توضیحات

Description

(BP2022)

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

1.1. Nomenclature (ICH 3.2.S.1.1)

International non-proprietary name:  Deferasirox (Brand Name: Exjade)

Compendial name: Deferasirox

Chemical name:  4-[3,5-Bis(2-hydroxypheyl)[1,2,4]triazole-1-yl]benzoic acid;4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid; 4-[(3Z,5E)-3,5-bis(6-oxocyclohexa-2,4-dien-1-ylidene)-1,2,4-triazolidin-1-yl]benzoic acid.

Arasto’s code:  DES

CAS Registry Number:  [201530-41-8]

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

1.2. Structure (ICH 3.2.S.1.2)

Empirical Formula: C21H15N3O4

Molecular Weight: 373.36 g/mol

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

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

Deferasirox is a white to off-white crystalline substance.  It is a tri-dentate iron chelator administered orally for the treatment of iron over-load condition cause by routine blood transfusion in thalassemia major.  It is insoluble in water but soluble at basic pH due to salt formation (> pH 9, phenoxide).   It is reasonably soluble in highly polar organic solvent such as DMF and DMSO and slightly soluble in alcohol.  The pK_a values of have been reported to be 4.57, 8.71 and 10.56 and log P 6.3 (http://www.druglead.com/cds/ deferasirox.html).Deferasirox is relatively stable in  acid and base (see Stability Studies).         Reported LD₅₀values for Deferasirox are: mouse oral 300 mg/kg; rabbit oral 3200 mg/kg; rat oral 980 mg/kg (http://www.clearsynth.com/docs/MSD-CS-O-00553.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.

Deferasirox Impurities

Structure	Chemical Name	BP Code	Arasto Code
	2-hydroxy-N-(2-hydroxybenzoyl)benzamide	Deferasirox Impurity A	Deferasirox Impurity A
	2-(2-hydroxyphenyl)-4H-I,3-benzoxazin-4-one	Deferasirox Impurity B	Deferasirox Impurity B
	2-[3,S-bis(2-hydroxyphenyl)-IH-1,2,4-triazol-I-yl]benzoicacid	Deferasirox Impurity C	Deferasirox Impurity C
	3-[3,S-bis(2-hydroxyphenyl)-1H-I,2,4-triazol-I-yl]benzoicacid	Deferasirox Impurity D	Deferasirox Impurity D
	ethyl 4-[3,S-bis(2-hydroxyphenyl)-IH-I,2,4-triazol-I-yl]benzoate	Deferasirox Impurity E	Deferasirox Impurity E

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

 5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for Deferasirox is available from pharmacopoeia. We will use a secondary Primary Standard (previously referred to as Working Standard) for direct control of all batches of Deferasirox.

As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3) the Secondary Primary Standard, 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 Deferasirox 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 Secondary Standard for Deferasirox was produced from a released batch of Deferasirox 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