Cryochemical Production of Drug Nanoforms: Particle Size and Crystal Phase Control of the Antibacterial Medication 2,3-Quinoxalinedimethanol-1,4-dioxide (Dioxidine)

Abstract

Increasing the effectiveness of known, well-tested drugs is a promising low-cost alternative to the search for new drug molecular forms. Powerful approaches to solve this problem are (a) an active drug particle size reduction down to the nanoscale and (b) thermodynamically metastable but kinetically stable crystal modifications of drug acquisition. The combined cryochemical method has been used for size and structural modifications of the antibacterial drug 2,3-quinoxalinedimethanol-1,4-dioxide (dioxidine). The main stage of the proposed technique includes the formation of a molecular vapor of the drug substance, combined with a carrier gas (CO2) flow, followed by a fast condensation of the drug substance and CO2 molecules on a cooled-by-liquid nitrogen surface of preparative cryostate. It was established that the molecular chemical structure of the drug substance remained unchanged during cryochemical modification; however, it led to a significant decrease of the drug particles’ size down to nanosizes and changes in the crystal structures of the solid drug nanoforms obtained. Varying carrier gas (CO2) flow led to changes in their solid phase composition. A higher dissolution rate and changes in antibacterial activity were demonstrated for cryomodified dioxidine samples in comparison to the properties of the initial pharmacopeia dioxidine.

Pharmaceutical Nanoparticles Formation and Their Physico-Chemical and Biomedical Properties

“…Cryochemical methods of synthesis and modification of drug nanoparticles are based on the combination of the processes of evaporation or sublimation of a drug substance by heating under vacuum conditions, followed by condensation of the drug molecular vapor at support surfaces cooled to cryogenic temperatures (77-100 K) [56,57] (Figure 7). Another powerful cryogenic technology is the spray freeze-drying technique of frozen water or mixed water-organic solutions of drug substances under vacuum conditions [56,[58][59][60][61][62][63][64][65] Supercritical technologies have been shown to reduce the particle size of Fenofibrate down to 1.8-8.33 µ m compared to untreated Fenofibrate (24.2 ± 0.8 µ m) [51].…”

“…Moreover, temperature and pressure play a decisive role in the formation of certain polymorphic modifications, since they determine the conditions of their stability and solubility. Let us consider specific examples of the cryochemical synthesis of nanosized drug powders [56,57,[68][69][70][71][72][73][74][75][76][77][78].…”

“…Dioxidine (2,3-bis-(hydroxymethyl)quinoxaline-N,N,N′-dioxide) is a widely used antimicrobial agent known for effectively inhibiting the growth of numerous Gram-positive and Gram-negative bacteria (Figure 15) [72][73][74][75][76][77][78]. The initial Dioxidine powder underwent cryochemical modification through two methods: freeze-drying of sprayed frozen aqueous solution and low-temperature condensation of molecular vapor from the gas state.…”

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

“…Dioxidine ( 4 , Figure 2 ) does not exhibit cross-resistance with other antimicrobial drugs. Recent studies have confirmed the low toxicity of dioxidine, including the absence of cardiotoxicity, immunotoxicity, and toxic effects on the adrenal glands and other organs, which makes it suitable for use as a new dosage form for the treatment of pharyngitis and tonsillitis [ 131 , 132 ].…”

Cryoformation and Properties of Dioxidin/Gelatin Systems

“…[3] Уменьшение размера частиц лекарственных веществ увеличивает их биодоступность как в результате повышения скорости растворения, так и благодаря проницаемости биологических барьеров для частиц с размером менее 200 нм. Поэтому синтез наноформ лекарственных веществ становится одним из основных направлений создания новых высокоэффективных лекарственных препаратов [4][5][6].…”