Cefoxitin (35607-66-0) Physical and Chemical Properties
Cefoxitin
Semisynthetic cephamycin (beta-lactam) antibiotic used as an API for parenteral formulations, valued in formulation development and microbiology for its relative stability to many beta‑lactamases.
| CAS Number | 35607-66-0 |
| Family | Beta-lactams — cephamycin/cephalosporin |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, USP |
Cefoxitin is a semisynthetic cephamycin (beta-lactam) antibiotic belonging to the extended cephalosporin/cephamycin structural class. The core scaffold is a 5-thia-1-azabicyclo[4.2.0]oct-2-ene (beta-lactam fused to a dihydrothiazine/cepham ring) bearing a 7α-methoxy substituent, a 2-thienylacetylamido side chain and a carbamoyloxymethyl ester at C-3. Electronically, the molecule contains a strained four-membered beta-lactam amide adjacent to an electron-withdrawing ketone and carboxylic acid, multiple H-bond donor/acceptor sites (including an amide, carbamate and carboxylate), and an aromatic heterocycle (thiophene) that contributes a modest hydrophobic patch. The 7α-methoxy group increases steric protection of the beta-lactam carbonyl, conferring enhanced stability toward many serine beta-lactamases.
Physicochemically, cefoxitin is a polar, low-lipophilicity molecule with a high topological polar surface area and multiple hydrogen-bonding functionalities; these features favour aqueous solubility of ionic forms and rapid renal elimination but limit passive membrane permeability. The molecule is expected to behave as an acidic carboxylate at neutral pH (carboxylic acid deprotonation); the amide and carbamate functionalities are essentially non-basic under physiological conditions. The beta-lactam nucleus is hydrolytically labile to strong acid or base and to nucleophilic attack (including enzymatic hydrolysis), while the 7α-methoxy substitution reduces enzymatic cleavage by many beta-lactamases. Oxidative transformations of the thiophene ring or N-oxidation at labile heteroatoms are potential minor degradation routes under harsh oxidative conditions.
Cefoxitin is an approved antibacterial active ingredient widely used in systemic (intravenous) therapy as a sterile parenteral formulation (administered as the sodium salt in clinical products). Its principal industrial and pharmaceutical relevance is as a broad‑spectrum cephamycin antibiotic active against many gram-negative and anaerobic organisms and as a beta-lactamase‑resistant therapeutic option in clinical practice. Common commercial grades reported for this substance include: BP, EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid.
No experimentally established density value for this property is available in the current data context.
Qualitatively, cefoxitin is isolated and handled as a crystalline or amorphous solid in commercial and pharmaceutical supply chains; formulations for parenteral use are normally prepared from the more soluble sodium salt to improve aqueous dissolution during reconstitution.
Melting Point
Reported melting point values (experimental): \(165\text{–}167\,^\circ\mathrm{C}\); \(149.5\,^\circ\mathrm{C}\).
These differing values reflect reported experimental determinations that may depend on sample form (free acid versus salt or different polymorphs), heating rate, or residual solvent content. Melting point variability is common for complex beta-lactam antibiotics that can adopt multiple solid-state packing arrangements.
Solubility and Dissolution Behavior
Reported aqueous solubility: \(1.95\times10^{-1}\,\mathrm{g}\,\mathrm{L}^{-1}\).
The free acid form is moderately soluble in water at ambient conditions as reported; conversion to the sodium salt commonly used for parenteral formulations substantially increases water solubility and dissolution rate, facilitating sterile reconstitution for intravenous administration. High polar surface area and multiple ionizable groups promote solvation of ionic species but limit solubility in nonpolar organic solvents.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Cefoxitin possesses a carboxylic acid functionality on the beta-lactam-derived bicyclic ring and non-basic amide/carbamate functionalities. At physiological pH the carboxyl group will predominantly exist in its deprotonated (anionic) form, contributing to overall aqueous solubility and renal excretion. The amide and carbamate groups are not expected to be protonated at physiological pH and do not confer significant basicity.
No experimentally established numeric \(\mathrm{p}K_a\) value for this property is available in the current data context.
Reactivity and Stability
- Beta-lactam reactivity: The strained beta-lactam amide is intrinsically susceptible to nucleophilic ring opening (hydrolysis) under strongly acidic or basic conditions and to enzymatic hydrolysis by beta-lactamases. The 7α-methoxy substituent reduces susceptibility to many beta-lactamases, improving enzymatic stability relative to unsubstituted cephalosporins.
- Hydrolysis: Chemical hydrolysis (acidic or alkaline) and prolonged exposure to moisture accelerate degradation; therefore dry storage and avoidance of extreme pH are recommended for stability.
- Oxidation and other pathways: The thiophene ring and heteroatom-rich scaffold present potential minor oxidative or desulfurization pathways under strong oxidizing conditions. Thermal stress and prolonged aqueous storage can promote decomposition.
- In vivo stability: Minimal metabolic transformation is reported clinically; approximately 85% of administered dose is excreted unchanged in urine within the early post-dose period, consistent with limited metabolic biotransformation and high renal clearance.
Collectively, handling and formulation strategies aim to minimize exposure to nucleophiles, extremes of pH, moisture and strong oxidants to preserve beta-lactam integrity.
Molecular Parameters
Molecular Weight and Formula
Molecular formula: C16H17N3O7S2
Molecular weight: \(427.5\,\mathrm{g}\,\mathrm{mol}^{-1}\)
Exact/monoisotopic mass: \(427.05079224\)
Heavy atom count: 28
Defined stereocenters: 2
LogP and Structural Features
Computed XLogP3: 0
Reported experimental LogP: \(-0.02\)
Topological polar surface area (TPSA): 202
Hydrogen bond donors: 3
Hydrogen bond acceptors: 9
Rotatable bond count: 8
The combination of low computed/experimental partition coefficients and a very high TPSA indicates low lipophilicity and high polarity; these parameters are consistent with limited passive transmembrane permeability, extensive aqueous solvation, and predominant renal excretion. Structural features that control activity and stability include the 7α-methoxy substitution (beta-lactamase resistance), the 2-thienylacetyl side chain (modulates spectrum and protein interactions), and the carbamoyloxymethyl group at C-3 (influences solubility and reactivity).
Structural Identifiers (SMILES, InChI)
SMILES (plain text): CO[C@@]1([C@@H]2N(C1=O)C(=C(CS2)COC(=O)N)C(=O)O)NC(=O)CC3=CC=CS3
InChI (plain text): InChI=1S/C16H17N3O7S2/c1-25-16(18-10(20)5-9-3-2-4-27-9)13(23)19-11(12(21)22)8(6-26-15(17)24)7-28-14(16)19/h2-4,14H,5-7H2,1H3,(H2,17,24)(H,18,20)(H,21,22)/t14-,16+/m1/s1
InChIKey (plain text): WZOZEZRFJCJXNZ-ZBFHGGJFSA-N
These structural identifiers correspond to the stereochemically specified cefoxitin free acid isomer.
Identifiers and Synonyms
Registry Numbers and Codes
- CAS Registry Number: 35607-66-0
- European Community (EC) Number: 252-641-2
- UNII: 6OEV9DX57Y
- InChIKey: WZOZEZRFJCJXNZ-ZBFHGGJFSA-N
- ChEBI: CHEBI:209807
- ChEMBL: CHEMBL996
- DrugBank: DB01331
- KEGG: C06887; D02345
- DSSTox Substance ID: DTXSID1022764
- HMDB: HMDB0015426
- RXCUI: 2189
(Registry and identifier list limited to items present in the substance metadata.)
Synonyms and Brand-Independent Names
Selected synonyms and systematic names reported for this substance include: cefoxitin; Mefoxin; Cefoxitina; Cefoxitine; Cefoxitinum; (6R,7S)-3-(carbamoyloxymethyl)-7-methoxy-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; CAS-35607-66-0; C16H17N3O7S2. A fuller list of depositor-supplied synonyms is available in supplier and regulatory communications.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Cefoxitin is used as an antibacterial active ingredient for systemic therapy, particularly administered intravenously (commonly formulated as the sodium salt). It is classified pharmacologically as a cephalosporin/cephamycin antibacterial with broad activity including many gram-negative organisms and anaerobes. Mechanistically, cefoxitin exerts bactericidal action via covalent binding and inactivation of penicillin‑binding proteins (PBPs), thereby inhibiting peptidoglycan cross-linking and inducing cell lysis.
Formulation and Development Contexts
In pharmaceutical development, cefoxitin is supplied and formulated primarily for parenteral use. Typical formulation approaches include conversion to the sodium salt to improve aqueous solubility and reconstitution characteristics, sterile lyophilized powders for injection, and liquid IV preparations. During development and manufacturing, emphasis is placed on controlling moisture, pH exposure and oxidative stress to preserve beta-lactam integrity; analytical control focuses on assay, related beta-lactam degradation products, and residual solvents. No concise application summary beyond its role as a systemic antibacterial is available in the current data context; in practice this substance is selected based on its general properties described above.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Common pharmaceutical supply grades applicable to cefoxitin include pharmacopoeial and quality control grades used in drug substance and drug product manufacture. Reported commercial grades: BP, EP, USP. These grades correspond to widely used pharmacopoeial monograph specifications and analytical requirements; selection of a grade depends on intended use (clinical formulation, analytical standard, or research).
General Quality Attributes (Qualitative Description)
Typical quality attributes for cefoxitin batches include: identity and assay of the active moiety, purity and profile of related substances (beta-lactam degradation products, desulfurized or oxidized impurities), residual solvents, water content, stereochemical purity, and microbiological control for sterile drug substance. Pharmaceutical-grade material is supplied with certificates of analysis reporting these attributes and is typically manufactured under appropriate GMP conditions. Technical or research grades may have broader impurity limits and are not intended for parenteral administration.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
- Sensitization: Reports indicate skin sensitization potential (hazard code H317 in some notifications) and potential respiratory sensitization (H334 in some notifications). Appropriate controls to avoid inhalation or skin exposure are warranted.
- Drug-induced liver injury (DILI): Annotated as an ambiguous DILI concern with a reported severity grade of 3 in clinical safety annotations; hepatotoxic risk should be assessed in clinical and occupational contexts.
- Clinical safety: Cefoxitin has an established clinical safety profile and carries post-marketing and label warnings pertinent to clinical use (including a documented boxed/black-box warning in clinical product labelling in some jurisdictions); such clinical warnings relate to therapy-specific risk management rather than typical laboratory occupational handling.
For occupational exposure, standard protective measures include use of gloves, eye protection and respiratory protection where dust/aerosol generation is possible; implement engineering controls (local exhaust, closed handling) and good hygiene practices. For detailed hazard, transport and regulatory information, users should refer to the product-specific Safety Data Sheet (SDS) and local legislation.
Storage and Handling Guidelines
Store in a tightly closed container in a cool, dry place protected from light and moisture. Avoid exposure to strong acids, bases and oxidizing agents that can catalyse beta-lactam hydrolysis or oxidative degradation. For pharmaceutical drug substance and sterile drug product manufacture, maintain validated environmental controls for particulate and microbial contamination. For detailed storage conditions, shelf life and reconstitution instructions refer to product-specific documentation and pharmacopeial monographs.
