TOLAZAMIDE

Tolazamide is a white to off-white crystalline powder belonging to the first-generation sulfonylurea class of oral hypoglycemic agents, with molecular formula C₁₄H₂₁N₃O₃S, molecular weight 311.40 g/mol, CAS number 1156-19-0, EC number 214-588-3, melting point 165–173°C, density approximately 1.2228 g/cm³, and very slight solubility in water, slight solubility in alcohol, and free solubility in chloroform; it is the 1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea derivative synthesised at The Upjohn Company and first marketed under the trade name Tolinase in 1964.
Tolazamide acts by binding to and inhibiting ATP-sensitive potassium channel receptors (SUR1/KIR6.2; IC50 = 4.2 µM) on pancreatic beta-cell membranes, causing membrane depolarisation, calcium ion influx through voltage-gated calcium channels, and exocytosis of insulin-containing granules into the bloodstream; it also produces a mild diuretic effect by enhancement of renal free water clearance, and in vivo reduces glomerulosclerosis and albumin excretion in streptozotocin-induced diabetic rat models.
Tolazamide is classified under GHS as Warning (H302 harmful if swallowed) and is used clinically as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in adults; it has been discontinued in the United States but remains available for research use and as a USP reference standard, and is approximately five times more potent than tolbutamide and equivalent in milligram potency to chlorpropamide.

CAS Number: 1156-19-0
EC Number: 214-588-3
Molecular Formula: C₁₄H₂₁N₃O₃S
Molecular Weight: 311.40 g/mol

Synonyms: Tolinase, Tolanase, Norglycin, Diabewas, Ronase, Tolonase, U-17835, NSC 70762, NSC-70762, NSC-758149, HY-B0920, Tolazolamide, Tolazamida, Tolazamidum, 1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea, 1-(hexahydro-1H-azepin-1-yl)-3-(p-toluenesulfonyl)urea, N-(p-toluenesulfonyl)-N′-hexamethyleniminourea, N-[[(hexahydro-1H-azepin-1-yl)amino]carbonyl]-4-methylbenzenesulfonamide, 1-(azepan-1-yl)-3-(4-methylphenyl)sulfonylurea, Benzenesulfonamide N-[[(hexahydro-1H-azepin-1-yl)amino]carbonyl]-4-methyl-, Tolbutamide EP Impurity C, BRN 1323565, HSDB 3192, CCRIS 591, CHEBI:9613, ChEMBL817, DB00839, CAS 1156-19-0

Appearing as a white to creamy-white powder, Tolazamide belongs to the first generation of sulfonylurea compounds.
A sulfonylurea group, a p-tolyl unit, and a seven-membered azepane ring form the molecular structure of Tolazamide.

With a molecular formula of C₁₄H₂₁N₃O₃S, Tolazamide has a molecular weight of 311.40 g/mol.
Originally developed as an oral glucose-lowering agent, Tolazamide has been used in the management of type 2 diabetes.

Blood glucose reduction occurs when Tolazamide stimulates insulin release from functioning pancreatic beta cells.
By interacting with the SUR1/Kir6.2 potassium-channel complex, Tolazamide promotes the cellular events that lead to insulin secretion.

Closure of ATP-sensitive potassium channels contributes to the pharmacological activity of Tolazamide.
Although the acute action is linked to insulin release, the complete long-term mechanism of Tolazamide has not been fully established.

After oral administration, Tolazamide undergoes rapid and extensive absorption from the gastrointestinal tract.
Peak serum concentrations generally develop within three to four hours after a single oral dose of Tolazamide.

An average biological half-life of approximately seven hours has been reported for Tolazamide.
Following repeated administration, Tolazamide generally reaches a steady state after the fourth to sixth dose.

Metabolism transforms Tolazamide into five major metabolites with varying degrees of glucose-lowering activity.
Urinary excretion represents the principal elimination route for Tolazamide and its metabolites.

Within five days of a radiolabelled dose, approximately 85% of Tolazamide-related material was recovered in urine and 7% in faeces.
Most urinary elimination associated with Tolazamide occurs during the first 24 hours after administration.

In addition to lowering blood glucose, Tolazamide can produce mild diuresis by increasing renal free-water clearance.
On a milligram basis, Tolazamide demonstrated greater glucose-lowering potency than tolbutamide in historical clinical comparisons.

Only limited dissolution occurs when Tolazamide comes into contact with water around neutral pH.
A melting range of approximately 165–173°C characterises the solid form of Tolazamide.

Multiple crystalline forms have made Tolazamide a useful model compound in pharmaceutical polymorphism research.
Crystal-growth studies indicate that two-dimensional nucleation contributes to the crystallisation behaviour of Tolazamide.

Hydrogen bonding and aromatic stacking interactions influence the solid-state arrangement of Tolazamide.
Changes in pressure can modify the intermolecular contacts found within Tolazamide crystals.

The synthesis of Tolazamide can begin with the conversion of p-toluenesulfonamide into a tosylurethane intermediate.
Reaction of a tosylurethane intermediate with an azepane-derived component produces Tolazamide.

Pharmaceutical and biochemical studies use Tolazamide as a reference compound for investigating sulfonylurea receptors and pancreatic potassium channels.
Under the trade name Tolinase, Tolazamide became one of the established early oral sulfonylurea agents.

Uses of Tolazamide:
Tolazamide is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 (non-insulin-dependent) diabetes mellitus whose hyperglycaemia cannot be satisfactorily controlled by diet alone.
Tolazamide is approximately five times more potent than tolbutamide on a milligram basis and equivalent in milligram potency to chlorpropamide; it is effective in approximately one third of patients who have failed on tolbutamide, chlorpropamide, or phenformin, and may be effective as a rescue therapy in some patients unresponsive to one or more other sulfonylureas.
Tolazamide is used to reduce insulin dose in type 2 diabetic patients previously treated with insulin; patients whose prior insulin dosage was less than 20 units may be switched directly to 100 mg/day, while those requiring more than 40 units undergo a 50% insulin dose reduction concurrent with initiation of tolazamide.
Tolazamide produces a mild diuresis by enhancement of renal free water clearance, which may be advantageous in patients who have a tendency to retain water, distinguishing it from other first-generation sulfonylureas that may cause water retention (antidiuretic effect).
Tolazamide is used as a USP and analytical reference standard for the determination of sulfonylurea residues and impurities in pharmaceutical matrices by HPLC and GC; it also serves as Tolbutamide EP Impurity C in pharmacopoeial impurity profiling.
Tolazamide is used in preclinical research as a pharmacological tool to inhibit SUR1/KIR6.2 potassium channels in cell-based assays, in vitro receptor binding studies, and in vivo models of diabetes and renal disease.

Benefits and Advantages of Tolazamide:
Tolazamide offers once-daily dosing for the majority of patients (doses up to 500 mg/day as a single morning dose), which simplifies the treatment regimen compared to older sulfonylureas requiring multiple daily administrations.
The intermediate duration of action of tolazamide (peak hypoglycaemic effect 4–6 hours post-dose in fasting diabetics; duration of maximal effect approximately 10 hours in fed patients) provides sustained glycaemic control without the prolonged half-life associated with chlorpropamide-related hypoglycaemia accumulation.
Unlike chlorpropamide, tolazamide lacks antidiuretic (ADH-potentiating) activity and instead produces a mild diuresis, making it more suitable for patients at risk of hyponatraemia or fluid retention.
The oral LD50 of tolazamide in rats and mice exceeds 5,000 mg/kg, placing it among the safest sulfonylureas in terms of acute systemic exposure profile, while the intraperitoneal LD50 of 2,239 mg/kg in rodents confirms adequate safety margins.
Tolazamide is metabolised to five major metabolites with hypoglycaemic activity ranging from 0–70%, providing a prolonged pharmacodynamic effect beyond what the plasma half-life of 7 hours alone would suggest, and none of its principal metabolites were identified as carcinogenic by IARC, ACGIH, NTP, or OSHA assessments.

Features of Tolazamide:
Tolazamide appears as a white to off-white (creamy-white) crystalline powder with no significant odour; melting point 165–173°C (crystals from ethanol: 170–173°C), density 1.2228 g/cm³, XLogP3 1.5, TPSA 86.9 Ų, pKa 3.6 (25°C) and 5.68 (37.5°C); hydrogen bond donors 2, hydrogen bond acceptors 4, rotatable bonds 3.
Tolazamide is very slightly soluble in water (solubility at pH 6.0: 27.8 mg/100 mL; minimum solubility at 37.5°C: 0.09 g/L at pH 4.5 rising to 1.97 g/L at pH 7.0), slightly soluble in alcohol (4–5 g/L in 95% ethanol), soluble in acetone, and freely soluble in chloroform; the low aqueous solubility is offset by high urinary solubility (93% of urinary metabolites are more water-soluble than the parent drug), preventing crystalluria.
Tolazamide is rapidly and well absorbed from the gastrointestinal tract; peak serum concentrations occur at 3–4 hours following a single oral dose; onset of hypoglycaemic action in normal subjects occurs within 20 minutes of a 500 mg dose, with peak hypoglycaemic effect at 2–4 hours; in fasting diabetic patients peak effect occurs at 4–6 hours; the drug reaches steady state after 4–6 doses without further accumulation.
Tolazamide is metabolised in the liver to five major metabolites (including two hydroxy-metabolites, p-toluenesulfonamide, p-carboxytolazamide, and one unidentified metabolite) with hypoglycaemic activity from 0–70%; excreted principally in urine (85%) and faeces (7%) over five days; elimination half-life is 7 hours; protein binding exceeds 99% (principally albumin); volume of distribution is small.

Chemical Properties of Tolazamide:
Tolazamide has IUPAC name 1-(azepan-1-yl)-3-(4-methylphenyl)sulfonylurea (alternative IUPAC: N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide), SMILES O=S(=O)(c1ccc(cc1)C)NC(=O)NN2CCCCCC2, InChI=1S/C14H21N3O3S/c1-12-6-8-13(9-7-12)21(19,20)16-14(18)15-17-10-4-2-3-5-11-17/h6-9H,2-5,10-11H2,1H3,(H2,15,16,18), InChIKey OUDSBRTVNLOZBN-UHFFFAOYSA-N; PubChem CID 5503, ChemSpider 5302, ChEBI CHEBI:9613, ChEMBL ChEMBL817, DrugBank DB00839, KEGG D00379, ECHA InfoCard 100.013.262, CompTox DTXSID3021358, UNII 9LT1BRO48Q, IUPHAR/BPS 6847, Beilstein BRN 1323565.
Tolazamide is an N-sulfonylurea in which the two nitrogen atoms of the urea are substituted: one nitrogen carries a p-toluenesulfonyl group (forming the sulfonylaminocarbonyl moiety), and the other is part of a hexamethylene imine (azepane) ring; the molecular framework is C 54.00%, H 6.80%, N 13.49%, O 15.41%, S 10.30% by elemental composition.
The mechanism of action involves selective binding to the SUR1 subunit of the ATP-sensitive potassium channel complex (ABCC8/SUR1 + KCNJ11/KIR6.2), reducing potassium conductance, depolarising the beta-cell membrane, opening voltage-sensitive calcium channels, raising intracellular Ca²⁺, and triggering exocytosis of insulin; tolazamide also enhances insulin sensitivity in peripheral tissues including muscle and fat, and reduces hepatic basal glucose output.
Tolazamide is stable under recommended storage conditions; incompatible with strong acids/alkalis and strong oxidising/reducing agents; under fire conditions may decompose and emit irritating fumes; not considered carcinogenic by IARC, ACGIH, NTP, or OSHA.

Production of Tolazamide:
Tolazamide is synthesised by a two-step process: first, p-toluenesulfonamide reacts with ethyl chloroformate in the presence of a base to form tosylurethane (ethyl N-tosylcarbamate, CAS 5577-13-9) as the reactive intermediate.
The tosylurethane intermediate is then heated with azepane (hexamethyleneimine), which displaces the ethoxy group via aminolysis to yield tolazamide; this synthetic route was developed by J. B. Wright at The Upjohn Company (GB Patent 887886, 1962) and has been the established industrial method since the compound's introduction in 1964.
Tolazamide is commercially available as a white to light yellow powder or crystal at ≥98% purity (HPLC or GC), in tablet form (100 mg, 250 mg, 500 mg) as prescription pharmaceutical, and as USP Reference Standard and analytical-grade material; storage at −20°C (powder, 3 years shelf life) or 4°C (powder, 2 years), and at −80°C or −20°C in solution.

Tolazamide Material Safety Data Sheet (MSDS):

Handling of Tolazamide:
Tolazamide is a prescription pharmaceutical compound and research chemical classified GHS Warning (H302); avoid inhalation and contact with eyes and skin, avoid dust and aerosol formation, and use only in areas with appropriate exhaust ventilation.
Do not eat, drink, or smoke when using this product; wash hands thoroughly after handling; contaminated clothing and shoes should be removed and the area cleaned before re-entering; provide accessible safety shower and eyewash station in laboratory settings.

Tolazamide SDS:

Stability and Reactivity of Tolazamide:

Chemical stability:
Tolazamide is stable under recommended storage conditions at −20°C (powder) or 4°C in a tightly closed container. No hazardous reactions are expected under normal handling conditions.

Reactivity:
Tolazamide may decompose under fire conditions and emit irritating fumes. Incompatible with strong acids, strong alkalis, and strong oxidising and reducing agents.

Conditions to avoid:
Excessive heat and ignition sources.
Moisture (hygroscopic degradation in solution).
Strong acids and strong alkalis.
Direct sunlight.

Incompatible materials:
Strong acids and alkalis.
Strong oxidising agents.
Strong reducing agents.

Hazardous decomposition products:
Under fire conditions: irritating fumes including sulfur oxides (SOₓ) and nitrogen oxides (NOₓ).
Carbon monoxide (CO) and carbon dioxide (CO₂) upon combustion.

Handling and Storage of Tolazamide:

Handling:
For research use only — not for human or veterinary use unless prescribed.
Avoid inhalation, contact with eyes and skin; avoid dust and aerosol formation.
Use only in areas with appropriate exhaust ventilation.
Wash hands thoroughly after handling; do not eat, drink, or smoke in work areas.

Storage:
Powder: −20°C (shelf life 3 years); 4°C (shelf life 2 years).
In solvent: −80°C (shelf life 2 years); −20°C (shelf life 1 year).
Store in a tightly sealed container in a cool, well-ventilated area away from direct sunlight and ignition sources.
Ship at room temperature if transit time is less than 2 weeks.

First Aid Measures for Tolazamide:

Inhalation:
Remove the affected person to fresh air immediately; if breathing is difficult, give cardiopulmonary resuscitation (CPR) — avoid mouth-to-mouth resuscitation.
Consult a physician.

Skin contact:
Rinse skin thoroughly with large amounts of water; remove contaminated clothing and shoes.
Consult a physician.

Eye contact:
Remove contact lenses, locate eyewash station, and flush eyes immediately with large amounts of water for at least 15 minutes, separating eyelids with fingers to ensure adequate flushing.
Consult a physician promptly.

Ingestion:
Wash out the mouth with water; do not induce vomiting; consult a physician immediately.
Note: overdose may cause severe or prolonged hypoglycaemia requiring glucose administration and medical monitoring.

Firefighting Measures for Tolazamide:

Suitable extinguishing media:
Water spray, dry chemical powder, foam, or carbon dioxide.

Specific hazards:
Tolazamide is a combustible solid; during combustion it may emit irritating fumes including sulfur oxides and nitrogen oxides.

Protective equipment for firefighters:
Self-contained breathing apparatus (SCBA) and full protective clothing must be used.

Firefighting procedures:
Prevent contaminated firefighting water from entering drains or water courses.
Cool containers exposed to fire with water spray.

Accidental Release Measures for Tolazamide:

Personal precautions:
Use full personal protective equipment; avoid breathing vapours, mist, dust, or gas.
Ensure adequate ventilation; evacuate personnel to safe areas.

Environmental precautions:
Keep the product away from drains or water courses; prevent further leakage or spillage.

Clean-up methods:
Absorb solutions with finely powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces by scrubbing with alcohol.
Dispose of contaminated material according to applicable regulations.

Exposure Controls / Personal Protective Equipment for Tolazamide:

Engineering controls:
Ensure adequate ventilation; provide accessible safety shower and eyewash station.
No established occupational exposure limits for tolazamide.

Eye protection:
Safety goggles with side shields.

Hand protection:
Protective chemical-resistant gloves.

Skin and body protection:
Impervious protective clothing.

Respiratory protection:
Suitable particulate or combination respirator where dust or aerosol may form.

Hygiene measures:
Wash hands before breaks and at the end of the workday; do not eat, drink, or smoke in work areas.

Tolazamide Identifiers:
CAS Number: 1156-19-0
EC Number: 214-588-3
IUPAC Name: 1-(azepan-1-yl)-3-(4-methylphenyl)sulfonylurea
Molecular Formula: C₁₄H₂₁N₃O₃S
Molecular Weight: 311.40 g/mol
Exact Mass: 311.13036271 g/mol
SMILES: O=S(=O)(c1ccc(cc1)C)NC(=O)NN2CCCCCC2
InChI: InChI=1S/C14H21N3O3S/c1-12-6-8-13(9-7-12)21(19,20)16-14(18)15-17-10-4-2-3-5-11-17/h6-9H,2-5,10-11H2,1H3,(H2,15,16,18)
InChIKey: OUDSBRTVNLOZBN-UHFFFAOYSA-N
PubChem CID: 5503
ChemSpider: 5302
ChEBI: CHEBI:9613
ChEMBL: ChEMBL817
DrugBank: DB00839
KEGG: D00379
ECHA InfoCard: 100.013.262
CompTox (EPA): DTXSID3021358
UNII: 9LT1BRO48Q
IUPHAR/BPS: 6847
Beilstein: BRN 1323565
ATC Code: A10BB05
GHS Signal Word: Warning
GHS Hazard Statement: H302 (harmful if swallowed)
GHS Precautionary Statements: P264, P270, P330, P501
Rat oral LD50: >5000 mg/kg
Rat/mouse i.p. LD50: 2239 mg/kg
pKa: 3.6 (25°C); 5.68 (37.5°C)
XLogP3: 1.5
TPSA: 86.9 Ų
HBD: 2; HBA: 4; RotB: 3
Protein binding: >99% (albumin)
Elimination half-life: 7 hours
Excretion: Renal 85%, faecal 7%
Metabolism: Hepatic (CYP2C9); 5 major metabolites (0–70% activity)
US status: Discontinued (prescription); available as reference standard
ATC: A10BB05 (WHO)

Properties of Tolazamide:
Physical state: Solid
Appearance: White to off-white (creamy-white) crystalline powder
Odour: Odourless or slight odour
Molecular formula: C₁₄H₂₁N₃O₃S
Molecular weight: 311.40 g/mol
Melting point: 165–173°C (crystals from ethanol: 170–173°C)
Density: 1.2228 g/cm³
Water solubility: Very slightly soluble; 27.8 mg/100 mL at pH 6.0; 0.09 g/L at pH 4.5 (37.5°C)
Solubility in alcohol: Slightly soluble; 4–5 g/L in 95% ethanol
Solubility in chloroform: Freely soluble
Solubility in acetone: Soluble
pKa: 3.6 (25°C); 5.68 (37.5°C)
XLogP3: 1.5 (logP: 1.34 by CLOGP)
TPSA: 86.9 Ų
Heavy atom count: 21
Complexity: 431
GHS Classification: Warning — H302
Storage temperature: −20°C (powder, 3 yr); 4°C (powder, 2 yr)

Tolazamide Properties — Specifications:
Product name: Tolazamide (Tolinase)
CAS Number: 1156-19-0
EC Number: 214-588-3
Molecular Formula: C₁₄H₂₁N₃O₃S
Molecular Weight: 311.40 g/mol
Purity: ≥98% (HPLC or GC); USP Reference Standard grade available
Appearance: White to light yellow powder or crystal
Melting point: 165–173°C
Density: 1.2228 g/cm³
Storage: −20°C (powder, 3 yr); 4°C (powder, 2 yr); −80°C in solvent (2 yr)
Format: Solid (neat); tablet formulations (100 mg, 250 mg, 500 mg) — Rx only
Documents: CoA (Certificate of Analysis), MSDS/SDS available
For research use only; not for human or veterinary use without prescription.

Names of Tolazamide:
Tolazamide
Tolinase
Tolanase
Norglycin
Diabewas
Ronase
Tolonase
Tolazolamide
Tolazamida
Tolazamidum
U-17835
NSC 70762
NSC-758149
HY-B0920
1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea
1-(hexahydro-1H-azepin-1-yl)-3-(p-toluenesulfonyl)urea
1-(azepan-1-yl)-3-(4-methylphenyl)sulfonylurea
N-(p-toluenesulfonyl)-N′-hexamethyleniminourea
N-[[(hexahydro-1H-azepin-1-yl)amino]carbonyl]-4-methylbenzenesulfonamide
Benzenesulfonamide N-[[(hexahydro-1H-azepin-1-yl)amino]carbonyl]-4-methyl-
Tolbutamide EP Impurity C
BRN 1323565
HSDB 3192
CCRIS 591
CAS 1156-19-0