Ethambutol (74-55-5) Physical and Chemical Properties

Chemical Profile

Ethambutol

An ethylenediamine-derived small molecule with antimyobacterial activity, typically handled as a crystalline API or salt for pharmaceutical formulation and development.

CAS Number	74-55-5
Family	Ethylenediamines
Typical Form	White crystalline powder / solid
Common Grades	EP

Used as an active pharmaceutical ingredient or intermediate in combination antimyobacterial formulations, ethambutol is relevant to formulation development, salt selection and crystallization studies. Suppliers and QA teams typically focus on solid-state form, assay, impurity profiling and solubility characteristics during scale-up, analytical method development and stability testing.

Ethambutol is an aliphatic ethylenediamine derivative bearing two chiral 1-hydroxybutan-2-yl substituents on the nitrogen atoms (S,S stereochemistry in the active enantiomer). Structurally it is a small, flexible diamine–diol with two secondary amine functions and two secondary alcohol groups distributed along an eight‑carbon backbone; the computed molecular formula is \(\ce{C10H24N2O2}\). The molecule’s polar functionality (two basic nitrogens and two hydrogen‑bonding alcohols) and modest molecular size produce a high topological polar surface area (TPSA = 64.5 Å^2) and a low lipophilicity, consistent with good aqueous solubility for the free base and with formation of water‑soluble salts (notably the dihydrochloride).

Because of the two basic centres, ethambutol behaves as a polybasic aliphatic amine under physiological conditions and is typically supplied and dosed clinically as a hydrochloride salt to control solid‑state and dissolution properties. The presence of two hydroxyl groups and two amines yields multiple hydrogen‑bond donors and acceptors (H‑bond donor count = 4; H‑bond acceptor count = 4), which contributes to low membrane partitioning (XLogP ≈ −0.1; experimental logP values reported in the literature vary around 0.4 to −0.3) and favors renal elimination of the unchanged parent. The free‑base and salt forms are chemically robust toward light and heat under normal handling but are hygroscopic and prone to moisture uptake in high relative‑humidity environments; oxidative pathways are more relevant biologically (metabolic oxidation of the alcohol to an aldehyde and subsequent dicarboxylic acid).

Ethambutol is an established antitubercular agent used as an adjunct in combination therapy for tuberculosis; it is formulated as oral tablets and as hydrochloride salt forms for medicinal use. Common commercial grades reported for this substance include: EP.

Basic Physicochemical Properties

Density and Solid-State Form

• Physical description: Solid.
• Color / form: Crystals; WHITE, CRYSTALLINE POWDER.
• Optical properties reported for sample batches: specific optical rotations reported (for example: +3 deg at 20 \(\mathrm{°C}\)/D (c = 5% in water); +13.7 deg at 25 \(\mathrm{°C}\)/D (c = 2 in water); other values also reported).
• Crystal structure data (selected reported cell parameters and symmetry):
• Hermann–Mauguin space group symbol: P 1 21 1; Hall space group symbol: P 2yb; space group number: 4.
• Unit cell (example set 1): a = 7.157, b = 8.440, c = 10.193; α = 90.00, β = 95.631, γ = 90.00; Z = 2; Z' = 1; residual factor = 0.0606.
• Unit cell (example set 2): a = 7.1428, b = 8.4149, c = 10.1973; α = 90.00, β = 95.633, γ = 90.00; Z = 2; Z' = 1; residual factor = 0.0526.
• Solid‑state considerations: the free base and salt forms show distinct melting behavior and solubility; hygroscopicity under high relative humidity is a practical consideration for storage and tablet formulation.

Melting Point

Reported melting points (values presented as reported): - 171.5-174.5 - 87.5-88.8 \(\mathrm{°C}\) - 88 \(\mathrm{°C}\)

Additional experimental melting point reports (sample-/salt‑dependent): - MP: 198.5-200.3 \(\mathrm{°C}\); also reported as mp 201.8-202.6 \(\mathrm{°C}\). - White powder, crystallizes as needles, mp 121-122 \(\mathrm{°C}\) (dec) (reported for a specific form).

Note: multiple melting point ranges reflect different crystalline forms, salts (dihydrochloride vs free base), and experimental conditions.

Solubility and Dissolution Behavior

• Reported solubility data (values reproduced as reported):
• "1000" (value without unit in source).
• Soluble in chloroform, methylene chloride; less soluble in benzene; sparingly soluble in water.
• 7.58e+00 g/L.
• Additional solubility notes: soluble in water and DMSO; sparingly soluble in ethanol; poorly soluble or difficultly soluble in acetone and chloroform for certain salt/forms (note: solubility depends strongly on free‑base versus dihydrochloride form).
• Practical implication: the hydrochloride salt is used in pharmaceutical formulations to improve aqueous solubility and ensure reliable dissolution for oral dosing.

Chemical Properties

Acid–Base Behavior and Qualitative pKa

• No experimentally established value for this property is available in the current data context.
• Qualitative assessment: ethambutol contains two aliphatic secondary amine centres that are protonatable under mildly acidic to physiological conditions; formation of the dihydrochloride salt is common for pharmaceutical formulations. Protonation increases aqueous solubility and reduces membrane partitioning; the molecule therefore behaves as a hydrophilic, cationic species at low to neutral \(\mathrm{pH}\).

Reactivity and Stability

• Reported stability: "STABLE IN LIGHT & HEAT BUT IS HYGROSCOPIC WHEN EXPOSED TO HIGH RELATIVE HUMIDITIES."
• Chemical reactivity: under ambient handling conditions ethambutol is chemically stable; oxidative transformation of the alcohol groups is relevant in metabolic contexts (oxidation to an aldehyde intermediate and conversion to a dicarboxylic acid has been observed biologically). Hydrolytic cleavage is not a typical degradative pathway for the intact molecule under normal storage conditions.
• Handling implication: control of moisture (avoid high relative humidity), protection from prolonged exposure to water during processing, and selection of appropriate salt form are key to maintain shelf life and reproducible dissolution.

Molecular Parameters

Molecular Weight and Formula

• Molecular formula: \(\ce{C10H24N2O2}\).
• Molecular weight: 204.31 (reported value).
• Exact mass / monoisotopic mass: 204.183778013.

Other computed descriptors: - Heavy atom count: 14. - Formal charge: 0. - Defined atom stereocenter count: 2. - Complexity: 109.

LogP and Structural Features

• Computed XLogP3‑AA: −0.1.
• Experimental/log literature values reported: 0.4; −0.3.
• Polar surface and H‑bonding: TPSA = 64.5; hydrogen‑bond donor count = 4; hydrogen‑bond acceptor count = 4.
• Rotatable bond count: 9.
• Interpretation: the low/near‑zero logP values, substantial TPSA and multiple H‑bond donors/acceptors indicate a highly polar, low‑lipophilicity profile consistent with renal clearance of the neutral/salt form and limited passive diffusion across lipophilic membranes. The two protonatable amine centers dominate acid–base and salt‑form chemistry.

Structural Identifiers (SMILES, InChI)

• SMILES: CC[C@@H](CO)NCCN[C@@H](CC)CO
• InChI: InChI=1S/C10H24N2O2/c1-3-9(7-13)11-5-6-12-10(4-2)8-14/h9-14H,3-8H2,1-2H3/t9-,10-/m0/s1
• InChIKey: AEUTYOVWOVBAKS-UWVGGRQHSA-N

Identifiers and Synonyms

Registry Numbers and Codes

• CAS number: 74-55-5
• Other identifiers reported in available technical records: European Community (EC) number 200-810-6; UNII 8G167061QZ; ChEBI CHEBI:4877; ChEMBL CHEMBL44884; DrugBank DB00330; ATC code J04AK02.

Synonyms and Brand-Independent Names

Selected synonyms and systematic names reported in supplier and regulatory lists: - Ethambutol - Ethambutolum - Diambutol - Myambutol - EMB - (2S)-2-[2-[[(2S)-1-hydroxybutan-2-yl]amino]ethylamino]butan-1-ol - (+)-N,N'-Bis(1-(hydroxymethyl)propyl)ethylenediamine

(Several additional depositors’ and historic synonyms exist; the above are examples reported in authoritative identifier listings.)

Industrial and Pharmaceutical Applications

Role as Active Ingredient or Intermediate

• Ethambutol functions clinically as an antitubercular agent with bacteriostatic action against actively dividing Mycobacterium species; its mechanism involves inhibition of mycobacterial arabinosyltransferases (embA, embB, embC), producing impaired arabinan and arabinogalactan synthesis in the cell wall. It is used in combination therapy for pulmonary and extrapulmonary tuberculosis to reduce the emergence of resistant strains.
• Formulation: usually supplied as the dihydrochloride salt for oral tablets and as specified parenteral solutions in some formularies; both free base and hydrochloride forms are encountered in manufacturing and analytical laboratories.

Formulation and Development Contexts

• Typical formulation forms reported: oral tablets (e.g., 100 mg and 400 mg hydrochloride tablets; dispersible tablet forms are reported) and parenteral injections where clinically indicated.
• Development considerations: selection of the hydrochloride salt to ensure consistent aqueous solubility and handling; hygroscopicity requires moisture‑protective packaging. Chiral composition is important — the pharmacologically preferred enantiomer and historical evidence that the D and L isomers have different activity/toxicity profiles influence manufacturing and quality control strategies.

Specifications and Grades

Typical Grade Types (Pharmaceutical, Analytical, Technical)

• Typical commercial grade concepts applicable to ethambutol include:
• Pharmaceutical (pharmacopeial) grade — for finished drug product manufacture, requiring defined salt form and impurity controls.
• Analytical grade — high purity standards for method development and reference standards.
• Technical grade — for non‑clinical or industrial uses where lower purity thresholds may be acceptable.
• If supplied as a salt, the pharmacopeial monograph (where applicable) will specify the salt form (commonly dihydrochloride) and the appropriate quality attributes for pharmaceutical use.

The following commercial grade label was reported for this substance: - EP

General Quality Attributes (Qualitative Description)

• Important qualitative quality attributes: correct salt form (free base vs dihydrochloride), enantiomeric purity (given stereochemistry dependence of activity/toxicity), low water content and protection against hygroscopic uptake, control of residual solvents and related organic impurities, and defined assay and impurity profiling for pharmaceutical use. Stability testing should address moisture uptake and polymorphic/crystalline form transitions; dissolution testing is required to demonstrate adequate release from oral solid dosage forms.

Safety and Handling Overview

Toxicological Profile and Exposure Considerations

• Principal toxicological concerns:
• Ocular neurotoxicity: optic neuritis is the most clinically significant adverse effect (decreased visual acuity, central scotoma, color‑vision defects); risk is dose‑ and duration‑dependent and can be reversible if detected early and the drug discontinued.
• Neurological and peripheral effects: peripheral neuropathy and other neuropsychiatric effects have been reported.
• Hepatic effects: transient aminotransferase elevations are reported when used in combination regimens; clinically apparent liver injury is rare but has been described.
• Other effects: increases in serum uric acid and occasional precipitation of gout have been observed in some patients.
• Acute toxicity data reported: LD50 (mouse, oral) 2800 mg/kg (reported for a mixture with isoniazid methane sulfonate in a toxicology note).
• Occupational handling: avoid ingestion, inhalation of dust, and eye contact; use suitable gloves and eye protection and work in well‑ventilated areas or localized exhaust when handling powders. Given the potential for organ toxicity on repeated exposure, avoid chronic dermal exposure and minimize aerosolization.

Storage and Handling Guidelines

• Storage conditions reported: protect from light, moisture, and excessive heat; store in well‑closed containers at 15–30 \(\mathrm{°C}\) where possible; some recommendations state to store below 40 \(\mathrm{°C}\) (104 \(\mathrm{°F}\)), preferably between 15 and 30 \(\mathrm{°C}\).
• Hygroscopic behaviour: maintain low relative humidity and suitable desiccation/packaging for bulk powders and intermediate materials.
• Emergency and regulatory guidance: implement standard spill and disposal controls for pharmaceutical active substances; for detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.

For clinical or laboratory use, standard SDS guidance should be followed and visual function monitoring (in clinical treatment) or exposure prevention measures (in manufacturing and QC environments) should be applied as appropriate to the use case.