N-Benzyloxycarbonyl-D-alanine is a purine nucleoside analog with potent antiviral and, to a lesser extent, antineoplastic (anti-cancer) activity. As a raw material (Active Pharmaceutical Ingredient, API), it is a white to off-white, odorless crystalline powder. Chemically, it is designated as 9-β-D-arabinofuranosyladenine (Ara-A). Its molecular formula is C₁₀H₁₃N₅O₄, and it possesses a molecular weight of 267.24 g/mol. The CAS registry number for Vidarabine is 5536-17-4. The raw material is typically supplied with a purity of ≥98% (often ≥99% by HPLC for high-grade pharmaceutical use).
As a raw material, the physical characteristics of Vidarabine are critical for formulation (e.g., ophthalmic ointments, intravenous injections, or research solutions).
-
Appearance: Fine, crystalline powder.
-
Solubility: Vidarabine is slightly soluble in water (approx. 1.5–2.0 mg/mL at 25°C) and very slightly soluble in ethanol and chloroform. It is more soluble in dilute acids and alkalis. This low aqueous solubility is a key parameter formulators must address when developing liquid dosage forms.
-
Melting Point: The substance decomposes upon melting, typically in the range of 257–260°C.
-
Stability: In the solid state, Vidarabine is relatively stable when stored in a dry, light-resistant container. However, in aqueous solution, it is susceptible to deamination (enzymatic or chemical conversion) to hypoxanthine arabinoside (Ara-Hx), which has significantly reduced antiviral activity. Therefore, solutions must be freshly prepared or stabilized.
Vidarabine acts primarily as a DNA polymerase inhibitor. Once taken up by virally infected cells, Vidarabine is phosphorylated intracellularly to the active triphosphate (Vidarabine triphosphate, Ara-ATP). The mechanism involves two key steps:
-
Selective Inhibition: Ara-ATP preferentially inhibits viral DNA polymerase (specifically Herpesviridae) compared to host cellular DNA polymerases. This selective toxicity is the basis of its antiviral action.
-
Chain Termination: Ara-ATP is incorporated into the growing viral DNA chain. Because it lacks the required 3'-hydroxyl group (present in deoxyadenosine), it acts as a non-reversible chain terminator, halting viral replication.
-
ITEMS | STANDARDS | RESULTS |
Description | White to almost white powder | White powder |
UV absorbance ratio | A250/A260 A280/A260 | 0.41-0.49 2.03-2.71 | 0.45 2.14 |
PH | 2.0-4.0 | 2.68 |
Loss on drying | ≤5.0% | 2.64% |
Assay (UV) | ≥98.0% | 99.17% |
Transmittance | ≥98.5% | 99.1% |
Heavy metals | ≤10ppm | ＜10ppm |
Purity (HPLC) | ≥98.0% | 99.6% |
Conclusion | It complies to the standard |
For regulatory compliance (e.g., USP, EP, JP), raw material Vidarabine must meet several rigorous standards:
-
Assay (by HPLC): 98.0% – 102.0% on an anhydrous basis.
-
Related Substances: Limits for specific impurities, notably Ara-Hx (NMT 2.0%), as well as any unspecified individual impurity (NMT 0.1%) and total impurities (NMT 2.0%).
-
Residual Solvents: Must comply with ICH Q3C guidelines (Class 1 and 2 solvents limited or absent).
-
Heavy Metals: NMT 20 ppm (typically lower for injectable grades).
-
Water Content (Karl Fischer): NMT 6.0% (the material is hygroscopic to a degree).
-
Microbial Limits: Total aerobic microbial count (TAMC) ≤ 1000 CFU/g, absence of S. aureus, P. aeruginosa, and Candida albicans.
As a raw material for finished pharmaceuticals, Vidarabine is historically recognized for its activity against:
-
DNA Viruses: Herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Varicella-zoster virus (VZV), and Cytomegalovirus (CMV).
-
Clinical Use: Prior to the widespread use of Acyclovir, Vidarabine was a first-line therapy for severe Herpes simplex encephalitis and neonatal herpes. Today, its primary topical application is in the treatment of acute keratoconjunctivitis and recurrent epithelial keratitis caused by HSV. It is also used systemically (intravenous infusion) in some regions for immunocompromised patients with VZV infections.
Vidarabine is classified as a potential reproductive hazard and an irritant. Safety Data Sheets (SDS) mandate the following:
-
Hazard Statements (H360): May damage fertility or the unborn child (Category 1B).
-
Precautionary Measures: Use fume hoods and wear impermeable gloves (e.g., nitrile), lab coats, and safety goggles. Avoid generating airborne dust.
-
First Aid: In case of skin contact, wash immediately with copious soap and water. If inhaled, move to fresh air.
-
Storage: Store in tightly sealed, light-resistant containers at 2°C to 8°C (refrigerated) for long-term stability. Avoid freezing.
-
While superseded by newer nucleoside analogs (Acyclovir, Ganciclovir) for systemic use due to better bioavailability and lower toxicity, Vidarabine retains niche value. Its primary current application is ophthalmic ointment (3%) . Pharmacokinetically, the raw material has poor oral bioavailability (<10%) and is rapidly deaminated in the gastrointestinal tract, necessitating parenteral or topical administration.
Vidarabine API is a well-characterized, stable crystalline nucleoside analog. While its systemic use has declined, it remains a critical raw material for topical antiviral ophthalmic preparations, particularly where resistance to other agents occurs. Manufacturers must strictly control impurities (especially Ara-Hx) and water content to ensure final drug product efficacy.
