Fenofibric Acid (22-14-9) Physical and Chemical Properties
Fenofibric Acid
A fibric-acid derivative and the active metabolite of fenofibrate, supplied for analytical, formulation and R&D use in pharmaceutical and chemical manufacturing contexts.
| CAS Number | 22-14-9 |
| Family | Fibric acid derivatives (aromatic carboxylic acids) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, USP |
Fenofibric acid is a small-molecule monocarboxylic acid belonging to the phenoxy‑isobutyric acid structural class; structurally it is a 2‑methylpropanoic acid substituted at the tertiary carbon by a 4‑(4‑chlorobenzoyl)phenoxy group. Key structural motifs include two linked aromatic rings (one para‑chlorinated), an aromatic ketone (benzoyl) and an ether (phenoxy) linkage connecting the aryl system to the isobutyric acid moiety. The molecule therefore combines a single ionizable carboxyl group with a substantial hydrophobic aromatic surface and a moderately polar complement of oxygen atoms (one H‑bond donor, four H‑bond acceptors). These features produce amphiphilic behaviour: an ionizable acidic headgroup imparting pH‑dependent ionisation and a lipophilic aromatic tail controlling membrane and protein interactions.
Electronically, conjugation across the phenoxy–benzoyl framework stabilises the aromatic ketone and reduces the intrinsic reactivity of the carbonyl toward simple hydrolysis; the para‑chloro substituent further increases lipophilicity and can modulate electronic density on the ring system. Physicochemically the compound has a calculated lipophilicity (XLogP3) of 3.9 and a topological polar surface area (TPSA) of 63.6 \(\text{Å}^2\), consistent with limited aqueous solubility but sufficient polarity to permit glucuronidation and protein binding. In clinical and pharmacokinetic contexts fenofibric acid is the active moiety of the prodrug fenofibrate and acts as a peroxisome proliferator‑activated receptor alpha (PPAR‑α) agonist used to lower elevated triglycerides and modify lipoprotein profiles; prodrug forms and salts (for example choline fenofibrate) have been developed to overcome challenging solubility and absorption properties.
Common commercial grades reported for this substance include: EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
No experimentally established value for this property is available in the current data context.
Single‑crystal X‑ray diffraction data describe an orthorhombic crystalline form with space group symbol P b c a (space group number 61). Reported unit‑cell parameters are \(a = 18.2168\,\text{Å}\), \(b = 7.5623\,\text{Å}\), \(c = 22.1355\,\text{Å}\) with \(Z = 8\) and a reported residual factor of 0.0485, indicating a resolved crystal structure suitable for defining molecular conformation and packing. Such experimentally determined crystal data are useful for polymorph screening, solid‑state formulation and analytical specification development.
Melting Point
No experimentally established value for this property is available in the current data context.
Solubility and Dissolution Behavior
No precise aqueous solubility values are provided in the current data context. Qualitatively, fenofibric acid displays limited water solubility in its free‑acid form: the combination of a single carboxylic acid group with two large hydrophobic aromatic rings and an XLogP3 of 3.9 favours partitioning into organic phases and contributes to low intrinsic aqueous solubility. This physicochemical profile underlies the development of fenofibrate prodrugs and salt or ester formulations (e.g., choline fenofibrate, fenofibrate esters) designed to improve dissolution, gastrointestinal absorption and oral bioavailability. In formulation work, conversion to more soluble forms, particle‑size reduction, solid dispersions or lipid‑based delivery approaches are common strategies for drugs with this balance of ionisable headgroup and extensive hydrophobic surface.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context.
Reactivity and Stability
Fenofibric acid behaves chemically as a stable aromatic carboxylic acid/ketone under typical storage and handling conditions. Metabolic and transformation data indicate that oxidative metabolism by cytochrome P450 isoenzymes is not a dominant pathway; instead the primary biotransformation route is phase II conjugation (glucuronidation) of the carboxyl moiety, yielding fenofibryl glucuronide which is excreted in urine. A minor metabolic route involves reduction of the aromatic carbonyl to a benzhydrol derivative, followed by conjugation and elimination. The aromatic ketone and ether linkages are generally resistant to simple hydrolysis; however, the carboxylic acid functionality is capable of salt formation and conjugation, which are relevant to formulation and environmental fate. Environmental hazard classifications and aquatic toxicity indicators (see Safety section) reflect persistence and ecotoxicological concern in aquatic systems.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C17H15ClO4
- Molecular weight: 318.7
- Exact mass / Monoisotopic mass: 318.0658866
LogP and Structural Features
- XLogP3 (calculated): 3.9
- Topological polar surface area (TPSA): 63.6 \(\text{Å}^2\)
- Hydrogen bond donors: 1
- Hydrogen bond acceptors: 4
- Rotatable bonds: 5
- Heavy atom count: 22
- Formal charge: 0
Structural summary: fenofibric acid is a 2‑methylpropanoic (isobutyric) acid linked via an ether (phenoxy) to a biphenyl‑like benzoyl system bearing a para‑chloro substituent. The molecule therefore presents a single acidic site and multiple aromatic rings that dominate hydrophobic interactions, contributing to high plasma protein binding (reported ~99%) and the observed need for prodrug/salt forms to enhance aqueous exposure.
Collision cross section (reported experimental values): 177.78 \(\text{Å}^2\) ([M+H]+) and 185.72 \(\text{Å}^2\) ([M–H]–), which are relevant for ion mobility and analytical method development.
Structural Identifiers (SMILES, InChI)
- SMILES: CC(C)(C(=O)O)OC1=CC=C(C=C1)C(=O)C2=CC=C(C=C2)Cl
- InChI: InChI=1S/C17H15ClO4/c1-17(2,16(20)21)22-14-9-5-12(6-10-14)15(19)11-3-7-13(18)8-4-11/h3-10H,1-2H3,(H,20,21)
- InChIKey: MQOBSOSZFYZQOK-UHFFFAOYSA-N
Identifiers and Synonyms
Registry Numbers and Codes
- CAS: 22-14-9
- European Community / EINECS numbers: 255-626-9; 447-850-2
- UNII: BGF9MN2HU1
- ChEBI: CHEBI:83469
- ChEMBL: CHEMBL981
- DrugBank: DB13873
- NSC Number: 281318
- RXCUI: 24852
(Additional registry and cross‑reference identifiers exist and are routinely used in procurement, regulatory and informatics workflows.)
Synonyms and Brand-Independent Names
Selected synonyms and systematic names reported for the substance include:
- Fenofibric acid
- 2‑[4‑(4‑chlorobenzoyl)phenoxy]‑2‑methylpropanoic acid (IUPAC)
- Fenofibrate free acid
- Procetofenic acid
- FNF acid
- 2‑(4‑(4‑chlorobenzoyl)phenoxy)‑2‑methylpropionic acid
- NSC‑281318
(Where trade or proprietary names appear in supplier catalogs they should be cross‑checked with the nonproprietary identifiers above for specification consistency.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Fenofibric acid is the pharmacologically active moiety (active form) of the prodrug fenofibrate and functions as a PPAR‑α agonist. Clinically it is used to reduce elevated triglycerides and to favourably modify lipoprotein profiles (reducing total cholesterol, LDL‑C and apoB while increasing HDL‑C) in specified dyslipidaemias. It is also encountered as the principal metabolite in pharmacokinetic and environmental monitoring contexts. In chemical manufacturing, fenofibric acid can appear as an isolated active pharmaceutical ingredient (API) or as a component/impurity in fenofibrate synthesis and formulation processes.
Formulation and Development Contexts
Because the free acid form exhibits limited aqueous solubility and high plasma protein binding, formulation strategies typically use prodrug esters, salts or lipid‑based delivery systems to enhance oral absorption and bioavailability. Choline fenofibrate and fenofibrate (isopropyl ester) are two examples of approaches that improve solubility and gastrointestinal uptake relative to the free acid. Pharmacokinetic attributes relevant to formulation and dosing include a reported elimination half‑life on the order of \(20\,\mathrm{h}\) following once‑daily dosing and a high apparent protein binding fraction (~99%), both of which influence dose selection, drug–drug interaction potential and release profiles in extended‑release designs.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade categories applicable to fenofibric acid are pharmaceutical (for use as an API or reference standard in regulated drug products), analytical (certified reference materials and standards for assay and impurity testing), and technical (for research or intermediate use where compendial certification is not required). Reported commercial grades for this substance include EP and USP.
General Quality Attributes (Qualitative Description)
Typical quality attributes addressed in specifications and certificates of analysis include identity (SMILES/InChI/InChIKey), assay/purity by validated chromatographic methods, residual solvents, water/moisture content, particle size or polymorphic form (where solid form matters), and limits for specified and unspecified impurities. Given the presence of a resolved crystal structure, polymorph screening and control, together with stability under expected storage conditions, are commonly part of pharmaceutical quality programmes. Suppliers and purchasers should agree on the relevant quality attributes (grade, analytical methods, acceptable impurity profile) prior to procurement.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
- Acute hazard indicators reported include classification consistent with oral acute toxicity (H302: harmful if swallowed) and aquatic toxicity concerns (H400: very toxic to aquatic life; H413: may cause long lasting harmful effects to aquatic life). Aggregated hazard notification summaries indicate classifications such as Acute Tox. 4 and aquatic hazard categories.
- Drug safety data note an ambiguous drug‑induced liver injury (DILI) concern with a moderate severity grade in pharmacovigilance annotations; clinical monitoring and label‑directed precautions for hepatic function apply when used therapeutically.
- Pharmacokinetic attributes relevant to exposure: substantial plasma protein binding (~99%), reported elimination half‑life approximately \(20\,\mathrm{h}\), and a reported volume of distribution of \(70.9\pm27.5\,\mathrm{L}\). Renal excretion of glucuronide conjugates is the primary elimination route.
- For analytical laboratories, the molecule produces characteristic LC–MS/MS fragmentation (precursor m/z ≈ 319.0732 for [M+H]+; negative mode [M–H]– precursor m/z ≈ 317.0586) and distinctive MS‑MS product ions useful for identification and quantitation.
Appropriate exposure controls include containment of dusts, use of appropriate personal protective equipment (gloves, eye protection, lab coat) and engineering controls (local exhaust ventilation) to minimise inhalation and dermal contact. Given aquatic toxicity, spills and waste should be contained to prevent release to waterways.
Storage and Handling Guidelines
Store in a cool, dry, well‑closed container in a chemically compatible material and protect from prolonged exposure to heat and light. Avoid release to the environment; handle under standard chemical hygiene practices. For industrial or pharmaceutical use, adhere to product‑specific Safety Data Sheet (SDS) guidance, compendial storage and handling instructions, and applicable local regulations for hazardous substances and waste. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
