Description

Description

(USP44)

Description

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

1.1. Nomenclature (ICH 3.2.S.1.1)

International Non-proprietary Name: Temozolomide (Brand Name: Temodar)

Compendial Name: Temozolomide

Chemical Name: 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide

Arasto’s Code: TEM

CAS Registry Number: [85622-93-1]

Official Pharmacopoeia Monograph: USP 44

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

1.2. Structure (ICH 3.2.S.1.2)

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

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

TEMODAR contains temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The material is a white to light tan/light pink powder with a molecular formula of C6H6N6O2 and a molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence TEMODAR can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.

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.

Temozolomide USP Related Compounds

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

5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for Temozolomide 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 Temozolomide.

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 Temozolomide has undergone extensive characterization (UV, IR, 1HNMR, 13CNMR, Mass Spec) to assure its structure, assay and purity (HPLC and/or titration) and specification.

The House Primary Standard for Temozolomide was produced from a released batch of Temozolomide 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