- 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].
- 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
- 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.
- 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
|Product: Valacyclovir Hydrochloride||Cas No: 124832-27-5||Spec. No.: APC-QC-SPEC-359-00|
|Issue Date: Apr, 2023||Valid up to: Apr, 2024||Reference: USP44|
|Description||White to off-white powder.|
|Solubility||Soluble in water; insoluble in dichloromethane.|
|Identification||A: Infrared Spectroscopy|
B: The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
C: Test chloride
|Residue on ignition||NMT 0.1%|
|Limit of palladium||NMT 10 ppm|
|Water determination||5.0% to 11.0%|
|Organic impurities, Procedure 1 (TLC)||Valacyclovir related compound E: NMT 0.2%|
Valacyclovir related compound F: NMT 0.1%
Valacyclovir related compound G: NMT 0.05%
|Organic impurities, Procedure 2 (HPLC)||Acyclovir alaninate: NMT 0.2%|
Valacyclovir related compound C: NMT 0.3%
Valacyclovir related compound D: NMT 0.5%
Acyclovir isoleucinate: NMT 0.2%
N-Formyl valacyclovir: NMT 0.8%
Guaninyl valacyclovir: NMT 0.2%
Bis valacyclovir: NMT 0.3%
Any unspecified impurity: NMT 0.1%
|Organic impurities, Procedure 3 (HPLC)||Guanine and Acyclovir: NMT 2.0%|
Acyclovir related compound A: NMT 0.2%
D-valacyclovir: NMT 3.0%
Total organic impurities: NMT 5.0% for the sum of all impurities from Organic impurities, Procedure1, 2 and 3
|Residual solvents||Acetone: Max. 5000 ppm (Class III)|
Isopropanol: Max 5000 ppm (Class III)
n-Heptane: Max. 5000ppm (Class III)
Dimethyl formamide: Max. 880ppm (Class II)
|Assay (HPLC)||95.0% to 102.0% (on the anhydrous and solvent-free basis)|
|Prepared by: M. Shahbazi, B.Sc.Chem.||Checked by: A. Forghani, B.Sc.Chem.|
|Approved by: F. Javadizadeh, M.Sc.Chem.|
|Storage: Preserve in tight containers, and store at a temperature below 30°.|