- Drug Substance General Information (ICH 3.2.S.1)
1.1. Nomenclature (ICH 3.2.S.1.1)
International Non-proprietary Name: Abiraterone acetate (Brand Name: ZYTIGA)
Compendial Name: Abiraterone acetate
Chemical Name: (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate
Arasto’s Code: ABR
CAS Registry Number: [154229-18-2]
Official Pharmacopoeia Monograph: USP 44
1. Drug Substance General Information (ICH 3.2.S.1)
1.2 Structure (ICH 3.2.S.1.2)
- Drug Substance General Information (ICH 3.2.S.1)
1.3. General Properties (ICH 3.2.S.1.3)
Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains either 250 mg or 500 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate. Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.
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), 13CNMR d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.
Abiraterone acetate USP Related Compounds
|Structure||Chemical name||USP Code||Arasto Code|
|3β-Ethoxy-17-(pyridin-3-yl)androsta-5,16-diene||Abiraterone ethyl ether||Abiraterone ethyl ether|
|3β-Isopropoxy-17-(pyridin-3-yl)androsta-5,16-diene||Abiraterone isopropyl ether||Abiraterone isopropyl ether|
|17-(Pyridin-3-yl)androsta-3,5,16-triene||Anhydro abiraterone||Anhydro abiraterone|
|1-[17-(Pyridin-3-yl)androsta-3,5,16-trien-3-yl]ethanone||3-Deoxy-3-acetyl abiraterone-3-ene||3-Deoxy-3-acetyl abiraterone-3-ene|
|17-(Pyridin-3-yl)-16α,17α-epoxyandrost-5-en-3β-ylacetate||α-Epoxyabiraterone acetate||α-Epoxyabiraterone acetate|
|17-(Pyridin-3-yl)-16β,17β-epoxyandrost-5-en-3β-ylacetate||β-Epoxyabirateroe acetate||β-Epoxyabiraterone acetate|
|7-Oxo-17-(pyridin-3-yl)androsta-5,16-dien-3β-ylacetate||7-Ketoabiraterone acetate||7-Ketoabiraterone acetate|
5. Primary and Secondary Reference Standard (ICH 3.2.S.5)
5.1. Active Pharmaceutical Ingredient
Primary Reference Standard for Abiraterone acetate is 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 Abiraterone acetate.
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 Abiraterone acetate has undergone extensive characterization (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 Abiraterone acetate was produced from a released batch of Abiraterone acetate 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.
SPECIFICATION OF ANALYSIS
|Product: Abiraterone Acetate||CAS No.: 154229-18-2||Spec. No.: APC-QC-SPEC-358-01|
|Issue Date: Apr, 2023||Valid up to: Apr, 2024||Reference: USP44|
|Description||White to off white powder.|
|Solubility||Freely soluble in methylene chloride, in tetrahydrofuran, and in toluene; soluble in methanol, in ethanol, in ethyl acetate, in isobutyl methyl ketone, in N,N-dimethylformamide, and in acetone; sparingly soluble in acetonitrile and in dimethyl sulfoxide; slightly soluble in hexane; very slightly soluble in 0.1 N hydrochloric acid; practically insoluble in aqueous media over a wide range of pH values.|
|Identification||A) Infrared spectroscopy|
B) The retention time of the major peak of the sample solution in the chromatogram of assay preparation corresponds to that in the chromatogram of the standard preparation, as obtained in the Assay.
|Residue on ignition||NMT 0.1%|
|Water determination||NMT 0.25%|
|Residual Solvents||Methanol: Max. 3000 ppm (Class II)|
Acetone: Max. 5000 ppm (Class III)
Isopropanol: Max. 5000 ppm (Class III)
|Organic Impurities (HPLC)||α-Epoxyabiraterone acetate: NMT 0.25%|
β- Epoxyabiraterone acetate: NMT 0.25%
Abiraterone: NMT 0.20%
Abiraterone ethyl ether : NMT 0.20%
Abiraterone isopropyl ether: NMT 0.20%
Unspecified impurity: NMT 0.10%
Total impurities: NMT 0.80%
|Prepared by: M. Shahbazi, B.Sc.Chem.||Checked by: A. Forghani, B.Sc.Chem.|
|Approved by: F. Javadizadeh, M.Sc.Chem.|
|Storage: Preserve in well-closed containers. Store at controlled room temperature and protect from light.|