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

1.1. Name (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 Related Compounds

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

5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for Zoledronic acid 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 Zoledronic acid.

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 Zoledronic acid 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 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. It was crystallized twice more to ensure high level of purity.