Rosuvastatin Calcium

 

(In House)

1. Drug Substance General Information (ICH 3.2.S.1 )

1.1. Name (ICH 3.2.S.1.1)

International non-proprietary name: Rosuvastatin Calcium (Brand Name: Crestor)

Compendial name: Rosuvastatin Calcium
Chemical name:   
bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt.

Arasto’s code: ROS
CAS Registry Number: [287714-41-4]

 

1. Drug Substance General Information (ICH 3.2.S.1)

1.2. Structure (ICH 3.2.S.1.2)

Empirical formula: (C22H28FN3O6S)2Ca

Molecular Weight: 1001.14

 

 

 1. Drug Substance General Information (ICH 3.2.S.1 )

 

1.3.  General Properties (ICH 3.2.S.1.3)

Rosuvastatin is a white amorphous substance. It is an orally administered agent, is a member of the drug class of statins, used in combination with exercise, diet, and weight-loss to treat high cholesterol and related conditions, and to prevent cardiovascular disease.

 Rosuvastatin is insoluble in water and some organic solvents, very slightly soluble in alcohol and somewhat soluble in DMSO, Acetone and Acetonitrile. It is soluble in water at alkaline pH due to salt formation of carboxylic acid moiety.

 The determination of purity and assay of APIs require comparison of the product with their respective Reference Standards (RS) and Related Compounds (RC or known impurities).  Accordingly, ICH regulations on the purity and assay of reference standard and related compounds are clearly defined and must be followed by drug substance and drug product manufacturers.

According to ICH Q7, 11.1 there are 3 types of standards.  This is summarized in the following chart and discussed in detail below.

The impurities provided in the following table represent Secondary Reference Standards (SRS) that are prepared in-house by synthesis or by isolation. Each SRS has undergone extensive characterization ( IR, UV, 1HNMR, 13CNMR. Mass Spec) and determination of its purity and assay (HPLC). For specification of the SRS of those products that have a monograph, the SRS is compared with a pharmacopoeia Primary Reference Standard (UV, HPLC retention time). For specification of those products that do not have a monograph (known as House Primary Standard), we compare their UV ε or ג /max , IR major absorptions, 1HNMR d (ppm) , 13 CNMR d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.

 

Rosuvastatin Related Compounds

Structure

Chemical Name

USP Code

Arasto code

 

N-{4-(4-fluoro-phenyl)-5-[2-(4-hydroxy-6-ox o-te trahydro-pyran-2-yl)-vinyl]-6-isopropyl-pyrimidin-2-yl}-Nmethyl-methanesulfonami de (Lactone impurity).

 

 

 

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RCA

 

 

 

 

bis[(Z)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[ methyl(methylsulfon yl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (Cis impurity).

 

 

 

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RCB

 

 

 

 

(6E,3R,5R)-7-[4-(4-fluorophenyl)-6-isopropy l-2-(N-methylmethane)-3-ylsulfonamido)py rimidin-5-yl)3,5-dihydroxyhept-6-enoicacid (Anti isomer impurity).

 

 

 

 

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RCC

 

 

 

 

 

 5. Primary and Secondary Reference Standard (ICH 3.2.S.5)

5.1. Active Pharmaceutical Ingredient

 

Primary Reference Standard for Rosuvastatin is not available from United States Pharmacopoeia. We will use a House Primary Standard (previously referred to as Working Standard) for direct control of all batches of Rosuvastatin. 

  As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3)House Primary  Standards, which include the API and its Related Compounds, must be examined for their proof of structure (characterization), assay and purity and specification (identification by comparison). Furthermore, ICH Guideline on the Preparation of Common Technical Document (Q4M) requires that the data obtained from characterization, assay and purity and specification must be included in section 3.2.S.3.2 for Related Compounds (already discussed in that section) and section 3.2.S.5 of the DMF for the API. To this end, the House Primary Standard of the API Rosuvastatin has undergone extensive characterisation (UV, IR, 1 H NMR, 13C NMR, Mass Spec) to assure its structure, assay and purity (HPLC and/or titration) and specification .

  The House Primary Standard for Rosuvastatin was produced from a released batch of Rosuvastatin by subjecting it to an additional crystallization from the final solvent system used in the production of the API to avoid the possibility of other polymorph formation. It was crystallized twice more to ensure high level of purity.