(USP 34)

 

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

1.2.  Name(ICH 3.2.S.1.1)

 

International non-proprietary name:  Amitriptyline hydrochloride (Brand Name: Elavil, Endep, and Vanatrip)

 

Compendial name:  Amitriptyline hydrochloride

 

Chemical name:1-Propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-         N,N-dimethyl Hydrochloride,  10,11-Dihydro-N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-Δ-5, γ-propylamineHydrochloride

 Arasto’s code: AMI

CAS Registry Number: [549-18-8]

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

 1.2. Structure (ICH 3.2.S.1.2)

Empirical formula: C20H23N.HCl

Molecular Weight: 313.86

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

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

Amitriptyline hydrochloride is a tricyclic antidepressant.  It is orally administered for the

 It is a white to off-white crystalline substance.  It is administered orally for the treatment of depression.  Amitriptyline hydrochloride is soluble in water and polar organic solvents such as alcohols, DMF and DMSO.  The pKa of the secondary amine function is 9.4 (K. Florey, Ed., Analytical Profiles of Drug Substances, Vol. 3,  New York, Academic Press, 1974). Its log P has been reported to be 4.9 (S.H.Hansen, S.Pedersen-Bjergraad, K.E.Rasmusse, Introduction to Pharmaceutical Analysis, 2012, John Wiley & Sons, Ltd. UK, p.300). Amitriptyline hydrochloride is inert to acid and base (see Stability Studies).  Acute oral LD50: has been reported to be 140 mg/kg in mouse and 240 mg/kg in rat (see http://www.sciencelab.com/ mMSDS-amitriptyline_hydrochloride).

 
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 Sstandard for Amitriptyline hydrochloride is available from United States Pharmacopoeia. We will use a Secondary Reference Standard (also known as House Standard or Working Standard) for direct control of all batches of amitriptyline hydrochloride.
 
As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3)the Secondary Reference Standards must be examined for their identity by proof of structure (characterization), assay and purity and specification. 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 and section 3.2.S.5 of the DMF for the API. To this end, the Secondary Reference Standards of the API amitriptyline hydrochloride has undergone extensive characterisation (UV, IR, 1 H NMR, 13C NMR, Mass Spec) to assure their identity, 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 amitriptyline HCl was produced from a released batch of amitriptyline HCl 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. 
 
  Impurities nomenclature

 

 

 

Certificate of analysis of a typical batch with USP method