Clobazam (18-13-8) Physical and Chemical Properties
Clobazam
A 1,5-benzodiazepine active pharmaceutical ingredient (API) used in formulation and analytical development for anticonvulsant and anxiolytic products.
| CAS Number | 18-13-8 |
| Family | 1,5-Benzodiazepines |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, FCC, USP |
Clobazam is a 1,5-benzodiazepine derivative containing a 1,5-benzodiazepine-2,4-dione core substituted at the 7-position with chlorine, with an N‑1 methyl and an N‑5 phenyl substituent (IUPAC: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione). Its constitution corresponds to the neutral organic molecule \(\ce{C16H13ClN2O2}\). The structure combines an aromatic phenyl ring, a chlorinated benzodiazepine ring system and two lactam (dione) carbonyls; these features create a planar, moderately rigid scaffold with a single low‑flexibility linker (rotatable bond count = 1) connecting the phenyl substituent. The two carbonyl groups act as hydrogen‑bond acceptors but the parent compound has no hydrogen‑bond donors (H‑bond donor count = 0), yielding a modest topological polar surface area (TPSA = 40.6 Å^2) consistent with central nervous system activity and oral bioavailability.
Electronically, the molecule is largely neutral under ambient conditions (formal charge = 0) and is not expected to possess appreciable acid–base ionization within the physiological pH range; there is no experimentally established pKa in the current data context. Lipophilicity is moderate (XLogP ≈ 2.1; reported experimental log Kow values ≈ 2.12–2.3), which supports rapid tissue distribution and high plasma protein binding (≈ 80–90% for parent compound). The combination of moderate lipophilicity, low polar surface area and two carbonyl acceptors favors good membrane permeability but also a propensity to undergo hepatic phase I metabolism (N‑demethylation and hydroxylation), consistent with known biotransformation to an active N‑desmethyl metabolite.
Common commercial grades reported for this substance include: EP, FCC, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: solid; the material is obtained as white to almost white crystalline powder and can form crystals from 50% ethanol. No experimentally established numeric value for bulk or crystal density is available in the current data context. The low rotatable bond count (1) and aromatic, fused-ring character predict a crystalline packing with relatively low conformational disorder, consistent with reported crystalline behavior.
Melting Point
Reported experimental melting ranges include: - 182–185 °C - 166–168 °C - MP: 182–185 °C
The presence of more than one reported melting point range suggests sample- or method-dependent variation (polymorphism, differing solvate/crystallization history, or measurement technique). Users should reference the specific batch crystallization history when comparing melting ranges for quality control.
Solubility and Dissolution Behavior
Solubility descriptors reported: - "Slightly soluble in water" - "Sparingly soluble in ethanol; freely soluble in methylene chloride" - Numerical solubility: 1.64e-01 g/L
These data indicate limited aqueous solubility (approximately \(1.64\times10^{-1}\,\mathrm{g\,L^{-1}}\) reported), markedly greater solubility in moderately nonpolar organic solvents (methylene chloride) and reduced solubility in polar protic organic solvents (ethanol). Practically, formulation strategies for oral solid dosage forms rely on particle-size reduction, salt/prodrug approaches (where applicable), or use of suspending agents and solubilizers; the parent neutral lactam does not offer an obvious ionizable handle for simple salt formation.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Clobazam is formally neutral under physiological conditions (formal charge = 0) and lacks classical ionizable functional groups with pKa values within the aqueous pH range; no experimentally established pKa value for the parent compound is available in the current data context. The molecule’s basicity is weak (tertiary amide/lactam nitrogen atoms are not strongly protonated at physiological pH), which aligns with observed high oral absorption and lack of pH‑dependent ionization.
Reactivity and Stability
Clobazam contains two lactam carbonyls and an aryl‑chloride substituent. Class‑level reactivity considerations: - Hydrolysis: the 2,4‑dione (lactam) motif is relatively robust under neutral conditions but can be susceptible to hydrolytic or ring‑opening reactions under strongly acidic or basic media; standard handling avoids extremes of pH. - Oxidation: aromatic chlorides confer some resistance to oxidative dehalogenation, but oxidative metabolism in biological systems proceeds via hepatic enzymes (phase I N‑demethylation and hydroxylation). - Incompatibilities: incompatible with strong oxidizing agents. - Thermal behavior: melting ranges are reported (see above); decomposition products on combustion are expected to include carbon oxides, nitrogen oxides and hydrogen chloride.
Storage in a dry, well‑ventilated environment away from strong oxidizers and heat sources is recommended to maintain chemical stability.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C16H13ClN2O2}\)
- Molecular weight: 300.74 (reported)
- Exact/monoisotopic mass: 300.0665554
These mass values should be used for mass spectrometric method development and for conversion between molar and mass units in formulation calculations.
LogP and Structural Features
Reported lipophilicity descriptors: - XLogP (computed): 2.1 - Experimental logP / log Kow values reported: 2.12 (log Kow = 2.12), 2.3
Structural contributors to lipophilicity include the phenyl substituent and chlorinated aromatic ring, balanced by two carbonyl groups that modestly increase polarity. The moderate logP is consistent with a volume of distribution and protein binding behavior reported clinically (see pharmacokinetic sections): rapid tissue distribution and high plasma protein binding (≈ 80–90%).
Additional computed descriptors: TPSA = 40.6 Å^2, HBond donor count = 0, HBond acceptor count = 2, rotatable bond count = 1, structural complexity = 423.
Structural Identifiers (SMILES, InChI)
- SMILES:
CN1C(=O)CC(=O)N(C2=C1C=CC(=C2)Cl)C3=CC=CC=C3 - InChI:
InChI=1S/C16H13ClN2O2/c1-18-13-8-7-11(17)9-14(13)19(16(21)10-15(18)20)12-5-3-2-4-6-12/h2-9H,10H2,1H3 - InChIKey:
CXOXHMZGEKVPMT-UHFFFAOYSA-N
(Identifiers above are provided for unambiguous structure representation and are suitable for integration into analytical methods and LIMS workflows.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 18-13-8
- EC number: 244-908-7 (reported)
- UNII: 2MRO291B4U
- ChEBI: CHEBI:31413
- ChEMBL: CHEMBL70418
- DrugBank ID: DB00349
- ATC code: N05BA09
- DEA Controlled Substances Code Number: 2751 (Schedule IV)
These registry codes are commonly used for procurement, regulatory submissions and cross‑referencing in laboratory systems.
Synonyms and Brand-Independent Names
Reported synonyms and non‑proprietary names include (selection): Clobazam; Frisium; Urbanyl; Onfi; LM-2717; HR 376; Clorepin; Urbadan; Mystan; Clobazamum. The IUPAC/computed name is 7‑chloro‑1‑methyl‑5‑phenyl‑1,5‑benzodiazepine‑2,4‑dione. Use of standardized non‑proprietary names is recommended in specification and labeling documents.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Clobazam is an active pharmaceutical ingredient (API) in the 1,5‑benzodiazepine class with documented use as an anticonvulsant and anxiolytic. It is indicated as adjunctive therapy for seizures associated with Lennox‑Gastaut syndrome in patients 2 years and older and has historical use for short‑term management of anxiety in some jurisdictions. It functions pharmacologically as a GABAA receptor positive allosteric modulator and has activity as a CYP2D6 inhibitor and weak CYP3A4 inducer.
Clobazam is a Schedule IV controlled substance in several regulatory jurisdictions; regulatory handling, record‑keeping and controlled‑substance security requirements apply during manufacture, distribution and storage.
Formulation and Development Contexts
Commercial formulations include oral tablets and oral suspension; film formulations have also been reported. The compound’s limited aqueous solubility and moderate lipophilicity influence formulation choices: solid oral dosage forms typically employ particle‑size control and appropriate excipients to ensure consistent dissolution; oral suspensions require stabilizers and suitable suspending media to maintain homogeneity. For analytical method development, clobazam shows strong response in ESI positive LC‑MS ([M+H]+ m/z ≈ 301.07) and GC‑MS fragmentation with prominent m/z 300 and 77 ions, facilitating routine QC and forensic assays.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade categories applicable to an API like clobazam include pharmaceutical (API for human use, manufactured under GMP), analytical standards (certified reference materials at specified concentrations), and technical/industrial grades for research use. The following commercial grades have been reported for clobazam: EP, FCC, USP.
General Quality Attributes (Qualitative Description)
For pharmaceutical API supply, key quality attributes include identity (structure, SMILES/InChI), assay/potency (by validated HPLC/LC‑MS), impurity profile (related substances and specified degradants), residual solvents, microbiological limits (where applicable), and polymorphic form control (melting point and XRPD fingerprinting). Analytical reference materials commonly supplied at known concentrations in solvent are used for method validation and stability studies. Batch‑to‑batch crystalline form and residual solvent history can affect melting point and dissolution behavior and should be controlled in specification documents.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Clobazam is a CNS depressant with clinical effects including sedation and somnolence; overdose can cause profound CNS depression, respiratory depression and, rarely, coma. Dependence and withdrawal phenomena are recognized with benzodiazepines, and abrupt discontinuation can precipitate seizures in susceptible individuals. Rare but severe hypersensitivity reactions (including Stevens–Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; vigilance during the first 8 weeks of therapy is particularly important.
Acute toxicity values reported (non‑human): - LD50 guinea pig oral: 109 mg/kg - LD50 rabbit oral: 320 mg/kg - LD50 rat subcutaneous: >5000 mg/kg - LD50 rat intraperitoneal: 740–1526 mg/kg
Pharmacokinetic considerations relevant to safety: clobazam is rapidly absorbed after oral dosing, extensively metabolized in the liver (major active metabolite N‑desmethylclobazam), and exhibits mean elimination half‑lives of approximately 36–42 hours for the parent and 71–82 hours for the major metabolite. High plasma protein binding (~80–90%) and CYP‑mediated metabolism (notably CYP3A4 and CYP2C19) create clinically relevant drug–drug interaction potential and interindividual variability (notably in CYP2C19 poor metabolizers).
Occupational exposure considerations: avoid inhalation of dust; the potential for combustible dust formation exists when processing solids. Personal protective equipment (gloves, eye protection, respirators where dust or aerosols may be generated) and local exhaust ventilation are recommended. Avoid concurrent exposure to other CNS depressants, including alcohol.
Storage and Handling Guidelines
- Store tablets and oral suspensions at \(20\ \degree\mathrm{C}\) to \(25\ \degree\mathrm{C}\) (68–77 °F) in a dry, well‑ventilated place; keep containers tightly closed.
- Avoid contact with strong oxidizing agents.
- Use appropriate containment and dust control when handling bulk powder; implement GMP and controlled‑substance security measures as required by local regulation.
- For disposal, follow applicable controlled‑substance and pharmaceutical waste regulations; do not dispose via drains or general waste streams without authorization from licensed waste contractors.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
