124832-26-4

Basic information

• Product Name: Valaciclovir
• Synonyms: VALACICLOVIR;VALACICLOVIR HCL;VALACICLOVIR HYDROCHLORIDE;VALACV;VALACYCLOVIR;VALACICLOVIR 99+%;ValaciclovirBase;Valaciclovir Hydrochloride 124832-27-5 / Base
• CAS NO: 124832-26-4
• Molecular Formula: C₁₃H₂₀N₆O₄
• Molecular Weight: 324.34
• EINECS: 1312995-182-4
• Mol File: 124832-26-4.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 588.4 °C at 760 mmHg
• Flash Point: 309.7 °C
• Appearance: white to off-white crystalline powder
• Density: 1.55 g/cm³
• Solubility: Soluble in DMSO
• PKA: 9.34±0.20(Predicted)
• CAS DataBase Reference: Valaciclovir(CAS DataBase Reference)
• NIST Chemistry Reference: Valaciclovir(124832-26-4)
• EPA Substance Registry System: Valaciclovir(124832-26-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 124832-26-4(Hazardous Substances Data)

Usage

Description

Valaciclovir, also known as BW256U87 or valaciclovir, is the hydrochloride salt of the L-valyl ester of acyclovir, an antiviral medication. It is marketed under the trade name Valtrex by GlaxoSmithKline. This acyclovir prodrug is rapidly and virtually completely converted to acyclovir following oral administration, resulting in aciclovir plasma levels nearly equivalent to those achieved by intravenous administration.
Used in Pharmaceutical Industry:
Valaciclovir is used as an antiviral agent for the treatment of various viral infections. It demonstrates activity against herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus, and cytomegalovirus. It exerts its effects by interfering with DNA synthesis through phosphorylation by viral thymidine kinase and subsequent inhibition of viral DNA polymerase, thereby inhibiting viral replication.
Valaciclovir is used as a prodrug for acyclovir to improve its bioavailability and efficacy. Its modified structure allows increased intestinal absorption and concomitant higher plasma levels of acyclovir, making it more effective than oral acyclovir for the treatment of zoster and equivalent to oral acyclovir in the treatment of first and recurrent episodes of genital herpes.

Originator

Valcivir,Cipla Limited

Indications

Valacyclovir (Valtrex) is the 1-valine ester (prodrug) of acyclovir that exhibits no activity until hydrolyzed in the intestinal wall or liver to acyclovir and its active metabolite. Its modified structure allows increased intestinal absorption and concomitant higher plasma levels of acyclovir. It demonstrates activity against HSV types 1 and 2, varicella-zoster virus, and cytomegalovirus. It exerts its effects by interfering with DNA synthesis through phosphorylation by viral thymidine kinase and subsequent inhibition of viral DNA polymerase, thereby inhibiting viral replication. Valtrex is indicated for the treatment of acute herpes zoster and recurrent genital herpes in immunocompetent adults. The most common side effects are headache, nausea, and vomiting.Valacyclovir is the only antiviral agent approved for herpes labialis, for a 3-day course in the episodic treatment of recurrent genital herpes (2). Valacyclovir is indicated for recurrent genital herpes and is administered at 500 mg twice daily for 3 days at the onset of prodromal symptoms or at the first sign of infection.

Manufacturing Process

By dicyclohexylcarbodiimide catalyzed esterification of acyclovir (6H-purin-6- one, 1,9-dihydro-2-amino-9-((2-hydroxyethoxy)methyl)-) with the butyloxycarbonyl valine. Treatment of ester obtained with trifluoroacetic acid leads to scission of the BOC group to provide L-valine ester with 9-((2- hydroxyethoxy)methyl)guanine (valacyclovir).

Therapeutic Function

Antiviral

Biological Activity

valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5].

Pharmacology

Valacyclovir (Valtrex), a valine ester prodrug of acyclovir, has a bioavailability three to five times that of acyclovir. This is due to its improved gastrointestinal absorption compared to acyclovir. Valacyclovir is rapidly and almost completely converted to acyclovir after oral administration, with levels comparable to those of intravenous acyclovir. This allows for twice-daily dosing, which may improve compliance and ultimate clinical efficacy. It is more costly than acyclovir.

Clinical Use

Antiviral: Herpes zoster and simplex Prevention of cytomegalovirus (CMV) disease after renal transplantation

in vivo

for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].

Drug interactions

Potentially hazardous interactions with other drugs Ciclosporin: may alter ciclosporin levels; possibly increased risk of nephrotoxicity. Mycophenolate: higher concentrations of both aciclovir and mycophenolic acid on concomitant administration. Tacrolimus: possibly increased risk of nephrotoxicity

IC 50

value: 2.9 microg/ml (for hsv-1 w)[4]. valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5]. in vivo: for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].

Metabolism

Valaciclovir is readily absorbed from the gastrointestinal tract after oral doses, and is rapidly and almost completely converted to aciclovir and valine by first-pass intestinal or hepatic metabolism. Aciclovir is converted to a small extent to the metabolites 9(carboxymethoxy)methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (8-OH-ACV) by aldehyde oxidase. Approximately 88% of the total combined plasma exposure is attributable to aciclovir, 11% to CMMG and 1% to 8-OH-ACV. Valaciclovir is eliminated mainly as aciclovir and its metabolite 9- CMMG; less than 1% of a dose of valaciclovir is excreted unchanged in the urine.

Toxicity evaluation

In general, the adverse reactions with valaciclovir are similar to those seen with its active metabolite, aciclovir. Preclinical toxicology studies with valaciclovir toxicology studies in animals showed no toxicity separate to that expected from the active metabolite. In a phase 1 study of valaciclovir dosed at either 1 or 2 g four times daily for 30 days, the main reported side-effects were gastrointestinal, with nausea, vomiting, diarrhea, and abdominal pain in up to onethird of patients; no renal or neurologic side-effects were notetoxd, but four patients developed grade 3 or 4 neutropenia. None of the sideeffects observed appeared to be drug related.

InChI:InChI=1/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1

Upstream product

• 124832-31-1 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate 
• 13734-41-3 N-Boc-(S/R)-valine 
• 516-06-3 D,L-valine 
• 142963-59-5 valacyclovir 
• 59277-89-3 acycloguanosine 
• 13734-41-3 t-Boc-L-valine 
• 502421-44-5 Boc-L-valacyclovir 

Downstream Products

• 847670-62-6 N-formyl-valacyclovir 
• 124832-27-5 valacyclovir Hydrochloride 
• 72-18-4 L-valine 
• 1612850-51-7 C₂₀H₂₃ClFN₇O₅ 
• 1612850-52-8 C₂₁H₂₃ClF₃N₇O₅ 
• 1612850-43-7 C₂₀H₂₅N₇O₄S 
• 1612850-44-8 C₂₀H₂₄FN₇O₄S 
• 1612850-45-9 C₂₀H₂₄ClN₇O₄S 
• 1612850-46-0 C₂₀H₂₄N₈O₆S 
• 1612850-47-1 C₂₀H₂₄BrN₇O₄S 
• 1612850-48-2 C₂₀H₂₄BrN₇O₅ 
• 1612850-49-3 C₂₀H₂₄FN₇O₅ 
• 1612850-50-6 C₂₀H₂₃Cl₂N₇O₅ 

Relevant articles and documents

Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability

The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by 1H NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm2 for 2 h led to modest ACV skin deposition (QDEP,ACV) of 4.6 ± 0.3 nmol/cm2. In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, QDEP,TOTAL = QDEP,ACV + QDEP,ACV-X. QDEP,TOTAL for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 ± 44.0, 358.8 ± 66.8, 434.1 ± 68.2, 249.8 ± 81.4, 156.1 ± 76.3, 785.9 ± 78.1 nmol/cm2, respectively. The extent of bioconversion of ACV-X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV-X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm2); the effect of duration of current application (5, 10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm2 for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 ± 5.7 nmol/cm2 and 40.3 ± 6.1 nmol/cm2, respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short-duration iontophoresis of ionizable, biolabile ACV-X prodrugs.

Crystalline forms of valacyclovir hydrochloride

Provided are novel crystalline forms of valacyclovir hydrochloride, in particular a novel hydrated form of valacyclovir hydrochloride having about 6% to about 10% by weight water. Also provided are methods for making the novel crystalline forms.

Crystalline forms of valacyclovir hydrochloride

Provided are novel polymorphs and pseudopolymorphs of valacyclovir hydrochloride and pharmaceutical compositions containing these. Also provided are methods for making the novel polymorphs and pseudopolymorphs, which include valacyclovir hydrochloride monohydrate and valacyclovir hydrochloride dihydrate.