Voriconazole (188416-29-7) Physical and Chemical Properties
Voriconazole
Voriconazole is a triazole antifungal API used in pharmaceutical R&D and manufacturing, notable for selective inhibition of fungal sterol 14α-demethylase and relevance in formulation and analytical workflows.
| CAS Number | 188416-29-7 |
| Family | Triazole antifungals |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, JP, USP |
Voriconazole is a synthetic triazole antifungal of the conazole class; structurally it is a difluorophenyl‑substituted, triazole‑containing tertiary alcohol linked to a fluorinated pyrimidinyl moiety. The molecule combines aromatic fluorination (two fluorines on one phenyl ring and an additional fluorine on the pyrimidine ring) with a polar tertiary‑alcohol center and an N‑linked 1,2,4‑triazole. This arrangement yields a neutral, heteroatom‑rich scaffold with multiple hydrogen‑bond acceptors (heterocycles and an alcohol oxygen) and a single hydrogen‑bond donor (the tertiary alcohol OH), producing a moderate topological polar surface area and limited basicity localized on the triazole/pyrimidine nitrogens.
Electronically, the aromatic fluorines increase metabolic stability of the aryl ring toward non‑enzymatic oxidation while slightly increasing lipophilicity; the triazole ring provides coordinate binding capability to heme iron centers of fungal 14‑alpha‑sterol demethylase (CYP51), which underpins activity. Chemically the tertiary alcohol is not readily ionizable under physiological pH; the heterocycles are weakly basic and do not impart significant aqueous ionization at neutral pH. Overall physicochemical behavior is characterized by moderate lipophilicity, limited aqueous solubility, a neutral formal charge, and susceptibility to oxidative metabolism (N‑oxidation and hydroxylation) mediated by cytochrome P450 enzymes.
Voriconazole is a widely used systemic antifungal active ingredient for treatment of invasive aspergillosis, invasive candidiasis and other serious fungal infections in immunocompromised patients; it is supplied in oral and parenteral dosage forms and has well‑documented pharmacokinetic properties and metabolic pathways relevant for formulation and safety assessment.
Common commercial grades reported for this substance include: EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid.
No experimentally established value for this property is available in the current data context.
The solid state is documented by single‑crystal structure determinations (see Crystal Structure data under Chemical Properties), and typical pharmaceutical handling is consistent with a crystalline organic small molecule that may show polymorphism and require attention to particle size and flow properties during formulation.
Melting Point
Reported melting behaviour: \(134\,^\circ\mathrm{C}\) and \(127 - 130\,^\circ\mathrm{C}\).
Multiple melting point entries reflect different reported measurements and/or polymorphic or measurement‑method differences; crystallinity and enantiomeric/state purity can influence the observed melting range.
Solubility and Dissolution Behavior
Aqueous solubility is reported as: low; quantitative value reported as \(9.78\times 10^{-2}\,\mathrm{g}\,\mathrm{L}^{-1}\).
Voriconazole’s low intrinsic aqueous solubility is consistent with a neutral, moderately lipophilic molecule (see LogP/TPSA). In pharmacokinetic context, oral absorption is generally high in healthy adults (oral bioavailability approximately \(96\%\)), and is not strongly pH‑dependent; however, food (high‑fat meal) reduces \(C_\mathrm{max}\) and AUC (reported decreases: \(C_\mathrm{max}\) by \(34\%\), AUC by \(24\%\)), indicating formulation and dosing timing can affect systemic exposure. Limited solubility often necessitates formulation strategies (salt/co‑solvent systems, micronization, suspensions or lipid‑based approaches) for reliable oral or parenteral delivery.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Voriconazole is essentially non‑ionized across physiological pH: the tertiary alcohol is not acidic in the usual sense and the heterocyclic nitrogens (triazole/pyrimidine) are weakly basic, yielding a neutral formal charge under typical conditions. The molecule behaves as a neutral, non‑zwitterionic small molecule in aqueous systems, which contributes to membrane permeability and oral bioavailability.
No experimentally established value for this property is available in the current data context.
Reactivity and Stability
Voriconazole is chemically stable under neutral conditions but is a substrate for oxidative biotransformations. Enzymatic N‑oxidation (primarily at the tertiary amine/triazole linkage) and aromatic or benzylic hydroxylation are major metabolic routes mediated by CYP2C19, CYP2C9 and CYP3A4; the primary circulating metabolite is the N‑oxide. From a non‑biological reactivity perspective, the aromatic C–F bonds are resistant to hydrolytic cleavage and non‑enzymatic oxidation is limited; the tertiary alcohol is not readily hydrolyzed. The triazole heterocycle is chemically robust to routine processing conditions but can coordinate metal centers under specialized conditions.
Crystal structure information documents a monoclinic unit cell: space group P 1 21 1 (Hall symbol: P 2yb), with unit cell parameters \(a = 7.5332\), \(b = 8.349\), \(c = 12.989\), \(\alpha = 90.00\), \(\beta = 100.062\), \(\gamma = 90.00\); \(Z = 2\), \(Z' = 1\), residual factor \(0.0635\). A single‑crystal structure (CCDC 636166) has been reported, indicating well‑defined molecular packing in the solid state.
For handling and storage, avoid conditions that promote strong oxidizing exposure or extended high temperatures; for detailed stability data (shelf life, degradation products under forced‑degradation) consult product‑specific analytical reports.
Molecular Parameters
Molecular Weight and Formula
Molecular formula: C16H14F3N5O
Molecular weight: \(349.31\,\mathrm{g}\,\mathrm{mol}^{-1}\).
Exact/monoisotopic mass: \(349.11504457\) (reported as ExactMass/MonoisotopicMass).
LogP and Structural Features
Reported partition coefficients: XLogP3‑AA = \(1.5\); alternative LogP entry reported as \(1\).
Topological polar surface area (TPSA): \(76.7\).
Hydrogen bond donors: \(1\). Hydrogen bond acceptors: \(8\). Rotatable bond count: \(5\). Formal charge: \(0\).
These parameters indicate moderate lipophilicity with a significant polar surface area contributed by heterocycles and the tertiary alcohol; the combination of moderate LogP and TPSA is consistent with good passive membrane permeability yet limited aqueous solubility. Protein binding is reported at \(58\%\), which is relevant for distribution and free drug concentration.
Structural Identifiers (SMILES, InChI)
SMILES: CC@@HC@(C3=C(C=C(C=C3)F)F)O
InChI: InChI=1S/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3/t10-,16+/m0/s1
InChIKey: BCEHBSKCWLPMDN-MGPLVRAMSA-N
(Identifiers provided verbatim as supplied.)
Identifiers and Synonyms
Registry Numbers and Codes
CAS (primary listed): 188416-29-7
EC Numbers reported: 629-701-5; 941-833-8
UNII: JFU09I87TR; USG4B1CD29
ChEMBL: CHEMBL638
DrugBank: DB00582
InChIKey: BCEHBSKCWLPMDN-MGPLVRAMSA-N
Synonyms and Brand-Independent Names
Common synonyms and non‑proprietary names appearing in supplier/registry information include: Voriconazole; Vfend; UK‑109496; Voriconazol; Voriconazolum; NSC‑759888; (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol; VORICONAZOLE [INN/USAN/BAN].
(Selection of synonyms is taken from available registry and depositor nomenclature; trade names and pharmacopeial references are included where provided.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Voriconazole is used clinically as a systemic triazole antifungal active ingredient for treatment of invasive aspergillosis, candidaemia in non‑neutropenic patients, fluconazole‑resistant invasive Candida infections (including C. krusei), and serious infections due to Scedosporium and Fusarium species. It inhibits fungal 14‑alpha‑sterol demethylase (CYP51), blocking ergosterol synthesis and inhibiting fungal growth. Pharmacologically it also exhibits inhibitory interactions with human cytochrome P450 enzymes (notably CYP2C19, CYP2C9 and CYP3A4), which is important for drug–drug interaction risk assessment.
Voriconazole is listed among essential antifungal medicines and is supplied in oral and parenteral formulations for clinical use.
Formulation and Development Contexts
Reported pharmaceutical formulations/formats include parenteral powder for solution for intravenous use (e.g., \(200\,\mathrm{mg}\) vial), oral suspension powder (e.g., \(40\,\mathrm{mg}\) per mL when reconstituted), and film‑coated tablets (e.g., \(50\,\mathrm{mg}\) and \(200\,\mathrm{mg}\) strengths). Low aqueous solubility prompts formulation strategies such as use of solubilizing excipients, suspensions, or appropriate parenteral vehicles for reliable dosing; additionally, the clinically observed food effect (reduced exposure with high‑fat meal) supports dosing guidance related to meal timing for optimal absorption.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade categories relevant to procurement and quality control include pharmaceutical (pharmacopoeial) grades and analytical reference standards. Pharmacopoeial and regional reference materials are commonly identified (EP, JP, USP), consistent with regulatory and compendial quality systems for active pharmaceutical ingredients (APIs).
Reported commercial grades: EP, JP, USP.
General Quality Attributes (Qualitative Description)
Quality attributes important for specification and release include: identity (structure, stereochemistry), assay (HPLC potency), impurities and specified related substances (including known synthetic or degradation impurities), enantiomeric purity where applicable, residual solvents, water content (moisture), and particle size/morphology for formulation performance. Solid‑state form (polymorphism/crystallinity) and residual catalyst or reagent levels from manufacture are also critical considerations. Certificates of analysis and pharmacopeial monographs are typically used to define acceptance criteria for API supply.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Voriconazole therapy is associated with hepatotoxicity: transient serum aminotransferase elevations occur in approximately \(11\%\) to \(19\%\) of patients and roughly \(1\%\) of patients may require discontinuation due to ALT elevations. Clinically apparent acute liver injury has been reported, with variable patterns (hepatocellular to cholestatic) and typical recovery occurring over weeks after treatment cessation. Protein binding in plasma is reported as \(58\%\).
Aggregate hazard notifications indicate acute oral toxicity and specific target organ toxicity concerns under prolonged exposure; hazard classifications and precautionary statements have been reported in industry notifications. Additionally, an authoritative carcinogenicity classification is reported as Group 1 (carcinogenic to humans) in available classification summaries; such classifications and organ‑system toxicities should be considered when preparing risk assessments and occupational controls.
For exposure control, standard pharmaceutical PPE is required: gloves, eye protection, and respiratory protection where dust or aerosol can be generated. Minimize skin contact and inhalation; control workplace exposures using engineering controls (local exhaust, closed transfer systems) and good manufacturing practice.
Storage and Handling Guidelines
Store in a cool, dry, well‑ventilated area away from strong oxidizers and sources of heat; protect from prolonged light exposure and moisture to preserve solid‑state stability. Handle to minimize dust generation and prevent environmental release; containment and spill control procedures should be in place for handling bulk API. For cleaning, validation, and waste disposal, follow institutional procedures and applicable local regulations.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
