Atorvastatin is the drug for lipid-lowering and preventing cardiovascular disease, including in the statin class of medication. Atorvastatin calcium tablets are sold as Lipitor under the brand name and Pfizer packages the medication in combination with other medications such as Atorvastatin / Amlodipine.
Atorvastatin calcium in other countries is in the form of tablets by generic manufacturers under the brand names like Atorva, Atorvastatin Parke-Davis, Litorva, Tord, Curator, etc. Pfizer has its own generic version under the name Zarate.
What is the main use of Atorvastatin?
The main use of Atorvastatin drug for lipid-lowering and for the treatment of dyslipidemia and the prevention of cardiovascular disease. Atorvastatin got patented in 1986 and got approved in Unites states in 1996 for medical use. The U.S. Patent on Lipitor by Pfizer got expired on 30th November 2011.
Atorvastatin was first synthesized by Dr. Bruce Roth in 1985 and got approved in 1996 by FDA. Atorvastatin unlike other members of the statin group is an active compound and does not require activation.
Atorvastatin an overview:
The structure of Atorvastatin is represented as:
IUPAC Name -(3R,5R)-2-(4-Fluorophenyl)-3,5-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid
CAS No. – 134523-00-5
The Synthesis of Atorvastatin at Parke-Davis happened first during the drug discovery and was racemic and the separation of the enantiomers was done by chiral chromatography. The use of the ester chiral auxiliary was the early enantioselective route to make Atorvastatin set the stereochemistry via a diastereoselective aldol reaction for the first two alcohol functional groups.
The compound first entered the pre-clinical development stage; the process chemistry is developed for scalable synthesis and is also a cost-effective process. The main key element in the case of Atorvastatin case was the overall synthesis and ensuring the stereochemical purity of the final drug substance and also the key aspect of the overall design is in establishing the first stereocentre.
Atorvastatin’s final commercial production mainly approach depend on the chiral pool, the first alcohol functional group, and its stereochemistry was taken into the synthesis with an easily sourced plant-derived natural product and inexpensive i.e. an ascorbic acid. In Atorvastatin calcium complex involves one calcium ion, three water molecules, and two Atorvastatin ions.
During the manufacturing process of the active substance, the impurity profile is considered the critical part and overall it depends on the manufacturing process and its parameters. There are different analytical techniques that are used to control the impurities at different stages and can be analyzed by column chromatography and other techniques to get the final product purity as per the required pharmacopeia.
The specification and the critical intermediates have limits for the specified and unspecified impurities and also the impurity profile as specified for the final active pharmaceutical ingredient (API). To have control over impurities, process parameters and method of manufacturing recent strategy QbD can be used for development and manufacturing i.e. quality by design QbD.
QbD is the method that helps to ensure that the final drug substance is as per the purity, quality, and other parameters. Quality by design in the manufacturing process has advantages over process controls, analytical techniques, and quality assurance. As it is very important to control the quality of the final active substance and presently there are various rapid, simple, existing analytical techniques available like a broad-based method of analysis, robust like high performance liquid chromatographic techniques, validation, and also the ICH International Conference of Harmonization guidelines.
What are the types of pharmacopeia and non-pharmacopeia Impurities reported for Atorvastatin?
Several impurities of Atorvastatin have been isolated and purified by chemical synthetic methods and analytical techniques and are reported in pharmacopeia and also available at Veeprho.
LIST OF ATORVASTATIN IMPURITIES:
Atorvastatin EP Impurity A / Atorvastatin Related Compound A / Desfluoro Atorvastatin (Free base) CAS No.: 433289-84-0 Molecular Weight: 540.65 g/mol IUPAC : (3R, 5R)-7-[3-(Phenylcarbamoyl)-5-phenyl-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3, 5-dihydroxyheptanoic acid |
Atorvastatin EP Impurity C / Atorvastatin Related compound C / Fluoro Atorvastatin / Atorvastatin Difluoro Analog (free base) CAS No.: 693793-53-2 Molecular Weight: 1191.3 IUPAC Name: (3R, 5R)-7-[3-(phenylcarbomoyl)-4, 5-bis(4-fluorophenyl)-2-isopropyl-1H-pyrrol-1- yl]-3, 5-dihyroxyheptanoic acid, calcium salt. |
Atorvastatin EP Impurity D CAS No.: 148146-51-4 Molecular Weight: 431.46 IUPAC Name: Atorvastatin epoxide impurity OR 3-(4-fluorophenyl)-2-isobutyryl-3-phenyloxirane- 2-carboxylic acid phenylamide |
Atorvastatin EP Impurity F (free acid) / Atorvastatin Diamino Impurity / Atorvastatin Related Compound F CAS No.: 887196-24-9 Molecular Weight: 717.84 IUPAC Name: (3R, 5R)-7-[[(3R, 5R)-7-[2-(4-Fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3, 5-dihydroxy-1-oxoheptyl]amino]-3, 5-dihydroxy-heptanoic Acid |
Atorvastatin EP Impurity G CAS No.: 887196-29-4 Molecular Weight: 612.50 g/mol(Salt);572.50 g/mol(Free Base) IUPAC Name: 2-(4-Fluorophenyl)-δ-hydroxy-β-methoxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic Acid Calcium Salt |
Atorvastatin EP Impurity G / Atorvastatin -3-O-Methyl CAS No.: 887324-53-0 Molecular Weight: 572.67 g/mol IUPAC Name: (3R, 5R)-7-[3-(Phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-methoxy-heptanoic acid |
Atorvastatin EP Impurity H / Atorvastatin Lactone / Atorvastatin USP Related comp H CAS No.: 125995-03-1 Molecular Weight: 540.62 IUPAC Name: 5-(4-Fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[2-[(2R, 4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1H-pyrrole-3-carboxamide |
Atorvastatin EP Impurity K / Atorvastatin Methyl Ester / Diol Methyl Ester Impurity CAS No.: 345891-62-5 Molecular Weight: 572.67 IUPAC Name: (3S, 5R)-7-[3-(Phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3, 5-dihydroxyheptanoic acid methyl ester |
Atorvastatin Epoxy Tetrahydrofuran Analog CAS No.: 873950-19-7 Molecular Weight: 449.47 IUPAC Name: 4-(4-Fluorophenyl)-2, 4-dihydroxy-2-isopropyl-N, 5-diphenyl-3, 6-dioxabicyclo[3.1.0]hexane-1-carboxamide |
Atorvastatin Ethyl Ester impurity CAS No.: 1146977-93-6 Molecular Weight: 586.69 IUPAC Name: (βR, δR)-2-(4-Fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic Acid Ethyl Ester |
Atorvastatin FXA Impurity / Atorvastatin 6-Hydroxy analog / Atorvastatin Cyclo IP CAS No.: 1316291-19-6 Molecular Weight: 612.62 IUPAC Name: 4-{6-(4-Fluorophenyl)-7, 8-epoxy-6-hydroxy-8a-isopropyl-7-phenyl-8-(phenylcarbamoyl)hexahydro-2H-pyrrolo[2, 1- b][1, 3]oxazin-2-yl}-3-hydroxybutanoic acid sodium salt |
Atorvastatin Isopropyl Ester CAS No.: 1035205-25-4 Molecular Weight: 600.72 g/mol IUPAC Name: (3R, 5R)-7-[3-(Phenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3, 5-dihydroxyheptanoic acid isopropyl ester |
Atorvastatin tert-Butyl Ester / Atorvastatin Butyl Ester Impurity/Atorvastatin EP Impurity N CAS No.: 134395-00-9 Molecular Weight: 614.76 IUPAC Name: 5-(4-Fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[2-[(2R, 4R)-tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1H-pyrrole-3-carboxamide. |
Atorvastatin-FX1 Impurity (Na Salt) / Atorvastatin Cyclo FP Impurity / 7-hydroxy analog CAS No.: 1315629-79-8 Molecular Weight: 590.64g/mol (Acid); 612.22g/mol (Na Salt) IUPAC Name: 4-(1b-(4-fluorophenyl)-7-hydroxy-7-isopropyl-1a-phenyl-7a- (phenylcarbamoyl)hexahydro-1aH-oxireno[2’, 3’:3, 4]pyrrolo[2, 1- b][1, 3]oxazin-3-yl)-3-hydroxybutanoic acid Sodium salt |
5-Oxo Atorvastatin CAS No.: 1391052-82-6 Molecular Weight: 556.62 g/mol IUPAC Name: (γR)-2-(4-Fluorophenyl)-γ-hydroxy-5-(1-methylethyl)-δ-oxo-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic Acid |
References:
- “Atorvastatin Calcium Monograph for Professionals”. Drugs.com. AHFS. Retrieved 23 December 2018.
- Fischer J, Ganellin CR (2006). Analog-based Drug Discovery. John Wiley & Sons. p. 473. ISBN 9783527607495.
- World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533.
- Hitchings A, Lonsdale D, Burrage D, Baker E (2014). The Top 100 Drugs e-book: Clinical Pharmacology and Practical Prescribing. Elsevier Health Sciences. p. 197.
- Corey E., Czako B. and Kurti L. (2007). Molecules and medicine. John Wiley & Sons, Inc. (ISBN 978-0-470-26096-8).
- Ray SK, Rege NN: Atorvastatin: in the management of hyperlipidemia. J Postgrad Med. 2000 Jul-Sep;46(3):242-3.
- Medical Product Reviews. “Atorvastatin Calcium (Lipitor Tablets) – Uses, Dosage and Side Effects”. Retrieved 3 May 2012.
- “Pfizer’s 180-Day War for Lipitor”. PM360. Retrieved 12 April 2020.
- News Medical (March 2010). “Lipitor – What is Lipitor?”. Retrieved 3 May 2012.
- Rapley L (31 May 2012). “Atorvastatin sole funding announced”. PharmacyToday.co.nz. Archived from the original on 17 July 2014. Retrieved 16 July 2014.
- Roth BD (2002). The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Progress in Medicinal Chemistry. Vol. 40. pp. 1–22. doi:10.1016/S0079-6468(08)70080-8.
- Roth BD, Blankley CJ, Chucholowski AW, Ferguson E, Hoefle ML, Ortwine DF, Newton RS, Sekerke CS, Sliskovic DR, Wilson M (1991). “Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran 2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus”. J. Med. Chem. 34 (1): 357–366. doi:10.1021/jm00105a056
- Li JJ, Johnson DS, Sliskovic DR, Roth BD (2004). “Chapter 9. Atorvastatin Calcium (Lipitor)”. Contemporary Drug Synthesis. John Wiley & Sons, Inc. pp. 113–125.Fig. 1. Chemical structure of Atorvastatin Calcium”. Researchgate.net.