Heroin (25-16-6) Physical and Chemical Properties
Heroin
Semi-synthetic opioid (diacetylmorphine) used in analytical, forensic and pharmaceutical R&D as a lipophilic prodrug of morphine, relevant for formulation development and reference-standard work.
| CAS Number | 25-16-6 |
| Family | Opioid (opiate derivative) |
| Typical Form | White crystalline powder |
| Common Grades | BP, EP, USP |
Heroin (diacetylmorphine, diamorphine) is a semisynthetic morphinan alkaloid derived by acetylation of morphine at the 3‑ and 6‑hydroxyl positions. Structurally it is an O,O‑diacetylated morphine ester that retains the morphinan tetracyclic core and the tertiary N‑methyl amine; the two acetyl esters increase lipophilicity relative to morphine and markedly accelerate brain uptake when administered parenterally. The molecule contains no free hydrogen bond donors (0 H‑bond donors) and multiple oxygen heteroatoms (6 H‑bond acceptors) distributed in ester and ether functionalities, giving a moderate topological polar surface area (TPSA = 65.1 Å^2) while preserving sufficient lipophilicity (log P ~1.5–1.58) for rapid blood–brain barrier penetration.
Electronically, the tertiary amine can be protonated (basic pKa ≈ 7.95–7.96), so the compound exists as a mixture of protonated and neutral species near physiological pH; protonation increases aqueous solubility and alters distribution between plasma and tissues. The ester groups are labile to hydrolysis (enzymatic and base‑catalyzed), producing 6‑monoacetylmorphine (6‑MAM) and morphine; this metabolic and chemical hydrolysis underpins both its pharmacology (prodrug behavior) and chemical stability profile. Heroin is of primary pharmacological and forensic importance as a potent mu‑opioid prodrug with rapid onset following parenteral use; in some regulated jurisdictions it is also used clinically (as diamorphine) for severe analgesia and opioid‑maintenance therapy.
Common commercial grades reported for this substance include: BP, EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Solid-state descriptions report white crystals or crystalline powder and orthorhombic plates or prisms obtained from organic solvents (ethyl acetate, methanol). Experimental appearance notes include odorless material that "turns pink" and "emits acetic odor on prolonged exposure to air," indicating slow oxidative or hydrolytic surface changes in air. A reported density value is "1.56 g/cu m at 25 °C"; storage and handling practice should assume a crystalline solid with hygroscopic tendencies (see storage guidance below).
Reported crystalline forms and optical rotations vary with salt or derivative state (free base vs. hydrochloride monohydrate), and crystalline habit depends on solvent of recrystallization (ethyl acetate, methanol).
Melting Point
An experimental melting point is given as "173" and elsewhere explicitly as "173 °C" for the free base in the compiled experimental properties. Other reported solid‑state thermal data appear in the literature in association with salts or derivatives (examples: "Needles, mp 242 °C" and "Fine crystals; mp 243–244 °C" reported for diamorphine hydrochloride forms). No single universal m.p. applies to all isolated forms; salt form and hydration state substantially influence melting behavior. If an exact melting point value is required for a particular material form, determine it on the specific batch/formulation.
Solubility and Dissolution Behavior
Solubility data are form‑dependent and partly inconsistent across reports; recorded experimental entries include: - "Solubility: 600" (unit not specified in that line), - "In water, 60 mg/L at 25 °C" (\(60\,\mathrm{mg}\,\mathrm{L}^{-1}\) at \(25\,^\circ\mathrm{C}\)), - "1 g dissolves in 1,700 mL water" (i.e., \(1\,\mathrm{g}\) per \(1700\,\mathrm{mL}\)), - Organic solvent solubilities: "1 g dissolves in: 1.5 mL chloroform; 31 mL alcohol; 100 mL ether", - "Soluble in alkalies; slightly soluble in ammonia or sodium carbonate solution", - "Very soluble in benzene".
Interpretation: the free base is sparingly soluble in neutral water but shows substantially greater solubility in organic solvents and in alkaline media (due to deprotonation of any trace acidic functionalities and enhanced organic solvent miscibility). The hydrochloride salt and other pharmaceutically prepared salts are substantially more water‑soluble; therefore formulators select the appropriate salt and solvent system depending on route of administration and desired concentration. Hydrolysis of the acetyl esters in aqueous solution (pH‑dependent) reduces concentration of intact diacetylmorphine over time.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Reported dissociation constants include "Basic pKa 7.96" and "pKa 7.95 (at 25 °C)". The lone tertiary amine center is the principal basic site; with a pKa near 7.95 the amine is substantially protonated at physiological pH (pH 7.4), which increases aqueous ionization and affects distribution and plasma binding. Protonation state governs solubility, membrane permeability, and interactions with ion‑exchange chromatographic media; it also affects extraction efficiency during forensic and analytical sample workups.
Reactivity and Stability
- Hydrolysis: the 3‑ and 6‑acetyl esters are susceptible to hydrolysis. A base‑catalyzed hydrolysis rate constant has been estimated such that half‑lives are pH‑dependent (examples reported: half‑lives of ~120 days at pH 7 and ~12 days at pH 8 under certain model estimates), and aqueous hydrolysis yields 6‑monoacetylmorphine and morphine. Hydrolysis is an important degradation pathway both in biological systems and in environmental/analytical contexts.
- Thermal behavior: "Decomposes by boiling with water" and "When heated to decomposition it emits toxic fumes of nitrogen oxides." Thermal decomposition risks toxic combustion products.
- Storage stability: material is described as "Stable under recommended storage conditions" but several reports note color change and an acetic odor on prolonged exposure to air, consistent with slow surface hydrolysis/oxidation. Use of airtight containers and desiccants is advised for long‑term retention of purity.
- Reactivity considerations: susceptibility to ester hydrolysis makes solutions (especially at alkaline pH or elevated temperature) chemically unstable; processing and analytical methods should minimize exposure to moisture, elevated temperature and basic conditions.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C21H23NO5
- Molecular weight: 369.4
- Exact/monoisotopic mass: 369.15762283
These values correspond to the neutral free base composition of diacetylmorphine (heroin).
LogP and Structural Features
Computed and experimental partitioning metrics recorded: - XLogP (computed): 1.5 - Experimental/log Kow value: 1.58
Key structural/physicochemical descriptors: - HBondDonorCount: 0 - HBondAcceptorCount: 6 - Topological Polar Surface Area (TPSA): 65.1 - Rotatable Bond Count: 4 - Formal charge: 0 (neutral free base) - Defined atom stereocenter count: 5 (multiple defined stereocenters in morphinan scaffold)
Interpretation: moderate lipophilicity combined with limited H‑bond donation and moderate TPSA supports rapid membrane permeation (particularly in neutral form) but also allows significant aqueous partitioning when the tertiary amine is protonated.
Structural Identifiers (SMILES, InChI)
- SMILES: CC(=O)O[C@H]1C=C[C@H]2[C@H]3CC4=C5[C@]2([C@H]1OC5=C(C=C4)OC(=O)C)CCN3C
- InChI: InChI=1S/C21H23NO5/c1-11(23)25-16-6-4-13-10-15-14-5-7-17(26-12(2)24)20-21(14,8-9-22(15)3)18(13)19(16)27-20/h4-7,14-15,17,20H,8-10H2,1-3H3/t14-,15+,17-,20-,21-/m0/s1
- InChIKey: GVGLGOZIDCSQPN-PVHGPHFFSA-N
(SMILES and InChI presented here as plain text for interoperability with cheminformatics systems.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS: 25-16-6
- Related CAS for hydrochloride salt noted in documentation: 1502-95-0 (hydrochloride)
- European Community (EC) number: 209-217-7
- UNII: 70D95007SX
- DEA code number: 9200 (noting controlled substance scheduling)
- ChEBI: CHEBI:27808
- ChEMBL: CHEMBL459324
- DrugBank: DB01452
These registry identifiers are commonly used for procurement, regulatory filings, and analytical reference materials.
Synonyms and Brand-Independent Names
Common synonyms and systematic names include: Heroin; Diacetylmorphine; Diamorphine; 3,6‑Diacetylmorphine; Acetomorphine; Morphine diacetate; O,O'‑Diacetylmorphine. Numerous street and regional synonyms exist but are not listed here for brevity; analytic reports and pharmacopoeial materials will reference the INN/BAN terms diamorphine or diacetylmorphine where applicable.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Heroin is principally an opioid analgesic prodrug of morphine; medically it acts as a rapid‑onset prodrug (the acetyl groups facilitate brain penetration and are removed in vivo to yield active metabolites including 6‑MAM and morphine). In many jurisdictions heroin is a controlled illicit substance; nonetheless, in some regulated healthcare systems (under the name diamorphine) it is approved for hospital‑use indications such as severe acute and palliative pain, certain perioperative analgesia contexts, and opioid‑maintenance programs for treatment‑resistant dependence. Regulatory scheduling and national law strongly govern any legitimate medical use.
Formulation and Development Contexts
Pharmaceutical presentations historically reported include injectable powder (hydrochloride salt) for solution for injection, linctuses and elixirs (historical formulations combining diamorphine with other agents), and concentrated analytical standards. Formulation considerations emphasize salt selection (e.g., diamorphine hydrochloride) to achieve desired aqueous solubility and stability; ester hydrolysis in aqueous formulations is an important degradative pathway and must be controlled by formulation pH, low temperature storage, and appropriate excipients. For forensic and analytical method development, multiple LC‑MS/MS and GC‑MS methods are described for quantitation and profiling of heroin and its characteristic impurities and metabolites.
If a concise application summary is required beyond the above, note that access and use are tightly restricted by national laws and clinical protocols.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Commercial grades reported for diamorphine/heroin include BP, EP and USP grades. Typical grade distinctions applicable to small‑molecule active substances generally include: - Pharmaceutical (pharmacopoeial) grade: material suitable for medicinal product manufacture subject to pharmacopeial monographs and stringent impurity and microbial limits. - Analytical standard (reference) grade: high‑purity certified reference materials for method validation and forensic analysis. - Technical grade: material intended for non pharmaceutical research, forensic, or industrial uses where pharmacopeial compliance is not required.
The explicit grade strings reported here are: BP, EP, USP.
General Quality Attributes (Qualitative Description)
Quality attributes of relevance include: assay/potency of the free base or salt, control of organic‑solvent residuals from recrystallization, control of acetylated and non‑acetylated morphine‑family impurities (e.g., monoacetylmorphine, morphine, codeine, noscapine), control of water content/hydration state (affecting solid‑state form and melting point), and particulate/sterility attributes for parenteral preparations. Because ester hydrolysis is a principal degradation pathway, shelf‑life specifications typically address limits for 6‑MAM and morphine impurity levels over time. Specific numeric assay and impurity limits are product‑ and supplier‑specific and must be obtained from the relevant certificate of analysis and pharmacopeial monograph.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Heroin is a potent mu‑opioid prodrug with substantial acute toxicity risk, particularly by parenteral, inhalational or mucosal exposure. Reported human toxic and lethal concentration ranges include "Toxic heroin blood concentration: 10–100 µg·dL^-1; Lethal heroin blood concentration: >400 µg·dL^-1" (reported units in source material). Fatal dose reports are variable; one historical entry states "the fatal dose is between 1/6 and 2 grains" and individual fatalities have been observed after doses as low as \(10\,\mathrm{mg}\) in some contexts. Animal toxicity values include LD50 entries: mouse intracerebral \(137\,\mu\mathrm{g}\,\mathrm{kg}^{-1}\), mouse subcutaneous \(261.6\,\mathrm{mg}\,\mathrm{kg}^{-1}\), and mouse intravenous \(21.8\,\mathrm{mg}\,\mathrm{kg}^{-1}\).
Acute hazards include central nervous system and respiratory depression (which can be fatal), miosis, nausea, sedation, and in overdose noncardiogenic pulmonary edema. Chronic exposure and repeated use produce tolerance, dependence and a characteristic withdrawal syndrome; perinatal exposure is associated with neonatal abstinence and other adverse fetal/neonatal outcomes. Combustion or decomposition can emit carbon oxides and nitrogen oxides; avoid inhalation of combustion products.
Emergency treatment: resuscitation and airway/ventilatory support are primary; opioid receptor antagonists such as naloxone are antidotal and should be administered as clinically indicated.
Storage and Handling Guidelines
- Store in tightly closed, airtight containers in a dry, well‑ventilated place; material is described as hygroscopic in some reports and storage with desiccant is recommended.
- Minimize exposure to air and moisture; prolonged exposure can cause discoloration and an acetic odor consistent with surface hydrolysis/oxidation.
- Engineering controls: apply local exhaust ventilation to control dust and aerosol generation. Avoid creating dust; avoid inhalation.
- Personal protective equipment: chemical‑resistant gloves, eye/face protection (safety glasses or face shield), and protective clothing as appropriate. Where airborne exposure risk exists, use respiratory protection evaluated by a competent authority (examples noted in reports: N100/P3 particulate filters or supplied‑air respirators).
- Spill and release: avoid dust formation, evacuate and ventilate area, use respiratory protection for cleanup, collect material without creating aerosols, and transfer to appropriate waste containers for disposal by licensed hazardous‑waste contractors. For disposal, incineration in a chemical incinerator with afterburner and scrubber is often specified by waste contractors.
- Regulatory note: heroin/diamorphine is controlled in many jurisdictions; handling, storage, transfer and disposal must comply with applicable controlled‑substances legislation and institutional controls. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
For laboratory, clinical or manufacturing operations involving heroin (diamorphine), adherence to controlled‑substance regulations, secure storage, rigorous inventory control and appropriate occupational‑health provisions are mandatory.
