- Drug Substance General Information (ICH 3.2.S.1)
1.1. Nomenclature (ICH 3.2.S.1.1)
International Non-proprietary Name: Zoledronic acid (Brand Name: Reclast, Zometa, Aclasta)
Compendial Name: Zoledronic acid
Chemical Name: (1-Hydroxy-2-imidazol-1-ylethylidene) diphosphonic acid, monohydrate.
Arasto’s Code: ZOL
CAS Registry Number: [165800-06-6]
1. Drug Substance General Information (ICH 3.2.S.1)
1.2 Structure (ICH 3.2.S.1.2)
Empirical Formula: C5H10N2O7P2. H2O
Molecular Weight: 290.10 g/mol
1. Drug Substance General Information (ICH 3.2.S.1)
1.3. General Properties (ICH 3.2.S.1.3)
Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Zoledronic acid treatment rapidly reduces the rate of bone turnover. It is a white crystalline non-hygroscopic powder, highly soluble in sodium hydroxide solution (due to formation of sodium salt), soluble in hot water but slightly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents.
The pH is between 1.5-2.5 for 0.7% solution, its melting range is 238-240°C with decomposition. Zoledronic acid is slightly hygroscopic and its pKa is 1.42 (http://mri. medagencies.org/download/IS_H_0198_001_PAR.pdf).
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.
Zoledronic acid Impurities
|phosphonic acid (phosphorous acid)||Impurity|
5. Primary and Secondary Reference Standard (ICH 3.2.S.5)
5.1. Active Pharmaceutical Ingredient
Primary Reference Standard for Zoledronic acid is available from international Pharmacopoeias. We will use a Secondary Reference Standard (previously referred to as Working Standard) for direct control of all batches of Zoledronic acid.
As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3) the Secondary Reference 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 Secondary Reference Standards of the API Zoledronic acid has undergone extensive characterization (UV, IR, 1 H NMR, 13C NMR, and Mass Spec) to assure its structure, assay and purity (HPLC and/or titration) and specification (comparison of its HPLC retention time and UV ג /max with USP Primary Reference Standard.
The Secondary Reference Standard for Zoledronic acid was produced from a released batch of Zoledronic acid 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.
SPECIFICATION OF ANALYSIS
|Product: Zoledronic acid||CAS No.: 165800-06-6||Spec. No.: APC-QC-SPEC-395-00|
|Issue Date: Apr, 2023||Valid up to: Apr, 2024||Reference: BP2022|
|Appearance||White or almost white crystalline powder.|
|Solubility||Slightly soluble in water, practically insoluble in anhydrous ethanol and in heptane.|
|Identification||A: Infrared absorption spectrophotometry.|
|Appearance of solution||The solution is clear and not more intensely coloured than reference solution B7 or BY7|
|Water||5.0% to 7.5%|
|pH||1.8 to 2.8 (3.0mg/ml solution)|
|Residual Solvent||Methanol: Max 3000 ppm (Class II)|
|Related substances (HPLC)||Impurity B: Max.0.5%|
Unidentified impurities: For each impurity, Max. 0.10%
Total: Max. 0.5%
|Impurities E and F (HPLC)||Impurity E: Max.0.15%|
Impurity F: Max.0.15%
|Assay (Titration)||99.0% to 102.0% (anhydrous substance)|
|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, light-resistant containers. Store at controlled room temperature.|