Solubilization and Stability of Bumetanide in Vehicles for Intranasal Administration, a Pilot Study

Abstract

The solubility of bumetanide in vehicles of various polarities, suitable for intranasal administration in acute situations, has been investigated. The solubility at 4 degrees C in glycofurol and polyethylene glycol 200 was high (167 and 143 mg/mL, respectively), decreasing exponentially with addition of phosphate buffer or coconut oil. Vehicles containing coconut oil and glycofurol did not seem to improve the solubility relative to mixtures between glycofurol and buffer. Adequate solubility (approximately 50 mg/mL) was achieved in vehicles containing about 80% cosolvent. The stability of bumetanide was studied at 5 degrees C and 57 degrees C. No degradation was observed at low temperature. At high temperature, bumetanide decomposes in nonaqueous vehicles with half-lifes ranging from 69 to 400 days, but sufficient stability may be obtained by adjustment of pH to 7.4. It may be concluded that it is possible to prepare a clinically relevant formulation for intranasal delivery of bumetanide.

Supramolecular Synthons in Bumetanide Cocrystals and Ternary Products

“…31−33 There are very few reports on ternary cocrystals, especially for sulfonamide drugs. 13,14 A ternary cocrystal of acetazolamide drug with nicotinamide and 2-pyridone was reported recently. 14 On the basis of the learning from previous studies, and analysis of binary cocrystal structures, we attempted ternary adducts for BUM.…”

“…13,14 A ternary cocrystal of acetazolamide drug with nicotinamide and 2-pyridone was reported recently. 14 On the basis of the learning from previous studies, and analysis of binary cocrystal structures, we attempted ternary adducts for BUM. Four new ternary phases of bumetanide were crystallized: BUM−INA− PCA (1:1:1), BUM−INA−PASA (1:1:1), BUM−INA−VLA (1:1:1), and BUM−2HP−PCA (1:1:1).…”

“…This study deals with another sulfonamide drug bumetanide, which is in the same class as the well-known furosemide (lasix), piretanide, azosemide, and torsemide , (Scheme ). Bumetanide (BUM) is often used on patients with an acute diuretic condition when furosemide is not effective. , Bumetanide is a powerful fluid-reducing drug that is 40 times more potent than furosemide . Sodium and potassium salts of BUM and density functional theory (DFT) calculations on BUM–4-aminobenzoic acid molecular cocrystal are reported. , Cocrystals of BUM with pyridones (labeled as AB1, Scheme a,b) such as 2-hydroxy pyridone (2HP), 6-methyl-2-pyridone (MeHP), 3-methoxypyridone (OMeHP), with pyridine caboxamides (labeled as AB2, Scheme a,b), e.g., isonicotinamide (INA), picolinamide (PAM), and cytosine (CYT, salt-cocrystal) were crystallized.…”

Sodium and potassium salts of bumetanide trihydrate: Impact of counterion on structure, aqueous solubility and dehydration kinetics

“…It is indicated to manage oedema typically associated with congestive heart failure, hepatic and renal disease, and to treat mild to moderate hypertension. 11 Currently prescribed as the free acid in solid oral dosage and injectable forms, bumetanide has low aqueous solubility (0.1 mg mL À1 ), 12 which subsequently limits its utility in low-volume injectable delivery. Though bumetanide sodium trihydrate 13 was independently determined to have an aqueous solubility of 5.6 mg mL À1 , which is significantly more soluble than the free acid, identification of alternative salts with higher aqueous solubilities could facilitate the development of low-volume, parenteral formulations of bumetanide.…”

Investigation of the photochemical properties and in vitro phototoxic potential of bumetanide

“…5 Bumetanide's stability in vehicles for intranasal administration has been also evaluated. 7 The drug is considered a photolabile compound and protection from light is a recommended precaution for its storage, 1,8,9 but specific photochemical studies have not been performed. Currently, the photostability of the drug is a matter of concern, because light-induced decomposition can impair drug potency and induce phototoxic effects.…”