Benzphetamine (13-16-9) Physical and Chemical Properties
Benzphetamine
Amphetamine-class small molecule with sympathomimetic and anorectic activity, commonly supplied as the hydrochloride salt for pharmaceutical development, analytical reference standards and formulation work.
| CAS Number | 13-16-9 |
| Family | Amphetamine derivatives |
| Typical Form | White crystalline powder (hydrochloride salt) |
| Common Grades | EP, USP |
Benzphetamine is a tertiary-amine phenylalkylamine belonging to the amphetamine structural class. Its core structure comprises a substituted isopropylamine (alpha-methylphenethylamine) bearing two N‑substituents: a methyl and a benzyl group, and a single stereocenter at the alpha carbon (reported configuration (2S) in computed descriptors). Structurally it contains two aromatic rings (a phenyl on the alpha carbon and a benzyl on nitrogen) connected by an aliphatic linker to the tertiary amine. The molecule presents low polar surface area and minimal hydrogen-bonding functionality (no hydrogen-bond donors and a single acceptor), features that favour high lipophilicity and central nervous system penetration in the neutral or protonated form.
As a basic tertiary amine the compound is protonated under physiological conditions and typically exists as a cation in aqueous media below its amine dissociation constant. The free base is poorly water soluble and preferentially partitions into nonpolar solvents, whereas the corresponding hydrochloride salt is crystalline and water-soluble. Metabolic handling is hepatic (cytochrome P450 mediated); N‑dealkylation and oxidative pathways yield active and semi‑active metabolites including amphetamine‑type products. Pharmacologically it is a sympathomimetic anorectic with stimulant properties; it increases synaptic catecholamine levels via release and uptake inhibition and has been used as the active moiety (hydrochloride salt) in short‑term management of exogenous obesity. It is controlled for clinical use due to abuse and dependence potential.
Common commercial grades reported for this substance include: EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
- Physical description (experimental): Solid.
- Color / form (experimental): Liquid.
- Additional experimental notes: the hydrochloride salt is reported as a white to off‑white crystalline powder; crystals have been grown from ethyl acetate. Polymorphism is noted for the salt with distinct crystalline forms.
Qualitative explanation: the apparent discrepancy between "Solid" and "Liquid" in experimental annotations reflects differences between the free base (typically an oil or low‑melting material) and the crystalline hydrochloride salt (solid). Salt formation converts a lipophilic, low‑polarity free base into a crystalline, ionic form with substantially increased aqueous solubility and different bulk physical properties (melting point, refractive index, particle habit).
Melting Point
- Reported melting points (experimental): 129-130 ; 152 - 153 °C.
Interpretation: multiple melting point values reflect polymorphism of the crystalline hydrochloride form (distinct crystalline modifications melt at approximately 130 °C and approximately 152–153 °C). Higher‑temperature transitions may be associated with decomposition. When form selection is required for manufacturing or formulation, polymorph screening and control is necessary to ensure consistent melting and dissolution properties.
Solubility and Dissolution Behavior
- Reported solubility descriptors (experimental): "Readily soluble"; "Practically insol in water; sol in methanol, ethanol, ether, chloroform, acetone, benzene".
- Quantitative solubility (experimental): 2.33e-02 g/L.
- Salt form solubility note (experimental): "1 g soluble in 1.5 mL water, 1.5 mL alcohol, 1.5 mL chloroform" (Benzphetamine hydrochloride).
Explanation: the neutral free base displays very low aqueous solubility (practically insoluble), with appreciable solubility in organic solvents; the hydrochloride salt is substantially more water‑soluble and is the form used in oral solid dosage formulations. Protonation of the tertiary amine (see pKa below) increases aqueous solubility; consequently, dissolution rate and apparent solubility in aqueous media depend strongly on salt form, pH, and presence of co‑solvents or surfactants.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
- Estimated dissociation constant: \(\mathrm{p}K_a = 8.8\).
As a tertiary aliphatic amine benzphetamine is a moderately strong base that will be largely protonated (cationic) at physiological pH. Protonation increases aqueous solubility and reduces membrane partitioning relative to the unprotonated base, but the compound’s low topological polar surface area and overall lipophilicity mean it still readily crosses biological membranes (including the blood–brain barrier) when administered systemically. Environmental speciation is likewise dominated by the cation at typical environmental pH values.
Reactivity and Stability
- Decomposition on heating (experimental): "When heated to decomposition it emits very toxic fumes of /hydrogen chloride and nitrogen oxides/." (Benzphetamine hydrochloride)
- Reactions and metabolic stability: resistant to monoamine oxidase (qualitative); hepatic oxidation by cytochrome P450 yields N‑dealkylated and oxidized metabolites (including amphetamine and methamphetamine in metabolism studies).
Interpretation: benzphetamine is chemically stable under normal handling conditions but the hydrochloride salt will release corrosive and toxic gases upon strong thermal decomposition. The tertiary amine and aromatic rings are not hydrolytically labile under neutral conditions, but the molecule is a substrate for oxidative metabolism in liver microsomes; metabolite formation may include species that complex with P450 (spectral evidence for a 455 nm metabolite–P450 complex has been reported). Storage and processing should avoid high temperatures that could induce decomposition.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C17H21N}\).
- Molecular weight (computed): 239.35.
- Exact / monoisotopic mass (computed): 239.167399674.
Notes: the listed molecular weight and exact mass correspond to the free base. The hydrochloride salt has a correspondingly higher molar mass (reported experimental MW for the hydrochloride: 275.82).
LogP and Structural Features
- LogP / XLogP3 (computed / experimental): 4.1.
- Topological polar surface area (TPSA): 3.2 Å^2.
- Hydrogen-bond donors / acceptors: 0 / 1.
- Rotatable bond count: 5.
Implications: a LogP of 4.1 combined with TPSA of 3.2 and zero hydrogen-bond donors indicates pronounced lipophilicity and low polarity for the free base; these properties favour high membrane permeability and central nervous system exposure. High protein binding (reported 75–99% in biological annotations) and substantial metabolic clearance via hepatic enzymes are consistent with these lipophilicity and polar surface area metrics.
Structural Identifiers (SMILES, InChI)
- SMILES:
C[C@@H](CC1=CC=CC=C1)N(C)CC2=CC=CC=C2 - InChI:
InChI=1S/C17H21N/c1-15(13-16-9-5-3-6-10-16)18(2)14-17-11-7-4-8-12-17/h3-12,15H,13-14H2,1-2H3/t15-/m0/s1 - InChIKey:
YXKTVDFXDRQTKV-HNNXBMFYSA-N
These identifiers correspond to the chiral free base (defined atom stereocenter count = 1). Use of the hydrochloride salt will change the mass and some experimental properties but not the connectivity information in SMILES/InChI (salt vs. free base distinction should be encoded explicitly where needed).
Identifiers and Synonyms
Registry Numbers and Codes
- CAS (as presented in this document): 13-16-9
- UNII: 0M3S43XK27
- ChEBI: CHEBI:3044
- ChEMBL: CHEMBL3545985
- DrugBank: DB00865
- DEA code / scheduling: 1228 (Schedule III controlled substance)
Note: the CAS string above is the registry string associated with this presentation; other registry identifiers and database accession codes are provided for cross‑reference in operational contexts.
Synonyms and Brand-Independent Names
Selected non‑proprietary synonyms and systematic names appearing in the identifier lists include: - Benzphetamine - Benzfetamine - benzphetaminum - N‑benzyl‑N‑methyl‑1‑phenylpropan‑2‑amine - (2S)-N‑benzyl‑N‑methyl‑1‑phenylpropan‑2‑amine - N‑benzylmethamphetamine - benzyl(methyl)[(2S)-1‑phenylpropan‑2‑yl]amine
These terms reflect alternative nomenclature and historical naming conventions used for the free base and stereoisomeric forms.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Benzphetamine has been used pharmaceutically as an anorectic (appetite suppressant) in short‑term management of exogenous obesity; clinical administration is performed using the hydrochloride salt in oral solid dosage forms. Pharmacologically it acts as a sympathomimetic amine with central nervous system stimulant activity, promoting release and inhibiting uptake of catecholamines (noradrenaline and dopamine), which underlies appetite suppression and stimulant effects.
Formulation and Development Contexts
- The hydrochloride salt is the formulation form typically employed to produce stable, crystalline tablets; reported formulations include 25‑ and 50‑mg tablet strengths.
- Key development considerations include control of polymorphism of the crystalline salt, selection of a stable crystalline form for reproducible melting and dissolution, and control of particle size and residual solvents to meet dosage uniformity and dissolution targets.
- Stereochemistry is relevant to activity: the compound has a single defined stereocenter and enantiomeric composition may affect pharmacokinetics and pharmacodynamics; analytical control of stereochemical purity is therefore a routine part of drug substance characterization.
If detailed application or use‑case specifics are required for product selection, formulation design, or regulatory submissions, consult product‑specific technical documentation and regulatory guidance.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Commercial grade designations reported for this substance include: EP, USP.
Typical grade concepts relevant to procurement and specification: - Pharmaceutical (pharmacopoeial) grade — suitable for manufacture of drug products and conforming to compendial criteria where applicable. - Analytical grade — high purity material for use in method development and calibration. - Technical grade — for non‑clinical uses where compendial purity is not mandated.
General Quality Attributes (Qualitative Description)
Quality attributes typically controlled in specifications (qualitative): - Physical form and polymorphic identity (crystalline form selection for salts). - Assay of active substance (identity and purity analytics). - Residual solvent profile and limits for solvents used in crystallization. - Particle size distribution and bulk density for tablet manufacturing. - Microbial limits and heavy metals as applicable for regulatory compliance.
Note: specific assay limits, impurity thresholds, and acceptance criteria must be established per regulatory requirements and contractual specifications for each grade and intended use.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
- Pharmacological/toxicological class: central nervous system stimulant; sympathomimetic amine.
- Acute toxicity (reported): LD50 (oral, rat) = 160 mg/kg.
- Biological half‑life (reported): ranges reported 16 to 31 hours (also annotated as 6–12 hours in some sources).
- Protein binding (reported): 75–99%.
- Key adverse effects: central nervous system stimulation (restlessness, tremor, agitation, insomnia), cardiovascular effects (tachycardia, hypertension, arrhythmias), potential for dependence and abuse, and psychiatric effects with chronic misuse including psychosis.
- Special populations and contraindications: contraindicated in advanced arteriosclerosis, symptomatic cardiovascular disease, severe hypertension, hyperthyroidism, glaucoma, history of drug abuse, and similar conditions; distributed into breast milk and thus generally not recommended during nursing.
Occupational exposure risks are principally via inhalation and dermal contact during manufacture or handling of the free base or bulk material. In case of acute overdosage, management is largely supportive (sedation, cardiovascular support, control of hyperthermia and seizures); specific emergency measures depend on clinical presentation.
Storage and Handling Guidelines
- Storage conditions (reported for hydrochloride): store in tight containers at 15 to 30 °C.
- Handling precautions: use standard industrial hygiene controls — minimize dust generation, use local exhaust ventilation, and employ appropriate personal protective equipment (gloves, eye protection, lab coat). Avoid heating the material; thermal decomposition of the hydrochloride salt can generate corrosive and toxic gases (hydrogen chloride and nitrogen oxides).
- Disposal and spill response: collect spills to avoid dust dispersion, sweep or vacuum with appropriate filtration, and dispose of in accordance with local environmental and waste regulations; consider returning unused material to manufacturer when feasible.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and applicable local legislation.
