1.1. Name (ICH 3.2.S.1.1)

International non-proprietary name: Nilotinib hydrochloride monohydrate (Brand Name: Tasigna)

Compendial name: Nilotinib hydrochloride monohydrate

Chemical name:  4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate.

Arasto’s code: NIL

CAS Registry Number: [923288-90-8]

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

1.2 Structure (ICH 3.2.S.1.2)




Empirical formula: C28H22F3N7O•HCl•H2O

Molecular Weight: 584.00



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

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

Nilotinib drug substance, in the form of monohydrochloride monohydrate, is a white to slightly yellowish to slightly greenish yellow powder with the molecular formula and weight, respectively, of C28H22F3N7O.HCl .H2O and 584 (corresponding molecular formula and weight of Nilotinib base, anhydrous are C28H22F3N7O and 529 respectively) (https://www.rxlist.com/tasigna-drug.htm#description). It is very soluble in dimethyl sulfoxide, practically insoluble in water, sparingly soluble in ethanol and methanol, very slightly soluble in acetonitrile and n-Octanol (https://www.novartis.ca/sites/www.novartis.ca/files/ tasigna_scrip_e.pdf). Nilotinib has pH-dependent solubility, the solubility of Nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4 (https://www.rxlist.com/tasigna-drug.htm#description). The pH value of a 0.02% solution of Nilotinib hydrochloride monohydrate in water/ethanol 50:50 (V/V) was found to be 4.3. The pH value of a 0.1% suspension of Nilotinib hydrochloride monohydrate in water was determined to be 5.3. The distribution coefficient for Nilotinib hydrochloride monohydrate in n-Octanol/0.1N HCl buffer at 37.0 ± 0.5°C was determined to be 0.08. Nilotinib hydrochloride monohydrate may undergo dehydration prior to melting, therefore no range can be defined (https://www.novartis.ca/sites/www.novartis.ca/files/ tasigna_scrip_e .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), 13CNMR d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.


 Nilotinib hydrochloride monohydrate Related Compounds

 Nilotinib035. Primary and Secondary Reference Standard (ICH 3.2.S.5)
5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for Nilotinib 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 Nilotinib.  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 Nilotinib 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 House Primary Standard for Nilotinib was produced from a released batch of Nilotinib 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.