Atropine Chemical Properties

Melting point:

115-118 °C

Boiling point:

431.53°C (rough estimate)

Density 

1.0470 (rough estimate)

refractive index 

1.5200 (estimate)

Flash point:

2℃

storage temp. 

-20°C

solubility 

H₂O: 2 mg/mL

form 

powder

pka

9.7(at 21℃)

color 

white

Water Solubility 

1.6g/L(18 ºC)

Sensitive 

Light Sensitive

Merck 

14,875

BRN 

91260

InChIKey

RKUNBYITZUJHSG-SPUOUPEWSA-N

CAS DataBase Reference

51-55-8(CAS DataBase Reference)

NIST Chemistry Reference

Atropine(51-55-8)

EPA Substance Registry System

Atropine (51-55-8)

Safety Information

Hazard Codes 

T+,Xn,F

Risk Statements 

26/28-36/37/38-20/21/22-36-11

Safety Statements 

25-45-36-26-36/37-16

RIDADR 

1544

WGK Germany 

3

RTECS 

CK0700000

F 

8-10-23

TSCA 

Yes

HazardClass 

6.1

PackingGroup 

III

HS Code 

29399900

Hazardous Substances Data

51-55-8(Hazardous Substances Data)

Toxicity

LD50 orally in rats: 750 mg/kg (Cahen, Tvede)

MSDS

• Language:English Provider:SigmaAldrich

Atropine Usage And Synthesis

Overview

Atropine is an alkaloid extracted from the Atropa bell-adonna, Datura stramonium, or Hyosc-yamus niger. What is naturally occurring is the unstable L-hyoscyamine, which can be converted to the stable racemate atropine after chemical treatment. It can also be chemically synthesized; what is commonly used in its sulfate. It appears as white crystalline powder, being odorless, bitter, and soluble in water and alcohol. Upon contact with alkaline drugs, it can cause decomposition. Atropine blocks the M-choline receptor, thereby antagonizing the M-like effect of acetylcholine or its quasi-drug (muscarinic effect).
The main effect is as follows:

1. Relax the smooth muscle: This product has the role of relaxation of many visceral smooth muscle; it has remarkable relaxation effect on over-activity or spammed smooth muscle, while having less effect on the normal activity of the smooth muscle.
2. Inhibition of glandular secretion: inhibit the glandular secretion by blocking the M-choline receptor. The most obvious effect occurs on salivary glands and sweat glands. It can also greatly reduce the secretion of lacrimal glands and respiratory glands, but the impact on gastric acid secretion is smaller.
3. The effect on the eye: atropine, through blocking the pupil sphincter and ciliary muscle M-choline receptors, is manifested as mydriasis, increased intraocular pressure and adjust paralysis. All three effects have important clinical implications.
4. The effect on the cardiovascular: a larger dose (1 ~ 2mg) atropine can get rid of the inhibitory effect of the vagus nerve on the heart, thus accelerating the heart rate. Large doses can dilate the skin and visceral blood vessels, and relieve arteriolar spasm. Its mechanism of dilating blood vessels and relieving small vasospasm is unknown.
5. Excitement of the central nervous system: high-dose cause irritability, prolonged talk and delirium. Poisoning dose (more than 10mg) can produce hallucinations, disorientation, involuntary exercise and convulsions.

Chemical properties

It appears as white crystalline powder, odorless, tasteless. Mp 114-116°C; sublimation at 93-110 °C under high vacuum. The solubility of this product in each solvent: 80 ℃ hot water (1:90), ethanol (1: 2), chloroform (1: 1), ether (1:25), dissolved in benzene and dilute acid solution. Low toxicity, LD50 (rat, oral): 622mg / kg.

Pharmacokinetics

It can be quickly absorbed by the gastrointestinal tract after oral administration and quickly distributed to the body tissue. It can also penetrate through the placenta into the fetal circulation. Clinical studies have shown that after intramuscular injection of 2 mg, 85 ~ 88% is subject to urine excretion within 24 hours. Approximately 5% of them were found in their prototypes and 33% of their metabolites; only a small amount was excreted in feces and other secretions.

Side effects

Dry mouth, blurred vision, heart palpitations, dry skin and constipation. High-dose poisoning switches excitement into inhibition, causing coma and respiratory paralysis and death.

Production

It can be extracted from the root of Solanaceae Scoparia Anisodus tanguticus or Himalayan Scoparia; can also be obtained by artificial synthesis.
Belladonna leaf is extracted out of the scopolamine (L-body), followed by racemization, recrystallization to make it.

Category

toxic substances

Toxicity grade

highly toxic

Acute Toxicity

Oral - Rat LD50: 500 mg / kg; Oral - Mouse LD50: 75 mg / kg

Flammability Hazard characteristics

Flammable; Combustion produces toxic nitrogen oxide fumes; Patient medication side effects: Visual changes; Dilated pupils, Muscle weakness.

Storage and transportation

Ventilated, dry and low temperature; Separated from foodstuffs in storehouse

Extinguishing agent

dry powder, foam, sand, carbon dioxide, water mist

Description

Atropine is a naturally occurring tropane alkaloid extracted from plants of the family Solanaceae including deadly nightshade (A. belladonna). It is a non-selective, competitive antagonist of the muscarinic acetylcholine receptor types M₁, M₂, M₃, M₄, and M₅ (pKBs range from 8.9-9.8). Atropine increases firing of the sinoatrial node and conduction through the atrioventricular node of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions. It is classified as an anticholinergic (parasympatholytic) drug and commonly used to dilate the pupils, increase heart rate, reduce salivation and other secretions, and as an antidote against organophosphate poisoning.

Description

Atropine is considered to be the most effective antidote for both OP and CB intoxication. By effectively competing with acetylcholine for the same cellular receptors, it prevents overstimulation of the autonomous parasympathetic system. Most importantly, it helps prevent asphixia, the main cause of death. In human subjects, it is customary to constantly infuse atropine in order to maintain optimal concentration throughout recovery from the “cholinergic crisis.” In wildlife rehabilitation, this is impractical and subjects need to be repeatedly injected with atropine.

Chemical Properties

Atropine, also known as daturine, C17H23NO3, white, crystalline substance, optically inactive, but usually contains levorotatory hyoscyamine. Compound is soluble in alcohol, ether, chloroform, and glycerol; slightly soluble in water.

Chemical Properties

White or almost white, crystalline powder or colourless crystals.

Physical properties

Appearance: atropine appears as colourless, odourless crystals or a white crystalline powder. Solubility: very soluble in water and soluble in ethanol. Melting point: melting point of atropine isn’t higher than 189?°C (melting time decomposition) (Chinese Pharmacopoeia), 114–118?°C (United States Pharmacopeia) and 115– 119?°C (British Pharmacopoeia). The chemical structure of atropine is made up of amino alcohol esters. It is easy for atropine to be hydrolysed into tropine and despun tropic acid under alkaline condition. Atropine is stable in faintly acid and neutral aqueous solution, most stable at pH 3.5–4.0.

Originator

Atromed,Promed Exports,India

History

Mandragora (mandrake) was described for treatment of wounds, gout and sleeplessness and as a love potion in the fourth century BC by Theophrastus. Atropine extracted from the Egyptian henbane was used by Cleopatra in the last century BC to dilate her pupils in the hope that she would appear more alluring. In the Renaissance, women used the juice of the berries of Atropa belladonna to enlarge the pupils of their eyes for cosmetic reasons. It isn’t until the first century AD that Dioscorides found that wine containing mandrake can be used as an anaesthetic treatment for pain or sleeplessness in surgery or cautery. The combination of extracts containing tropane alkaloids and opium was used to treat diseases, which was popular in the Roman and Islamic Empires and Europe. The combination was replaced by the use of ether, chloroform and other modern anaesthetics about 100?years ago. The mydriatic effects of atropine were studied by the German chemist Friedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F.? G. Mein (1799–1864) succeeded in separating pure atropine from plants. The substance was first synthesized by German chemist Richard Willst?tter in 1901. In 1889, Richard Willst?tter first confirmed the chemical structure of atropine. Atropine was first synthesized by A.?Ladenburg. Homatropine, a kind of tropic alkaline ester, is used in the diagnosis and treatment in ophthalmology, and it has a shorter acting time than atropine. Quaternary ammonium compounds of atropine obtained by alkylation of nitrogen atoms have anticonvulsant function, which does not affect the central nervous system, due to their polarity. In 1970, atropine sulphate was synthesized in Hangzhou, the location of the first pharmaceutical factory in China, which increased the yield, reduced the cost and met the requirements of clinics.

Uses

anticholinergic, mydriatic

Uses

Atropine is used in medicine and is an antidote for cholinesteraseinhibiting compounds, such as organophosphorus insecticides and certain nerve gases. Atropine is commonly offered as the sulfate. Atropine is used in connection with the treatment of disturbances of cardiac rhythm and conductance, notably in the therapy of sinus bradycardia and sick sinus syndrome. Atropine is also used in some cases of heart block. In particularly high doses, atropine may induce ventricular tachycardia in an ischemic myocardium. Atropine is frequently one of several components in brand name prescription drugs.

Uses

Scopolamine is found in the leaves of Daturametel L., D. meteloides L., and D. fastuosavar. alba (Cordell 1978). It is used as asedative, a preanesthetic agent, and in thetreatment of motion sickness (Merck 1989).

Production Methods

Atropine is prepared by extraction from Datura stramonium, or synthesized. The compound is toxic and allergenic.

Definition

An alkaloid that is the 3(s)-endo isomer of atropine.

Definition

atropine: A poisonous crystalline alkaloid,C₁₇H₂₃NO₃; m.p. 118–119°C. Itcan be extracted from deadly nightshadeand other solanaceous plantsand is used in medicine to treat colic,to reduce secretions, and to dilatethe pupil of the eye.

Indications

This product was recorded in the Pharmacopoeia of the People’s Republic of China (2015), the British Pharmacopoeia (2017), the United States Pharmacopeia (40), the Japanese Pharmacopoeia (17th ed.), the Indian Pharmacopoeia (2010), the European Pharmacopoeia (9.0th ed.), the International Pharmacopoeia (5th ed.) and the Korean Pharmacopoeia (10th ed.). Atropine sulphate is commonly used in clinics. Dosage forms are injection, tablet and eye ointment; atropine sulphate was mainly used to treat toxic shock and organic phosphorus pesticide poisoning, to relieve visceral colic, as preanaesthetic medication and to reduce bronchial mucus secretion. The indications of atropine sulphate eye gel are iridocyclitis, fundus examination and mydriasis.

Manufacturing Process

Atropin was obtained from belladonna roots and by racemisation of Lhyoscyamine with dilute alkali or by heating in chloroform solution. The alkaloid was crystallised from alcohol on addition of water, or from chloroform on addition of light petroleum, or from acetone in long prisms, m.p. 118°C, sublimed unchanged when heated rapidly. It is soluble in alcohol or chloroform, less soluble in ether or hot water, sparingly so in cold water (in 450 L at 25°C) and almost insoluble in light petroleum. Atropine is optically inactive.

brand name

Atrophate [Veterinary] (Schering-Plough Animal Health); Atropisol (Ciba Vision, US Ophthalmics); Isopto Atropine (Alcon).

Therapeutic Function

Anticholinergic

World Health Organization (WHO)

Atropine, an alkaloid with anticholinergic activity extracted from Atropa belladonna, has been widely used in medicines for centuries for its antispasmodic and mydriatic properties. It is also used for premedication prior to anaesthesia. Preparations containing atropine remain available and the substance is included in the WHO Model List of Essential Drugs.

General Description

Atropine is the tropine ester of racemictropic acid and is optically inactive. It possibly occurs naturallyin various Solanaceae, although some claim, with justification,that whatever atropine is isolated from naturalsources results from racemization of (-)-hyoscyamine duringthe isolation process. Conventional methods of alkaloidisolation are used to obtain a crude mixture of atropine andhyoscyamine from the plant material. This crude mixture isracemized to atropine by refluxing in chloroform or by treatmentwith cold dilute alkali. Because the racemizationprocess makes atropine, an official limit is set on thehyoscyamine content by restricting atropine to a maximumlevorotation under specified conditions.
Atropine occurs in the form of optically inactive, white,odorless crystals possessing a bitter taste. It is not very solublein water (1:460, 1:90 at 80°C) but is more soluble inalcohol (1:2, 1:1.2 at 60°C). It is soluble in glycerin (1:27),in chloroform (1:1), and in ether (1:25). Saturated aqueoussolutions are alkaline in reaction (pH 9.5). The free baseis useful when nonaqueous solutions are to be made, such asin oily vehicles and ointment bases. Atropine has a plasmahalf-life of about 2 to 3 hours. It is metabolized in the liverto several products, including tropic acid and tropine.

Hazard

Extremely toxic, poison, paralyzes the parasympathetic nervous system by blocking the action of acetylcholine at nerve endings.

Health Hazard

The toxic effects are similar to atropine. Thesymptoms at toxic doses are dilation of the pupils, palpitation, blurred vision, irritation,confusion, distorted perceptions, hallucinations,and delirium. However, the mydriaticeffect is stronger than that of many othertropane alkaloids. Scopolamine is about threeand five times more active than hyocyamineand atropine, respectively, in causing dilationof the pupils. Its stimulating effect on thecentral nervous system, however, is weakerthan that of cocaine but greater than thatof atropine. The oral LD50 value in mice iswithin the range of 1200 mg/kg.
The histidine reversion–Ames test formutagenicity gave inconclusive results.

Pharmacology

Atropine is a blocker of typical M-choline receptor. In addition to terminating the gastrointestinal smooth muscle spasm, inhibiting glands, dilating pupils, increasing intraocular tension, adjusting vision through paralysis, accelerating heart rate and dilating bronchi, large doses of atropine dilate blood vessels, terminating the spasmodic contraction and improving minicirculation. Atropine can excite or inhibit the central nervous system in a dose-dependent manner. Atropine exerts longer and stronger effect on heart, intestine and bronchial smooth muscle than other belladonna alkaloids. Atropine also relaxes the pupillary sphincter and the ciliary muscle and dilates the pupils by blocking M-choline receptor in ocular tissue. Blockers of M-choline receptor included atropine, scopolamine, anisodamine and anisodine. Belladonnas not only block M-choline receptor in internal organ cells but also in the central nervous system. Compared with atropine, scopolamine has an oxygen bridge, which increases central nervous system function. The oxygen bridge of scopolamine is partially broken and then becomes anisodamine, which is difficult to pass through the blood-brain barrier, and symptoms caused by atropine in the central nervous system were less than that caused by atropine. Peak concentration of plasma can be reached at 15–20?min after intramuscular injection of atropine and at 1–2?h after oral administration and can last for 4–6?h. Most of the atropine can be absorbed by the gastrointestinal tract and other mucous membranes, and a little of the atropine can be absorbed by the eyes and skin. The t1/2 is 3.7–4.3?h. Binding rate of plasma protein is 14–22%. Volume of distribution is 1.7?L/kg after oral administration. Atropine can rapidly distribute to different organ systems and pass the blood-brain barrier and the placenta. After absorption by the eye’s conjunctiva, 30% of the products are excreted unchanged via the kidneys; the others become metabolites by hydrolysis and glucuronidation or glucosidation. After 1% gel eye drop, enlarged pupil function lasts for 7–10?days, and regulatory paralysis lasts for 7–12?days.

Clinical Use

The best known of the muscarinic blocking drugs are the belladonna alkaloids, atropine (Atropine) and scopolamine (Scopolamine).They are tertiary amines that contain an ester linkage. Atropine is a racemic mixture of DL-hyoscyamine, of which only the levorotatory isomer is pharmacologically active.Atropine and scopolamine are parent compounds for several semisynthetic derivatives, and some synthetic compounds with little structural similarity to the belladonna alkaloids are also in use.All of the antimuscarinic compounds are amino alcohol esters with a tertiary amine or quaternary ammonium group.

Safety Profile

Poison by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Human systemic effects by ingestion and intramuscular routes: visual field changes, mydriasis @updlary dtlation), and muscle weakness. An experimental teratogen. Other experimental reproductive effects. An alkaloid. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Atropine, the D,L-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester of |á-hydroxymethyl phenylacetic acid (14.1.4), can be synthesized by a standard scheme of synthesizing of tropane alkaloids. Condensation of maleyl aldehyde with methylamine and acetonedicarboxylic acid gives tropenone (14.1.1), which is the main starting material for the synthesis of both atropine and scopolamine. The carbonyl group of tropenone is reduced, thus forming tropenol (14.1.2), after which the double bond between C6 and C7 of the tropane ring is hydrogenated, giving tropine (14.1.3). Esterification of the tropenol gives the desired atropine (14.1.4) [1¨C6].

Environmental Fate

Atropine competitively antagonizes acetylcholine at the neuroreceptor site. Atropine prevents acetylcholine from exhibiting its usual action but does not decrease acetylcholine production. Cardiac muscle, smooth muscle, and the central nervous system are most affected by the antagonism of acetylcholine.

Purification Methods

Atropine crystallises from acetone or hot water, and sublimes at ~ 100o/high vacuum. [Beilstein 21/1 V 235.]

Toxicity evaluation

Free atropine is only slightly soluble in cold water. It melts at 115°C but decomposes upon boiling.
Environmental monitoring of atropine is not routinely performed by regulatory bodies. Hazardous short-term degradation products are not likely to occur. Accidental environmental exposure may occur through unintentional ingestion of toxic plants of the Solanaceae family, such as the deadly nightshade.

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