Diltiazem hydrochloride Property

Melting point:

212-214 °C

alpha 

D24 +98.3 ± 1.4° (c = 1.002 in methanol)

Density 

1.30 g/cm3

refractive index 

118 ° (C=1, H2O)

Flash point:

2℃

storage temp. 

2-8°C

solubility 

Freely soluble in water, in methanol and in methylene chloride, slightly soluble in anhydrous ethanol.

form 

Powder

color 

White to off-white

PH

pH (10g/l, 25℃) : 4.3～5.3

Water Solubility 

soluble

Merck 

13,3226

BRN 

4228706

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20°C for up to 3 months.

CAS DataBase Reference

33286-22-5(CAS DataBase Reference)

EPA Substance Registry System

1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, hydrochloride (1:1), (2S,3S)- (33286-22-5)

Safety

Hazard Codes 

Xn,Xi,F

Risk Statements 

22-40-36/37/38-36-20/21/22-11

Safety Statements 

36-45-36/37-26-16

RIDADR 

3249

WGK Germany 

3

RTECS 

DL0310000

F 

8-10

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29349990

Toxicity

LD50 in male, female mice, male, female rats (mg/kg): 61, 58, 38, 39 i.v.; 260, 280, 520, 550 s.c.; 740, 640, 560, 610 orally (Nagao, 1972)

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

Diltiazem hydrochloride Chemical Properties,Usage,Production

Description

Diltiazem HCl (33286-22-5) is a?non-dihydropyridine-type blocker of L-type Ca2+ channels.1,2 Reduces Ca2+ oscillations in subcellular compartments in vascular smooth muscle cells.3?Also blocks P-type Ca2+ channels in freshly dissociated rat cerebellar Purkinje neurons.4 Clinically useful antihypertensive agent.5?Cell permeable.

Chemical Properties

Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. It has a molecular weight of 450.98. Diltiazem hydrochloride injection is a clear, colorless, sterile, nonpyrogenic solution. It has a pH range of 3.7 to 4.1.

Originator

Herbesser,TANABE SEIYAKU,Japan,1974

Uses

Diltiazem Hydrochloride is a calcium channel blocker with vasodilating activity. Anti-anginal; anti-hypertensive; anti-arrhythmic (class IV).

Uses

antihypertensive, sedative, antibacterial

Uses

Peripheral Vasodilator

Uses

An antianginal, antihypertensive. Regulates Calcium release from intracellular stores in neutrophils

Definition

ChEBI: Diltiazem hydrochloride is a hydrochloride salt resulting from the reaction of equimolar amounts of diltiazem and hydrogen chloride. A calcium-channel blocker and vasodilator, it is used in the management of angina pectoris and hypertension. It has a role as an antihypertensive agent, a vasodilator agent and a calcium channel blocker. It contains a diltiazem(1+). It is an enantiomer of an ent-diltiazem hydrochloride.

Manufacturing Process

β-Diethylaminoethyl chloride is condensed with 2-(4-methoxyphenyl)-3- hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in a first step. Then a mixture of 1.5 grams of 2-(4-methoxyphenyl)-3-hydroxy-5-(βdimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 20 ml of acetic anhydride was heated on a water bath for 5 hours. The reaction mixture was evaporated under reduced pressure to remove acetic anhydride and the concentrated product was poured into ice water. The resulting mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The chloroform layer was dried and evaporated to remove the solvent. The residue was dissolved in acetone, and an ethanol solution containing hydrogen chloride was added thereto producing 1.53 grams of 2-(4-methoxyphenyl)3- acetoxy-5-(β-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride having a melting point from 187° to 188°C.
The starting material is made by reacting 4-methoxybenzaldehyde with ethyl chloroacetate; that product with sodium ethoxide; and that product with 2- aminothiophenol.

brand name

Cardizem (Biovail); Cartia (Andrx); Dilacor (Watson); Diltzac (Apotex); Taztia (Andrx); Tiazac (Biovail).

Therapeutic Function

Coronary vasodilator

General Description

Diltiazem hydrochloride is a calcium ion cellular influx inhibitor. It was developed and introduced inJapan as a cardiovascular agent to treat angina pectoris. Itwas observed to dilate peripheral arteries and arterioles. Thedrug increases myocardial oxygen supply by relieving coronaryartery spasm and reduces myocardial oxygen demandby decreasing heart rate and reducing overload. Diltiazemhydrochloride is used in patients with variant angina. Thedrug has electrophysiological properties similar to those ofverapamil and is used in clinically similar treatment conditionsas an antiarrhythmic agent, but it is less potent.
The drug is absorbed rapidly and almost completely fromthe digestive tract. It reaches peak plasma levels within 1hour after administration in gelatin capsules. Oral formulationson the market are sustained-release preparations providingpeak plasma levels 3 to 4 hours after administration.

Biological Activity

Antihypertensive and cardioprotective agent; an inhibitor of L-type Ca 2+ channels.

Biochem/physiol Actions

Product does not compete with ATP.

Clinical Use

Calcium-channel blocker:
Prophylaxis and treatment of angina
Hypertension

Metabolism

Diltiazem is almost completely absorbed from the gastrointestinal tract after oral doses, but undergoes extensive first-pass hepatic metabolism resulting in a bioavailability of about 40%. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4; one of the metabolites, desacetyldiltiazem, has been reported to have 25-50% of the activity of the parent compound
About 2-4% of a dose is excreted in urine as unchanged diltiazem with the remainder excreted as metabolites in bile and urine.

storage

Store at RT

Mode of action

Diltiazem Hydrochloride is a benzothiazepine calcium channel blocking agent. Diltiazem hydrochloride inhibits the transmembrane influx of extracellular calcium ions into select myocardial and vascular smooth muscle cells, causing dilatation of coronary and systemic arteries and decreasing myocardial contractility. Because of its vasodilatory activity, this agent has been shown to improve the microcirculation in some tumors, thereby potentially improving the delivery of antineoplastic agents to tumor cells.

References

1) Kraus?et al.?(1998),?Molecular mechanism of diltiazem interaction with L-type Ca2+ channels; J. Biol. Chem.,?273?27205 2) Godfraind?et al. (1986),?Calcium antagonism and calcium entry blockade; Pharmacol. Rev.,?38?321 3) Fedoryak?et al.?(2004),?Spontaneous Ca2+ oscillations in subcellular compartments of vascular smooth muscle cells rely on different Ca2+ pools; Cell Res.,?14?379 4) Ishibashi?et al. (1995),?Block of P-type Ca2+ channels in freshly dissociated rat cerebellar Purkinje neurons by diltiazem and verapamil; Brain Res.,?695?88 5) Chaffman and Bogden (1985),?Diltiazem. A review of its pharmacological properties and therapeutic efficacy; Drugs,?29?387