Qualification of Non-Halogenated Organic Solvents Applied to Microsphere Manufacturing Process

Abstract

As a non-halogenated dispersed solvent, ethyl acetate has been most commonly used for the manufacturing of poly-d,l-lactide-co-glycolide (PLGA) microspheres. However, ethyl acetate-based microencapsulation processes face several limitations. This study was aimed at proposing ethyl formate as an alternative. Evaluated in this study was the solvent qualification of ethyl formate and ethyl acetate for microencapsulation of a hydrophobic drug into PLGA microspheres. An oil-in-water emulsion solvent extraction technique was developed to load progesterone into PLGA microspheres. Briefly, right after emulsion droplets were temporarily stabilized, they were subject to primary solvent extraction. Appearing semisolid, embryonic microspheres were completely hardened through subsequent secondary solvent extraction. Changes in process parameters of the preparative technique made it possible to manipulate the properties of emulsion droplets, progesterone behavior, and microsphere quality. Despite the two solvents showing comparable Hansen solubility parameter distances toward PLGA, ethyl formate surpassed ethyl acetate in relation to volatility and water miscibility. These features served as advantages in the microsphere manufacturing process, helping produce PLGA microspheres with better quality in terms of drug crystallization, drug encapsulation efficiency, microsphere size homogeneity, and residual solvent content. The present ethyl formate-based preparative technique could be an attractive method of choice for the production of drug-loaded PLGA microspheres.

Assessment of Residual Solvent and Drug in PLGA Microspheres by Derivative Thermogravimetry

“…Progesterone-loaded PLGA microspheres were prepared following the microencapsulation method reported elsewhere [24]. Briefly, PLGA (250 mg) and progesterone (40, 70, 100, or 130 mg) were dissolved in 3 mL of ethyl formate.…”

“…Ethyl formate, a non-halogenated ICH 3 class 3 solvent, has been recently proposed as an attractive dispersed solvent that can be used in the preparation of drug-containing PLGA microspheres [24]. It was demonstrated that the ethyl formate-based preparative technique permitted the manufacturing of PLGA microspheres with excellent quality attributes.…”

In vitro studies and preclinical evaluation of benznidazole microparticles in the acute Trypanosoma cruzi murine model

“…Although there are several technological tools to produce MP (Paulo and Santos, 2017; Barrera et al , 2020) the spray-drying technique is a versatile and efficient method to produce particles <10 μm when spray-dryers with two-fluid nozzles are used (Kemp et al , 2016; Davis and Walker, 2018). It is important to note that MP prepared by spray-drying are usually organic solvent-free, in contrast to other methodologies that use toxic organic solvents and/or toxic reagents (Li et al , 2008; Shim and Sah, 2020). Furthermore, the selection of a suitable carrier is also a key step during the development of final products (Lengyel et al , 2019).…”

Clinical research progress of callisperes® of drug-loaded microsphere arterial chemoembolisation in the treatment of solid tumors

“…After that, it enters the vascular microenvironment and begins to release the drug under the action of the ionic structure [ 53 ]. At the same time, the volume of DEB gradually increases, and the enlarged microsphere is embedded in the blood vessel to achieve complete embolization [ 54 ]. When the blood vessel is embolized, the blood supply is blocked, which reduces tumor tissue perfusion, cuts off the nutrient source of tumor tissue, causes hypoxia and ischemia of tumor tissue, and inhibits tumor cell growth and differentiation, thereby resulting in tumor cell necrosis to achieve tumor shrinkage or remission.…”