Phase Separation Behavior of Fusidic Acid and Rifampicin in PLGA Microspheres

Abstract

The purpose of this study was to characterize the phase separation behavior of fusidic acid (FA) and rifampicin (RIF) in poly(d,l-lactic acid-co-glycolic acid) (PLGA) using a model microsphere formulation. To accomplish this, microspheres containing 20% FA with 0%, 5%, 10%, 20%, and 30% RIF and 20% RIF with 30%, 20% 10%, 5%, and 0% FA were prepared by solvent evaporation. Drug-polymer and drug-drug compatibility and miscibility were characterized using laser confocal microscopy, Raman spectroscopy, XRPD, DSC, and real-time video recordings of single-microsphere formation. The encapsulation of FA and RIF alone, or in combination, results in a liquid-liquid phase separation of solvent-and-drug-rich microdomains that are excluded from the polymer bulk during microsphere hardening, resulting in amorphous spherical drug-rich domains within the polymer bulk and on the microsphere surface. FA and RIF phase separate from PLGA at relative droplet volumes of 0.311 ± 0.014 and 0.194 ± 0.000, respectively, predictive of the incompatibility of each drug and PLGA. When coloaded, FA and RIF phase separate in a single event at the relative droplet volume 0.251 ± 0.002, intermediate between each of the monoloaded formulations and dependent on the relative contribution of FA or RIF. The release of FA and RIF from phase-separated microspheres was characterized exclusively by a burst release and was dependent on the phase exclusion of surface drug-rich domains. Phase separation results in coalescence of drug-rich microdroplets and polymer phase exclusion, and it is dependent on the compatibility between FA and RIF and PLGA. FA and RIF are mutually miscible in all proportions as an amorphous glass, and they phase separate from the polymer as such. These drug-rich domains were excluded to the surface of the microspheres, and subsequent release of both drugs from the microspheres was rapid and reflected this surface location.

Rifapentine-linezolid-loaded PLGA microspheres for interventional therapy of cavitary pulmonary tuberculosis: preparation and in vitro characterization

“…Thus, the release rate curve rose slowly during the sustained release phase 12,14,24. In 2012, Gilchrist et al19 fabricated fusidic acid-rifampicin-loaded PLGA microspheres, and fusidic acid-rifampicin-loaded PLGA microspheres was characterized exclusively by a large initial burst release phase but minimal release thereafter, which was similar to the findings of this study.…”

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

“…Therefore, the volume ratio, V w /V d , of wet and dry PLGA particle was calculated to be 1.16-1.37. By using the swelling ratio, we estimated a possible dry PLGA particle concentration of 1200-1400 mg/mL from our measured microparticles, which was quite a reasonable density value for pure PLGA (50:50), reported as ρ PLGA = 1340 mg/mL [29,72]. Figure 8b-ii shows that, when Ibp was added into the system, the final PLGA concentration became 1020 ± 11 mg/mL for DL 15 wt% Ibp, and the final Ibp concentration became 180 ± 2 mg/mL-calculated from the initial concentrations and the relative volume change of the droplet.…”

“…First used in a non-mechanical way in 1998 to simply position micro-hydrogel beads with and without a loaded-drug (doxorubicin) in a controlled flow field of different pH [23,24], the micropipette technique was then developed by Needham et al [1][2][3][4][25][26][27][28][29][30][31][32][33][34][35][36][37], Tony Yeung et al [38], and others, in a series of papers on adsorption at interfaces and two-phase oil-aqueous systems. It has now become a highly versatile experimental setup that allows a wide variety of studies at microscopic interfaces and with single-and pairs-of microparticles.…”

“…It has now become a highly versatile experimental setup that allows a wide variety of studies at microscopic interfaces and with single-and pairs-of microparticles. Among other applications, the technique has been established for studying solvent dissolution, measuring fundamental properties such as diffusion coefficients and solubilities of the dissolving liquids [4,27,30], and for evaluating the phase separation, precipitation of droplets containing different solutes upon solvent loss, such as the micro-glassification of proteins by fast removal of water into water-imbibing solvents like octanol [3,31], and drug-containing polymer microspheres by removal of the organic solvent into water [28,29]. It is this last application that has motivated and guided the current studies with poly(lactic-co-glycolic acid) (PLGA) microparticles containing Ibuprofen [34].…”

Effect of composition on morphology structure and cell affinity of poly(caprolactone‐co‐glycolide)‐co‐poly(ethylene glycol) microspheres

“…On the other hand, polymer microspheres can be well fabricated by an oil‐in‐water (o/w) emulsion and solvent‐evaporation technique . However the produced microspheres usually possess smooth surface and tight structure, which is disadvantageous for cell adhesion and growth .…”