineand methamphetamine, with which it shares many biologicalproperties. At low doses, it produces feelings of well-being,decreased fatigue, and increased alertness. Cocaine tends toproduce compulsive drug-seeking behavior, and a full-blowntoxic psychosis may emerge. Many of these effects appear tobe related to the effects of increased availability of DA for interactionwith postsynaptic receptors (D₂ and D₃ receptors arepertinent). Cocaine is a potent DA reuptake blocker, acting bycompetitive inhibition of the DAT. A phenethylamine moiety with added steric bulk may suffice for this action. An interactionbetween a hydrogen atom on the nitrogen of the protonatedform of cocaine and an oxygen of the benzoyl estergroup, or alternatively, an interaction between the unsharedelectron pair of the freebase nitrogen and the carbonyl of thebenzoyl ester group, could approximate this moiety.

Hazard

Poison; powerful central nervous system effects.

Health Hazard

The physiologic responses from the useof cocaine in humans are euphoria andexcitement, making it a habit-formingsubstance. Such addictive potential has alsobeen observed in rats (Hartman 1978). Highdoses can produce confusion, hallucinations,delirium, convulsions, hypothermia, andrespiratory failure. It is a toxicant to thecardiovascular and central nervous systems.The acute poisoning symptoms, in additionto those stated above, are nausea, vomiting,abdominal pains, and dilation of the pupils.
Cocaine may be inhaled, smoked, orinjected. Low to average inhalation dosesrange between 20 and 150 mg. Ether refinedpowder is more potent than the unrefinedsubstance. It may also be refined by otherchemical treatments. The lethal doses inhumans as reported in the literature arewidely varying. A dose of 1–1.5 g may befatal to humans.
LD50 value, oral (mice): 99 mg/kg
Bozarth and Wise (1985) compared thetoxicity of cocaine with that of heroinin rats, resulting from intravenous selfadministration.The animals were givenunlimited access to both compounds. Animalsself-administering cocaine showed aloss of 47% of their body weight and deteriorationof general health; 90% of the subjectsdied in 30 days. Whereas heroin showed stabledrug self-administration that increasedgradually, causing 36% mortality, cocaineshowed excessive self-administration. Thestudy showed that cocaine was much moretoxic than heroin when rats were givenunlimited access to intravenous drugs.
Langner and coworkers (1988) havereported arteriosclerotic lesions in rabbitsresulting from repeated injection of cocaine.These data indicate that the abuse of cocainemay cause damage to the aorta, resultingin the premature onset of cardiovasculardisease and its complications. Intravenousadministration of doses of 1 and 2 mg/kgdemonstrated dose-dependent increases insystolic, diastolic, mean arterial, and pulsepressures in pregnant and nonpregnant ewes(Woods et al. 1990). The study showedthat pregnancy increased the cardiovasculartoxicity caused by cocaine. In squirrelmonkeys, an increase in blood pressure wasnoted, along with increases in dopamine,epinephrine, and nonepinephrine plasmaconcentrations (Nahas et al. 1988). Hoskinsand coworkers (1988) investigated diabetespotentiation of cocaine toxicity in rats. Thestudy shows that diabetic subjects are atspecial risk to the toxicity and lethality ofthis alkaloid.
Rosenkranz and Klopman (1990) havepredicted the carcinogenic potential ofcocaine in rodents. There is no substantialevidence of its carcinogenic action. Exposureis linked to the risk of transplacental cancerinduction in the developing human fetus.
Conners and associates (1989) haveinvestigated interactive toxicity of cocainewith phenobarbitol, morphine, and ethanolin organ-cultured human and rat liver slices.The study indicated that cocaine combinedwith any of these substances showed greatertoxicity than that observed with singlecomponents. A similar interactive additiveeffect with alcohol on maternal and fetaltoxicity in Long-Evans rats has been reported(Church et al. 1988). In general, alcohol andcocaine in combination with drugs poses agreater risk to pregnancy than that of eithercompound alone.
Many anticonvulsant drugs have beenstudied for their efficacy against cocaineinducedtoxicity. Pretreatment with diazepamor phenobarbitol prevented seizure and deathfrom intoxication with cocaine in rats (Derletand Albertson 1990a). N-Methyl-D-aspartate,valproic acid, and phenytoin showed partialprotection against cocaine-induced seizures.In another paper, Derlet and associates(1990) reported that diazepam and propranololpretreatment afforded protectionagainst cocaine-induced death. Pretreatmentwith clonidine (0.25 mg/kg), prazosin(5–20 mg/kg), propranolol (8–32 mg/kg),or labetalol (40 mg/kg) protected rats againstintraperitoneal LD86 values of cocaine(70 mg/kg) (Derlet and Albertson 1990b).These substances interact with α- or β-adrenoreceptors. A combination of theseagents did not provide more protectionthan that provided by single agents. Trouveand Nahas (1986) reported the antidotalaction of nitrendipine against cardiac toxicity and the acutelethal effects of cocaine. These investigatorsreport that simultaneous administrationof nitrendipine (0.00146 mg/kg/min) andcocaine (2 mg/kg/min) increased the survivaltime of rats from 73 minutes to 309 minutesand the lethal dose of the alkaloid from146 mg/kg to 618 mg/kg..

Mechanism of action

Cocaine has been shown to block the reuptake of norepinephrine, serotonin, and dopamine; however, the reinforcing and stimulant nature of cocaine seems to be related primarily to blockade of dopamine reuptake, leading to the “ dopamine hypothesis” of cocaine's actions. [3H]Cocaine was used in an attempt to identify the “cocaine receptor,” and this was later shown to be similar to the dopamine transporter. Currently, it is thought that cocaine produces it reinforcing effects by interfering with dopamine reuptake by blocking the dopamine transporter. Although the human dopamine transporter has been cloned, it is unknown if the dopamine and cocaine binding domains are identical or how much they overlap.

Pharmacology

Cocaine can block the generation and transmission of nerve impulses in the epidermis and mucous membranes, which can last up to 20–40 min. Once it is absorbed in local or scattered to other parts of the body, the local anesthetic action disappears. It was generally used as a local anesthetic at concentration of 5–10%. Cocaine is used for topical mucosal anesthesia in clinic. Cocaine can cause changes of neurotransmitter in the central nervous system, which can lead to seizures or insanity . Cocaine stimulated the cerebral cortex, medulla oblongata, and spinal cord of the central nervous system by strengthening chemicals in the body activity and excited mood. In addition, cocaine can cause systemic vasoconstriction, which results in a number of cardiovascular complications.
Recent studies have shown that cocaine regulates gene expression associated with certain systems in the nucleus accumbens (NAc). Repeated cocaine effects lead to the change of gene expression in NAc and neuronal morphology in rodent animals. Cocaine directly induced the modification of NAc chromatin, leading to changes in histone acetylation and phosphorylation. The nucleus accumbens is a key center in the brain’s reward circuit. Cocaine addiction can cause persistent changes in gene expression in the loop which may be the basis of certain behavioral effects of cocaine addiction. The study also found that G9a overexpression can block repeated cocaine-induced enhancement of gene expression. The inhibition of G9a and dimethylated H3K9 under repeated cocaine promotes the hobby of cocaine, partly due to the transcriptional activation of the neuronal dendritic plasticity abnormality and the downregulation of G9a expression in NAc increasing the density of neuronal dendritic spines. Cocaine can pass through the blood-brain barrier and accumulate in the central nervous system. Cocaine can also pass through the placental barrier.

Clinical Use

Cocaine has a very interesting history. The coca plant was used by South American Indians for religious and mystical purposes and as a stimulant both to increase endurance and to alleviate hunger. It was introduced into Europe during the 1800s, and at the end of the 19th century, cocaine use was popular and socially acceptable. Various cocaine-containing preparations were available, and it also was used to “fortify” wines (e.g., Vin Coca). For a period of approximately 20 years, until just after the turn of the century, it was a constituent of the soft drink Coca-Cola. Additionally, cocaine was used for therapeutic reasons but was later supplanted by amphetamine.

Safety Profile

A human poison by ingestion and possibly other routes. Poison experimentally by ingestion, intraperitoneal, intravenous, subcutaneous, and parented routes. Human central nervous system effects by ingestion and possibly other routes: general anesthesia, hallucinations or distorted perceptions, and convulsions. An eye irritant. A widely abused, controlled substance. Abuse leads to habituation or addiction. In medcine, it is used as a local narcotic anesthetic applied topically to mucous membranes. The free base is solublein fats and thus is used for ointments and oily solutions. For water-soluble applications, the sulfate or hydrochloride is used. See also ESTERS. When heated to E decomposition it emits highly toxic fumes.

Environmental Fate

Cocaine primary organs of effect are the central nervous system and the cardiovascular system. Effects depend on the dose, the route of exposure, adulterants, impurities, and other substances ingested as well as individual differences in susceptibility to toxicity from cocaine. Cocaine acts as a reuptake inhibitor for the neurotransmitters serotonin, norepinephrine, and dopamine. In the periphery norepinephrine causes alpha-1 agonism, leading to vasoconstrictive effects and tachycardia. Cocaine also has nonspecific sodium channel antagonism, leading to local anesthetic effects. In overdose, cocaine can cause slowing of myocardial sodium channels similar to the quinidine-like effect seen in other sodium channel antagonists such as tricyclic antidepressants, lamotrigine, and even diphenhydramine (at high doses). This can lead to QRS widening and decreases in contractility. In addition to direct toxicity from cocaine, specific adulterants of illicit cocaine can be particularly toxic. In recent years, levamisole has emerged as a common adulterant, with nearly 80% of the world’s cocaine supply found to have significant concentrations of levamisole (up to 20% by weight). Levamisole can cause immunosuppression and vasculitis. Deaths from levamisole-mediated toxicity including infections (neutropenia-associated infections) and vasculitis have occurred. When cocaine is ingested in the presence of ethanol, cocaethylene is synthesized. Cocaethylene has similar actions to cocaine; however, it has a longer duration of action. Cocaine also can cause increases in platelet aggregation through its serotonergic effects and has direct end-organ toxicity primarily through vasoconstrictive effects.

Metabolism

Cocaine is active via nearly every possible route of administration; however, insufflation of “snow” or “coke” represents one of the most popular routes. Administered in this manner, peak effects and plasma levels are achieved within 30 minutes. Smoking the freebase form of cocaine (“crack”) results in an even more rapid effect. The freebase form rather than the hydrochloride salt is used for smoking, because the temperatures required for vaporization of the salt result in considerable decomposition. Intravenously administered cocaine can achieve peak blood levels within a few minutes. Cocaine is metabolized to benzoylecgonine, the methyl ester of ecgonine, and to a lesser extent, to ecgonine, norcocaine, and hydroxylated derivatives.

Purification Methods

(
)-Cocaine crystallises from EtOH and sublimes below 90o in a vacuum in an amorphous form. The hydrochloride crystallises from MeOH/Et2O with m 195o and [] D20 -72o (c 2 in H2O, pH 4.5), -78.5o (50% aqueous EtOH). [Sam & Reynolds J Chem Soc 97 1335 1910, Tufariello et al. J Am Chem Soc 101 2435 1979.] -Cocaine is the (+) enantiomer. [Beilstein 22 I 547, 22 II 150.]

Toxicity evaluation

Cocaine hydrochloride is a nearly odorless, bitter-tasting chemical that appears as white crystals. It is soluble in water at a rate of 200 g per 100 ml. In alcohol, 25 g is soluble in 100 ml. Cocaine hydrochloride is insoluble in ether. The melting point of cocaine hydrochloride is 197°C, and a 1% solution is of neutral (7) pH.
Cocaine freebase is volatile, anhydrous, and bitter tasting and appears as white or slightly yellow crystals. It is minimally soluble in water (0.17 g per 100 ml), somewhat soluble in alcohol (15.4 g per 100 ml), and soluble in ether (28.6 g per 100 ml). The melting point of cocaine freebase is 98°C and the boiling point is 187–188°C.
Street cocaine is often cut with various diluents and toxicity, and effect is often affected by the products used to cut cocaine (i.e., levamisole).

References

Palit, Khare, Phytochem., 8, 1559 (1969)

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