(In House)


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


1.1. Name(ICH 3.2.S.1.1)

International non-proprietary name: Imatinib Mesylate (Brand Name: Gleevec, Novartis, Switzerland)
Compendial name: Imatinib Mesylate
Chemical name:    4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamideMesylate
Arasto’s code: IMA
CAS Registry Number: [220127-57-1]

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


1.2 Structure (ICH 3.2.S.1.2)




Empirical formula: C29H31N7O . CH3SO3H
Molecular Weight: 589.71


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


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




Imatinib Mesylate is an  off-white to light yellow crystalline substance. It is soluble in water and polar organic solvents.  Imatinib Mesylate is orally administered  for the treatment of positive and chronic myeloid leukemia, relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis (ASM),  hypereosinophilic syndrome, unresectable recurrent and/or metastatic dermatofibrosarcomaprotuberans, positive unresectable and/or metastatic and malignant gastrointestinal stromal tumor ( tabs.pdf).  When fully protonated, Imatinib has 4 dissociable protons ant their pKas have been reported pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52 ( imatinib.html).Its log P is 1.27 (  Imatinib Mesylate is relatively stable in acid and base (see Stability Studies). LD50 of Imatinib Mesylate has been reported (600 mg/kg oral rat: LD50>100 mg/kg IV rat ( 1imatinib Gleevec_Capsules-_January 15_2003.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.






5. Primary and Secondary Reference Standard (ICH 3.2.S.5)
5.1. Active Pharmaceutical Ingredient


Primary Reference Standard for imatinib 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 imatinib. 




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 imatinib 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 imatinib was produced from a released batch of imatinib 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.