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

1.1. Nomenclature (ICH 3.2.S.1.1)

International non-proprietary name: Vorinostat (Brand Name: Zolinza, Merck, USA)

Compendial name: Vorinostat

Chemical name:    N-hydroxy-N’-phenyl-octanediamide

Arasto’s code: VOR

CAS Registry Number: [149647-78-9]

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

1.2 Structure (ICH 3.2.S.1.2)

Empirical formula: C14H20N2O3
Molecular Weight: 264.32 g/mol

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

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

Vorinostat is a white crystalline substance. It is soluble in hot water and polar organic solvents.  It is orally administered for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL), and more recently in combination therapy with many Targeted Cancer Therapy agent as well as reduction of infected T4 cells in HIV AIDS.  Its pKa has been reported to be 9.2 (http://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf) and its log p 1.88 (http://en.programva.com/health-treatment-pharmacy-drugs-medicine?u0=Drugs,%20 treatment,%20health%20-&uA=Vorinostat&opEvent=drug&searchValue=DB02546). Vorinostat is relatively stable in acid or base (see Stability Studies). LD50 of Vorinostat has been reported (2000 mg/kg, oral mouse, http://www.lclabs.com/MSDS/V-8477MSDS.php4).

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.

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

5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for Vorinostat 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 Vorinostat.

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 Vorinostat 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 Vorinostat was produced from a released batch of Vorinostat 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.


Product: VorinostatCAS No.: 149647-78-9Spec. No.: APC-QC-SPEC-402-00
Issue Date: Apr, 2023Valid up to: Apr, 2024Reference: In-house


AppearanceWhite to off-white powder.
IdentificationInfrared absorption spectrophotometry.
Loss on dryingNMT 1.0%
Residual SolventsMethanol: Max 3000 ppm (Class II)

Ethyl acetate: Max 5000 ppm (Class III)

Related substancesIndividual impurity: NMT 0.1%

Total impurities: NMT 0.5%

Assay98.0% to 102.0% (anhydrous substance)
Prepared by: M. Shahbazi, B.Sc.Chem.Checked by: A. Forghani, B.Sc.Chem.
Approved by: F. Javadizadeh, M.Sc.Chem.
Storage: Preserve in well-closed, light-resistant containers. Store at controlled room temperature.