Atorvastatin calcium Chemical Properties

Melting point:

176-178°C

storage temp. 

Keep in dark place,Inert atmosphere,2-8°C

solubility 

DMSO: ≥10mg/mL

form 

white powder

color 

White to Off-White

BCS Class

2

InChIKey

FQCKMBLVYCEXJB-MNSAWQCASA-L

SMILES

C(C1=C(N(CC[C@@H](O)C[C@@H](O)CC(=O)O)C(C2C=CC(F)=CC=2)=C1C1C=CC=CC=1)C(C)C)(=O)NC1C=CC=CC=1.[Ca] |&1:6,9,r|

CAS DataBase Reference

134523-03-8(CAS DataBase Reference)

EPA Substance Registry System

1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-.beta.,delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, calcium salt (2:1),(.beta.R,.delta.R)- (134523-03-8)

Safety Information

Hazard Codes 

Xn,T,F

Risk Statements 

20/21/22-36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

26-36-45-36/37-16-7

WGK Germany 

3

Atorvastatin calcium Usage And Synthesis

Overview

Atorvastatin calcium[trade name: Lipitor] is a statin-class medication used mainly for lowering the lipid as well as preventing the event associated with cardiovascular disease^{[1, 2]}. Being similar to other kinds of statins, atorvastatin take effects by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body. Atorvastatin acts primarily in the liver. Decreased hepatic cholesterol levels further increases hepatic uptake of cholesterol and reduces plasma cholesterol levels^{[3, 4]}.
Lipitor, since 1996, has become the world's best-selling medication to that point^{[5, 6]}, with more than US$125 billion in sales over approximately 14.5 years. As of 2016, in the UK, atorvastatin costs about £2 per month^[5].

Indication and application

LIPITOR is mainly indicated for the treatment of cardiovascular disease and dyslipidemia due to its effect in lowering the cholesterol in the blood^[7-9].
LIPITOR is a prescription medicine that lowers cholesterol in the blood. It lowers the LDL-C["bad” cholesterol] and triglycerides in your blood. It can raise your HDL-C["good" cholesterol] as well^[10]. LIPITOR is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone. LIPITOR can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as age, smoking, high blood pressure, low HDL-C, or heart disease in the family. LIPITOR can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as eye problems, kidney problems, smoking, or high blood pressure^[7-10].
As a drug for the treatment of cardiovascular, LIPITOR is indicated to reduce the risk of myocardial infarction, reduce the risk of stroke and reduce the risk for revascularization procedures and angina^{[7, 8, 10, 11]}. Moreover, for adults patients with type II diabetes[having multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension], it is also highly effective^{[12, 13]}. For adults diagnosed of clinically evident coronary heart disease, LIPITOR can reduce the risk of non-fatalmyocardial infarction, fatal and non-fatal stroke, revascularization procedures as well as hospitalization for CHF and angina.
As a drug for the treatment of hyperlipidemia, it is used as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TGlevels and to increase HDL-C in adult patients with primary hypercholesterolemia or in pediatric patients as well as for the treatment of adult patients with elevated serum TG levels^{[7, 8, 14]}.

Mode of action

Atorvastatin takes effect through selectively and competitively inhibiting the hepatic enzyme HMG-CoA reductase, which is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway^{[15, 16]}. This results in a subsequent decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations^{[9. 16]}.

Adverse reactions

The most serious adverse reactions associated with LIPITOR include Rhabdomyolysis and myopathy as well as liver enzyme abnormality^[18]. Common side effects include headache, hoarseness, lower back or side pain, pain or tenderness around the eyes and cheekbones, painful or difficult urination, stuffy or runny nose^[8]. Some less common side effects also include abdominal or stomach pain, back pain, belching or excessive gas, constipation, general feeling of discomfort or illness, heartburn, indigestion or stomach discomfort, lack or loss of strength, loss of appetite, nausea, shivering, sweating, trouble sleeping and vomiting^[8].

Warning and precaution

Pregnant or lactation women should be disabled from using LIPITOR. Serious drug interactions can occur when certain medicines are used together with atorvastatin. So you should provide those information to your doctor before taking LIPITOR^{[7, 8, 17]}.
In rare cases, LIPITOR can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine. Avoid eating foods that are high in fat or cholesterol. LIPITOR will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan^{[7, 17]}.
LIPITOR is not approved for use by anyone younger than 10 years old and those patients who are allergic to it, or of liver disease. Moreover, since LIPITOR may pass into breast milk and could harm a nursing baby. Do not breast-feed while you are taking this medicine^{[7, 17]}.
Patients who have a history of liver problems, muscle pain or weakness, kidney disease, diabetes. a thyroid disorder; or drink more than 2 alcoholic beverages daily should take with care^{[7, 17]}.

Reference

1. https://www.lipitor.com
2. Kokilambigai, K. S., R. Seetharaman, and K. S. Lakshmi. "Critical Review on the Analytical Techniques for the Determination of the Oldest Statin—Atorvastatin—in Bulk, Pharmaceutical Formulations and Biological Fluids." Critical Reviews in Analytical Chemistry 47.6(2017]:538.
3. Teckchandani, S., et al. "Rhabdomyolysis following co-prescription of Fusidic Acid and Atorvastatin, with review of Statin Antimicrobial Drug Interactions." Scottish Medical Journal 54.3(2009]:50-50.
4. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al.[September 2016]. "Interpretation of the evidence for the efficacy and safety of statin therapy". Lancet. 388: 2532–2561.
5. http://www.crainsnewyork.com/article/20111228/HEALTH_CARE/111229902
6. Maggon K: Best-selling human medicines 2002-2004. Drug Discov Today. 2005 Jun 1;10(11]:739-42.
7. https://www.webmd.com/drugs/2/drug-3330/lipitor-oral/details
8. https://www.drugs.com/monograph/atorvastatin-calcium.html
9. https://www.drugbank.ca/drugs/DB01076
10. Jukema, J. W., et al. "LDL-C/HDL-C ratio in subjects with cardiovascular disease and a low HDL-C: results of the RADAR[Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport] study. " Current Medical Research & Opinion 21.11(2005]:1865-1874.
11. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM[April 2006]. "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". JAMA. 
12. Chaturvedi, S., Zivin, J., Breazna, A., Amarenco, P., Callahan, A., & Goldstein, L. B., et al.[2009]. Atorvastatin, stroke, transient ischemic attack. Neurology, 72(8], 818-819.
13. Colhoun, H. M., et al. "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study[CARDS]: multicentre randomised placebo-controlled trial. " Lancet364.9435(2004]:685-696.
14. Milionis, H., et al. "Th-P16:381 Treating to target patients with primary hyperlipidemia: Comparison of the effects of atorvastatin and rosuvastatin[The atoros study]." Current Medical Research & Opinion22.6(2006]:1123-1131.
15. Youssef, S, et al. "The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. " Nature 420.6911(2002]:78-84.
16. Black, D. M., R. G. Bakkerarkema, and J. W. Nawrocki. "An overview of the clinical safety profile of atorvastatin[lipitor], a new HMG-CoA reductase inhibitor. " Archives of Internal Medicine 158.6(1998]:577.
17. https://www.rxlist.com/lipitor-drug.htm#side_effects_interactions

Description

Lipitor was launched in Canada, the Netherlands, the UK and the US as an orally-active hypocholesterolemic agent. It was the first pharmaceutical product ever to attain over one billion dollars in sales in its first year. It can be synthesized by a number of routes but the most efficient involves the Paal-Knorr reaction of an acetonide protected dihydroxy amino ester and a diaryl phenylacetamide diketone. Lipitor is a liver selective, reversible competitive inhibitor of HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis. Lipitor monotherapy resulted in a reduction of LDL cholesterol by up to 60%. Lipitor is about 2-4 times more potent, on a dosage basis, than Simvastatin. The superior properties of Lipitor can be attributed to its greater uptake and longer duration of action in the liver. In addition to its effects on cholesterol, Lipitor is also effective in lowering triglycerides. While the mechanism is not clear, two theories proposed are: a) the decrease in cholesterol causes a concomitant increase in hepatic LDL-receptor activity (mostly B and E type) which results in a decrease in triglycerides through an increase in binding of triglycerides to VLDL and LDL, and b) the decreased level of cholesterol impairs VLDL transport of triglycerides.

Chemical Properties

White Crystalline Powder

Originator

Parke-Davis (US)

Uses

A selective, competitive HMG-CoA reductase inhibitor. Atorvastatin is the only drug in its class specfically indicated for lowering both elevated LDL-cholesterol and triglycerides in patients with hypercholesterolemia.

Uses

antihyperlipidemic, HMGCoA reductase inhibitor

Uses

DMSO and EtOH soluble

Uses

The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease.

Uses

A selective, competitive HMG-CoA reductase inhibitor. The only drug in its class specfically indicated for lowering both elevated LDL-cholesterol and triglycerides in patients with hypercholesterolemia

Uses

Atorvastatin Calcium Salt Trihydrate is a compound used as standard in the method development and validation for simultaneous determination of Atorvastatin calcium (A791750) and Ezetimibe (E975000) in tablets using UV spectrophotometric, HPLC and HPTLC methods.

Definition

ChEBI: An organic calcium salt composed of calcium cations and atorvastatin anions in a 1:2 ratio.

Manufacturing Process

285 ml 2.2 M n-butyl lithium in hexane was added dropwise to 92 ml diisopropylamine at -50-60°C under nitrogen. The well stirred solutions warmed to about -20°C, then it was cannulated into a suspension of 99 g of S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute tetrahydrophuran (THF) at -70°C and the reaction mixture was allowed to warm to -10°C for 2 hours. A suspension of MgBr2 was made from 564 ml (0.63 mol) of bromine and 15.3 g of magnesium (0.63 mol) in 500 ml THF cooled to -78°C. The enolate solution was cannulated into this suspension within 30 min and was stirred for 60 min at -78°C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3- oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml absolute THF was added dropwise over 30 min, stirred 90 min at -78°C, then was added 200 ml acetic acid, this is removed to a cool bath, 500 ml of H2O was added and the mixture concentrate in vacuo at 40-50°C. After adding of 500 ml of 1:1 EtOAc/heptane the mixture was filtered. The filtrate was washed extensively with 0.5 N HCl, then several times with H2O and finally EtOAc/heptane (3:1) and cooled with dry ice to -20°C. The light brown crystalline product was dried in vacuum oven at 40°C. The yield was 194 g. 112 g of the same product was produced by evaporation of mother liquor after recrystallization and chromatographic purification on a silicagel.
162 g of this substance was suspended in methanol/THF (5:3) and was stirred with 11.7 g of sodium methoxide until everything was dissolved and kept in the freezer overnight. Later it was quenched with AcOH concentrated in vacuo, was added to 500 ml H2O and extracted twice with EtOAc (300 ml). The combined extracts was washed with saturated NaHCO3 brine and dried over anhydrous MgSO4, purified on silica-gel and gave 86.1 g of white crystals m.p. 125-126°C, αD 20=4.23° (1.17 M, CH3OH).
81 g of the last product in 500 ml absolute THF was added as quickly as possible to the mixture of 77 ml THF at diisopropylamine, 200 ml 2.2 M of nbutyl lithium and 62 ml of t-butylacetate in 200 ml THF -40-42°C under nitrogen. Stirring was continued for 4 hours at -70°C. The reaction mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water, then saturated NH4Cl, NaHCO3 (saturated), dried over anhydrous MgSO4, filtred and the solvent evaporated.
The organic phase was dried and concentrated in vacuo to yield 73 g crude product, that was dissolved in 500 ml absolute THF, 120 ml triehtylborane and 0.7 g t-butylcarboxylic acid, 70 ml methanol and 4.5 g sodium borohydride was added. The mixture was stirred at -78°C under a dry atmosphere for 6 hours, poured slowly into 4:1:1 mixture of ice/30%H2O2/H2O and stirred overnight. CHCl3 (400 ml) was added and organic layer washed extensively with H2O until no peroxide could be found, was dried over MgSO4, filtered and was treated by chromatography on silica gel to yield 51 g. The product was dissolved in THF/methanol and saponificated with NaOH and, concentrated to remove organic solvents at room temperature, added 100 ml H2O, and extracted with Et2O twice. Organic layer was thoroughly dried and it was left at room temperature for the next 10 days, then concentrated.
Chromatography on silica gel yielded 13.2 g racemate of lactone - trans-(+/- )-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di-diphenyl-1-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. This racemate was divided by chiral synthesis which was made analogously the method in US Pat. No. 4,581,893. Then each isomer was saponificated with NaOH and purificated by HPLC. The calcium salt corresponding acid was prepared by reaction with 1 eq. of CaCl2·2H2O in water.

brand name

Lipitor (Pfizer).

Therapeutic Function

Anticholesteremic

Biological Activity

Potent HMG-CoA reductase inhibitor (IC 50 = 8 nM). Reduces circulating LDL-C by inhibiting cholesterol biosynthesis and inducing expression of LDL receptors. Inhibits smooth muscle cell proliferation in vitro and exhibits antinociceptive effects in the inflammatory hypernociception model.

Atorvastatin calcium(134523-03-8)Related Product Information

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• PHENYL VALERATE
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• Atorvastatin Cyclic (Fluorophenyl) Impurity