Application research and toxicity of glutaric anhydride

Introduction

Glutaric anhydride (GA;Figure 1) is a saturated cyclic anhydride with very low toxicity, which can be used as an intermediate for synthetic chemicals, pharmaceutical raw materials,and biopharmaceuticals. Moreover, it can react with any nucleophilic substance in the solution. The local delivery of targeted drugs at the site of action can improve the bioavailability of tetracycline hydrochloride (TH) by loading TH into a GA modified agaric hydrogel carrier. In addition, the use of hydrophobic carriers is suitable for achieving controlled release of highly water soluble drug TH. [1] Glutaric anhydride also can be employed for the surface modification of cellulose. A ring-opening reaction generates a carbon spacer with a carboxylic acid end group on the cellulose backbone. Glutaric anhydride provides some merits over succinic anhydride (SA), a commonly used cyclic anhydride for cellulose modification. GA can be stored for a longer time and it retains its activity for a long time because the six-membered rings (pyranose) are more stable in exposure to oxygen and humidity compared with five-membered rings (furanose). Glutaric anhydride is easy to handle by non-experienced students and researchers and has lower toxicity [2].

Glutaric anhydride as the esterification agent is used to synthesize hydrogels

Agar was modified with glutaric anhydride (GA) in this study to expand its application in food and medicine.Glutaric anhydride-modified agar (GAR) can maintain high gel strength (1247.4 g/cm2) and improved transparency (82.7 %). The esterified agar formed by glutaric anhydride further formed a cross-linking molecule structure by increasing the reaction temperature. Glutaric anhydride plays a fundamental role in drug delivery systems because it reacts with agar by esterification and cross-linking, providing a solid swelling property for drug-loaded hydrogels and facilitating the adsorption of drug molecules. Second, it delivers the most significant amount of drug in alkaline media than in acidic media due to its molecular structure's two different forms of carboxyl groups. An increase in the release was observed when the drug-loaded hydrogel device passed through a simulated gastrointestinal fluid and was therefore considered an attractive material for drug delivery systems.Notably, excellent freeze-thaw stability (24.1 %) and swelling property(3116.6 %) of GAR indicated that the carboxyl-terminal of modified agar improves its affinity with water.Therefore, satisfactory water permeability and expansive stone enable agar films to achieve high water absorption. Furthermore, GAR films exhibit a specific absorption capacity of tetracycline hydrochloride in weak acid solution, thereby suggesting its potential application as a sustainable drug delivery carrier. Finally, the structure of the modified agar was analyzed to explain the mechanism of binding water. Cryo-scanning electronmicroscopy (SEM) depicted the porous structure of the agar gel responsible for swelling, drug loading, and release. Low-field NMR results showed that glutaric anhydride improves agar gel's binding and free water content. According to research results, these GAR hydrogel membranes with excellent properties have the potential to be used as effective drug delivery materials.[1] 

Glutaric anhydride for the functionalization of cellulose

According to the 12 principles of green chemistry, surface functionalization was performed using glutaric anhydride under solvent-free and catalyst-free conditions. FTIR spectra and DS analyses demonstrated the functionalization of HCl-hydrolyzed cellulose. The influence of two parameters, i.e., the glutaric anhydrideconcentration and the reaction time, on the functionalization of HCl-hydrolyzed cellulose was investigated.Protocol efficiency was studied by a degree of substitution (DS). It was found that higher concentrations ofglutaric anhydride cause an enhancement of DS to 0.75 and 0.87 for GA3–12 and GA9–12, respectively. Inaddition, the longer reaction time increased zeta potential from −12.2±1.7 for G9–6 to −34.57±2.2 for GA9–12. Morphology analysis by SEM showed a decrease in fiber length for the functionalized cellulose. DSC profiles confirmed dehydration at a range of 17 to 134◦C. A glass transition was revealed at −30 to −20◦C for all studied samples. The fusion, the depolymerization of cellulose chains, the cleavage of glycosidic linkages, and the decomposition of the crystalline parts of cellulose occur at 195 to 374◦C. Therefore, an efficient and greener process was developed to functionalize the HCl-hydrolyzed cellulose by glutaric anhydride, a safe and non-toxic anhydride, in the absence of the solvent and catalyst.[2] 

The toxicity of glutaric anhydride

Glutaric anhydride was found of moderate acute peroral lethal toxicity with LD₅₀ values (95% confidence limits) in the rat of 1.41 (0.80-2.49)g/kg (males) and 0.54 (0.36-0.79)g/kg (females), with death being due in part to gastrointestinal irritancy. Dilution with water given by gavage after peroral dosing had no effect on lethal toxicity. Acute percutaneous LD50 values (rabbit) by 24h occlusion were 6.25 (5.34-7.33)g/kg in males and 5.66 (3.21-9.95)g/kg in females; local skin effects included erythema, edema, necrosis and ulceration. A 6h exposure to a statically generated saturated vapor atmosphere (rat) produced no signs of toxicity or irritancy. A 4h, but not 1h or 3min occluded contact with 0.5g of moistened glutaric anhydride (rabbit) produced erythema, edema and necrosis. Contamination of the eye (rabbit) with 10 mg glutaric anhydride produced conjunctivitis (hyperemia, chemosis and discharge) which persisted 7 to 14 d, mild iritis of 2 to 14 d duration, and mild to severe corneal injury which healed within 14 d. A maximization study in guinea pigs by the method of Magnusson and Kligman showed no potential for skin sensitization with glutaric anhydride. The major acute hazards of glutaric anhydride were by swallowing, eye contact and sustained skin contact.[3]

References

1.Zhang L, Ye S, Chen F, Xiao Q, Weng H, Xiao A. Super absorbent glutaric anhydride-modified agar: Structure, properties, and application in biomaterial delivery. Int J Biol Macromol. 2023;231:123524. doi:10.1016/j.ijbiomac.2023.123524

2.Fahim H, Motamedzadegan A, Farahmandfar R, Khaligh NG. Surface analysis and thermal behavior of the functionalized cellulose by glutaric anhydride through a solvent-free and catalyst-free process. Int J Biol Macromol. 2023;232:123268. doi:10.1016/j.ijbiomac.2023.123268

3.Ballantyne B, Myers RC, Blaszcak DL. The acute toxicity, primary irritancy and skin sensitizing potential of glutaric anhydride. Vet Hum Toxicol. 1992;34(6):493-497.