توضیحات

Description

(USP 44)

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

1.1. Nomenclature (ICH 3.2.S.1.1)

International non-proprietary name:  Carbamazepine (brand name: Tegretol, Carbatrol, Equetro, Lamictal, Felbatol)

Compendial name: Carbamazepine

Chemical name:      5H-Dibenz [b, f] azepine-5-carboxamide, 5-Carbamoyl-5H-dibenz [b,f] azepine

Arasto’s code: CAM

CAS Registry Number: [298-46-4]

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

1.2. Structure (ICH 3.2.S.1.2)

Empirical formula: C₁₅H₁₂N₂O

Molecular Weight: 236.26

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

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

 Carbamazepine is a white to off-white crystalline substance.  It is administered orally for the treatment of the pain associated with trigeminal neuralgia and glossopharyngeal neuralgia.  Carbamazepine is practically insoluble in water but dissolve in polar organic solvent such as DMF, alcohols, acetone, ethyl acetate, and chloroform by gentle heating. Its log P has been reported to be 2.25 (http://www.aseanenvironment.info/Abstract/41013736.pdf).  Carbamazepine is relatively inert to acid and base, requiring potassium hydroxide fusion for hydrolysis of its urea function (see Stability Studies).  Its LD₅₀ has been reported (oral rat: 1957 mg/kg; IP rat 293 mg/kg; SC rat >1500 mg/kg, http://datasheets.scbt.com/sc-202518.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.

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

 5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for carbamazepine is available from United States Pharmacopoeia. We will use a Secondary Reference Standard (previously referred to as Working Standard) for direct control of all batches of carbamazepine.

As per ICH (Q7A, 11.1) and ICH (Q6A, 2.11, 3.2, 3.3) the Secondary Reference 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 Secondary Reference Standards of the API carbamazepine has undergone extensive characterization (UV, IR, ¹ H NMR, ¹³C NMR, and Mass Spec) to assure its structure, assay and purity (HPLC and/or titration) and specification (comparison of its HPLC retention time and UV ג/_max with USP Primary Reference Standard.

The Secondary Reference Standard for carbamazepine was produced from a released batch of carbamazepine 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