Atorvastatin and it’s Impurities: An Overview

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:

Atorvastatin Impurity
Atorvastatin Impurity

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

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