(In House)

 

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

  1.2. Name(ICH 3.2.S.1.1)

 

International non-proprietary name:  Celecoxib (Brand Name: Celebrex, Celebra)

 

Compendial name:  Celecoxib

Chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide

 Arasto’s code:  CEL

 CAS Registry Number: [169590-42-5]

 

 

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

  1.2. Structure (ICH 3.2.S.1.2)

 

 

 

Empirical formula: C17H14F3N3O2S

 

Molecular Weight: 381.38

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

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

 

Celecoxib is a white to off-white crystalline substance.  It is orally administered for the treatment of pain associated with osteoarthritisrheumatoid, arthritis juvenile rheumatoid, arthritis ankylosing, and acute pain as well as spondylitis and primary dysmenorrhea.  It is insoluble in waterand soluble in all organic solvents except linear and branched alkanes (hexane, heptane, etc.)It is soluble in water at high alkaline pH due to sulfonamide salt formation (pKa= 11.1, www.pfizer.ca, Product Monograph). Its log P has been reported to be 3.47 (http://www. chemicalland21.com/lifescience/phar/CELECOXIB).  Celecoxib is relatively inert to acid and base (see Stability Studies). Oral LD50 of Celecoxib has been reported to be greater than 2000 mg/kg in the rat (http://web.ncifcrf.gov/rtp/LASP/intra/forms/msds/msds_Celecoxib).

 
 
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 Celecoxib 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 Celecoxib. 
 
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 celecoxib 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 celecoxib was produced from a released batch of celecoxib 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.