Description

Description

(USP44/BP2022)

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

1.1. Nomenclature (ICH 3.2.S.1.1)

International Non-proprietary Name: Nortriptyline hydrochloride (Brand Name: Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen)

Compendial name:  Nortriptyline Hydrochloride

Chemical name:  1-Propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-,hydrochloride;  10, 11-Dihydro-N-methyl-5H-dibenzo [a,d] cycloheptene-Δ⁵,γ-propylamine hydrochloride

Arasto’s code: NOR

CAS Registry Number: [894-71-3]

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

1.2. Structure (ICH 3.2.S.1.2)

Empirical formula: C₁₉H₂₁N. HCl

Molecular Weight: 299.84 g/mol

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

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

Nortriptyline hydrochloride is a white crystalline substance.  It is administered orally for the treatment of depression.  Nortriptyline hydrochloride is soluble in water and polar organic solvents such as alcohols, as DMF and DMSO.  The pK_a of the secondary amine function is 9.7 (C. Hantsch, et al.  Comprehensive Medicinal Chemistry, Vol. 6, New York, Pergamon Press, 1990) and its log P has been reported to be 4.3 (http://pharmacycode.com/ Nortriptyline _Hcl.htm).  It is stable in acid and base (see Stability Studies).    Acute oral LD₅₀: has been reported to be mouse: PO. 327 mg/kg, IV 25.7 mg/kg, SC. 145 mg/kg, and rat: PO 5012 mg/kg,  IV 22.3 mg/kg, SC. 666 mg/kg ( http://www.scienedirect.com/Science).

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.

Nortriptyline hydrochloride Related Compounds

Structure	Chemical Name	USP Code	Arasto Code
	Dibenzosuberone	Amitriptyline Related Compound A	Amitriptyline Related Compound A
	5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-ol	Amitriptyline Related Compound B	Amitriptyline Related Compound B
	3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine, hydrochloride	Cyclobenzaprine Related Compound B	Cyclobenzaprine Related Compound B

5. Reference Standards (ICH 3.2.S.5)

5.1. Primary and secondary reference standards (API)  

Primary Reference Standard for nortriptyline 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 nortriptyline 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 nortriptyline hydrochloride has undergone extensive characterization (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 nortriptyline HCl is produced from a released batch of nortriptyline 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.

SPECIFICATION OF ANALYSIS