Histamine (51-45-6) Physical and Chemical Properties
Histamine
Endogenous imidazole-derived amine commonly handled as a reagent or reference standard in pharmaceutical research, analytical QC and formulation studies.
| CAS Number | 51-45-6 |
| Family | Imidazoles / Biogenic amines |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, FCC, Reagent Grade, USP |
Histamine is a small, heteroaromatic biogenic amine belonging to the imidazole class; structurally it is 1H-imidazole substituted at the C‑4 (or C‑5 depending on numbering) position by a 2‑aminoethyl side chain. The molecule contains an aromatic imidazole ring with two ring nitrogens (one pyrrole‑type N–H and one pyridine‑type N) and a primary aliphatic amine separated by a two‑carbon linker. This combination of an aromatic basic site and a flexible primary amine gives histamine distinct dual basicity and tautomeric/prototropic behaviour in solution with significant implications for receptor binding and ionization in physiological media.
Electronically, the imidazole ring provides a delocalized pi system and a site for ring protonation and methylation; the primary amino group on the ethyl chain is strongly basic relative to the ring nitrogens. These features produce two relevant dissociation equilibria in aqueous solution (reported pKa values summarized below) and a dipolar/polar profile that favors aqueous solubility as the free base can be protonated to a cationic histaminium species. The molecule is moderately polar (topological polar surface area 54.7) with two hydrogen bond donors and two acceptors, and it has low lipophilicity (reported XLogP/XLogP3 values around −0.7), consistent with ready aqueous solubility of the base and particularly of the pharmaceutically used salts.
Functionally and industrially, histamine is a central endogenous mediator in mammals (neurotransmitter, regulator of gastric acid secretion, vasodilator, bronchoconstrictor) and is used pharmaceutically and diagnostically (for example as histamine phosphate preparations to evaluate gastric acid secretory function). It is also widely used as an analytical standard and reagent in biochemical and pharmacological research.
Common commercial grades reported for this substance include: BP, EP, FCC, Reagent Grade, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Experimental descriptions characterize histamine as a solid. Physical descriptions in crystallographic notes report "COLORLESS LONG PRISMATIC CRYSTALS" and needle morphology from chloroform (noting "NEEDLES FROM CHLOROFORM"). The substance is also described as deliquescent in some preparations and as forming prismatic crystals from ethanol in certain salt forms (dihydrochloride). No precise bulk density value is available in the current data context.
Melting Point
Multiple experimental melting point observations are reported: - 139 - 83–84 °C - 86 °C Additional notes for salt forms: for the dihydrochloride salt, a reported melting range is 244–246 °C (reported in a salt/crystalline context). If a single definitive melting point for the free base is required, these differing values indicate variation with sample history, salt form, and drying/conditioning.
Solubility and Dissolution Behavior
Solubility observations include: - "14.1 [ug/mL] (The mean of the results at pH 7.4)" — interpreted here as 14.1 \(\mu\mathrm{g}\,\mathrm{mL}^{-1}\) at pH 7.4 (reported mean). - "1 g sol in about 4 mL water; aqueous solution is acid to litmus" — a qualitative concentration equivalent to ~250 \(\mathrm{mg}\,\mathrm{mL}^{-1}\) under the described conditions for the stated solid sample (note: context indicates free base sample behavior). - "FREELY SOL IN WATER, ALCOHOL, HOT CHLOROFORM; SPARINGLY SOL IN ETHER." Salt forms (e.g., dihydrochloride, phosphate) show markedly higher melting points and enhanced aqueous solubility; crystalline dihydrochloride is described as "FREELY SOL IN WATER, METHANOL /DIHYDROCHLORIDE/." The aqueous solutions are acidic due to protonation of the amine; the protonated species predominates at physiological and acidic pH.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Reported dissociation constants include: - Basic pKa: 9.756 - Additional reported pKa set: pKa1 = 9.68; pKa2 = 5.88
These values reflect the two principal ionizable centers: the aliphatic primary amine (higher pKa, principal site of protonation under physiological pH) and the imidazole ring nitrogen (lower pKa for the ring protonation/deprotonation equilibrium). At physiological pH (~7.4) histamine exists primarily as a singly protonated cation (histaminium), with the ring able to accept or donate a proton depending on microenvironment. The dual‑site acid–base profile underpins its biological receptor interactions (H1–H4 receptors) and its conversion between neutral and charged forms that control membrane permeability and receptor binding.
Reactivity and Stability
Histamine is described as "stable in air but is affected by light" in the experimental stability/shelf life notes. The molecule is susceptible to enzymatic metabolism (methylation by histamine‑N‑methyltransferase and oxidative deamination by diamine oxidase) under biological conditions. Chemically, the primary amine and the imidazole ring are sites for nucleophilic and electrophilic transformations: ring methylation, N‑alkylation, and oxidation/deamination are common reaction classes. A propensity to form salts (e.g., dihydrochloride, phosphate) modifies reactivity and greatly increases aqueous stability and handling convenience. Avoid prolonged exposure to light and oxidizing conditions for prolonged storage of the free base.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C5H9N3 — presented as \(\mathrm{C_5H_9N_3}\).
- Molecular weight (reported): 111.15 (reported molecular weight value).
- Exact/monoisotopic mass (reported): 111.079647300.
LogP and Structural Features
Reported partition coefficients: - XLogP: −0.7 - Experimental LogP: −0.70
These low/negative logP values are consistent with a polar heteroaromatic amine that exists predominantly as a charged species in aqueous environments. The topological polar surface area (TPSA) is reported as 54.7, and hydrogen bonding descriptors are HBondDonorCount = 2 and HBondAcceptorCount = 2 (reported). The structure contains two rotatable bonds (reported RotatableBondCount = 2), which confers modest conformational flexibility to the ethylamine side chain while retaining a rigid imidazole ring.
Structural Identifiers (SMILES, InChI)
- SMILES: C1=C(NC=N1)CCN
- InChI: InChI=1S/C5H9N3/c6-2-1-5-3-7-4-8-5/h3-4H,1-2,6H2,(H,7,8)
- InChIKey: NTYJJOPFIAHURM-UHFFFAOYSA-N
(Identifiers above are provided as plain text structural identifiers.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS: 51-45-6 Additional registry identifiers reported in the source materials include:
- EC number: 200-100-6
- UNII: 820484N8I3
- ChEBI: CHEBI:18295
- ChEMBL: CHEMBL90
- DrugBank: DB05381 (Only identifiers explicitly reported above are listed.)
Synonyms and Brand-Independent Names
Reported synonyms (selected, depositor-supplied strings as provided): histamine; 2-(1H-imidazol-5-yl)ethanamine; 1H-Imidazole-4-ethanamine; 2-(4-Imidazolyl)ethylamine; 5-Imidazoleethylamine; Histamine Base; Histamine, Free Base; beta-Aminoethylimidazole; Imidazole-4-ethylamine; 4-(2-Aminoethyl)-1H-imidazole; L-histamine; [2-(1H-imidazol-5-yl)ethyl]amine dihydrochloride; Histaminum (TN); Istamina. The full depositor list contains additional synonyms and salt descriptors; only supplied strings are presented here.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Histamine is used pharmaceutically in diagnostic formulations (e.g., histamine phosphate injections used as a diagnostic aid for evaluation of gastric acid secretory function). Historically and experimentally it has been administered in controlled settings to evaluate gastric secretory capacity and to probe histamine receptor physiology. As an active small molecule, histamine is also studied extensively in pharmacology for its action on H1–H4 receptor subtypes and in preclinical models of inflammation, bronchoconstriction, and gastric secretion.
Formulation and Development Contexts
Common pharmaceutical forms include salts such as histamine phosphate and histamine dihydrochloride; these salts provide improved aqueous solubility and defined dosing in ampoule/solution preparations. Reported formulation details note histamine phosphate injection strengths expressed per millilitre of solution (examples: 1 mg salt = 0.36 mg base per mL for a specific USP preparation; other concentrations and ampoule sizes are used in diagnostic products). In research and QC contexts, histamine is widely used as an analytical standard for LC‑MS, GC‑MS, and NMR-based assays; multiple mass spectral and NMR datasets are reported for reference and method development.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial grade categories applicable to histamine include: BP, EP, FCC, Reagent Grade, and USP (each presented as reported commercial grade labels). These grades correspond to common quality tiers used in procurement and specification: pharmacopeial grades (USP, EP, BP), reagent/analytical standards, and food chemical codex (FCC) where relevant.
General Quality Attributes (Qualitative Description)
Quality attributes that define different grades are generally control of assay (identity and potency), water content, residual solvents, specified impurities and degradants, and microbiological limits for injectable grades. Salt form (free base versus dihydrochloride or phosphate) is a critical specification dimension because it affects solubility, melting point, and handling. For analytical standards, traceability and certified purity (assay) are primary attributes. Specific numeric limits and assay criteria are not provided here.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Clinical and experimental observations report that histamine can cause marked pharmacological effects: vasodilation with flushing and hypotension, bronchoconstriction (H1‑mediated), stimulation of gastric acid secretion (H2‑mediated), increased capillary permeability leading to edema, and central nervous system effects at high doses. Human overdose or large exposures can produce headache, profound fall in blood pressure, bronchospasm, dyspnea, metallic taste, vomiting and diarrhea. Some topical ocular applications have caused transient conjunctival hyperemia and edema; in susceptible individuals, eye drops have produced rises in intraocular pressure. Reported regulatory hazard statements associated with supplied hazard notifications include: H301 (Toxic if swallowed), H315 (Causes skin irritation), H317 (May cause an allergic skin reaction), H319 (Causes serious eye irritation), H334 (May cause allergy or asthma symptoms or breathing difficulties if inhaled), and H335 (May cause respiratory irritation). Respiratory sensitization and skin sensitization potential warrant careful control of airborne dust and aerosols for solid forms.
Toxicological behavior is species‑dependent in animal models; in experimental animals, histamine can be acutely lethal by asphyxia at relatively low doses in certain species, whereas antihistaminic pretreatment is protective in some contexts. Metabolism is primarily hepatic (methylation by histamine‑N‑methyltransferase and oxidative deamination by diamine oxidase), producing metabolites with low pharmacological activity that are excreted in urine.
Storage and Handling Guidelines
Handling recommendations based on the chemical class and reported data: - Store solid and bulk material in a cool, dry, well‑ventilated area away from light to minimize photo‑induced degradation (noting reported "affected by light"). - Use appropriate PPE: gloves, eye protection, and lab coat; for dust or powder operations, use dust containment and local exhaust ventilation or respiratory protection as appropriate. - Avoid inhalation, ingestion, and contact with skin and eyes; the compound may cause respiratory and skin sensitization in susceptible individuals. - For aqueous preparations, be aware that solutions are acidic and may irritate skin and eyes. - For specific transport, regulatory and emergency response information, consult the product‑specific Safety Data Sheet (SDS) and applicable local legislation.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
