Description

Description

(USP44)

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

1.1. Name (ICH 3.2.S.1.1)

International non-proprietary name: Valacyclovir hydrochloride (Brand Name: Valtrex)

Compendial name: Valacyclovir

Chemical name:  (S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate.

Arasto’s code: VAL

CAS Registry Number: [124832-27-5].

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

1.2. Structure (ICH 3.2.S.1.2)

Empirical Formula: C₁₃H₂₀N₆O₄ · HCl

Molecular Weight: 360.80 g/mol

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

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

Valacyclovir hydrochloride is a white to off-white powder with a maximum solubility in water of 174 mg/mL at 25°C. Valacyclovir hydrochloride has no distinct melting point. It undergoes rapid decomposition above 200°C. A saturated solution (4.82 x 10-1 ) of valacyclovir HCl in distilled water has a pH of 3.5 at 25°C. The pKa values of valacyclovir are pKa1 = 1.90, pKa2 = 7.47 and pKa3 = 9.43 (http://ca.gsk.com/media/593038/valtrex.pdf).Valaciclovir (INN) or valacyclovir  (USAN) is an antiviral drug used in the management of herpes simplex, herpes zoster (shingles).

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 Valacyclovir 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 Valacyclovir.

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 Valacyclovir 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 Secondary Reference Standard for Valacyclovir was produced from a released batch of Valacyclovir 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