Diphenhydramine Hydrochloride (16-11-7) Physical and Chemical Properties
Diphenhydramine Hydrochloride
Hydrochloride salt of diphenhydramine, a first‑generation H1 antihistamine commonly supplied as an API and analytical reference for formulation development and quality control.
| CAS Number | 16-11-7 |
| Family | Ethanolamine antihistamines |
| Typical Form | White crystalline powder |
| Common Grades | BP, EP, JP, USP |
Diphenhydramine hydrochloride is the monohydrochloride salt of diphenhydramine, a tertiary-amine ethanolamine derivative in the benzhydryl ether class. Structurally it consists of a tertiary dimethylaminoethyl side chain linked via an ether linkage to a benzhydryl (diphenylmethyl) moiety, producing a molecule with two aromatic rings and a single basic nitrogen. As the hydrochloride salt the molecule exists predominantly in the protonated ammonium form under acidic to physiological pH, which significantly increases aqueous solubility relative to the free base. The low calculated topological polar surface area (TPSA = 12.5) and the presence of extensive aromatic surface area confer intrinsic lipophilicity for the free base, while the ionic salt form balances this to give a compound that is both membrane-permeable (free base) and highly water-dispersible (salt).
Electronically, the basic site is a tertiary aliphatic amine that is readily protonated; the ether oxygen and tertiary amine provide two weak hydrogen-bond acceptor sites and one hydrogen-bond donor is present only in protonated contexts (salts/solvates). The molecule is chemically an aromatic ether and a tertiary aliphatic amine salt; it is sensitive to strong oxidants and reducing environments and may slowly darken on prolonged light exposure. Pharmacologically it is a classical first-generation histamine H1 antagonist with central nervous system penetration (sedation) and antimuscarinic activity; these class-level properties drive much of its clinical and formulation use.
Common commercial grades reported for this substance include: BP, EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Diphenhydramine hydrochloride is supplied and encountered as a white to almost-white crystalline powder with an odorless, bitter-numbing taste. A 5% aqueous solution has a pH in the range 4–6, consistent with the presence of the protonated tertiary ammonium salt. Water solubility is high for the hydrochloride salt form and aqueous solutions are acidic.
No experimentally established value for this property is available in the current data context.
Melting Point
Melting point (reported): \(331\) to \(338\,^\circ\mathrm{F}\).
The relatively high reported melting point (expressed here as provided) is consistent with a crystalline ionic solid (salt) exhibiting substantial lattice stabilization versus the neutral free base. This crystalline packing contributes to formulation stability in many solid dosage forms.
Solubility and Dissolution Behavior
- Reported aqueous solubility (mean at pH 7.4): \(>43.8\,\mu\mathrm{g}\,\mathrm{mL}^{-1}\).
- Reported solubility at \(70.7\,^\circ\mathrm{F}\): \(\geq 100\,\mathrm{mg}\,\mathrm{mL}^{-1}\).
As a hydrochloride salt the compound is markedly more water-dispersible than the neutral free base; protonation of the tertiary amine increases polarity and dissolution rate. Solubility is pH-dependent in the sense that the free base is less soluble at higher pH where deprotonation occurs, while the salt remains highly soluble at neutral and acidic pH. These features make the hydrochloride suitable for immediate-release oral and oral-liquid formulations and for aqueous topical/anti-itch preparations.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context.
Qualitatively, the basic functionality is a tertiary aliphatic amine that forms the hydrochloride salt; under aqueous conditions at neutral and acidic pH the dominant species is the protonated ammonium salt (water-soluble), whereas the free base is substantially less polar. This protonation state under physiological pH contributes to the molecule’s pharmacokinetic distribution (balance of aqueous solubility and membrane permeability).
Reactivity and Stability
Diphenhydramine hydrochloride yields acidic aqueous solutions and will neutralize bases. It may react with strong oxidizing or reducing agents and can catalyze or participate in side reactions under strongly reactive conditions. The material slowly darkens on exposure to light, indicating some photochemical or oxidative instability over time. When heated to decomposition, materials containing this hydrochloride can emit toxic gases such as nitrogen oxides and hydrogen chloride. Aqueous solutions and spills should be handled to avoid unnecessary exposure and decomposition.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C17H22ClNO
- Molecular weight: \(291.8\,\mathrm{g}\,\mathrm{mol}^{-1}\)
- Exact/monoisotopic mass: 291.1389920
These values correspond to the 1:1 salt composition (diphenhydramine · HCl).
LogP and Structural Features
No experimental logP value is available in the current data context.
Structural features relevant to partitioning and permeability: - Two phenyl rings (benzhydryl group) impart substantial hydrophobic surface area in the free base. - Salt formation at the tertiary amine markedly increases aqueous solubility while reducing apparent lipophilicity of the solid/formulated salt. - Physicochemical descriptors (computed): TPSA = 12.5; hydrogen-bond donor count = 1; hydrogen-bond acceptor count = 2; rotatable bond count = 6. These parameters indicate a molecule with relatively low polar surface area and moderate conformational flexibility; the free base is lipophilic enough for central penetration, while the salt enables practical aqueous formulation.
Structural Identifiers (SMILES, InChI)
- SMILES: CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2.Cl
- InChI: InChI=1S/C17H21NO.ClH/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16;/h3-12,17H,13-14H2,1-2H3;1H
- InChIKey: PCHPORCSPXIHLZ-UHFFFAOYSA-N
These identifiers match the diphenhydramine monohydrochloride connectivity and are suitable for unambiguous electronic indexing and cheminformatics use.
Identifiers and Synonyms
Registry Numbers and Codes
- CAS (as provided in header): 16-11-7
- Alternative CAS strings present in source material (examples): 147-24-0 (parent/related)
- EC (EINECS) number: 205-687-2
- UNII: TC2D6JAD40
- ChEMBL ID: CHEMBL1620
- DSSTox Substance ID: DTXSID4020537
- KEGG: C07784; D00669
- NSC Number(s): 756729; 33299
- RXCUI: 1362
(Identifiers listed above appear in the available substance metadata and can be used for procurement, regulatory cross-referencing and inventory control.)
Synonyms and Brand-Independent Names
Common synonyms and systematic names reported include: - Diphenhydramine hydrochloride - Diphenhydramine HCl - 2-benzhydryloxy-N,N-dimethylethanamine; hydrochloride - 2-(Diphenylmethoxy)-N,N-dimethylethanamine hydrochloride - N-(2-Diphenylmethoxyethyl)-N,N-dimethylamine hydrochloride - Benadryl (brand synonym appearing in supplier/product lists) - Dimedrol hydrochloride
A large set of branded and depositor-supplied synonyms is associated with this active ingredient across formulations and reference materials.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Diphenhydramine hydrochloride is widely used as an active pharmaceutical ingredient (API) in antihistamine therapies. As a first-generation H1 antagonist it is employed to treat allergic symptoms (urticaria, pruritus), motion sickness, nausea and vomiting, insomnia (short-term sleep aid), and as an adjunctive antitussive agent in some formulations. It also has antimuscarinic effects that contribute to both therapeutic actions (e.g., antiemetic) and adverse-effect profiles (sedation, dry mouth, urinary retention).
Formulation and Development Contexts
The hydrochloride salt is the preferred form for oral solids, oral liquids, topical anti-itch products, and combination products (e.g., with analgesics or decongestants) due to its favorable aqueous solubility and handling properties. Formulation considerations include control of light exposure (slow darkening), excipient compatibility to limit degradation, and selection of dosage forms that mitigate sedative side effects where appropriate. The salt is used in immediate-release tablets, capsules, syrups, topical creams/lotions, and in some analytical standards and reference materials.
If detailed product-specific application summaries are required, selection is typically driven by the salt’s solubility, dose range, and its known pharmacodynamic profile.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Pharmacopoeial and commercial grade designations reported for this substance include: BP, EP, JP, USP.
Typical grade types distributed in commerce and industry are: - Pharmaceutical (pharmacopeial) grade for use as an API in drug products. - Analytical/reagent grade for assay, chromatography and reference standards. - Technical grade for nonclinical laboratory and manufacturing uses.
General Quality Attributes (Qualitative Description)
Pharmacopeial-grade material is supplied with certificates specifying identity, assay, residual solvents, and impurity limits; analytical standards are provided as certified reference materials in solution or solid form. Typical quality attributes monitored in manufacture and release include organoleptic appearance (white crystalline powder), assay/potency by validated HPLC or titration, residual solvents, water content, heavy metals, and microbiological limits where applicable. Some suppliers offer preservative-free or specific solvent-formulated certified solutions for analytical workflows.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
- Reported acute toxicity: LD50 \(= 500\,\mathrm{mg}\,\mathrm{kg}^{-1}\) (oral, rat).
- Toxicity profile includes prominent central nervous system effects (sedation, drowsiness, ataxia), anticholinergic effects (dry mouth, blurred vision, urinary retention, tachycardia), gastrointestinal symptoms, and in overdose situations severe anticholinergic syndrome, convulsions and cardiorespiratory compromise.
- Reproductive and developmental considerations: potential for effects on lactation and possible adverse effects in breastfed infants with large or prolonged maternal dosing; reproductive hazard signals have been reported in animal studies under certain conditions.
- Chronic/target-organ effects: animal studies reported equivocal evidence for certain neoplastic findings in rats under high-dose feed studies; no definitive human carcinogenicity classification is indicated in the available material.
- Combustion/decomposition hazards: upon thermal decomposition the material can emit nitrogen oxides and hydrogen chloride; fires should be managed with appropriate extinguishing media and respiratory protection.
Avoid ingestion, inhalation of dust, and prolonged skin contact. In case of suspected overdose, supportive and symptomatic medical treatment is required; there is no specific universal antidote, but severe anticholinergic toxicity has been treated clinically with physostigmine in select settings and supportive measures including benzodiazepines for agitation/seizures.
Storage and Handling Guidelines
- Store protected from light at ambient temperatures in tightly closed containers to minimize degradation and darkening.
- Handle solids and powders to minimize dust generation; for weighing and dilution of neat material use appropriate engineering controls (local exhaust ventilation) and personal protective equipment (gloves, eye protection, lab coat). For high-purity handling steps a respiratory protection strategy such as a half-face respirator fitted with organic vapor/acid gas cartridges and particulate filters is advised where dust or vapor exposure may occur.
- Small spill response: dampen spilled solid with water and collect dampened material into suitable containers, clean residues with soapy water and dispose of waste per local regulations.
- Fire fighting: use dry chemical, carbon dioxide or Halon-type extinguishers per general guidance for combustible organic solids; avoid inhalation of combustion gases and use appropriate self-contained breathing apparatus if required.
- For detailed hazard, transport and regulatory information, users should refer to the product-specific Safety Data Sheet (SDS) and local legislation.
